Neurology of Pregnancy, Continuum, 2022

CONTRIBUTORS
Mary Angela O’Neal, MD, Karissa L. Gable, MD

FAAN, Associate Professor of
Guest Editor Neurology, Duke University
Assistant Professor of Medical Center, Durham,
Neurology, Harvard Medical North Carolina
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School; Director, Women’s

Relationship Disclosure: Dr Gable serves
Neurology Program; Ambulatory as a consultant for Apellis Pharmaceuticals
Director of Neurology; Director, Inc and Medscape and has received
research/grant support from the American
Neurosciences Clinic, Brigham Neuromuscular Foundation and GBS/CIDP
and Women’s Hospital, Foundation International.
Boston, Massachusetts
Unlabeled Use of Products/Investigational
Relationship Disclosure: Dr O’Neal serves Use Disclosure: Dr Gable reports no
as a consultant for Teladoc Health, Inc; disclosure.
receives publishing royalties from Oxford
University Press and Springer Nature
Switzerland AG; and has served as an expert
consultant for CRICO medical malpractice Na Tosha N. Gatson, MD,
insurers. PhD, FAAN
Unlabeled Use of Products/Investigational Associate Professor of
Use Disclosure: Dr O’Neal reports no Medicine and Neurology;
disclosure. Medical Director,
Neuro-Oncology, Banner MD
Anderson Cancer Center,
Riley M. Bove, MD University of Arizona
Associate Professor of College of Medicine, Phoenix,
Neurology, University of Arizona; Adjunct Associate
California San Francisco, Professor of Medicine,
San Francisco, California Geisinger Commonwealth
Relationship Disclosure: Dr Bove has served School of Medicine,
as a consultant for Alexion Pharmaceuticals, Scranton, Pennsylvania
Inc; Biogen; EMD Serono; F. Hoffman-La
Roche Ltd; Momenta Pharmaceuticals, Relationship Disclosure: Dr Gatson has
Inc; Novartis AG; and Sanofi Genzyme and served as an advisory board consultant for
has received research/grant support from Novocure GmbH.
Biogen, F. Hoffman-La Roche Ltd,
and Novartis AG. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Gatson reports no
Unlabeled Use of Products/Investigational disclosure.
Use Disclosure: Dr Bove discusses
the unlabeled/investigational use of
rituximab for multiple sclerosis and
neuromyelitis optica spectrum disorder
and the unlabeled/investigational use of
immunosuppressives for neuromyelitis
optica spectrum disorder.
6 F EB R UA R Y 2 0 2 2
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Maria K. Houtchens, MD Yi Li, MD, PhD
Associate Professor of Clinical Assistant Professor of
Neurology, Harvard Medical Neurology and Neurological
School; Director, Clinical Care; Sciences, Stanford University,
Director, Women’s Health Palo Alto, California
Program; Associate Director,
Relationship Disclosure: Dr Li reports no
Women’s Neurology disclosure.
Fellowship, Brigham Multiple
Sclerosis Center, Brigham Use Disclosure: Dr Li reports no disclosure.
and Women’s Hospital,
Boston, Massachusetts
Relationship Disclosure: Dr Houtchens Janice M. Massey, MD, FAAN
has served as a consultant for Alexion Professor and Executive
Pharmaceuticals, Inc; Biogen; EMD Serono;
F. Hoffman-La Roche Ltd; Novartis AG; Vice-Chair of Neurology,
and Sanofi Genzyme and has received Duke University Medical
research/grant support from Biogen, F. Center, Durham,
Hoffman-La Roche Ltd, and Sanofi Genzyme.
Dr Houtchens has provided expert legal North Carolina
testimony on motor vehicle accidents in
patients with neurologic illness and has Relationship Disclosure: Dr Massey serves on
served as an expert witness in medical the editorial board of Clinical Neurophysiology
malpractice cases. Practice, as an investigator for UCB SA/Ra
Pharmaceuticals, on a scientific advisory
Unlabeled Use of Products/Investigational board for Argenx, and on a scientific advisory
Use Disclosure: Dr Houtchens discusses committee for Momenta Pharmaceuticals,
the unlabeled/investigational use of Inc. Dr Massey has received research/grant
rituximab for multiple sclerosis and support from Revance Therapeutics, Inc.
neuromyelitis optica spectrum disorder
and the unlabeled/investigational use of Unlabeled Use of Products/Investigational
immunosuppressives for neuromyelitis Use Disclosure: Dr Massey reports no
optica spectrum disorder. disclosure.
Joseph S. Kass, MD, JD, FAAN

Professor of Neurology,
Psychiatry and Medical Ethics,
Baylor College of Medicine,
Houston, Texas
Relationship Disclosure: Dr Kass serves as
associate editor of medicolegal issues for
Continuum, as a neurology section editor
of Ferri’s Clinical Advisor for Elsevier, and as
co-editor of Neurology Secrets, Sixth Edition
and has served as an associate editor for
Continuum Audio. Dr Kass serves as a principal
investigator for clinical trials for Alzheimer
disease from Biogen; Eisai Co, Ltd; Lilly; the
National Institutes of Health; Novartis AG;
Novo Nordisk; and Roche Diagnostics.

Use Disclosure: Dr Kass reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 7

CONTRIBUTORS (CONTINUED)
Kimford J. Meador, MD, FAAN, Heather E. Moss, MD,

FAES, FRCPE PhD, FAAN
Professor of Neurology Associate Professor of
and Neurological Sciences, Ophthalmology, Neurology, and
Stanford University, Neurological Sciences, Stanford
Palo Alto, California University, Palo Alto, California
Relationship Disclosure: Dr Meador receives Relationship Disclosure: Dr Moss has served
research/grant support from Eisai Co, on the editorial board of the Journal of
Ltd, and the National Institutes of Health/ Neuro-Ophthalmology and as an associate
National Institute of Neurological Disorders editor for Frontiers in Neurology and MedLink
and Stroke/National Institute of Child Health Neurology, an assistant editor for Frontiers in
and Human Development Ophthalmology, a review editor for Current
(2U01-NS038455). Dr Meador’s institution Eye Research, a guest editor for Current
receives financial support from The Opinion in Neurology and Current Neurology
Epilepsy Study Consortium for his services and Neuroscience Reports, and a special
as a consultant for Eisai Co, Ltd; GW issue editor for Life. Dr Moss has served as a
Pharmaceuticals plc; NeuroPace, Inc; consultant for Twenty/Twenty Therapeutics
Novartis AG; Supernus Pharmaceuticals, Inc; and Verana Health and on an advisory board
Upsher-Smith Laboratories, LLC; UCB, Inc; for Genentech, Inc; has received personal
and VIVUS LLC. compensation for speaking engagements
for Vindico Medical Education; and receives
Unlabeled Use of Products/Investigational research/grant support from the Department
Use Disclosure: Dr Meador reports no of Defense, the National Institutes of Health
disclosure. (P30 EY 026 877, R21 EY 031 726), and Research
to Prevent Blindness.

Eliza C. Miller, MD, MS Use Disclosure: Dr Moss reports no
disclosure.
Assistant Professor of
Neurology, Columbia University,
New York, New York
Melissa Rayhill, MD, FAHS
Relationship Disclosure: Dr Miller serves Assistant Professor of
as a section editor for Stroke and receives Neurology, University at Buffalo
research/grant support from the Gerstner
Family Foundation, the National Institutes
Jacobs School of Medicine,
of Health/National Institute of Neurological State University of New York,
Disorders and Stroke (K23NS107645, Buffalo, New York
1R01NS122815), and the National Institutes
of Health/National Institute on Aging Relationship Disclosure: Dr Rayhill has
(R21AG069111). Dr Miller has served as an served as an associate editor of Headache:
expert consultant for Argionis & Associates, The Journal of Head and Face Pain.
LLC; Finch McCranie LLP; Grower, Ketcham,
Edie, Telan & Meltz, PA; and Heyl, Royster, Unlabeled Use of Products/Investigational
Voelker & Allen, PC. Use Disclosure: Dr Rayhill discusses the use
of various medications for the treatment
Unlabeled Use of Products/Investigational of headache in pregnancy and lactation,
Use Disclosure: Dr Miller discusses none of which are approved by the US
the unlabeled/investigational use of Food and Drug Administration for use in
recombinant tissue plasminogen activator pregnancy/lactation.
for the treatment of acute ischemic stroke in
pregnant women.
8 F EB R UA R Y 2 0 2 2

CONTRIBUTORS (CONTINUED)
Rachel V. Rose, JD, MBA Janet F. R. Waters, MD,

Attorney, Rachel V. Rose MBA, FAAN
Attorney at Law, PLLC; Affiliated Associate Professor of
Faculty, Baylor College of Neurology; Division Chief,
Medicine, Houston, Texas Women’s Neurology, University
of Pittsburgh Medical Center;
Relationship Disclosure: Ms Rose serves
on the editorial board of BC Advantage and Chief of Neurology, Magee-
receives book royalties from the American Women’s Hospital,
Bar Association.
Pittsburgh, Pennsylvania
Relationship Disclosure: Dr Waters reports
Use Disclosure: Ms Rose reports no
no disclosure.
disclosure.
Use Disclosure: Dr Waters reports no
disclosure.
Self-Assessment and CME Test Writers
Nuri Jacoby, MD Allison L. Weathers, MD, FAAN

Associate Professor of Associate Chief Medical
Neurology, SUNY Downstate Information Officer, Cleveland
Health Sciences University; Clinic; Assistant Professor,
Attending Neurologist, Cleveland Clinic Lerner
Maimonides Medical Center, College of Medicine,
Brooklyn, New York Cleveland, Ohio
Relationship Disclosure: Dr Jacoby has Relationship Disclosure: Dr Weathers serves
received the Faculty Innovation in Education on the editorial board of Continuum and as
Award from the American Board of chair of the adult neurosciences specialty
Psychiatry and Neurology. steering board for Epic.
Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Use Disclosure: Dr Jacoby reports no Use Disclosure: Dr Weathers reports no
disclosure. disclosure.

Issue Overview
Neurology of Pregnancy, Volume 28, Number 1, February 2022
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Neurology of Pregnancy
issue, participants will be able to:
 Discuss the effects of pregnancy on inflammatory activity in women with demyelinating

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diseases and the major principles governing treatment use in relation to pregnancy
 Describe the risks and management of epilepsy in women preceding pregnancy, during
pregnancy, and postpartum
 Discuss the diagnosis, management, and treatment of neuromuscular disorders in

pregnancy
 Describe the effectiveness and safety data for both novel emerging and traditional
therapies for the treatment of headache in pregnancy and lactation and identify potentially
dangerous secondary headache syndromes that may occur in pregnancy
 Describe the risk factors, pathophysiology, evaluation, and treatment of pregnant and
postpartum patients with acute or chronic cerebrovascular disease
 Discuss the most reported central nervous system tumors during pregnancy and
commonly proposed mechanisms for pregnancy exacerbation of brain tumors and utilize
up-to-date guidelines, provide recommendations, and recognize special considerations in
the management of pregnant patients with brain tumors
 Describe how the approach to visual symptoms experienced by pregnant women differs
from the approach for other patients
 Discuss the effects of neurologic conditions on obstetric anesthesia and describe both the
serious and more benign complications of neuraxial anesthesia
 Discuss the complexities that arise from both a legal and a bioethical standpoint when a
patient is brain dead, but a fetus remains viable
Core Competencies
This Continuum: Lifelong Learning in Neurology Neurology of Pregnancy issue covers the
following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement

 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Mary Angela O’Neal, MD, FAAN, Guest Editor

Assistant Professor of Neurology, Harvard Medical School; Director, Women’s Neurology
Program; Ambulatory Director of Neurology; Director, Neurosciences Clinic, Brigham and
Women’s Hospital, Boston, Massachusetts
Relationship Disclosure: Dr O’Neal serves as a consultant for Teladoc Health, Inc; receives publishing royalties
from Oxford University Press and Springer Nature Switzerland AG; and has served as an expert consultant for
CRICO medical malpractice insurers.
Unlabeled Use of Products/Investigational Use Disclosure: Dr O’Neal reports no disclosure.
Riley M. Bove, MD
Associate Professor of Neurology, University of California San Francisco, San Francisco,
California
Relationship Disclosure: Dr Bove has served as a consultant for Alexion Pharmaceuticals, Inc; Biogen; EMD
Serono; F. Hoffman-La Roche Ltd; Momenta Pharmaceuticals, Inc; Novartis AG; and Sanofi Genzyme and has
received research/grant support from Biogen, F. Hoffman-La Roche Ltd, and Novartis AG.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bove discusses the unlabeled/investigational use of
rituximab for multiple sclerosis and neuromyelitis optica spectrum disorder and the unlabeled/investigational use of
immunosuppressives for neuromyelitis optica spectrum disorder.
Karissa L. Gable, MD
Associate Professor of Neurology, Duke University Medical Center, Durham, North Carolina
Relationship Disclosure: Dr Gable serves as a consultant for Apellis Pharmaceuticals Inc and Medscape and has
received research/grant support from the American Neuromuscular Foundation and GBS/CIDP Foundation
International.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gable reports no disclosure.
Na Tosha N. Gatson, MD, PhD, FAAN

Associate Professor of Medicine and Neurology; Medical Director, Neuro-Oncology, Banner
MD Anderson Cancer Center, University of Arizona College of Medicine, Phoenix, Arizona;
Adjunct Associate Professor of Medicine, Geisinger Commonwealth School of Medicine,
Scranton, Pennsylvania
Relationship Disclosure: Dr Gatson has served as an advisory board consultant for Novocure GmbH.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gatson reports no disclosure.

Maria K. Houtchens, MD
Associate Professor of Neurology, Harvard Medical School; Director, Clinical Care; Director,
Women’s Health Program; Associate Director, Women’s Neurology Fellowship, Brigham
Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, Massachusetts
Relationship Disclosure: Dr Houtchens has served as a consultant for Alexion Pharmaceuticals, Inc; Biogen; EMD
Serono; F. Hoffman-La Roche Ltd; Novartis AG; and Sanofi Genzyme and has received research/grant support from
Biogen, F. Hoffman-La Roche Ltd, and Sanofi Genzyme. Dr Houtchens has provided expert legal testimony on
motor vehicle accidents in patients with neurologic illness and has served as an expert witness in medical
malpractice cases.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Houtchens discusses the unlabeled/investigational use
of rituximab for multiple sclerosis and neuromyelitis optica spectrum disorder and the unlabeled/investigational use
of immunosuppressives for neuromyelitis optica spectrum disorder.
Joseph S. Kass, MD, JD, FAAN

Professor of Neurology, Psychiatry and Medical Ethics, Baylor College of Medicine, Houston,
Texas
Relationship Disclosure: Dr Kass serves as associate editor of medicolegal issues for Continuum, as a neurology
section editor of Ferri’s Clinical Advisor for Elsevier, and as co-editor of Neurology Secrets, Sixth Edition and has
served as an associate editor for Continuum Audio. Dr Kass serves as a principal investigator for clinical trials for
Alzheimer disease from Biogen; Eisai Co, Ltd; Lilly; the National Institutes of Health; Novartis AG; Novo Nordisk;
and Roche Diagnostics.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kass reports no disclosure.
Yi Li, MD, PhD

Clinical Assistant Professor of Neurology and Neurological Sciences, Stanford University, Palo
Alto, California
Relationship Disclosure: Dr Li reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Li reports no disclosure.
Janice M. Massey, MD, FAAN

Professor and Executive Vice-Chair of Neurology, Duke University Medical Center, Durham,
North Carolina
Relationship Disclosure: Dr Massey serves on the editorial board of Clinical Neurophysiology Practice, as an
investigator for UCB SA/Ra Pharmaceuticals, on a scientific advisory board for Argenx, and on a scientific advisory
committee for Momenta Pharmaceuticals, Inc. Dr Massey has received research/grant support from Revance
Therapeutics, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Massey reports no disclosure.

Kimford J. Meador, MD, FAAN, FAES, FRCPE
Professor of Neurology and Neurological Sciences, Stanford University, Palo Alto, California
Relationship Disclosure: Dr Meador receives research/grant support from Eisai Co, Ltd, and the National Institutes
of Health/National Institute of Neurological Disorders and Stroke/National Institute of Child Health and Human
Development (2U01-NS038455). Dr Meador’s institution receives financial support from The Epilepsy Study
Consortium for his services as a consultant for Eisai Co, Ltd; GW Pharmaceuticals plc; NeuroPace, Inc; Novartis
AG; Supernus Pharmaceuticals, Inc; Upsher-Smith Laboratories, LLC; UCB, Inc; and VIVUS LLC.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Meador reports no disclosure.
Eliza C. Miller, MD, MS

Assistant Professor of Neurology, Columbia University, New York, New York
Relationship Disclosure: Dr Miller serves as a section editor for Stroke and receives research/grant support from the
Gerstner Family Foundation, the National Institutes of Health/National Institute of Neurological Disorders and
Stroke (K23NS107645,1R01NS122815), and the National Institutes of Health/National Institute on Aging
(R21AG069111). Dr Miller has served as an expert consultant for Argionis & Associates, LLC; Finch McCranie
LLP; Grower, Ketcham,Edie, Telan & Meltz, PA; and Heyl, Royster, Voelker & Allen, PC.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Miller discusses the unlabeled/investigational use of
recombinant tissue plasminogen activator for the treatment of acute ischemic stroke in pregnant women.
Heather E. Moss, MD, PhD, FAAN

Associate Professor of Ophthalmology, Neurology, and Neurological Sciences, Stanford
University, Palo Alto, California
Relationship Disclosure: Dr Moss has served on the editorial board of the Journal of Neuro-Ophthalmology and as
an associate editor for Frontiers in Neurology and MedLink Neurology, an assistant editor for Frontiers in
Ophthalmology, a review editor for Current Eye Research, a guest editor for Current Opinion in Neurology and
Current Neurology and Neuroscience Reports, and a special issue editor for Life. Dr Moss has served as a consultant
for Twenty/Twenty Therapeutics and Verana Health and on an advisory board for Genentech, Inc; has received
personal compensation for speaking engagements for Vindico Medical Education; and receives research/grant
support from the Department of Defense, the National Institutes of Health (P30 EY 026 877, R21 EY 031 726), and
Research to Prevent Blindness.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Moss reports no disclosure.

Assistant Professor of Neurology, University at Buffalo Jacobs School of Medicine, State
University of New York, Buffalo, New York
Relationship Disclosure: Dr Rayhill has served as an associate editor of Headache: The Journal of Head and Face
Pain.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rayhill discusses the use of various medications for
the treatment of headache in pregnancy and lactation, none of which are approved by the US Food and Drug
Administration for use in pregnancy/lactation.
Rachel V. Rose, JD, MBA

Attorney, Rachel V. Rose Attorney at Law, PLLC; Affiliated Faculty, Baylor College of
Medicine, Houston, Texas
Relationship Disclosure: Ms Rose serves on the editorial board of BC Advantage and receives book royalties from
the American Bar Association.
Unlabeled Use of Products/Investigational Use Disclosure: Ms Rose reports no disclosure.

Janet F. R. Waters, MD, MBA, FAAN
Associate Professor of Neurology; Division Chief, Women’s Neurology, University of Pittsburgh
Medical Center; Chief of Neurology, Magee-Women’s Hospital, Pittsburgh, Pennsylvania
Relationship Disclosure: Dr Waters reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Waters reports no disclosure.
Self-Assessment and CME Test Writers
Nuri Jacoby, MD
Associate Professor of Neurology, SUNY Downstate Health Sciences University; Attending
Neurologist, Maimonides Medical Center, Brooklyn, New York
Relationship Disclosure: Dr Jacoby has received the Faculty Innovation in Education Award from the American
Board of Psychiatry and Neurology.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Jacoby reports no disclosure.
Allison L. Weathers, MD, FAAN

Associate Chief Medical Information Officer, Cleveland Clinic; Assistant Professor, Cleveland
Clinic Lerner College of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Weathers serves on the editorial board of Continuum and as chair of the adult
neurosciences specialty steering board for Epic.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Weathers reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing

neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
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The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
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can be met.

FEBRUARY 2022
VOL. 28 NO. 1 Neurology of Pregnancy
Guest Editor: Mary Angela O’Neal, MD, FAAN
10 Editor’s Preface
Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
12 Pregnancy Management in Multiple Sclerosis and Other

Demyelinating Diseases
Riley M. Bove, MD; Maria K. Houtchens, MD
34 Epilepsy and Pregnancy

Yi Li, MD, PhD; Kimford J. Meador, MD, FAAN, FAES, FRCPE
55 Neuromuscular Disorders and Pregnancy

Janice M. Massey, MD, FAAN; Karissa L. Gable, MD
72 Headache in Pregnancy and Lactation

93 Maternal Stroke Associated With Pregnancy

Eliza C. Miller, MD, MS
122 Managing Central Nervous System Tumors During Pregnancy

Na Tosha N. Gatson, MD, PhD, FAAN
147 Neuro-ophthalmology and Pregnancy

Heather E. Moss, MD, PhD, FAAN
162 Neurologic Complications of Obstetric Anesthesia

DENOTES CONTINUUM
Janet F. R. Waters, MD, MBA, FAAN
AUDIO INTERVIEW
DENOTES VIDEO
CONTENT

MEDICOLEGAL ISSUES
180 Legal and Ethical Challenges in the Care of the Pregnant Patient
After Brain Death
Joseph S. Kass, MD, JD, FAAN; Rachel V. Rose, JD, MBA
SELF-ASSESSMENT AND CME
4 Learning Objectives and Core Competencies
187 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
189 Postreading Self-Assessment and CME Test
201 Postreading Self-Assessment and CME Test—Preferred Responses
212 Index
List of Abbreviations (Back Cover)

EDITOR’S PREFACE
What to Expect When You’re

Expecting to See an Expectant
Patient
This issue of Continuum is devoted to the management and

counseling of patients with neurologic disorders that may occur in
association with pregnancy and to the diagnosis and management of
neurologic disorders presenting as a consequence of pregnancy or
the postpartum state. To help us prepare for these common,
although complex, clinical scenarios and management decisions, I am thankful that
Dr Mary Angela O’Neal accepted our invitation to be the guest editor for this issue
and for her recruitment of such outstanding expert subspecialty authors to guide
neurologists as we diagnose, manage, and counsel our patients who are pregnant or
may become pregnant.
The issue begins with the article by Drs Riley M. management of arterial or venous maternal ischemic
Bove and Maria K. Houtchens, who discuss the stroke (and reversible cerebral vasoconstriction
current information and recommendations regarding syndrome) associated with pregnancy as well as
pregnancy in patients with multiple sclerosis and pregnancy-associated acute hemorrhagic stroke,
other demyelinating diseases, particularly including subarachnoid and intracerebral hemorrhage.
neuromyelitis optica spectrum disorder (NMOSD). Dr Na Tosha N. Gatson discusses the effect of
In the next article, Drs Yi Li and Kimford J. Meador pregnancy on some of the more common central
review the many challenges involved in the care and nervous system neoplasms and provides current
counseling of patients with epilepsy before, during, recommendations regarding the management of
and after pregnancy. central nervous system tumors during pregnancy.
Drs Janice M. Massey and Karissa L. Gable discuss Next, Dr Heather E. Moss reviews the effect of
the management and counseling of pregnant patients pregnancy on neuro-ophthalmologic pathways and
with neuromuscular disorders (from the anterior discusses the examination, diagnosis, and
horn cell proximally to the muscle distally) and management of patients who are pregnant and have
review the neuromuscular disorders that may arise in neuro-ophthalmologic symptoms. In the final review
association with pregnancy or delivery. Dr Melissa article of the issue, Dr Janet F. R. Waters discusses the
Rayhill then provides an up-to-date review of the decision making with regard to choice of obstetric
management of primary headaches in patients who anesthesia, particularly neuraxial anesthesia, and the
are pregnant and lactating and discusses the potential neurologic complications of obstetric
diagnosis of secondary headache disorders that may anesthesia that neurologists need to be aware of as
occur in association with pregnancy. In the following we are called to provide input before delivery and
article, Dr Eliza C. Miller provides a contemporary when assessing patients with neurologic symptoms
review of the pathophysiology, diagnosis, and postprocedurally.
10 FEBRUARY 2022

In the Medicolegal Issues article, Dr Joseph S. Kass accredited by the Royal College of Physicians and
and Ms Rachel V. Rose discuss two real-life cases to Surgeons of Canada.
analyze the complex legal and ethical challenges in This issue is also included in a pilot program of
the care of the pregnant patient after brain death. Continuum issues read aloud. Different from
After reading the issue and taking the Postreading Continuum Audio, these are recordings read
Self-Assessment and CME Test written by Drs Nuri verbatim from the print articles by Dr Michael
Jacoby and Allison L. Weathers, and edited by Dr Kentris, a neurologist at the Clinical Neuroscience
Joseph E. Safdieh, Associate Editor of Continuum and Institute in Dayton, Ohio. The audio files are
Associate Editor of Self-Assessment and CME, available to all Continuum subscribers in the AAN’s
readers may earn up to 20 AMA PRA Category 1 Online Learning Center at continpub.com/CME. I
CreditsTM toward self-assessment CME or, for encourage you to listen and submit the survey with
Canadian participants, a maximum of 20 hours your feedback on this pilot.
toward the Self-Assessment Program (Section 3) of Finally, I would like to address the terminology
the Maintenance of Certification Program of the used in the issue. Although pregnant woman and
Royal College of Physicians and Surgeons of Canada. pregnant women are used in places throughout the
Additional credit can be obtained by listening to issue, Continuum recognizes that neurologists treat
Continuum Audio interviews associated with this and people of all gender identities, including people who
other Continuum issues, available to all subscribers, are cisgender, transgender, gender nonbinary, or
and completing tests on the Continuum Audio web otherwise gender expansive, and not all people who
platform or mobile app. Continuum Audio is also become pregnant identify as women.
My sincere thank you again to Dr O’Neal, with
special appreciation for recruiting such expert
authors, her skillful review of the content, and her
responsiveness beginning at the issue’s embryonic
stage, throughout its development, and leading to the
I am thankful that Dr Mary Angela delivery of an outstanding issue. This issue should
O’Neal accepted our invitation to be serve as an important resource to all of us who
the guest editor for this issue and for manage and counsel patients of childbearing age and
when we are called to see patients who are pregnant
her recruitment of such outstanding or postpartum and have neurologic disorders,
expert subspecialty authors to guide symptoms, or signs.
neurologists as we diagnose, manage, —STEVEN L. LEWIS, MD, FAAN
and counsel our patients who are EDITOR-IN-CHIEF
pregnant or may become pregnant. © 2022 American Academy of Neurology.
CONTINUUMJOURNAL.COM 11

REVIEW ARTICLE

Pregnancy Management
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
in Multiple Sclerosis and
Other Demyelinating
CITE AS:
CONTINUUM (MINNEAP MINN)
Diseases
2022;28(1, NEUROLOGY OF By Riley M. Bove, MD; Maria K. Houtchens, MD

PREGNANCY):12–33.
Address correspondence to
Dr Maria K. Houtchens, Building
for Transformative Medicine, ABSTRACT
Brigham Multiple Sclerosis
PURPOSE OF REVIEW: Multiple sclerosis (MS) and neuromyelitis optica
Center, 60 Fenwood Rd, Boston,
MA 02115, mhoutchens@bwh. spectrum disorders (NMOSDs) are chronic autoimmune demyelinating
harvard.edu. conditions of the central nervous system often diagnosed in women of
RELATIONSHIP DISCLOSURE: childbearing age. Therefore, safe family planning, pregnancy, and
Dr Bove has served as a postpartum management are important considerations for many patients
consultant for Alexion
with MS or NMOSD.
Pharmaceuticals, Inc; Biogen;
EMD Serono; F. Hoffman-La
Roche Ltd; Momenta RECENT FINDINGS: Many patients with MS can safely become pregnant and
Pharmaceuticals, Inc; Novartis
AG; and Sanofi Genzyme and has
remain well throughout pregnancy and the postpartum period with guidance
received research/grant support from specialists on treatment planning. During pregnancy, women with
from Biogen, F. Hoffman-La NMOSD may face some increased risk of both neurologic and obstetric
Roche Ltd, and Novartis AG.
Dr Houtchens has served as a complications. Recent attention has focused on evaluating the safety of
consultant for Alexion pharmacologic agents during pregnancy and breastfeeding. Unfortunately,
Pharmaceuticals, Inc; Biogen; care disparities remain common in both MS and NMOSD, and recovery of
EMD Serono; F. Hoffman-La
Roche Ltd; Novartis AG; and function is often not optimally managed in the postpartum period.
Sanofi Genzyme and has
received research/grant support
SUMMARY: This article reviews the current state of knowledge on peripartum
from Biogen, F. Hoffman-La
Roche Ltd, and Sanofi Genzyme. management in these neurologic conditions and offers practical
Dr Houtchens has provided considerations and case studies. When caring for women with MS and
expert legal testimony on motor
vehicle accidents in patients with
NMOSD of childbearing potential, treatment planning is important to
neurologic illness and has served optimize outcomes in both patient and newborn.
as an expert witness in medical
malpractice cases.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL INTRODUCTION
M
USE DISCLOSURE:
Drs Bove and Houtchens discuss any neuroinflammatory conditions affect women of
the unlabeled/investigational childbearing age and require specialized management during
use of rituximab for multiple
pregnancy. Among these conditions, multiple sclerosis
sclerosis and neuromyelitis
optica spectrum disorder and (MS) is the most common. MS is a chronic demyelinating
the unlabeled/investigational inflammatory autoimmune disease of the central nervous
use of immunosuppressives for
neuromyelitis optica spectrum
system affecting the integrity of myelin sheaths and axonal structure and
disorder. function.1,2 It is clinically characterized either by relapses and remissions of
neurologic deficits or by a progressive decline in neurologic function. In the
© 2022 American Academy United States, approximately 1 million people are affected by MS, with a 3:1
of Neurology. female to male predominance.2,3 With peak onset at around 30 years of age, MS
12 FEBRUARY 2022

mostly affects women of childbearing age, and up to 33% of women become KEY POINT
pregnant after disease onset.4,5 A significant increase in pregnancy rates in
● Many patients with
women with MS has been seen over the past 10 years, during which a relative multiple sclerosis (MS) can
decline in pregnancy rates was seen in women without MS. This suggests safely go through pregnancy
that more women with MS are feeling comfortable with pregnancy planning.6 and the postpartum period.
These data also point to the growing importance of childbearing to patients with
MS and thus to their treating neurologists.
More than 15 distinct and effective immunomodulating and
immunosuppressant medical treatments have now been approved for MS,
and modification in treatment dosing and frequency or complete discontinuation
of treatment in pregnancy may be needed. Careful timing of these interventions
is important for prevention of intrapartum or postpartum MS worsening,
which could result in loss of function and in an unplanned and stressful
need for MS treatment in the new mother. Because of the female predominance
in MS, the trend toward supporting childbearing in women with MS, and the
need for disease-modifying therapy (DMT) management, increasing numbers
of women with MS are in need of guidance regarding DMT use related to
family planning, pregnancy, and postpartum care. Recent studies indicate that
many women diagnosed with MS today can have children, breastfeed,
and resume MS treatment per their preference without incurring a greatly
increased risk of relapses during the postpartum period.7
Neuromyelitis optica spectrum disorders (NMOSDs) represent the second
most common type of demyelinating disease, affecting predominantly the
spinal cord and optic nerves. The female to male ratio in NMOSD is higher
than in MS (9:1), and the condition is also often diagnosed in women of
childbearing age. Most patients with NMOSD have elevated levels of antibodies
that target the protein aquaporin-4 in astrocytes, whereas some also have
antibodies against myelin oligodendrocyte glycoprotein (MOG). As in MS,
disease activity in NMOSD can be increased in the postpartum period, but unlike
in MS, it also appears to be increased during pregnancy; further, obstetric
complications may also commonly occur in patients with NMOSD.
Significant knowledge gaps exist about pregnancy and the course of other less
common demyelinating conditions affecting the central nervous system, such as
acute demyelinating encephalomyelitis (ADEM), Susac syndrome, and Behçet
disease (TABLE 1-18-18).
PREGNANCY AND MULTIPLE SCLEROSIS OUTCOMES

The pregnancy course of women with MS, now evaluated in many cohorts, is
overall reassuring.
Obstetric Outcomes
Most pregnancies in MS appear to have obstetric and neonatal outcomes
comparable to the general population. However, more recent studies in which
maternal factors were carefully adjusted suggest that patients with MS may
face elevated risk for adverse outcomes related to the peripartum state. A
retrospective US administrative claims study from 2006 to 2015 compared
data on pregnancy outcomes for all women with MS and a nationally
representative 5% random sample from approximately 58 million healthy
women.6 Patients with MS had a significantly higher overall rate of
intrapartum and postpartum complications, including infectious complications,

PREGNANCY MANAGEMENT IN MS AND OTHER DEMYELINATING DISEASES
hypertensive disorders, and cardiovascular disorders in pregnancy.6 Additional

studies have suggested that women with MS are more likely to have operative
deliveries, including the use of forceps or vacuum extractor or cesarean
delivery, and this is not directly related to neurologic disability.6,19-22 Reasons for
this elevated cesarean delivery rate may include patient or clinician preference,
as suggested by a 21.6% rate of planned unlabored cesarean deliveries in an
interim analysis of 122 pregnancies from the New England PREG-MS cohort.23
Further, after adjusting for maternal factors such as age, women with MS
may be more likely to have babies that are small for their gestational age (3.4%
versus 2.8%).22
Patients with more serious and active disease and patients with poor access to
neurologic and obstetric care, may face further risks of adverse outcomes during
pregnancy and postpartum. Disparities also exist in MS outcomes with respect to
race and ethnicity: people with MS who are Black or Hispanic tend to have a more
severe MS course, more rapid accrual of disability, and more frequent disease
exacerbations.24,25 The contribution of race and ethnicity to pregnancy outcomes
in MS or NMOSD is not known (CASE 1-1).26,27
Neurologic Outcomes
In numerous case series across various geographic and health care settings and
treatment epochs, relapse rates in MS have been reported to decrease during
pregnancy. A landmark article established a reduction of the relapse rate during
pregnancy followed by an increase in relapses in the first 3 to 6 months
postpartum.28 In fact, up to about one-third of women with MS have been
reported to experience an MS relapse in the first 3 months postpartum.29
Increased postpartum activity is evidenced both by increased rate of clinical
relapse and by radiographic activity, including new T2 hyperintense lesions or
gadolinium-enhancing lesions,30 which are noted often even in women without
clinical relapses.31,32 Risk factors for inflammatory activity include an active MRI
TABLE 1-1 Demyelinating Diseases of the Central Nervous System and the Current
State of Knowledge About Pregnancy
Demyelinating central nervous Relationship with Relationship with Obstetric Treatment in

system disease pregnancy postpartum complications pregnancy
Multiple sclerosis Relapses are stable Relapses may worsen for Similar to the Rare
or improved 1-6 months postpartum general
population
Neuromyelitis optica spectrum Relapses may Relapses may continue Common Common, with
disorder (NMOSD)8,9 continue variable outcomes
Acute disseminated Unknown (rare case Unknown Unknown Unknown

encephalomyelitis (ADEM)10,11 reports)
Susac syndrome12-15 Unknown (case reports Unknown Unknown Reported

and case series)
Behçet disease16-18 Unknown (case series) Unknown Common Common in active

phase of disease
14 FEBRUARY 2022

A 28-year-old nulliparous woman with a diagnosis of multiple sclerosis CASE 1-1
(MS) since the age of 19 presented for a consultation and to initiate care
as a new patient. She had recently moved to the state to start a new job.
Her disease onset had involved a brainstem syndrome (double vision and
dysarthria), and she had never fully recovered from the initial attack.
Unfortunately, MS was not suspected at first presentation due to the
clinician’s misbelief that MS was rare in people of African ancestry. She
was diagnosed with MS when she was hospitalized for a serious second
relapse involving leg weakness that required IV steroids. She saw a
neurologist once more 3 years following her diagnosis. She believed she
had experienced additional minor relapses, but they were not formally
assessed. Her last relapse was 6 months earlier, with right leg fatigue and
increased difficulty walking for 3 weeks. She had insufficient health
insurance with high deductibles and minimal prescription coverage
through her previous job and was not able to receive care for this reason.
Her last brain MRI scan was 5 years earlier.
She was now aware of the need for MS treatment and had better
health insurance through her new job. She was newly married, and
wanted to start a family within the next 1 to 2 years.
Her neurologic examination showed partial internuclear
ophthalmoplegia and a mild right hemiparesis. Her Expanded Disability
Status Scale (EDSS) score was 3. She had at least five contrast-enhancing
brain MRI lesions on repeat scan. Treatment options with high-efficacy
disease-modifying therapy were discussed, and the patient selected the
subcutaneous B-cell–depleting agent ofatumumab. While waiting to start
on her treatment with ofatumumab, she received a course of IV steroids
to help treat clinical and radiographic inflammatory disease activity. She
was also referred to physical therapy for strength and conditioning and to
neuro-ophthalmology to help with prismatic correction of her double
vision. Repeat imaging and reassessment of her neurologic examination
was planned in 3 to 6 months along with a detailed conversation about
family planning. The patient was encouraged to continue her hormonal
contraceptives until that time. She was also encouraged to establish care
with a maternal-fetal medicine specialist or obstetrician.
Gaps in insurance coverage and therefore neurologic management of this COMMENT

patient, as well as possible racial biases, unfortunately impacted her MS
management and disease control. Patients with suboptimal MS control,
whether because of high inflammatory activity or health care disparities, or
both, should stabilize their disease activity with appropriately effective
treatment before starting conception attempts. Clinical and radiographic
disease stability for a year before pregnancy is associated with better
postpartum outcomes and reduced risk of postpartum relapses in MS.
Effective contraception should be used in the interim.

before pregnancy and discontinuation of fingolimod or natalizumab without any

treatment planning to prevent rebound effects.
PREGNANCY AND NEUROMYELITIS OPTICA SPECTRUM

DISORDER OUTCOMES
Several case series have reported that, like women with MS, women with NMOSD
have an elevated risk of relapse or disease onset postpartum, but unlike women
with MS, they also have an apparent elevated relapse risk during pregnancy
compared to the prepartum period, both of which can result in a substantial
accumulation of disability.33,34 Therefore, stabilization of the disease before
conception is recommended. Clinically, pregnancy-related hyperemesis
gravidarum or severe nausea and vomiting may be confused with NMOSD-
associated area postrema syndrome (intractable nausea, vomiting, or hiccups). In
addition, an increased risk of pregnancy complications may exist, including
miscarriage (independent of comorbid autoimmune conditions such as
antiphospholipid syndrome35) and preeclampsia (in which comorbid autoimmune
conditions may contribute to risk). NMOSD obstetric outcomes data are needed,
with limited case series inconclusive to date.33
Additional challenges exist in managing women with NMOSD during
pregnancy. NMOSD is relatively rare and less well known to many non-
neurologists/ophthalmologists. Further, NMOSD overall affects a greater
proportion of people of color,36 who experience differential neurologic
outcomes,37-39 possibly resulting from broader structural inequities and other
forms of racism in health care. Therefore, it is important to ensure careful
interprofessional (neurologic, obstetric, neonatal) communication for women
with NMOSD planning pregnancy in order to optimize management.
For both MS and NMOSD, there is a trend to use anti-CD20 therapies before
pregnancy, which can provide clinical stability before conception, during
pregnancy, and, potentially, postpartum.7,40-42
FAMILY PLANNING AND PERSONALIZED CARE IN MULTIPLE

SCLEROSIS AND NEUROMYELITIS OPTICA SPECTRUM DISORDER
Intrapartum and postpartum outcomes in patients with MS or NMOSD are
closely linked to disease stability for a year preceding pregnancy.40,43 Up to 40%
of women with mild and stable MS who have no evidence of disease activity
before pregnancy do not require any treatment before conception or in the
postpartum period.42,44
Preconception Care Planning

Highly active disease should become well controlled before, throughout, and
after pregnancy through the use of effective DMTs that have safety data for
peripartum use. Therefore, the reproductive plan should be discussed during
every appointment with female patients of reproductive age with MS or NMOSD
and appropriate counseling should be provided (FIGURE 1-1), even when women
are not actively planning a pregnancy. As noted in TABLE 1-2,45 genetic risks
should be discussed, as should treatment (preventive and for relapse) options
before, during, and following the pregnancy. Since women may not have
established care with an obstetric clinician yet, recommendations about prenatal
vitamins, vitamin D supplementation, and smoking cessation, if applicable, may
also be discussed.
16 FEBRUARY 2022

KEY POINTS
● In patients with more

serious and active
neurologic disease and
patients who experience
health care disparities with
poor access to neurologic or
obstetric care, maternal
pregnancy and postpartum
outcomes are at risk.
● In MS, postpartum MRI

may reveal elevated
inflammatory activity even in
women deemed clinically
stable and is a useful
evaluation tool to decide on
treatment selection.
● Women with
neuromyelitis optica
spectrum disorder (NMOSD)
face elevated risk of
inflammatory activity both
during and after pregnancy
FIGURE 1-1
relative to prepartum and
Counseling algorithm for a patient of childbearing potential with demyelinating disease.
MS = multiple sclerosis; NMOSD = neuromyelitis optica spectrum disorder.
potentially greater
pregnancy complications
than the general population.
● For both MS and NMOSD,

ONE KEY QUESTION. Asking patients “Would you like to become pregnant in the there is a trend to use
next year?” allows for a screening assessment of the patient’s family planning anti-CD20 therapies before
pregnancy, which can
needs to help guide the health care provider’s treatment and care plan.46 If a provide clinical stability
patient is not ready to start a family, the discussion should focus on appropriate before conception, during
contraception and optimizing medical management of their disease. FIGURE 1-1 pregnancy, and, potentially,
provides an algorithm for family planning counseling for patients with MS postpartum.
or NMOSD.
● Intrapartum and
postpartum outcomes in
CONTRACEPTION. Any form of contraception is safe for patients with MS or patients with MS or NMOSD
NMOSD, and preference should be given to contraceptive options that are highly are linked to disease
stability for a year preceding
effective with easy-to-achieve compliance and rapid reversibility to allow
pregnancy.
for conception attempts when the patient is ready.47 In general, women who
are discontinuing their MS or NMOSD treatment before conception may be ● Asking patients “Would
advised to resume normal ovarian cycles (eg, by switching from a hormonal you like to become pregnant
contraceptive to a barrier method) before discontinuing the drug to minimize in the next year?” allows for
a screening assessment of
time off therapy. To this aim, they may also be advised how to optimize the patient’s family planning
conception chances (eg, charting, basal body temperature measurement, use needs to help guide the
of ovulation kits). health care provider’s
treatment and care plan.
INFERTILITY TREATMENTS AND PREGNANCY. In addition to possible differences in
preferences and decision making surrounding childbearing, evidence on whether
fertility is impaired in patients with MS or NMOSD is still sparse, and sometimes
conflicting.23,48-51 Some studies report decreased fertility because of lower levels
of antimüllerian hormone, increased endometriosis, and frequent comorbid

thyroid disorders, whereas others suggest normal fertility.48,52,53 In general, a

lower rate of fertility treatments was seen in patients with MS despite a higher
rate of infertility diagnosis.54
In general, if pregnancy is not achieved after 3 to 6 months of optimal
conception attempts, referral to a fertility clinic should be considered (in
contrast to the 12-month recommendation in a patient without MS or NMOSD)
to optimize time off therapy and minimize stressors.
In women with MS, an elevated annualized relapse rate following assisted
reproductive technologies has been reported in several case series55; notably,
these included mainly women on no DMT or on a lower-efficacy DMT that
was discontinued before the use of assisted reproductive technologies. Data
are needed on demyelinating events in women who receive higher-efficacy
longer-acting DMTs (such as ocrelizumab, rituximab, alemtuzumab, cladribine)
before undergoing assisted reproductive technologies or during ovarian
hyperstimulation for fertility preservation, to understand whether these
treatments offer additional protection against relapses. No data are available on
any possible association between NMOSD exacerbations and infertility
treatments.
DISEASE-MODIFYING THERAPIES AND PREGNANCY

Many treatments are now available for patients with MS and NMOSD.
They can be classified based on the mode of administration, the size of the
TABLE 1-2 Preconception Guidelines for Care of Patients With Multiple Sclerosis and
Neuromyelitis Optica Spectrum Disorder
For any woman of childbearing age with multiple sclerosis (MS) or neuromyelitis spectrum
disorder (NMOSD), begin with a preconception counseling session
◆ Discuss family planning, including timing, at every visit
◆ Discuss genetic risks: family history, one or both parents affected, level of anxiety about
disease transmission to offspring
◆ Assess disease activity in preconception phase and the risk of disease activity increase
intrapartum or postpartum
Discuss management of disease-modifying therapy before attempting conception
◆ Is discontinuation needed? If so, is washout needed?
◆ What is the risk of inflammatory rebound after stopping treatment compared to the risk of
early pregnancy exposure to treatment?
Prenatal vitamins and vitamin D supplementation (recommended vitamin D3 dose in
peripartum period is 1000-4000 IU/d, depending on the medical organization providing the
recommendations)45
Discuss optimization of conception chances (charting, basal body temperature
measurement, use of ovulation kits) with the goal of decreasing time off therapy while trying
to achieve pregnancy
◆ Referral to fertility clinic if pregnancy is not achieved after 3-6 months of optimal conception
attempts, in contrast to the 12-month recommendation in a patient without MS or NMOSD
Consider stabilizing a patient with active disease with an effective therapy optimized for
pharmacokinetic/pharmacodynamic effects and safety before starting conception attempts
18 FEBRUARY 2022

molecule, efficacy, safety, duration of biologic effects, and pregnancy KEY POINTS
compatibility (TABLE 1-356 and TABLE 1-457,58). When advising women about
● Any form of
DMT discontinuation before pregnancy or resumption postpartum, the contraception is safe for
pharmacokinetic and pharmacodynamic properties of pharmacologic agents patients with MS or NMOSD.
are increasingly being considered, in addition to their labeled indications. Each
pharmaceutical manufacturer maintains a pregnancy registry unique to each ● In patients with
demyelinating diseases, if
therapy as mandated by the US Food and Drug Administration (FDA) in the
pregnancy is not achieved
United States and the European Medicines Agency (EMA) in European after 3 to 6 months of
Union. To ensure complete elimination of products before conception, typically optimal conception
waiting at least 5 maximal half-lives is recommended (with the exception of attempts, referral to a
teriflunomide, for which an accelerated washout protocol is recommended).59 fertility clinic should be
considered.
However, in many cases, a less conservative approach may be entertained
to balance and optimize both maternal treatment and infant safety. Some ● Many disease-modifying
treatments are more challenging to manage in the peripartum period because therapies are used in MS. A
of concerns for possible rebound disease activity upon discontinuation thorough understanding of
prepregnancy washout and
(such as sphingosine-1-phosphate [S1P] receptor modulators or natalizumab), safety in pregnancy
insufficient data regarding breastfeeding, or dosing schedules that are different exposure recommendations
from the product label. is needed to optimize MS
Guidance for DMTs used for MS is discussed below. Evidence for safety of management.
treatments used for NMOSD is more patchy and is summarized in TABLE 1-4,
● To ensure complete
including broad-efficacy immunosuppressives, anti-CD20 monoclonal elimination of products
antibodies also used for MS, and newer treatments. before conception, typically
DMTs for MS can be broadly classified based on their route of administration, waiting at least 5 maximal
mechanism of action, efficacy, and overall safety profiles. The first-generation half-lives is recommended
(with the exception of
self-injectable treatments include glatiramer acetate and several interferons beta teriflunomide, for which an
(TABLE 1-3). These treatments are generally safe to continue up until the moment accelerated washout
of conception attempts or even missed menses. Because of apparent safety protocol is recommended).
gleaned from large pregnancy registries, glatiramer acetate may be continued
● If natalizumab is
throughout pregnancy at the discretion of the patient and their neurologist. continued into the mid to
Oral medications include S1P receptor modulators, fumarates, teriflunomide, late third trimester,
and cladribine; in general, all should be discontinued before conception hematologic screening
(TABLE 1-3). Teriflunomide has an extremely long half-life, and a rapid of the newborn is
necessary because of an
elimination protocol should be used before conception attempts to remove
increased risk of transient
the product from maternal circulation because of the risk of fetotoxicity. Fumarates thrombocytopenia and
may be continued up through the moment of conception. Although the general anemia in some newborns.
recommendation is to discontinue S1P receptor modulators (fingolimod, siponimod,
ozanimod) 2 months before conception attempts because of concerns about ● MRI without gadolinium
can be obtained and
potential congenital malformations, discontinuation can be associated with the compared to the
risk of rebound inflammatory activity, prompting the use of bridge therapies, preconception MRI in cases
such as anti-CD20 therapies (CASE 1-2). Patients who receive cladribine may of new neurologic
initiate conception attempts 6 months following the course of treatment. symptoms in pregnancy.
Intravenously administered DMTs include several IgG monoclonal antibodies; in
general, placental transfer of IgG is limited during the first trimester, and the
half-life is typically about 20 days (with 5 half-lives about 3 to 4 months)
(TABLE 1-3). The pharmacodynamic effects of anti-CD20 monoclonal antibodies
such as ocrelizumab and rituximab persist beyond their pharmacokinetic
clearance, providing a window for conception attempts while minimizing
risks of fetal exposure. Ofatumumab, also an anti-CD20 monoclonal antibody, is
given subcutaneously every month. Similar principles apply for alemtuzumab,
another infusible monoclonal antibody.

Natalizumab, however, is given monthly, with several additional

considerations. Although transplacental transport of natalizumab has been
observed in the second trimester,60,61 the product has not been shown to be
teratogenic in animal studies, and preliminary data show no increased risk of low
birth weight, incidence of malformation, or spontaneous abortion in humans.62
However, if natalizumab is discontinued in anticipation of pregnancy, up to
40% of women will experience an intrapartum relapse (rebound MS activity),
with a 10% to 20% risk of significant long-term disability resulting from these
relapses.63,64 Although FDA and EMA labeling suggest natalizumab washout
before conception, in some cases, a reasonable practice can be to continue the
treatment throughout pregnancy, with infusion frequency every 6 to 8 weeks,
until approximately gestation week 32 (CASE 1-3). If natalizumab is continued into
the mid to late third trimester, hematologic screening of the newborn is necessary
TABLE 1-3 Multiple Sclerosis Disease-modifying Therapies and Pregnancy Washout

Recommendationsa,b
Length of disease-modifying
Length of disease- therapy washout period
modifying therapy per pharmacokinetic/
washout period pharmacodynamic placental
Disease-modifying therapy per label transfer and potential risksc Characteristics
Self-injectable therapies
(platform)
Interferons beta (all brand No washout No washout Short half-life, lower efficacy,
formulations approved for extensive safety data with no
multiple sclerosis fetotoxicity; may be used up to
treatments and any conception
generic equivalents)
Glatiramer acetate No washout No washout Short half-life, lower efficacy,

(brand or any generic extensive safety data with no
formulations) fetotoxicity; may be used up to
conception and throughout pregnancy
Oral therapies
Teriflunomide Plasma levels must Accelerated elimination Very long half-life, intermediate
be <0.02 mg/L, protocol; no washout efficacy, animal evidence of
accelerated elimination when used and plasma fetotoxicity, not compatible with
can be achieved with concentration pregnancy
cholestyramine <0.02 mg/L confirmed
Sphingosine-1- 2 months 2 months High efficacy, long half-life, human

phosphate evidence of fetotoxicity; rebound
(S1P) receptor multiple sclerosis activity after
modulators stopping this disease-modifying
(fingolimod, ozanimod, therapy
ponesimod, siponimod)
CONTINUED ON PAGE 21
20 FEBRUARY 2022

because of an increased risk of transient thrombocytopenia and anemia in some
newborns. If natalizumab is to be discontinued before conception, then bridging
with anti-CD20 treatments (rituxamab, ocrelizumab, ofatumumab) can be
considered.
CARE DURING PREGNANCY

For many women with MS, the pregnancy period is a reprieve from their
bothersome MS symptoms. However, women with MS who are at higher risk of
rebound relapses (such as those discontinuing natalizumab or S1P receptor
modulators)65 and women with NMOSD may face elevated relapse risk
(CASE 1-4). If new neurologic symptoms arise and doubt exists about their nature
(ie, demyelinating versus another etiology), an MRI without gadolinium can be
obtained and compared to the preconception MRI.66 In the event of a relapse,
CONTINUED FROM PAGE 20
washout period pharmacodynamic placental
Disease-modifying therapy per label transfer and potential risksc Characteristics
Cladribine 6 months 4 months High efficacy, intermediate half-life,
prolonged biologic activity after
administration, no human evidence
of fetotoxicity
Dimethyl fumarate No washout No washout Very short half-life, intermediate

(brand and generics) efficacy, no human evidence of
fetotoxicity
Monoclonal antibodies
Alemtuzumab 4 months 4 months Infusion, high efficacy, intermediate

half-life but very prolonged biologic
activity after administration
B-cell–depleting agents 6 months 2 months Infusion and self-injectable; high

(ocrelizumab, rituximab,d efficacy, intermediate half-life but
and ofatumumab) prolonged biologic activity after
administration; emerging safety data
with pregnancy exposures reassuring
Natalizumab 3 months No washout Infusion, high efficacy, intermediate

half-life; reassuring emerging safety
data with pregnancy exposures;
rebound multiple sclerosis activity
after stopping this disease-
modifying therapy
a
Treatments reviewed in Wallach AI, et al, Neurol Clin.56
b
Pregnancy data reviewed in Mao-Draayer Y, et al, Nat Rev Neurol.9
c
Washout refers to the time period during which the drug has to be stopped before conception attempts can begin.
d
Rituximab is not US Food and Drug Administration (FDA) approved for multiple sclerosis treatment but is used off-label as a standard practice in
a variety of settings for relapsing-remitting multiple sclerosis therapy.

TABLE 1-4 Neuromyelitis Optica Spectrum Disorder Disease-modifying Therapies and

Pregnancy Washout Recommendationsa,b
Disease-modifying washout period per pharmacodynamic placental
therapy label transfer and potential risksc Characteristics
Immunosuppressive
therapies
Azathioprine No recommendation Could consider continuing Reassuring safety data across case series
during pregnancy for various indications
Methotrexate One menstrual cycle 1 month Associated with embryotoxicity, abortions,

fetal defects, and reduced fertility
Mycophenolate 6 weeks 6 weeks Embryotoxicity, pregnancy loss

mofetil
Tacrolimus No recommendation 1 month Neonatal complications in humans;

fetotoxicity in animals
Inebilizumab 6 months 2 months; could continue if Infusion, high efficacy, intermediate half-
(anti-CD19 IgG1) maternal benefit outweighs life but prolonged biologic activity after
theoretical risk to fetus administration; consider checking newborn
B cells and lymphocytes
Rituximab 6 months 2 months; could continue if Infusion, high efficacy, intermediate half-
(anti-CD20 IgG1)d maternal benefit outweighs life but prolonged biologic activity after
theoretical risk to fetus administration; reassuring emerging safety
data with pregnancy exposures; consider
checking newborn B cells and lymphocytes
Tocilizumab No recommendation 3 months Infusion or subcutaneous injection; in

(antiIL6 IgG1) monkeys treated during pregnancy,
abortifacient and embryotoxic and possible
delayed parturition; in humans, possible
increased risk of miscarriage, preterm birth,
and lower birth weight noted in women with
rheumatoid arthritis but potentially
confounded by methotrexate comedication57
Satralizumab No recommendation 2 months Subcutaneous, monthly; in monkeys treated

(anti-IL6 IgG2) during pregnancy, no adverse effects on
maternal animals or fetal development, but
some neonatal immune concerns
Eculizumab No recommendation 2 months; could continue if Infusion every 14 days; reassuring safety
(IgG2/4 kappa maternal benefit outweighs data for infants of women with paroxysmal
anti-C5 antibody) theoretical risk to fetus nocturnal hemoglobinuria treated during
pregnancy58
IgG = immunoglobulin G.
a
Treatments reviewed in Wallach AI, et al, Neurol Clin.56
b
Pregnancy data reviewed in Mao-Draayer Y, et al, Nat Rev Neurol.9
c
Washout refers to the time period during which the drug has to be stopped before conception attempts can begin.
d
Rituximab is not US Food and Drug Administration (FDA) approved for neuromyelitis optica spectrum disorder (NMOSD) treatment but is used
off-label as a standard practice in a variety of settings for NMOSD therapy.
22 FEBRUARY 2022

treatment can be considered when loss of function occurs. During pregnancy,
short courses of glucocorticoids are generally considered safe and are designated
as low risk by the American College of Obstetrics and Gynecology.67
Methylprednisolone, prednisone, and prednisolone are preferred in pregnancy as
they are inactivated by placental 11-β-hydroxysteroid dehydrogenase and
therefore do not enter the fetal circulation. In contrast, approximately 80% of a
maternal dexamethasone dose can cross the placenta into the fetal circulation
A 39-year-old woman with a 6-year history of multiple sclerosis (MS), CASE 1-2
gravida 1, para 1, with stable disease on fingolimod, presented to discuss
family planning. She wanted to become pregnant with her second child
before turning 40. She was aware that fingolimod must be discontinued
2 months before pregnancy attempts but was concerned about
compromising her well-controlled MS. Different treatment options were
discussed, including high-efficacy treatments that have long biological
activity and do not appear to result in rebound increase activity or
pregnancy-related complications (such as the anti-CD20 monoclonal
antibodies rituximab or ocrelizumab). She had experienced no issues
getting pregnant 5 years prior and delivered a healthy child with no
delivery-related complications. She had minimal MS-related symptoms
and reported only occasional leg spasms after intense exercise.
Her examination showed pallor in the right optic disc with an afferent
pupillary defect in that eye and mild bilateral spasticity in legs. She also
had some bladder urgency but no incontinence. MRI showed many T2
bright white matter lesions throughout the brain, with no recent new or
enhancing lesions.
After extensive research and considerations of her treatment options,
she agreed to stop fingolimod and transition to rituximab. The therapeutic
switch was smooth, and she had no intercurrent MS activity. Three
months after her full-dose rituximab treatment, she initiated conception
attempts and became pregnant quickly. Her pregnancy was uneventful,
and she delivered at term. She elected to breastfeed exclusively and
delay restart of rituximab for at least 6 months. However, postpartum
MRI performed at 5 months showed one new T2 lesion in the brain that
enhanced with contrast. After discussion and review of data, she
reinitiated rituximab treatment and continued to breastfeed her child.
She did not develop any clinical relapses postpartum, and her disability
was unchanged upon routine neurologic follow-up.
B-cell–depleting monoclonal antibodies may serve both as a bridge to COMMENT

abrogate rebound disease activity when discontinuing certain MS
treatments (sphingosine-1-phosphate [S1P] receptor modulators [fingolimod
and others] or natalizumab) and as an approach to stabilizing disease activity
before, during, and after pregnancy. Lack of placental transfer early in
pregnancy and minimal transfer into breast milk are favorable.

unmetabolized.68,69 Although a correlation between early pregnancy steroid

exposure and a risk of cleft palate in babies was reported in earlier studies, this
has not been confirmed in more recent analyses.70,71 However, if possible,
steroids should be used starting at the tenth week of gestation to avoid any
theoretical risks of complications during organogenesis. During the second and
third trimesters, repeated administration of high-dose steroids may be associated
with hypertension, preeclampsia, intrauterine growth restriction, and low birth
weight, but specific correlations between dosage and length of exposure are
unknown. It is also important to note that the data on possible maternal and fetal
concerns related to steroid pregnancy exposures stems from studies in patients
without MS, and the applicability of these data to pregnant patients with MS
is not known.72,73 In general, in the setting of MS/demyelinating disorders,
high-dose steroid treatments can be used in circumstances in which a pregnant
patient may incur significant neurologic disability and/or functional limitations
because of the intrapartum relapse.74,75
Rescue therapy for severe NMOSD attacks refractory to IV methylprednisolone
in pregnant women is not well established. Although either plasma exchange or
CASE 1-3 A 31-year-old woman with a 6-year history of multiple sclerosis (MS)
presented for her routine neurologic appointment. Her MS was initially
diagnosed when she woke up one morning with numbness in her right arm
and a shocklike sensation upon flexing her neck. Her disease course was
initially characterized by numerous clinical attacks, requiring multiple IV
steroid infusions despite escalation therapy with several successive
disease-modifying therapies. Three years before the current visit,
natalizumab treatment was suggested, and she agreed to try it to improve
disease control. She repeatedly tested negative for JC virus antibodies,
indicating an extremely low risk of progressive multifocal
leukoencephalopathy. Within 4 months after starting natalizumab, her
disease stabilized and she no longer had relapses or new changes on
brain MRI.
She was stable on natalizumab for 3 years and was newly married and
interested in starting a family. She remained on natalizumab as she was
trying to conceive, but her dosing interval was extended to every
6 weeks. After she became pregnant, she remained on natalizumab every
6 weeks throughout pregnancy until gestation week 32. She delivered a
healthy child at 39 weeks and resumed treatment immediately
postpartum. She elected to not breastfeed because of the lack of
conclusive evidence on safety.
COMMENT Natalizumab has been used throughout pregnancy, with careful discussion
or possible risks and benefits and with extended dosing intervals. This
helps avoid disease reactivation in pregnancy because of possible
rebound effects of natalizumab withdrawal. Most IgG monoclonal
antibodies only transfer in minute concentrations into breast milk,
including, according to emerging data, natalizumab.
24 FEBRUARY 2022

A 29-year-old woman, gravida 0, para 0, with a 3-year-history of CASE 1-4
aquaporin-4 antibody–confirmed neuromyelitis optica (NMO) presented
to discuss family planning. She had initially presented 3 years earlier with
a complete loss of vision in the right eye, which was responsive to
steroids, resulting in recovery of vision to 20/60 after a 5-day course of
high-dose IV methylprednisolone. MRI of the brain and spinal cord
showed no lesions other than in the optic nerve. She subsequently
developed transverse myelitis affecting the left arm. Since the diagnosis
of NMO, she had been treated with rituximab infusions twice per year and
had remained relapse free.
She was now interested in starting a family. She had a family history of
infertility in her mother and sister. After discussing treatment options,
she agreed to stop rituximab 2 months before attempting conception.
Preemptive infertility investigation was recommended because of
concerns for potentially prolonged time off from her NMO treatment in
the event of infertility.
Although the patient’s infertility workup was unremarkable, she had
difficulty with conception, finally becoming pregnant 10 months after
stopping rituximab. Her lymphocyte counts were monitored monthly
starting at 6 months from her last infusion, with B cells increasing into the
detectable range at 8 months, but the patient refused additional
treatment before pregnancy.
During pregnancy week 8, she developed numbness, tingling, and
progressive weakness in the right leg. Neurologic examination showed a
moderate right leg weakness (manual muscle strength of 3/5 in the right
leg hip flexors and knee extensor muscles), generalized hyperreflexia,
severe hypoesthesia in both legs and a mild bladder disturbance.
Noncontrast MRI of the spine revealed a new longitudinally extensive
T2-hyperintense lesion at T4 through T8. After a discussion of risks and
benefits involving the patient as well as her obstetrician, the patient
received a 5-day course of treatment with high-dose IV
methylprednisolone, with minimal improvement. Considering her
functionally significant neurologic disability, she then received a course
of IV immunoglobulin (IVIg) with successful resolution of her symptoms.
The remainder of her pregnancy was notable for mild gestational
hypertension, which resolved after delivery. She delivered a healthy
newborn at 38 weeks. Cord blood B cells were verified and normal. The
patient was redosed with rituximab 2 weeks after delivery.
Given the risk of relapses during pregnancy in women with NMOSD, careful COMMENT
treatment planning is recommended. If attempting conception after
infusion with B-cell–depleting monoclonal antibodies, regular laboratory
monitoring can be used to ensure undetectable CD19 counts, with repeat
treatment to be considered if levels become detectable.

IV immunoglobulin (IVIg) can be used in NMOSD for steroid-resistant relapses,

IVIg (0.4 g/kg/d) is preferred in pregnancy because of lower theoretical risks
of circulatory instability than with plasma exchange administration, although
recent case series of plasma exchange during pregnancy are encouraging.76
Case series also suggest reasonable clinical stability and pregnancy outcomes in
women treated with eculizumab or rituximab for various indications during
pregnancy (TABLE 1-4).
GENERAL POSTPARTUM CARE

Generally, planning early comprehensive postpartum care for MS or NMOSD
while a patient is still pregnant may enable sufficient time for scheduling and
insurance approvals and reduce future burden on the newly postpartum mother.
This includes scheduling neuroimaging, laboratory testing, and rehabilitation
evaluations.
CASE 1-5 A 36-year-old woman, gravida 3, para 2, presented to her neurologist for
urgent evaluation 7 weeks postpartum, reporting severe mood and
cognitive changes. She had been diagnosed with multiple sclerosis (MS)
6 years earlier. Her MS was initially managed with glatiramer acetate.
After 3 years, the patient had experienced a relapse, and her glatiramer
acetate was switched to fingolimod. Fingolimod was discontinued about
3 months before her pregnancy. The pregnancy was largely normal, with
a healthy girl born at term.
At her neurologic evaluation, the patient reported constant crying for
the past 3 weeks, cognitive fog, and lack of attachment to the infant. She
reported difficulties with establishing breastfeeding and had chosen to
feed her infant formula. She also reported some suicidal ideation. She
had no psychotic features. An urgent brain MRI was ordered, which
revealed a large new left frontal lesion with gadolinium enhancement.
The patient was referred for urgent psychiatric evaluation and
monitoring. She was treated with 5 days of IV methylprednisolone paired
with quetiapine given concerns for potential steroid-induced psychiatric
exacerbation. Following her acute treatment, she was started on a selective
serotonin reuptake inhibitor (SSRI) and began regular psychotherapy.
Ocrelizumab, a CD20-depleting monoclonal antibody, was initiated for her
MS. At follow-up evaluation 3 months later, the patient reported improved
mood and attachment to her infant. On follow-up neuroimaging, her lesion
had decreased in size and was no longer enhancing.
COMMENT Careful attention should be paid to women with MS or neuromyelitis optica

spectrum disorder (NMOSD) in the postpartum period to monitor for new
symptoms using a comprehensive survey of cerebral, motor, sensory, and
bowel/bladder function. MRI with gadolinium can be used to identify new
lesions. Prompt treatment of both the inflammatory activity (eg, with
steroids) and symptoms (eg, depression care) can improve function and
support a smoother postpartum course.
26 FEBRUARY 2022

Surveillance neuroimaging should be considered within the first few months KEY POINTS
postpartum to establish a new baseline and to evaluate for silent inflammatory
● Methylprednisolone,
activity in women not resuming effective DMTs early. Gadolinium is considered prednisone, and
compatible with breastfeeding.66 prednisolone are preferred
The patient’s current physical functional status should be comprehensively in pregnancy as they are
evaluated, including cardiovascular conditioning, spasticity, gait, pain, inactivated by placental
11-β-hydroxysteroid
and pelvic floor function. Both bladder and bowel function can be impacted
dehydrogenase and
by pregnancy and by MS.77,78 The first line of treatment for bladder symptoms is therefore do not enter the
pelvic floor therapy,79 followed by pharmacotherapy and other neuro-urologic fetal circulation.
procedures should function not normalize. Timely referral to experts (eg,
physical therapist, pelvic floor therapist, urologist) should be considered even ● Surveillance
neuroimaging should be
before the delivery, given that multiple competing priorities for new mothers can considered within the first
potentially result in low rates of rehabilitation use postpartum.80 few months postpartum to
Neurologists may be best positioned to evaluate the “invisible” symptoms establish a new baseline.
of demyelinating diseases that can substantially influence the quality of life
● Comprehensive
in postpartum patients, including fatigue, pain, and cognitive changes. evaluation of women with
Although formal prospective studies are needed to clarify whether the risk of MS and NMOSD is
peripartum depression or anxiety is increased in women with MS81,82 relative to recommended early
the general population83,84 and whether this risk could be associated with postpartum and should
include gait, balance,
inflammation (CASE 1-5), the elevated baseline risk of mood disorders in MS
bladder, bowel, mood,
likely increases the risk of peripartum depression in patients with MS and fatigue, cognition, strength,
formal screening is recommended, with prompt referral to a mental health pain, social supports, and
expert if warranted. Exercise may also help improve mood postpartum.85 neuroimaging review.
Comprehensive evaluation of prior history of a mood disorder (eg, depression,
● In MS, exclusive
anxiety); infant bonding; difficulties with breastfeeding, behavior, or breastfeeding is protective
attachment; sleep; and social stressors, including familial dynamics or against postpartum
work, is recommended. inflammatory activity.
● Safety data suggest that

BREASTFEEDING CONSIDERATIONS both first-line self-
Because exclusive breastfeeding appears to be protective against MS relapses injectable therapies
in the early postpartum period86 and because of its numerous beneficial (glatiramer and interferon
effects for both mothers and infants, breastfeeding should be supported in beta) and IgG monoclonal
antibodies (such as
women with MS who wish to do so. Support from a lactation consultant
ocrelizumab and rituximab)
may be warranted to optimize lactation. If a patient chooses to breastfeed, are reasonable to consider
the choice of DMT and timing of resumption depend on the likelihood of during breastfeeding.
breast milk transfer and the maternal risk of postpartum relapse. One option
is to maintain exclusive breastfeeding followed by a rapid wean to a high-efficacy ● Women with MS and
women with NMOSD may
medication with a short therapeutic lag. A second option is to maintain face disparities in their
breastfeeding with early resumption of a DMT unlikely to be present in obstetric and neurologic
significant amounts in the breast milk. Safety data on the topic of breastfeeding care and outcomes. Care
and DMTs are limited because of a lack of scientific inquiry, and product coordination between the
two specialists is important.
labels typically urge caution.87 When interpreting potential transfer of a
DMT through breast milk, however, the following physiologic mechanisms
should be considered in addition to the actual data: a drug’s molecular weight,
protein binding, and lipid solubility; the volume of distribution; transport
mechanisms, including the likelihood of newborn enteric absorption if
ingested in breast milk; and potential risk to the infant. These factors, along
with recent studies, suggest that both self-injectable and monoclonal antibody
DMTs are reasonable to consider and probably compatible with breastfeeding
(interferon beta is deemed compatible by the EMA), whereas caution remains

with oral disease-modifying therapies (TABLE 1-5). In women with more aggressive
MS, therefore, infusible therapies could be compatible with breastfeeding. A third
option for women who choose to breastfeed is to consider monthly pulsed
glucocorticoids (which also show minimal breast milk transfer, with a relative infant
dose of 0.50%88), with careful maternal symptom management (sleep and mood),
or monthly IVIg or subcutaneous immunoglobulins. Given the risk of more severe
relapses in women with NMOSD, similar data are needed before recommending
any delays in resuming effective DMT.
TABLE 1-5 Factors That Determine Compatibility of Multiple Sclerosis

Disease-Modifying Therapies With Breastfeeding and Summary
Recommendationa
Compatible
Disease-modifying Detectable in Transluminal Possible effects with with
therapy Description breast milk? transfer?b infant exposurec lactation?
Large molecules
Glatiramer acetate Large molecule Not done, unlikely Yes, as with None Yes
(4.7–13 kDa) any amino
heterogeneous acid
strings of amino
acids
Interferon beta Large molecule, 0.0006% relative Exceedingly Flulike symptoms Yes
protein infant dose low
Natalizumab IgG4; 149 kDa <1:200 of Low Infections,d impaired Probably

maternal serum vaccine responses or
level; 2-5% disseminated disease
relative infant from live vaccines,d
dose hepatitis,d anemiad
Rituximab IgG1; 145 kDa Approximately Low B-cell depletion, Probably

1:240 of maternal infections,d impaired
serum level; <1% vaccine responses or
relative infant disseminated disease
dose from live vaccinesd
Ocrelizumab IgG1; 145 kDa Humans not Low Infections,d impaired Probably
done; monkeys vaccine responses or
yes disseminated disease
from live vaccines,d
hepatitis,d anemiad
Ofatumumab IgG1; 146 kDa Humans not Low Infections,d impaired Probably
done; animals not vaccine responses or
reported disseminated disease
from live vaccines,d
hepatitis,d anemiad
28 FEBRUARY 2022

CONCLUSION
This article discussed pregnancy management and emphasized general
pregnancy safety in women with MS and women with NMOSD. However,
women with MS and women with NMOSD still face gaps in care and
knowledge that may adversely affect obstetric and neurologic pregnancy
outcomes. Collaborative and detailed cross-specialty care is important to
achieve optimal pregnancy outcomes while assuring stability of
neurologic disease.
Compatible
Disease-modifying Detectable in Transluminal Possible effects with with
therapy Description breast milk? transfer?b infant exposurec lactation?
Small molecules
Dimethyl fumarate Immediately Animals yes/ High Neurocognitive No

metabolized to humans not done impairment, lymphopenia,
monomethyl but highly likely in gastrointestinal upset,
fumarate (129 Da), high amounts infections,d vaccine
low protein binding responsesd
Sphingosine-1- Highly protein Animals yes/ Moderate Infections,d vaccine No

phosphate (S1P) bound, long humans not done responses,d
receptor half-life but highly likely in cardiovascular effects,d
modulators low amounts pulmonary toxicity,d
(fingolimod, hepatitisd
ozanimod,
ponesimod,
siponimod)
Teriflunomide Inhibits pyrimidine Animals yes/ High Pancytopenia, infections, No

synthesis, highly humans not done vaccine responses,d
protein bound, but highly likely hepatotoxicity, later-life
very long half-life neoplasmsd
Cladribine Inhibits nucleoside Humans not done High Lymphopenia,d No

metabolism, low infections,d liver injury,d
protein binding, later-life neoplasmsd
short half-life
IgG = immunoglobulin G; kDa = kilodalton.

a
Updated and modified with permission from Langer-Gould A, Continuum (Minneap Minn).42 © 2018 Kaiser Permanente.
b
Likelihood of transfer of disease-modifying therapy from infant’s gut into its circulation assuming a large amount of disease-modifying therapy is
present in breast milk.
c
Assumes large amounts of the disease-modifying therapy have entered the infant’s circulation.
d
Plausible but unknown risk.

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clineuro.2020.106118

REVIEW ARTICLE

Epilepsy and Pregnancy
CONTINUUM AUDIO By Yi Li, MD, PhD; Kimford J. Meador, MD, FAAN, FAES, FRCPE
INTERVIEW AVAILABLE
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Seizure disorders
are the most frequent major neurologic
complication in pregnancy, affecting 0.3% to 0.8% of all gestations. Women
Downloaded from http://journals.lww.com/continuum by dk0DVdnDV+fUlnl1Ul6LIOKG9b/NnbZSXSsgz6LbMijmA29e3msQ7A8r2fAzgSo/H2Nb9wN89d9MJGM/4JnjwKQoWw37vi+9LBO50DUrg9uHkqFalwhi1AkxNLj6hLUF on 02/13/2022
of childbearing age with epilepsy require special care related to

pregnancy. This article provides up-to-date information to guide
practitioners in the management of epilepsy in pregnancy.
RECENT FINDINGS: Ongoing multicenter pregnancy registries and studies

continue to provide important information on issues related to pregnancy
in women with epilepsy. Valproate poses a special risk for malformations
and cognitive/behavioral impairments. A few antiseizure medications pose
low risks (eg, lamotrigine, levetiracetam), but the risks for many antiseizure
CITE AS: medications remain uncertain. Although pregnancy rates differ, a
2022;28( 1 , N E U R O L O G Y O F
prospective study found no difference in fertility rates between women
PREGNANCY):34–54. with epilepsy who were attempting to get pregnant and healthy controls.
During pregnancy, folic acid supplementation is important, and a dose greater
Address correspondence to than 400 mcg/d during early pregnancy (ie, first 12 weeks) is associated with
Dr Kimford J. Meador, Stanford
University School of Medicine, better neurodevelopmental outcome in children of women with epilepsy.
Stanford Neuroscience Health Breastfeeding is not harmful and should be encouraged in women with
Center, 213 Quarry Rd, MC 5979,
Palo Alto, CA 94304,
epilepsy even when they are on antiseizure medication treatment.
kmeador@stanford.edu.
SUMMARY: Women with epilepsy should be counseled early and regularly
RELATIONSHIP DISCLOSURE:
Dr Li reports no disclosure.
about reproductive health. Practitioners should discuss the risks of various
Dr Meador receives research/ obstetric complications; potential anatomic teratogenicity and
grant support from Eisai Co, Ltd, neurodevelopmental dysfunction related to fetal antiseizure medication
and the National Institutes of
Health/National Institute of exposure; and a plan of care during pregnancy, delivery, and postpartum.
Neurological Disorders and Women with epilepsy should also be reassured that the majority of
Stroke/National Institute of Child
pregnancies are uneventful.
Health and Human Development
(2U01-NS038455). Dr Meador’s
institution receives financial
support from The Epilepsy Study
Consortium for his services as a
INTRODUCTION
E
consultant for Eisai Co, Ltd; GW pilepsy is one of the most common chronic neurologic conditions,
Pharmaceuticals plc; NeuroPace, estimated to affect almost 70 million people worldwide.1 The
Inc; Novartis AG; Supernus
Pharmaceuticals, Inc; Upsher- prevalence is similar in females and males (46.2 per 100,000 compared
Smith Laboratories, LLC; UCB, to 50.7 per 100,000).2 In the United States, 1.2% of the population have
Inc; and VIVUS LLC.
an active diagnosis of epilepsy,3 including more than one-half million
UNLABELED USE OF PRODUCTS/ women of childbearing age.4 In fact, epilepsy is one of the most common
INVESTIGATIONAL USE neurologic disorders that usually requires continuous treatment throughout
DISCLOSURE:
Drs Li and Meador report no
pregnancy. This article reviews fertility and contraception in women with
disclosures. epilepsy, the maternal outcomes of women with epilepsy, malformation and
cognitive outcomes of children of women with epilepsy, postpartum
© 2022 American Academy management (including breastfeeding), and suggested counseling for women of
of Neurology. childbearing age.
34 FEBRUARY 2022

FERTILITY KEY POINTS
Studies on birth rate in patients diagnosed with epilepsy have had conflicting
● Although pregnancy rates
results.5-7 Some have indicated that the birth rate is lower in patients with differ, no difference in
epilepsy than in the general population. In a population-based study in Finland fertility rate is seen between
with a mean follow-up time of 9 years, the birth rate was lower in patients with women with epilepsy who
epilepsy than in the reference cohort among both men (hazard ratio 0.58; 95% are attempting to get
pregnant and healthy
confidence interval, 0.54 to 0.62) and women (hazard ratio 0.88; 95% confidence
controls (60.7% compared
interval, 0.83 to 0.93).5 However, the lower birth rate does not mean lower to 60.2%).
fertility. The stigma related to epilepsy is known to affect interpersonal
relationships, marital status, economic status, and the desire to get pregnant; ● Certain medications,
hence, these psychosocial factors should be considered. A 2018 prospective including valproate and
phenobarbital, have been
observational trial that compared women with epilepsy without a preexisting linked to lower fertility, but
diagnosis of infertility who were attempting to get pregnant and a control group these findings require
of similar age demonstrated no difference in pregnancy rate (60.7% versus further validation in a larger
60.2%, respectively) and time to achieve pregnancy (6 months versus 9 months, cohort.
respectively) at 1 year.8 This is probably applicable to the common clinical
scenario in which women with epilepsy who are thinking about getting pregnant
seek information from a neurologist, although nearly all patients in the study
were on either lamotrigine or levetiracetam monotherapy and the influence of
antiseizure medications on fertility was not further addressed. The class of
antiseizure medication and whether or not patients are on antiseizure medication
polytherapy has been associated with impaired fertility. A prospective study in
India found that polypharmacy of more than three antiseizure medications and
the use of phenobarbital were associated with impaired fertility.9 In this study,
half of the women with epilepsy receiving phenobarbital were unable to conceive
over several years of attempt. US Epilepsy Birth Control Registry data from 2019
have also shown that the live birth to pregnancy ratio was higher with the use of
lamotrigine (89.1%) than valproate (63.3%).10 The association of certain
antiseizure medications and increased infertility risk has been raised, but it is
worth studying in a larger group of women with epilepsy.
CONTRACEPTION AND FAMILY PLANNING

Family planning allows women with epilepsy of childbearing age to attain their
desired number of children and timing of intervals between births. More than
half of the pregnancies (55% to 65%) in women with epilepsy in the United States
were unintended,11,12 which is similar to unplanned pregnancies in the general
population (45% to 51%).12 A well-planned pregnancy can reduce the likelihood
of seizure recurrence during pregnancy and delivery. Studies from the general
population have shown that unplanned pregnancies may be associated with poor
fetal and maternal outcomes, such as preterm delivery and low birth weight.13
In addition, spontaneous fetal loss was found to be 2 times more common in
unplanned pregnancies (137 out of 391 patients, 35%) than in planned pregnancies
(43 out of 262 patients, 16.4%) in women with epilepsy.14 Also, although many
women desire pregnancy, some may prefer never to become pregnant or may
want to delay for various reasons. Hence, contraception and family planning are
important topics when counseling women with epilepsy in clinical practice.
Forms of Contraception
Many forms of contraception are available to women with epilepsy. The most
common reversible contraceptive methods include oral contraceptives, the

EPILEPSY AND PREGNANCY
dermal patch, depot medroxyprogesterone acetate injection, vaginal rings that

contain hormonal steroids with combined progesterone and estrogen or
progesterone alone, copper T intrauterine device (IUD) or levonorgestrel IUD,
spermicides, and mechanical barriers such as condoms or a diaphragm. Generally
speaking, long-acting reversible contraceptives such as contraceptive implants
and IUDs have the lowest contraceptive failure rates of around 1%. The least
effective methods are condoms, withdrawal, and fertility awareness–based
methods, which have the highest risk of contraceptive failure (ranging from 13%
to 20%). The failure rate for all hormonal contraceptive methods combined has
been reported to range from 6% to 9% in the general population (TABLE 2-1).15
Interaction of Antiseizure Medication and Oral Contraceptives

Oral hormonal contraceptives are almost exclusively absorbed through the
intestines, and many of them are metabolized to an inactive compound by the
cytochrome P450 3A4 (CYP3A4) enzyme. Antiseizure medications that are
CYP3A4 enzyme inducers accelerate hepatic metabolism of both the estrogenic
and progestogenic components of systemic hormonal contraceptives. They
decrease the duration and intensity of contraceptives’ efficacy by reducing their
circulating levels and cause potential contraceptive failure (TABLE 2-216). This
occurs with phenytoin, phenobarbital, and carbamazepine, which are potent
CYP3A4 inducers. Several of the newer antiseizure medications, such as
oxcarbazepine, topiramate, and felbamate, are less potent CYP3A4 inducers, and
some of them may have different effects on the estrogenic and progestogenic
components. For example, felbamate predominantly induces metabolism of the
progestin component. In a randomized study of healthy women who were taking
a low dose of combination oral contraceptive containing 30 mcg ethinyl estradiol
and 75 mcg gestodene, treatment with 2400 mg/d felbamate resulted in 42%
TABLE 2-1 Contraceptive Effectivenessa
Contraceptive method Risk of contraceptive failureb
Tier 1 (most effective methods)
Intrauterine device or implant 1.4%
Tier 2 (moderately effective methods)
Hormonal contraceptives (progesterone-only or combined contraceptives)
Injectable form 4.0%
Oral form 7.2%
Tier 3 (least effective methods)
Male condom 12.6%
Withdrawal 19.9%
a
Data from Sundaram, et al., Perspect Sex Reprod Health.15
b
Contraceptive failure rates are from the general population assuming typical use, and no drug-drug
interactions were considered; the percentage for risk of contraceptive failure was calculated based on the
data from the 2006-2010 National Survey of Family Growth in the United States.15
36 FEBRUARY 2022

decrease in the area under the plasma concentration-time curve (AUC) of
gestodene (a synthetic progestogen), whereas a clinically relevant effect was not
observed for ethinyl estradiol.17 On the other hand, topiramate has a selective role
in reducing ethinyl estradiol levels but has no significant effect on the progestin
component of oral contraceptives. Topiramate also acts in a dose-dependent
manner; when patients were given a low dose of 50 mg/d to 200 mg/d, the
ethinyl estradiol AUC reduced 11% to 12%, but when patients were given a higher
dose of 400 mg/d, the ethinyl estradiol AUC reduced 22%.18,19 It is unclear how
much decrease of either estrogen or progestin level results in contraceptive
failure, since both components are important for preventing pregnancy: estrogen
suppresses ovulation, and progestin facilitates cervical mucus thickening to
prevent sperm passage. The authors usually recommend that women with
epilepsy who are concomitantly using an enzyme-inducing antiseizure
medication and an oral contraceptive should use a high-dose contraceptive that
contains at least 50 mcg of ethinyl estradiol and should use an additional form of
contraception such as condoms with spermicide or an intrauterine device.16
Levonorgestrel IUDs are suitable for use as efficacy is maintained, but the
progesterone-only pill, progestin/progesterone implants, combined
contraceptive patches, and vaginal ring are not recommended because of
reduced efficacy.20
Interaction of Hormonal Contraceptives and Antiseizure Medications TABLE 2-2
Considerations of concomitant use of hormonal

Antiseizure medication contraceptives
Enzyme-inducing
Phenytoin, phenobarbital, Consider high-dose contraceptives that contain at least

primidone, carbamazepine, 50 mcg ethinyl estradiol
eslicarbazepine acetate,
If treated with depot medroxyprogesterone acetate
oxcarbazepine, rufinamide,
injections, they should be given at more frequent intervals
topiramate (≥200 mg/d),
(10-week interval rather than 12-week interval)16
perampanel (≥12 mg/d),
cenobamate, felbamate Additional form of contraception method should
be considered
Progesterone-only pill, progestin implant, combined
contraceptive patches, and vaginal ring are not
recommended because of reduced efficacy
Intrauterine devices are not affected by antiseizure
medications
Non–enzyme-inducing
Acetazolamide, These antiseizure medications do not alter the

brivaracetam, cannabidiol, effectiveness of hormonal contraceptives
clobazam, clonazepam,
Lamotrigine levels are decreased 40-60% by ethinyl
ethosuximide, gabapentin,
estradiol/levonorgestrel, which could potentially cause
lacosamide, levetiracetam,
breakthrough seizures; lamotrigine levels should be
lamotrigine, pregabalin,
monitored, and dose may need to be increased if
sodium valproate,
indicated
stiripentol, tiagabine,
vigabatrin, zonisamide

Antiseizure medications that do not induce CYP3A, such as lamotrigine,

levetiracetam, and zonisamide (TABLE 2-2), are not expected to affect hormonal
contraceptives with significant impact. Of note, although progestogens do not
alter lamotrigine serum concentrations, the estrogenic component of oral
contraceptives induces glucuronidation pathways, which results in a 40% to 60%
decrease in lamotrigine level, potentially causing breakthrough seizures. This
effect is transient, and lamotrigine levels increase during the hormone-free week
of the cycle when not taking the active contraceptive. Patients may experience
toxic symptoms during the hormone-free week since they often need higher
doses during the active contraceptive period. However, some women with
epilepsy on lamotrigine may achieve effective levels during the active
contraceptive period and not become toxic during the placebo pill phase. To
address this interaction, dose adjustments of lamotrigine should be considered
based on the serum level before and after contraceptives are added, or alternative
methods, such as an intrauterine device, should be discussed. Knowledge
regarding the interaction of oral contraceptives and some of the newest
antiseizure medications, such as cannabidiol and fenfluramine, is limited.
Cannabidiol is a known CYP3A inhibitor and theoretically should not reduce the
estrogenic and progestogenic level, but no studies have been completed thus far.
Clinical trials are currently under way to address this question.
MATERNAL AND OBSTETRIC OUTCOMES IN WOMEN WITH EPILEPSY

Seizure disorders are the most frequent major neurologic complication in
pregnancy, affecting 0.3% to 0.8% of all gestations.21,22 Approximately 1.3 million
women with epilepsy in the United States are in their active reproductive years,
and approximately 25,000 infants are born to women with epilepsy each year.23
In general, more than 90% of pregnancies in women with epilepsy result in a
normal delivery without any apparent complications.22 However, women with
epilepsy are often considered at high risk in pregnancy because of increased
obstetric and fetal risks, and maternal mortality is 10 times higher in women with
epilepsy than in the general population.24 Women with epilepsy face particular
challenges during their pregnancies, including spontaneous abortion,
antepartum hemorrhage, gestational hypertension, preeclampsia, breech
position, induction of labor, cesarean delivery, and preterm birth.4,25
Seizure Frequency During Pregnancy

Convulsions are dangerous to women with epilepsy not only because of the risk
of seizure-related falls and blunt trauma but also because of potential harm to the
fetus from the possibility of hypoxemia and asphyxia. Focal seizures that do not
evolve to convulsions are thought unlikely to have a major impact on the fetus,
but anecdotal evidence indicates that they may cause transient fetal distress, with
fetal heart rate deceleration for up to 2.5 minutes.26 The fundamental reason that
women with epilepsy are continuously treated with antiseizure medications
throughout pregnancy is to avoid recurrence of seizure activity and its related
adverse effects. Seizure burden may increase during labor and delivery, but this
occurs in no more than 1% to 2% of pregnancies in women with epilepsy. Most
women with epilepsy will not experience a change in the frequency of seizures
during pregnancy.27 A recent prospective study in the United States showed that
about two-thirds (62%) of women with epilepsy had no change of seizure
frequency during pregnancy, which was similar to the number (65%) observed
38 FEBRUARY 2022

in the control group of nonpregnant women with epilepsy over the same time KEY POINTS
period. In the study cohort, the percentage of pregnant women with epilepsy
● Patients treated with
who had a higher incidence of seizures during pregnancy than during the CYP3A4 enzyme-inducing
postpartum period was also similar to that of women with epilepsy who were not antiseizure medications
pregnant during the corresponding time period (23% versus 25%).28 The should consider alternative
pregnant women with epilepsy in this cohort had more frequent changes in doses methods of contraception.
of antiseizure medication than nonpregnant women with epilepsy during similar
● Lamotrigine may require
time periods (74% versus 31%), suggesting that close antiseizure medication dose substantial titration when it
monitoring is important for patients during pregnancy to maximize seizure is used in combination with
control because of antiseizure medication clearance changes during pregnancy oral hormonal
(FIGURE 2-1). contraceptives.
● Knowledge is limited
Cesarean Delivery regarding the interaction of
Cesarean delivery was originally intended as an emergency lifesaving procedure oral contraceptives and
for both the mother and the baby, but indications have increased over time. some of the new antiseizure
medications.
Changing risk profiles (eg, older primiparae) or elective procedures at patients’
request are often cited as reasons for the rise in cesarean deliveries.29 The overall ● Most women with
cesarean delivery rate in the United States was 32.7% in 2013,30 and common epilepsy will not experience
indications in North America are elective repeat cesarean delivery (30%), seizure frequency changes
during pregnancy.
dystocia or failure to progress (30%), malpresentation (11%), and fetal heart rate
tracings that suggest fetal distress (10%).31 The rate of cesarean delivery varies in ● The diagnosis of epilepsy
different population-based or community-based studies, with a rate of 29.2% alone should not be
globally, 37% in United States, and the highest rate reported as 66% in western considered as an indication
China.32-38 This difference may indirectly reflect that gaps exist in the for cesarean delivery.
management of pregnancy among different sociodemographic groups.
In a population-based cohort study in Iceland, the frequency of cesarean
delivery in women with epilepsy was almost twice of the general population.
Among the most common indications for cesarean deliveries in women with
epilepsy were previous cesarean delivery (20%), seizure activity during delivery
(11.4%), or carrying the diagnosis of epilepsy (11.4%).21 Notably, about one-
fourth of the cesarean deliveries were directly attributable to epilepsy. Studies
have shown that women with epilepsy are more likely to have either elective
cesarean delivery (up to 1.5-fold increase) or emergency cesarean delivery.39 In
addition, antiseizure medication exposure has been indicated as an independent
risk factor for emergency cesarean delivery.40 It is important to establish
multidisciplinary care that includes the patient’s primary care physician,
neurologist, and obstetrician and make it clear that the diagnosis of epilepsy
itself should not be an indication for cesarean delivery. Seizures during labor
are still best treated with the usual rescue therapy using a quick-acting
benzodiazepine.41
Gestational Hypertension and Preeclampsia

Gestational hypertension and preeclampsia can occur during pregnancy, and the
majority of the cases develop at or near term. Preeclampsia is a pregnancy-
specific disease characterized by de novo development of concurrent
hypertension and proteinuria, sometimes progressing into a multiorgan cluster
of varying clinical features.42 Early studies failed to show significant differences
in the incidence of preeclampsia between women with epilepsy and controls.43
However, a pooled analysis including 17 studies showed an increased risk of
gestational hypertensive disorders (odds ratio, 1.37; 95% confidence interval,

FIGURE 2-1
Changes in seizure frequency and antiseizure medication dose. A, Changes in the frequency
of seizures that impair awareness in women during pregnancy as compared with postpartum
and during equivalent time periods for nonpregnant women. B, Changes in the dose or
medication of an antiseizure medication by the time of delivery in pregnant women and by
9 months after enrollment for nonpregnant women.
ASM = antiseizure medication.
Modified with permission from Pennell PB, et al, N Engl J Med.28 © 2020 Massachusetts Medical Society.
1.21 to 1.55) in women with epilepsy.25 In a 2017 national cohort study in Sweden,
the incidence of preeclampsia was 4% in women with epilepsy compared to
2.8% in the control group,39 which is similar to the rate of preeclampsia in women
with epilepsy in the United States (5.9%).38 A registry-based cohort study in
Norway collected during 2004 to 2012 similarly observed an increased risk of
gestational hypertension in women with epilepsy (odds ratio, 1.5; 95% confidence
interval, 1.0 to 2.2), with the most frequent hypertensive complication being
mild preeclampsia.44 The risk factors included antiseizure medication use (odds
ratio, 1.5; 95% confidence interval, 1.0 to 2.2) and primiparity (odds ratio, 2.4;
95% confidence interval, 1.0 to 5.4).22 Exposure to different antiseizure medications
was associated with different outcomes; lamotrigine and levetiracetam did not
predispose for mild preeclampsia, whereas valproate was associated with an
increased risk of mild preeclampsia.44
40 FEBRUARY 2022

FETAL OUTCOMES OF WOMEN WITH EPILEPSY KEY POINTS
Although the vast majority of women with epilepsy have uneventful pregnancies
● The risk of gestational
and 90% of children born to women with epilepsy are healthy, fetal risks have hypertension and
been associated with maternal epilepsy. These include increased risk of stillbirth, preeclampsia may be
preterm birth, small for gestational age at birth, low Apgar score at 5 minutes, slightly increased in women
neonatal hypoglycemia, neonatal infection, respiratory distress syndrome, major with epilepsy.
congenital malformations, and adverse effects on cognitive and behavioral
● The majority of women
development.39 with epilepsy have
uneventful pregnancies, and
Spontaneous Abortion 90% of children born to
Spontaneous abortion is defined by noninduced fetal death or passage of products women with epilepsy are
healthy.
of conception before 20 weeks’ gestation. Significant variation exists in reported
outcomes in women with epilepsy across geographic regions in countries with
different economic status.38 Several registries or retrospective studies have
reported spontaneous abortion in women with epilepsy ranging from 0.5% to
39.2%, with an overall rate of 9.1% globally.25,32,38,45-47 The lowest incidence was
reported in Norway as 0.5% in women with epilepsy compared to 0.3% in women
without epilepsy in a population study that included a total of 372,128 births.22 The
reported incidence was moderate in some Asian countries. In a retrospective study
based on a Thai population that investigated 44,708 pregnancies, the spontaneous
abortion rate was 2.7% in women with epilepsy compared to 0.4% in the control
group,32 and a similar rate of 4.2% in women with epilepsy (compared to 2.38% in
the control group) was reported in India.48 When interpreting the discrepancy
between different studies, it is important to keep in mind the limitations of
retrospective studies because of the potential bias secondary to retrospective recall
or gestational age at the time of enrollment. Miscarriages occur more frequently
early in pregnancy, so many miscarriages may not be recognized. Further, access
and availability of prenatal care varies between countries.
Preterm Birth
Preterm birth (ie, delivery at <37 weeks of gestation) has been associated with
various adverse adult outcomes, such as increased prevalence of medical
disabilities, learning difficulties, and behavioral and psychological problems.
The rate of preterm birth, either medically indicated or spontaneous, has been
consistently shown to be increased in women with epilepsy across various
studies.22,25,32,39,49,50 The overall rate of preterm birth in women with epilepsy
is 7.6%, with the highest rate seen in the United States and the lowest in
European countries (10.1% compared to 6.1%).38 Exposure to antiseizure
medications significantly increases the risk of premature birth in both women
with epilepsy (9.3%) and women without epilepsy who were on antiseizure
medications for other neuropsychiatric indications (10.5%), when compared to
those with neither exposure to antiseizure medication nor diagnosis of epilepsy
(6.2%).49,50 In addition, uncontrolled seizure activity, especially the presence of
seizures within 6 months of conception, also increases the incidence of
premature birth.32
Congenital Malformations
Children of women with epilepsy are at increased risk of congenital malformations
when compared with children of women without epilepsy. The incidence of major
congenital malformations seems to be associated with early antiseizure medication

exposure (first trimester),51,52 polytherapy versus monotherapy of antiseizure

medication,53-56 the dose and type of antiseizure medication,54-57 low serum folate
concentrations, and low maternal level of education.58 The type of epilepsy or
seizures during pregnancy have not been reported to be significantly correlated
with the number of minor or major malformations.58,59 In addition, children of
women with epilepsy have more minor and major malformations than children of
fathers with epilepsy or controls.59 Women with epilepsy who have had a child
with a malformation are at increased risk of having other children with
malformations when compared with women with epilepsy whose first child did
not have a malformation (16.8% compared to 9.8%), indicating the genetic
influences on the teratogenic risk.60,61 Hence, the cause is likely multifactorial,
with a combination of endogenous and exogenous factors.
When compared to children of healthy women, children of women with
epilepsy have been reported to have significantly higher overall rates of
congenital malformations, with an approximately threefold increase.62,63 One of
the main contributing factors is the teratogenic effects of antiepileptic drugs,
although other factors, such as genetically determined individual susceptibility,
are also likely to contribute. The most common malformations noted in children
of women with epilepsy were cardiovascular defects (in descending order of
frequency: atrial or ventricular septal defect, tetralogy of Fallot, patent ductus
arteriosus) followed by musculoskeletal defects, which are also the most
common defects in offspring of healthy women, although with lower
frequency.62,63 The risk of spina bifida was substantially elevated, with 11-fold to
14.7-fold higher risk in the offspring of women with epilepsy, primarily because
of use of valproate.63,64 The European Surveillance of Congenital Anomalies
(EUROCAT) used a case-control approach employing its antiseizure medication
study database derived from 19 population-based congenital anomaly registries
including 98,075 cases with malformations among 3.8 million births in Europe.
They found an increased risk for spina bifida for two antiseizure medications:
valproate (odds ratio, 12.7; 95% confidence interval, 7.7 to 20.7) and
carbamazepine (odds ratio, 2.6; 95% confidence interval, 1.2 to 5.3).65,66
A meta-analysis including 65,533 pregnancies in women with epilepsy exposed
to carbamazepine, lamotrigine, phenobarbital, phenytoin, or valproate showed
that the overall incidence of congenital malformations in children born to women
with epilepsy is approximately threefold that of healthy women (7.08%
compared to 2.28%), with the highest incidence for antiseizure medication
polytherapy (16.78%).63 Studies have shown that the lowest risk of major
congenital malformations was seen in patients with exposure to lamotrigine and
levetiracetam, whereas the highest risk was seen with exposure to valproate. A
2016 Cochrane Review conducted a meta-analysis for antiseizure medication
monotherapy, and pooled data showed that the malformation prevalence is
1.47% for gabapentin, 1.77% for levetiracetam, 2.39% for oxcarbazepine, 4.28%
for topiramate, 4.93% for carbamazepine, 6.26% for phenytoin, 7.10% for
phenobarbital, 8.49% for primidone, and 10.93% for valproate (FIGURE 2-2).67
Similarly, it found no difference in malformation prevalence between the
children exposed to lamotrigine and the control group, with the majority of
evidence coming from pregnancy registries. Of note, the data related to
gabapentin are limited, with total cases under 200, so the results should be
interpreted with caution. Increased risk was observed for clobazam monotherapy
in a very small sample size study.68 Data on zonisamide are also scarce, with 90
42 FEBRUARY 2022

KEY POINTS
● The risk of major

congenital malformations
has been associated with
first trimester antiseizure
medication exposure, the
dose and type of antiseizure
medication (especially
FIGURE 2-2 valproate), polytherapy, low
Risk of major congenital malformations associated with antiseizure medication exposure. folate concentrations, and
Pooled data from a meta-analysis of antiseizure monotherapy showed that the malformation low maternal level of
prevalence associated with antiseizure medication is 1.47% for gabapentin, 1.77% for education.
levetiracetam, 2.39% for oxcarbazepine, 4.28% for topiramate, 4.93% for carbamazepine,
6.26% for phenytoin, 7.10% for phenobarbital, 8.49% for primidone, and 10.93% for valproate. ● The teratogenic risks for
a
The sample size for gabapentin-exposed cases is small. many antiseizure
Data from Weston J, et al, Cochrane Database Syst Rev.67 medications are uncertain.
Valproate is the poorest
choice of antiseizure
medication based on the
cases followed by the North American Antileptic Drug Pregnancy Registry; no higher risk profile of both
major congenital malformations were found, but no definite conclusion could be anatomic and behavioral
drawn. Virtually no data are available on other newer antiseizure medications, teratogenicity. If used, the
dose should be as low as
and further efforts are needed to gain more information.
possible.
Neuromodulation therapy, including vagus nerve stimulation, direct brain-
responsive neurostimulation, and deep brain stimulation, has been used as a ● The impact of
nonpharmacologic approach to treat cases of refractory epilepsy. The safety of neuromodulation therapy on
neuromodulation treatments during pregnancy in women with epilepsy is largely pregnancy outcomes is
limited.
unknown. Among these devices, the most evidence exists for vagus nerve
stimulation as it has been used to treat epilepsy for longer than the others.
Current literature does not show a clear signal of vagus nerve stimulation–related
teratogenicity, although a trend of increased obstetric intervention was reported
in vagus nerve stimulation–exposed pregnancies.69,70 A 2021 study showed that
no major congenital malformations were identified in direct brain-responsive
neurostimulation–exposed pregnancies in 14 women with epilepsy. One child
had a minor congenital anomaly of cryptorchidism, but this case was
complicated by risk factors of advanced maternal age and bicornuate uterus.71 No
studies have been conducted to evaluate the safety of deep brain stimulation in
women with epilepsy so far, but it has been shown to have no significant adverse
effects on pregnancy outcomes in patients affected by disabling movement
disorders and psychiatric diseases.72 All of these data should be interpreted
cautiously as sample sizes are small.
Developmental Outcome
Besides having a higher risk of malformations, children born to women with
epilepsy are also potentially affected in various domains of their long-term
developmental milestones, including language and other cognitive and social/
emotional functions.
COGNITIVE IMPAIRMENT. Children born to women with epilepsy have been shown
to have lower mean IQ scores, which remains significant after adjustment for
multiple confounding factors such as maternal education level, maternal age,
maternal marital status, birth order, year of birth, and weight and length at
birth.73 Several factors have been identified as related to cognitive outcomes,

including frequent tonic-clonic seizures in pregnancy,74 low maternal IQ,

maternal education level, and antenatal antiseizure medication exposure.75 Both
the NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) cohort and a
study from the Liverpool and Manchester Neurodevelopmental Group
confirmed the adverse cognitive effects of valproate and accounted for maternal
IQ. A significantly lower IQ (mean IQ score of 97) was found in children of
women with epilepsy treated with valproate than in children of women with
epilepsy taking carbamazepine (mean IQ score of 105), lamotrigine (mean IQ
score of 108), or phenytoin (mean IQ score of 108).76,77 Similar effects were
also observed for other antiseizure medications, such as phenobarbital
(approximately 0.5 standard deviation less than predicted).78 Data from the UK
Epilepsy and Pregnancy Register showed that prenatal exposure to levetiracetam
or topiramate was not found to be associated with reductions in child cognitive
abilities, although sample sizes were small (FIGURE 2-3).79 Unlike major
congenital malformations, antiseizure medication exposure during the last
trimester may be the most detrimental for cognitive performance.78
BEHAVIORAL IMPAIRMENT. In utero exposure to antiseizure medication has been

shown to be associated with a significantly increased risk of autism spectrum
disorder in the offspring.80,81 Studies have shown that the risk of autism
spectrum disorder with valproate exposure was 4.4%, compared to 1.5% in the
general population.80 In another study, the correlation of autism spectrum
disorder to fetal antiseizure medication exposure was not seen in children
exposed to polytherapy without valproate, suggesting that valproate (or
valproate dose) rather than polytherapy is the critical determinant of the
relationship.82 No significant increase has been found among children exposed
to carbamazepine or lamotrigine.83 In addition, children with in utero exposure
to valproate are also at a significantly greater risk for a diagnosis of attention-
deficit/hyperactivity disorder (ADHD).84 The increased likelihood of autism
spectrum disorder and difficulty with adaptive functioning with fetal valproate
FIGURE 2-3
Neurodevelopmental outcome in children associated with antiseizure medication exposure
in women with epilepsy. A significantly lower IQ was found in children of women with
epilepsy treated with valproate than in children of women with epilepsy taking
carbamazepine, lamotrigine, or phenytoin.76 Similar effects were also observed for other
antiseizure medications such as phenobarbital.78 Data from the UK Epilepsy and Pregnancy
Register showed that prenatal exposure to levetiracetam and topiramate was not found to be
associated with reductions in child cognitive abilities.79
44 FEBRUARY 2022

exposure should be communicated to women with epilepsy when counseling KEY POINTS
in clinic.
● Children born to women
with epilepsy may have
COUNSELING FOR WOMEN WITH EPILEPSY OF CHILDBEARING AGE impaired cognitive
All practitioners who care for women with epilepsy should be familiar with the development; the
relevant information and provide counseling when an antiseizure medication is contributing factors include
antenatal antiseizure
first prescribed and yearly on how epilepsy and its treatment may interact with
medication exposure,
their contraception, conception, and pregnancy. Counseling should be tailored to frequent tonic-clonic
each individual patient, depending on their age, seizure burden, and antiseizure seizures in pregnancy, low
medication exposure. maternal IQ, and maternal
education level.
Prenatal Care ● Women with epilepsy of

Family planning and pregnancy should be discussed with all women with childbearing potential
epilepsy of childbearing age who are prescribed an antiseizure medication, even should be taking folic acid
if they are not seeking pregnancy. Guidance should be delivered carefully to 0.4 mg/d to 4 mg/d.
cover the potential risks but not create needless worry. Patients should be ● Monitoring of antiseizure
reassured that the majority of pregnancies in women with epilepsy are medication levels during
uneventful. The goal is to provide the information before pregnancy given that pregnancy should be
the incidence of unplanned pregnancy is more than 50% (CASE 2-1). The considered.
discussion should include the possibility of adjusting antiseizure medication
management from polytherapy to monotherapy or monotherapy to a lower dose,
if possible, and the potential adverse fetal outcomes of the specific antiseizure
medication the patient is prescribed. If the patient is being treated with
valproate, the potential anatomic and behavioral teratogenic risks should be
conveyed, and trials of other antiseizure medications with better teratogenic
profiles should be considered if this has not already been done. If the patient is
sexually active, the authors recommend folic acid supplementation of 0.4 mg/d
to 4 mg/d even if the patient is not seeking pregnancy at the time. The
importance of achieving good seizure control before pregnancy should be
discussed with the patient, since studies have shown that women with epilepsy
who are seizure free in the 9 months before pregnancy have an 84% to 92%
chance of remaining seizure free during pregnancy on their current antiseizure
medication regimen.4 A therapeutic range of antiseizure medication should be
established preconception as a baseline, and patients should be made aware that
regular antiseizure medication level monitoring during pregnancy should be
considered since the dosage may need to be increased.
FOLIC ACID SUPPLEMENTATION. During pregnancy, folate requirements are 5- to

10-fold higher compared to nonpregnant women, and adequate periconceptional
folate status is essential for structural and functional development of the fetal
brain. Periconceptional folate is particularly important to women with epilepsy
who are taking antiseizure medications given the fact the several antiseizure
medications, especially those that induce cytochrome P450 enzymes, are known
to decrease folate levels.85 Folic acid supplementation in early pregnancy is
shown to have a preventive effect not only on major congenital malformations in
the general population but also on language delay and autistic traits associated
with fetal antiseizure medication exposure.86-88 Periconceptional folic acid
supplementation at a dose greater than 400 mcg/d is associated with better
neurodevelopmental scores across a variety of long-term cognitive variables in
children of women with epilepsy at 6 years old.89 The American Academy of

Neurology practice guideline recommends 0.4 mg/d to 4 mg/d of

preconceptional folic acid supplementation.88 Unfortunately, a current low
prevalence of preconception folic acid supplementation (47.6%) in women with
epilepsy of childbearing age reflects a need for more education.90
Pregnancy Care
A plan for epilepsy management during pregnancy should be established for
women with epilepsy. Patients often have many concerns, including fear about
CASE 2-1 A 21-year-old woman had a history of convulsions since the age of 8. Her
seizure symptomatology included generalized tonic-clonic seizures and,
less frequently, staring episodes. She had tried lamotrigine in the past,
but it caused a skin rash. She was currently taking levetiracetam 1500 mg
2 times a day and had been seizure free in the past 18 months. When she
was on a lower dose of 1000 mg 2 times a day, she had more frequent
staring episodes and occasional generalized tonic-clonic seizures.
This was her first visit to an adult epilepsy clinic, and during the visit,
her previous records were carefully reviewed, including EEG, MRI, and
seizure-related history, and confirmed that she had generalized epilepsy
of unknown etiology. Contraception and family planning were discussed.
The patient indicated that she was sexually active and open-minded
about having a child in the future but would defer pregnancy for now. She
was not taking folic acid and was using an estrogen-progesterone oral
contraceptive. A baseline antiseizure medication level was ordered, and
she was prescribed 1 mg/d folic acid.
The neurologist explained that although the antiseizure medication she
was currently taking did not have interactions with her oral
contraceptive, more than half of pregnancies are unplanned and she
might discuss with her OB/GYN about an intrauterine device that has
better efficacy than her oral contraceptive. She was reassured that
levetiracetam has a better teratogenic profile compared to most other
antiseizure medications and would be an optimal choice of antiseizure
medication if she were to get pregnant. She was also asked to inform her
neurologist if she became pregnant so her antiseizure medication level
could be monitored monthly to help adjust the dose as needed
throughout pregnancy.
COMMENT This case illustrates key points that should be conveyed to patients when
discussing family planning. Patients should be provided with information
on the potential teratogenic effects of the antiseizure medication that they
are taking and the importance of folic acid supplementation. If the patient
is currently on an oral contraceptive, the potential interaction of the oral
contraceptive and the antiseizure medication they are being treated with
should be discussed. If the patient is on an enzyme-inducing antiseizure
medication, an intrauterine device is the best choice to avoid
contraceptive failure.
46 FEBRUARY 2022

worsening seizures, the possibility of adverse medication effects on their fetus, KEY POINTS
and potential complications during childbirth. Clinicians should discuss the
● The most marked decline
importance of starting folic acid supplementation if the patient has not already in serum concentration of
been taking it; the need for frequent monitoring of antiseizure medication antiseizure medications in
concentrations during pregnancy, which could be done in coordination with pregnancy is seen with
their obstetrician visits; and the possible need to have their antiseizure lamotrigine, levetiracetam,
and oxcarbazepine
medication dose adjusted based on pregnancy drug levels in comparison to their
(decrease ranging from 40%
prepregnancy level. Patients should be reassured that most women with epilepsy to 70%). Carbamazepine and
have an uneventful delivery, with seizures reported in only 2% of women with valproate have minimal
epilepsy during delivery,91 and that the diagnosis of epilepsy is not an indication decreases in serum
concentration, usually 10%
per se for cesarean delivery. Patients should also be screened for depression and
to 20%.
anxiety and treated or referred, if needed.
● Breastfeeding while
ANTISEIZURE MEDICATION MANAGEMENT DURING PREGNANCY. Maternal physiologic taking antiseizure
changes during pregnancy include increased blood volume and cardiac output, medication appears to be
safe.
decreased plasma protein concentrations including hypoalbuminemia, delayed
gastric emptying, and altered hepatic enzyme activities. Rapid pharmacokinetic
changes during pregnancy can result in significant antiseizure medication level
changes and put patients at risk of breakthrough seizures. Pronounced declines in
serum concentrations can be seen for lamotrigine, which is eliminated by
glucuronidation. A decrease in its serum concentration can be seen as early as the
third week after conception but is most marked in the mid third trimester.41,92 Its
level returns rapidly postpartum and reaches the preconception range within
3 weeks of delivery. Marked interindividual variability has been noted, and
pharmacokinetic modeling analysis has demonstrated that most patients (77%)
have a 220% increase in lamotrigine clearance, but a subset of patients (23%)
have only a 20% increase in lamotrigine clearance.93 Levetiracetam, another
antiseizure medication commonly used during pregnancy, also has a significant
decline in plasma concentrations (40% to 60%) noted as early as the first
trimester. The mechanism is hypothesized to be due to a combination of an
increased renal elimination and enhanced enzymatic hydrolysis. Currently,
approximately 30 antiseizure medications are approved by the US Food and Drug
Administration (FDA), but only a handful of antiseizure medications have been
investigated for potential alterations in concentrations in pregnant women with
epilepsy. Based on a 2019 International League Against Epilepsy Task Force report
on women and pregnancy, the most marked decline in serum concentration is
seen with lamotrigine, levetiracetam, and oxcarbazepine (decrease ranging from
40% to 70%). Phenobarbital, phenytoin, topiramate, and zonisamide have a
moderate decrease in serum level (ranging from 30% to 60%). In contrast,
relatively small changes in serum concentration are seen with carbamazepine and
valproate, which usually decrease 10% to 20% (FIGURE 2-4).41 Studies have shown
that when antiseizure medication levels decrease by more than 35% when
compared to the targeted level, the risk of worsening seizures increases.94 It is
important to have a preconception antiseizure medication level established while
seizures are effectively controlled, which can then be used as a baseline level to
guide antiseizure medication titration during pregnancy (CASE 2-2).
Postpartum Care
Postpartum care is important since women with epilepsy experience many
challenges involving physical, social, and psychological well-being. It is a

FIGURE 2-4
Projected decrease of antiseizure medication concentrations during pregnancy if no dose
changes are made.
Data from Tomson T, et al, Epileptic Disord.41
vulnerable time not only because of physical recovery from birth but also because
of medication adjustment, sleep deprivation and fatigue, increased stress, and
the challenges of breastfeeding.
BREASTFEEDING. The proportion of women reported to be breastfeeding is lower

in women with epilepsy despite studies indicating the safety of breastfeeding in
women with epilepsy.11 Breastfeeding provides many benefits to both mothers
and children.93 It is associated with decreased risk of type 2 diabetes and breast
and ovarian cancer for mothers. Infants who are breastfed also benefit from
reduced risk of infections, asthma, obesity, diabetes, childhood leukemia, and
sudden infant death syndrome.95 Patients are often concerned that the exposure
to antiseizure medication via breast milk could potentially affect their children’s
development. Valproate, phenobarbital, phenytoin, and carbamazepine are not
thought to penetrate into breast milk at a clinically important level, whereas
lamotrigine, levetiracetam, primidone, gabapentin, and topiramate probably
penetrate into breast milk in potentially clinically important amounts.88
However, a 2020 study showed the median percentage of infant-to-mother
antiseizure medication concentration was 0.3% for oxcarbazepine, 5.3% for
levetiracetam, 5.4% for carbamazepine epoxide, 17.2% for topiramate, 21.4% for
valproic acid, 28.9% for lamotrigine and 44.2% for zonisamide; all of which were
substantially lower than maternal blood concentrations.96 A Norwegian cohort
study showed that continuous breastfeeding in children of women using an
antiseizure medication was associated with less impaired development at ages 6
and 18 months compared with children who were not breastfed or were breastfed
for less than 6 months.97 In the NEAD cohort in the United States, no adverse
effects of antiseizure medication exposure via breast milk were observed at age
3 years,98 and breastfed children exhibited higher IQs and enhanced verbal
abilities at 6 years of age.99 Although further studies of exposure to other newer
antiseizure medications via breast milk are necessary, women with epilepsy
should be encouraged to breastfeed their children irrespective of antiseizure
medication treatment.
SLEEP DEPRIVATION, DEPRESSION, AND ANXIETY. Fragmentedsleep and fatigue are

commonly encountered in the postpartum period, especially if women are
48 FEBRUARY 2022

breastfeeding every 2 to 4 hours. Sleep deprivation and missed medication during
the postpartum period are known to increase the risk of seizures; hence, patients
should be encouraged to request family members’ help in feeding infants with
either expressed breast milk or formula, allowing them to have some uninterrupted
sleep for a longer interval. Furthermore, studies also show that women with
epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than
women without epilepsy (18.9% and 14.8%, respectively), which is linked to high
A 26-year-old woman had a history of focal aware seizures that occurred, CASE 2-2
on average, once per month; rare focal impaired-awareness seizures that
occurred once every 1 to 2 years, which were often triggered by alcohol;
and convulsions years earlier. She had been followed in the epilepsy
clinic for the past year. Her seizure symptomatology included an aura of
déjà vu feeling for 10 seconds. She did not feel the aura interrupted her
daily activities.
She returned to clinic stating that she was 11 weeks pregnant and had
experienced two focal impaired-awareness seizures in the past month,
with her typical aura followed by blanking out and right-sided facial
twitching. This was an unplanned pregnancy. She was on lamotrigine
200 mg 2 times a day and took folic acid 1 mg/d but admitted taking the
folic acid irregularly.
At her first visit to the clinic a year earlier, her lamotrigine level was
9.2 mcg/mL. During this first pregnancy visit, her level of lamotrigine
showed a decrease to 5.4 mcg/mL. The neurologist recommended
increasing lamotrigine to 250 mg 2 times a day for 1 week followed by an
increase to 300 mg 2 times a day and continuing her prenatal vitamins with
folic acid supplement 1 mg/d regularly.
On a follow-up visit 1 month later, her lamotrigine level was 7.9 mcg/mL.
She had not had any further focal impaired-awareness seizures since her
last visit but had continued focal aware seizures, so her lamotrigine was
increased to 350 mg 2 times a day. Further follow-up 1 month later
showed her lamotrigine level was 9.1 mcg/mL. Monthly monitoring of her
antiseizure medication continued, with appropriate dose adjustments.
She did not experience any further focal impaired-awareness seizures
during the pregnancy and had a normal vaginal delivery of a healthy child.
This case illustrates the importance of close monitoring of antiseizure COMMENT

medication levels during pregnancy and establishing a baseline antiseizure
medication target level before conception. Antiseizure medication levels
can fluctuate substantially during pregnancy because of the
pharmacokinetic changes related to pregnancy. Monthly monitoring is
recommended, but more frequent monitoring may be needed if dose
changes are required. Regular folic acid supplementation is recommended
before pregnancy since more than half of pregnancies are unplanned and
patients may not recognize the pregnancy until they have already missed a
critical time window for positive periconceptional folate effects.

seizure frequency.100 These risks should be discussed with patients, and they
should be encouraged to reach out to mental health care providers for proper care
with coping techniques and medication treatment if symptoms are identified.
CONCLUSION
Epilepsy brings special issues for women, particularly in pregnancy. In birth
control, conception, pregnancy, and postpartum care, women with epilepsy face
challenges to carefully balance maintaining seizure freedom with minimizing
adverse effects from antiseizure medications and other nonpharmacologic
treatments. Management of epilepsy in patients of childbearing age requires
careful counseling and planning. Practitioners who care for women with epilepsy
should keep up-to-date with the latest guidelines and recommendations to
provide the best possible care.
ACKNOWLEDGMENT
This work was supported by Dr Meador’s grant from the National Institutes of
Health/National Institute of Neurological Disorders and Stroke/National
Institute of Child Health and Human Development (2U01-NS038455).
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54 FEBRUARY 2022

Neuromuscular Disorders REVIEW ARTICLE

and Pregnancy C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Janice M. Massey, MD, FAAN; Karissa L. Gable, MD
ABSTRACT
PURPOSE OF REVIEW: This article provides an overview of neuromuscular

disorders in pregnancy, with a focus on diagnosis and management.
RECENT FINDINGS:Neuromuscular disorders with issues that occur in

pregnancy include conditions that are acquired (including autoimmune) or
genetic; each requires a unique approach to management and treatment
prepartum, peripartum, and postpartum. Guidance in the literature
regarding management and treatment options is predominantly from case
series and retrospective reviews. Treatment can be complex, particularly
in autoimmune neuromuscular diseases, because of the risks of side
effects of the treatments that may affect the patient and fetus. CITE AS:
2022;28(1, NEUROLOGY OF
SUMMARY: This article summarizes expectations, diagnosis, and PREGNANCY):55–71.
management for a wide range of neuromuscular disorders in pregnancy.

Dr Karissa L. Gable, DUMC 3909,
Durham, NC 27710, karissa.
gable@duke.edu.
INTRODUCTION
N
euromuscular disorders comprise a wide range of diseases, RELATIONSHIP DISCLOSURE:
including those that may be acquired (including autoimmune) or Dr Massey serves on the
editorial board of Clinical
genetic. Preconception counseling and well-thought-out plans for Neurophysiology Practice, as an
delivery in women with autoimmune or genetic disorders is investigator for UCB SA/Ra
important. However, autoimmune diseases in particular ideally Pharmaceuticals, on a scientific
advisory board for Argenx, and
require preconception counseling on medication adjustment and management on a scientific advisory
throughout pregnancy and in the postpartum stage, as medications used to committee for Momenta
Pharmaceuticals, Inc. Dr Massey
treat these disorders not only have risks for the mother but also potential risks has received research/grant
for the fetus. With the ideal appropriate counseling and management, support from Revance
maternal and fetal outcomes can be optimized in women with neuromuscular Therapeutics, Inc. Dr Gable
serves as a consultant for
disorders. Apellis Pharmaceuticals Inc and
Medscape and has received
research/grant support from
NEUROPATHIES the American Neuromuscular
Peripheral neuropathies requiring management in pregnancy may be preexisting Foundation and GBS/CIDP
Foundation International.
or new in onset and include autoimmune neuropathies, nutritional neuropathies,
hereditary neuropathies, and focal neuropathies (including radiculopathies UNLABELED USE OF
and plexopathies). PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Drs Massey and Gable report no
Autoimmune Neuropathies disclosures.
These types of acquired neuropathies can occur de novo during pregnancy or
begin before pregnancy or after delivery. The treatment approach can vary © 2022 American Academy
depending on the type of autoimmune neuropathy. of Neurology.

NEUROMUSCULAR DISORDERS AND PREGNANCY
CASE 3-1 A 37-year-old woman presented at 18 weeks’ gestation with proximal and
distal weakness that had progressed over the course of 2 months. She
had numbness and tingling that initially affected her feet and had slowly
progressed up to her knees bilaterally as well as sensory changes in her
hands. She had begun using a walker for assistance because of weakness.
On examination, she had proximal and distal weakness, decreased
sensation to the knees and to the wrists bilaterally to pinprick, and
absent reflexes. Her Inflammatory Neuropathy Cause and Treatment
(INCAT) disability score was 3 in the upper extremities and 3 in the lower
extremities, for a total of 6. Her Inflammatory Rasch-built Overall
Disability Scale (I-RODS) score was 25, and grip strength measured by
hand dynamometer was 20 kg on the right and 0 kg on the left.
CSF testing demonstrated albuminocytologic dissociation, with
increased protein of 91 mg/dL, nucleated cell count of 2 cells/mm3, and
normal glucose. Blood testing was normal for serum protein
electrophoresis and immunofixation, complete blood cell count,
comprehensive metabolic panel, erythrocyte sedimentation rate,
C-reactive protein, vitamin B12, folate, and thiamine.
Electrodiagnostic testing demonstrated a demyelinating sensory and
motor neuropathy with acquired features of segmental demyelination,
including conduction block in both ulnar nerves of greater than 50% with
temporal dispersion as well as temporal dispersion of both tibial motor
nerves with prolonged F-wave minimum latencies meeting European
Federation of Neurological Societies/Peripheral Nerve Society criteria
for definite chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).11
The clinical history, examination, and electrodiagnostic testing
confirmed the diagnosis of CIDP. Treatment was initiated with 2 g/kg IV
immunoglobulin (IVIg) split over 5 days of infusion followed by 1 g/kg IVIg
3 weeks later and another 1 g/kg IVIg 3 weeks after that.
Follow-up examination 2 months after discharge demonstrated normal
strength proximally in the upper and lower extremities, with mild residual
distal upper extremity weakness, left greater than right; decreased
sensation to pinprick in the fingertips and dorsum of feet; and a return of
reflexes. Her INCAT disability score was 2 in the upper extremities and 0
in the lower extremities, for a total of 2, and her I-RODS score was 40.
Grip strength was 24 kg on the right and 4 kg on the left.
COMMENT This patient had classic features of CIDP, with improvement of outcome
measures and clinical examination with treatment. She went into remission
a year after delivery, and treatment was discontinued.
56 FEBRUARY 2022

GUILLAIN-BARRÉ SYNDROME. Guillain-Barré syndrome (GBS), of which acute KEY POINTS
inflammatory demyelinating polyradiculoneuropathy (AIDP) is the most
● Treatment of Guillain-
common subtype, is a condition that manifests with symptoms of rapidly Barré syndrome in pregnant
progressive bilateral limb and, at times, facial weakness; sensation changes; and women is similar to
loss of reflexes. GBS often reaches peak disability approximately 2 weeks after treatment in nonpregnant
onset, without progression beyond 8 weeks.1 Heterogeneous clinical subtypes can patients. Both IV
immunoglobulin (IVIg) and
vary in presentation. Infections are often reported to trigger GBS, which is
plasma exchange are
thought to be a consequence of an aberrant immunologic response to the considered to be safe.
infection resulting in peripheral nerve damage. Campylobacter jejuni, human
cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae have been ● Accurate diagnosis of
reported to have a higher association with the incidence of GBS, and, more chronic inflammatory
demyelinating
recently, Zika virus has also been implicated. Interestingly, the incidence of GBS polyradiculoneuropathy
has not increased with COVID-19 infection. Other viral infections, such as relies on clinical history,
human immunodeficiency virus (HIV), present with a GBS clinical phenotype examination findings, and
and can be treated with antiretrovirals in addition to the typical treatment for electrodiagnostic testing
meeting European
GBS.1-3 Cytomegalovirus has been reported in infants of mothers with GBS, Federation of Neurological
which can have quite detrimental effects on the fetus.4 Societies/Peripheral Nerve
The diagnosis of GBS is reliant on patient history, clinical examination, Society criteria.
electrodiagnostic testing, and CSF analysis that demonstrates albuminocytologic
dissociation. The incidence of GBS does not appear to be increased during
pregnancy, although it appears the incidence is increased within the first 30 days
after delivery.5
Treatment for GBS in pregnant women is no different than treatment in
other patients. IV immunoglobulin (IVIg) or plasma exchange is the treatment
of choice, and treatment is most effective within 2 to 4 weeks of symptom
onset.1,6-9 Depending on the severity of maternal neurologic decline and physical
disability or need for ventilatory support, induced labor may be required; the need
for cesarean delivery can be decided based on obstetric requirements depending
on the status of the fetus.10 The possible increased risk of thrombosis with IVIg in
the hypercoagulable state of pregnancy should also be considered.
CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY. Chronic

inflammatory demyelinating polyradiculoneuropathy (CIDP) is an
inflammatory autoimmune neuropathy most often characterized by gradually
progressive and relatively painless proximal and distal weakness in the upper and
lower extremities over the course of 8 weeks or more, sensory changes, and
areflexia or diminished reflexes. Atypical variants also exist. Diagnosis relies on
clinical history, examination findings, and electrodiagnostic testing meeting
European Federation of Neurological Societies/Peripheral Nerve Society
criteria.11 CSF can also be examined, if needed, for supportive criteria. This
condition is rare in women of childbearing age and has not been well studied, so
no evidence from controlled clinical trials or guidelines on treatment in pregnant
women are available. However, a retrospective review of 24 cases that is the most
comprehensive analysis of CIDP and pregnancy to date found that onset and
relapse can occur during pregnancy and that the risk of relapse is higher in the
third trimester for unclear reasons. The timing of onset of symptoms can vary
(CASE 3-1). Approximately one-third of women with CIDP with onset or relapse
during pregnancy go into remission after delivery.12
Treatment options for exacerbations of CIDP during pregnancy include
corticosteroids, IVIg, and plasma exchange, which appear to be safe for both

mother and the fetus.13 Ideally, tapering of steroid-sparing agents, such as

cyclosporine, cyclophosphamide, and mycophenolate mofetil, is recommended
at least 6 months before planned attempts at conception to limit risk to the fetus.
Of the steroid-sparing agents, increasing literature supports relatively less risk
with the use of azathioprine during pregnancy.14 However, treatment choices
should be determined based on individual risk assessment. Rituximab bears
special mention for patients with nodal and paranodal antibodies
(antineurofascin, anti–contactin-associated protein-1, and anticontactin
antibodies), who respond best to this treatment.15 In women with multiple
sclerosis, no increase in adverse pregnancy outcomes was seen in patients treated
1 to 5 months before conception with rituximab.16
MULTIFOCAL MOTOR NEUROPATHY. Multifocal motor neuropathy (MMN) is an

immune-mediated neuropathy defined by predominately distal, gradually
progressive, painless asymmetric weakness most often affecting the upper
extremities, with no significant sensory loss. This differs from the typical and
atypical variants of CIDP (eg, multifocal acquired demyelinating sensory and
motor neuropathy [MADSAM]) because of the lack of sensory nerve involvement.
Diagnosis is based on clinical history, examination, and electrodiagnostic studies
demonstrating motor nerve demyelination with conduction blocks and no sensory
impairment. MMN responds best to treatment with IVIg, and case reports have
described worsening of symptoms with corticosteroid treatment. This is of interest
in pregnancy given the shift of endogenous steroid levels during pregnancy. In a
case series of three patients with MMN, all had worsening symptoms during
pregnancy that required IVIg treatment. After delivery, the patients had
significant improvement back to their prepregnancy state.17
Nutritional Neuropathies
It is important to consider the development of peripheral neuropathy related to
nutritional deficiency, in particular because nausea and vomiting are common in
pregnancy, affecting nearly 50% of pregnant women. In a small percentage of
women who have hyperemesis gravidarum, peripheral neuropathy related to
nutritional deficiency can be of particularly high risk. Deficiencies in thiamine,
pyridoxine, and cobalamin are often seen in women with hyperemesis
gravidarum.18 Symptoms of thiamine deficiency include a length-dependent
axonal sensorimotor neuropathy and can also include ophthalmoparesis or
Wernicke encephalopathy. Pyridoxine deficiency or toxicity is a risk in
pregnancy, as pyridoxine supplementation is often recommended for
symptomatic treatment of nausea. Both pyridoxine deficiency and toxicity can
cause a painful sensorimotor peripheral neuropathy or neuronopathy, with
clinical symptoms of abnormal sensation, normal strength, and a sensory ataxia.
Cobalamin deficiency can manifest as a myelopathy or sensorimotor neuropathy
with large or small fiber involvement. Serum levels of vitamins can be assessed,
although wait times for the return of results are variable. Repletion of vitamins is
the treatment of choice; if thiamine deficiency is suspected, repletion is
recommended while awaiting laboratory results.
Hereditary Neuropathies
Charcot-Marie-Tooth disease (CMT) is a sensory and motor hereditary
neuropathy and one of the most common inherited neurologic disorders.
58 FEBRUARY 2022

Symptoms often manifest in the first to third decades of life. The clinical KEY POINTS
phenotype most commonly includes distal upper and lower extremity weakness
● IVIg, plasma exchange, or
and sensory loss in a stocking-glove distribution, often accompanied by pes cavus corticosteroids can be used
and hammer toes. Less commonly, tremor, respiratory involvement, pupillary in treatment of chronic
dysfunction, hearing loss, or scoliosis may occur. inflammatory demyelinating
Higher rates of placenta previa, abnormal fetal presentations, and preterm polyradiculoneuropathy
during pregnancy, and IVIg is
deliveries have been reported in women with CMT.19 However, ultimate
most effective for multifocal
pregnancy outcomes and newborn weight and health findings were similar to motor neuropathy.
women without CMT.19 No special considerations for anesthetic management
were noted.20 In one study in which 193 pregnancies from 86 women with CMT ● If thiamine deficiency is
were evaluated, the authors reported that 16.3% of women with CMT had suspected in pregnant
women, treatment with
worsened weakness, sensory loss, or fatigue during pregnancy; however, vitamin repletion is
ambulation ability was unchanged in 97.9% of pregnancies.19 Another study that recommended even while
evaluated 54 women with a total of 98 pregnancies reported that one-third of awaiting laboratory results
women with CMT reported an exacerbation of the disease during or after for serum levels of vitamins
as no significant harm exists
pregnancy. Ultimately no increased complication rates for pregnancy and in treatment. Treatment can
delivery were seen, which is consistent with prior studies.20 be stopped if levels are
found to be within normal
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES. Hereditary limits.
neuropathy with liability to pressure palsies (HNPP) is allelic to CMT type 1A
● Pregnancy outcomes in
and is caused by a mutation in the PMP22 gene, with the majority of the women with Charcot-Marie-
mutations secondary to a large deletion and a small percentage of the mutations Tooth disease have been
secondary to a point mutation in the gene. This genetic condition results in found to be similar to
women without the disease.
multifocal demyelinating focal painless mononeuropathies at compressible sites.
Common activities such as squatting, leaning on an elbow, or crossing the legs
can result in focal mononeuropathies resulting in symptoms of sensory loss or
weakness, or both, in that nerve distribution. The primary concern in pregnancy
is to ensure that any one position is not maintained for a prolonged period of time
during labor.
Focal Neuropathies in Pregnancy

Several focal neuropathies can occur during the course of pregnancy. Some of
these are secondary to hormonal changes that occur in pregnancy, focal
compression, or other etiologies.
CARPAL TUNNEL SYNDROME. Of the focal neuropathies that occur in pregnancy,

median nerve compression at the wrist, as may be seen in carpal tunnel
syndrome, is the most common mononeuropathy. The phenotypic presentation
is often bilateral, with symptoms of intermittent or constant numbness and
tingling affecting both hands that are often worse at night. At times, the sensory
disturbances are felt in a median nerve distribution; however, the entire hand can
be affected, with symptoms radiating up the arms as well. Weakness is unlikely
to be an issue given the short time frame for development and typical resolution
of symptoms within the first month postpartum. However, one longitudinal
study reported that 50% of patients still had persistent symptoms at 1 year after
delivery. Those who had onset of symptoms earlier in pregnancy and those with
greater weight gain were more likely to have prolonged symptoms.21 The
underlying mechanism is not completely understood, but the causes of carpal
tunnel syndrome in pregnancy are most likely related to either hormonal changes
affecting the musculoskeletal system or fluid retention during pregnancy.

Diagnosis is made by history; physical examination, including testing for the

Tinel sign over the median nerve at the wrist and by the Phalen maneuver;
electrodiagnostic testing; and sonographic evaluation. In mild symptomatic
cases, further testing may not be required; however, electrodiagnostic testing
is helpful to clarify the severity of carpal tunnel syndrome, whether it be mild,
moderate, or severe. The objective findings of the degree of the severity can
guide management and treatment. Sonographic evaluation is helpful in
supporting the diagnosis of carpal tunnel syndrome as well as in uncovering
anatomic variability but is not universally available. Treatment is
conservative, given the likely resolution of symptoms postpartum. Avoidance
of repetitive hand movements is recommended, as is wearing wrist splints at
night that keep the wrists in a neutral position. If symptoms continue to
persist after delivery and bracing and steroid injections are not successful,
surgical release can be considered.22
ULNAR AND RADIAL NEUROPATHIES. Ulnar and radial focal mononeuropathies are
rare in pregnancy. If clinical symptoms manifest in these peripheral nerve
distributions, electrodiagnostic testing and sonographic evaluation of the nerves
can help clarify the diagnosis. Treatment is initially conservative, with
recommendations for ulnar neuropathy including protecting from focal pressure
or trauma along the path of the ulnar nerve and avoiding leaning on elbows.
Some positioning during labor, if prolonged, could potentially result in these
mononeuropathies. Electrodiagnostic testing can assist not only with diagnosis
but also prognosis if symptoms persist.23
NEURALGIC AMYOTROPHY/BRACHIAL PLEXOPATHY. Idiopathic brachial plexopathy,

or neuralgic amyotrophy, typically presents with symptoms of severe
neuropathic pain in an upper extremity followed by sensory changes and
weakness. Pain usually subsides; however, in a small percentage of patients, pain
can persist, although it typically becomes less severe. The phrenic or spinal
accessory nerves can sometimes be affected as well, and the brachial plexus can
be affected in a patchy heterogeneous pattern that varies from patient to patient.
In a large review of the clinical spectrum of neuralgic amyotrophy, 8.7% of cases
were found to be associated with pregnancy. Diagnosis is based on clinical
history, examination, and electrodiagnostic testing. Treatment with
corticosteroids within the first 2 weeks after symptom onset can shorten the time
frame of recovery. Treatment is otherwise supportive, with an expectation that
recovery may be partial and could take months to years.24
LUMBOSACRAL PLEXOPATHY AND LUMBAR RADICULOPATHY. Although rare, in

circumstances of fetal macrosomia and malpresentation, the lumbosacral plexus
is at risk for compression in prolonged labor.25 Weakness and sensory loss often
follows a L4-L5 distribution. Similar symptoms in that distribution can occur,
although rarely, as a complication of epidural anesthesia. The overall risk of the
occurrence of this complication from epidural anesthesia or from compression
during labor is low; however, any acute symptoms of weakness, sensory changes,
or radicular pain should prompt urgent imaging to further evaluate.
FEMORAL AND OBTURATOR NEUROPATHY. The femoral nerve originates from the
lumbar plexus and has contribution from the posterior divisions of the ventral
60 FEBRUARY 2022

rami of the L2 to L4 spinal nerves. The pathway of the nerve continues between KEY POINTS
the psoas and iliacus muscles and under the inguinal ligament innervating the
● Supportive care is often
knee extensor muscles. Clinical symptoms of an isolated femoral neuropathy all that is necessary for
include weakness of knee extension and sensory loss along the distribution of the carpal tunnel syndrome in
femoral nerve over the thigh and potentially along the medial aspect of the lower pregnancy. Resolution has
leg if the saphenous nerve is involved as well. The incidence of postpartum variable timing.
femoral neuropathy is low and seems to potentially be related to prolonged labor.
● Recovery from idiopathic
The lithotomy position may contribute directly to the development of a femoral brachial plexopathy may be
neuropathy, and prolonged positioning in the lithotomy position increases the partial and can take months
risk of obturator nerve compression. The obturator nerve can also be at risk for to years.
compression against the pelvic brim because of forceps delivery or hematoma
● Focal neuropathies
from pudendal nerve blocks.25,26 Clinical manifestations of obturator neuropathy associated with pregnancy
include hip adduction weakness and sensory loss along the medial thigh. Pelvic often improve over time
imaging should be performed to evaluate for any structural cause; otherwise with supportive care.
stretch injury can be presumed, which should improve with time with
● Recurrence of facial
supportive care.
nerve palsy in future
pregnancies is rare.
FIBULAR (PERONEAL) NEUROPATHY. Fibular (peroneal) neuropathy in pregnancy
most often occurs secondary to focal compression and often during delivery.
Both the deep and superficial branches of the nerve can potentially be affected.27
Clinical symptoms include ankle dorsiflexion and eversion weakness along with
sensory loss along the lateral aspect of the leg and dorsum of the foot.
Electrodiagnostic testing and sonographic evaluation can help localize the
symptoms and differentiate the clinical symptoms from an L5 radiculopathy or
lumbar plexopathy. Sonographic evaluation can be helpful to demonstrate
focal enlargement at compression sites. Avoiding keeping patients in certain
positions for too long can help prevent fibular (peroneal) neuropathy. Care is
supportive if the neuropathy occurs.
FACIAL NERVE PALSY (BELL’S PALSY). Bell’s palsy presents with a lower motor
neuron pattern of facial weakness. Interestingly, pregnant women have 3 times
the risk of developing Bell’s palsy compared with nonpregnant individuals, and it
most often occurs in the third trimester or the first few weeks postpartum. A
retrospective study reported that pregnant women who develop complete facial
paralysis have a poorer prognosis for satisfactory recovery compared to the
general population.28 Recurrence in future pregnancies is rare. The diagnosis
can be made clinically, and electrodiagnostic studies can be performed to
determine prognosis. Treatment often includes the use of corticosteroids within
3 to 7 days of symptom onset to help with facial nerve recovery; antivirals, if
added, may be more strongly considered in cases with severe facial nerve
paralysis.29
INTERCOSTAL NEURALGIA. In intercostal neuralgia in pregnancy, thoracic nerve

roots typically become affected at one or two levels, creating mild to severe pain
and sensory disturbances.30,31 EMG may even demonstrate abnormal
spontaneous activity indicating nerve root irritability at the corresponding level.
Symptoms resolve within hours of delivery, and before delivery, topical lidocaine
can be considered for treatment. Lidocaine is US Food and Drug Administration
(FDA) Category B according to the pre-2015 letter category ratings, so risks and
benefits must be weighed.

NEUROMUSCULAR JUNCTION/MYASTHENIA GRAVIS

Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular
junction and resulting in symptoms of fatigable weakness due to defective
neuromuscular transmission. The distribution of this weakness can vary from
being ocular only, causing intermittent double vision and ptosis, to generalized
weakness resulting in diplopia, ptosis, dyspnea, oropharyngeal dysphagia, limb
weakness, or chewing fatigue.
Diagnosis of Myasthenia Gravis During Pregnancy

Diagnosis of MG is based on clinical history and symptoms and positive
antibody testing for the acetylcholine receptor (AChR) binding antibody.
However, 10% to 15% of patients with MG are seronegative for the AChR binding
antibody and should be tested for muscle-specific tyrosine kinase (MuSK)
antibody or low-density lipoprotein receptor–related protein 4 (LRP4), although
some patients may have seronegative MG.32 Electrophysiologic testing is helpful
CASE 3-2 A 28-year-old woman who was 5 weeks postpartum presented with
rapidly progressive severe oropharyngeal dysphagia, dysarthria,
dyspnea, limb weakness, ptosis, and diplopia. The diplopia and ptosis
intermittently worsened, and all of her symptoms worsened at the end of
the day. Her bulbar symptoms were the most severe of her symptoms.
Examination demonstrated moderate eye closure weakness, moderate
fatigable ptosis, diplopia on horizontal gaze that was elicited
immediately, bifacial weakness, mild jaw closure weakness, moderate
tongue protrusion weakness, and mild neck flexion weakness. She
showed no accessory muscle use and had mild proximal limb weakness.
She was admitted to the hospital for five sessions of plasma exchange.
Serologic testing for myasthenia gravis (MG) antibodies (acetylcholine
receptor [AChR] binding, modulating, and antistriational) was negative.
Electrodiagnostic testing demonstrated normal nerve conduction studies
and blink reflexes with significant decrement on repetitive nerve
stimulation testing. Given this result, her clinical symptoms, and
examination findings, she was diagnosed with seronegative MG, and
while she was admitted, she received five sessions of plasma exchange
and 60 mg/d of prednisone was initiated.
After discharge from the hospital, she was prescribed pyridostigmine
but could not tolerate the side effects. She continued 60 mg/d
prednisone after discharge from the hospital. She continued to have
significant symptoms of MG, although less severe after treatment.
Muscle-specific tyrosine kinase (MuSK) antibodies were positive. She
was prescribed rituximab and improved significantly back to baseline
over the next 1 to 2 months.
COMMENT This case illustrates that women with MG can have an initial presentation
postpartum. Additionally, MuSK MG can often present with a rapid
progression of severe bulbar symptoms.
62 FEBRUARY 2022

to support the diagnosis, including repetitive nerve stimulation testing (which KEY POINTS
should demonstrate significant decrement) or single-fiber EMG (which should
● Exacerbations of
demonstrate increased jitter); either of these supports the diagnosis. myasthenia gravis occur
more often in the first
Changes During Pregnancy and Delivery trimester and postpartum.
The incidence of MG peaks in females in the second and third decades,
● Preconception
which is typically also the peak fertility time period. The hormonal effects of
counseling is very important
pregnancy on MG are important to understand so that treatment may be to select the appropriate
adjusted accordingly. The severity of MG symptoms can vary during medications for treatment
pregnancy, often involving respiratory insufficiency, and it has been reported of myasthenia gravis.
that 0.1% to 0.2% of women with MG can develop the need for mechanical
ventilation at some point during pregnancy.33-35 Exacerbations can occur, with
worsening of symptoms typically in the first trimester of pregnancy and
during the menstrual cycle, so fluctuation appears to be associated with
hormonal changes.36 An MG exacerbation can also be triggered postdelivery; in
one study, pregnancy preceded the onset of a new diagnosis of MG in 15% of
women patients with MG (CASE 3-2).36 However, most women with MG can be
reassured that if their disease is well controlled before pregnancy, it will likely
stay well controlled. The highest risk period for exacerbations is the first few
months after delivery.
For women who have a new diagnosis of MG during pregnancy, chest imaging
can be delayed, unless a strong clinical suspicion for thymoma exists. Typically,
chest CT without contrast is performed to evaluate for thymoma. However, this
type of imaging is a risk for the fetus; if imaging is required, MRI of the
mediastinum is recommended. In women with MG who are younger than
30 years of age, thymoma is less common; most thymomas are benign and slow
growing, so imaging can be deferred until after delivery. Furthermore, the
benefits of thymectomy in nonthymomatous seropositive generalized MG shows
delayed benefit up to 3 years postthymectomy, so it is considered an elective
procedure rather than an urgent one. Thus, it is typically recommended that
thymectomy be delayed until after delivery.27,37
Treatment options and requirements for MG generally vary based on the
severity of disease manifestations. Pyridostigmine is recommended as the initial
treatment of choice and is safe in pregnancy.38 If pyridostigmine does not control
symptoms, corticosteroids are typically the next option for treatment, often in
combination with pyridostigmine. Low-dose prednisone is often adequate to
control mild ocular or generalized symptoms. However, treatment becomes
more complicated in patients whose symptoms are not well controlled by
low-dose corticosteroids. In these patients, steroid-sparing agents are often
started in combination with high-dose corticosteroids and pyridostigmine with
future tapering after improvement with the high-dose corticosteroids. In general,
azathioprine and mycophenolate mofetil are most frequently used in the
United States as oral steroid-sparing agents, with other options for treatment
including rituximab and eculizumab. These steroid-sparing agents have
implications for potential risk to the fetus and require appropriate counseling,
ideally preconception.
Preconception Counseling
Ideally, the risks and benefits of medication treatments with regard to pregnancy
should be discussed with any woman of childbearing age before initiating a

medication given the risk of potential unplanned pregnancies. When a

pregnancy is later planned, the risks of treatment options can be readdressed.
Fertility is not affected by MG itself. However, some treatments used for MG,
including methotrexate and mycophenolate mofetil, can affect fertility, can be
teratogenic, and are not safe for use during pregnancy. Thus, it is recommended
to stop methotrexate at least 3 months before planning to conceive and to stop
mycophenolate mofetil at least 6 weeks before attempting conception.
Azathioprine and corticosteroids do not appear to affect fertility.39,40 Less is
known about rituximab, so it is often recommended to wait 12 months, if
possible, after the last treatment before attempting to conceive. Rituximab is
discussed further in the section on management during pregnancy below. Data
on the effects of eculizumab, a recombinant humanized monoclonal antibody
that binds to C5 complement protein and inhibits the activation of terminal
complement, on fertility are not yet sufficient. However, the treatment appears
to be safe based on limited data in case series.41
CASE 3-3 A 32-year-old woman with seropositive nonthymomatous generalized

myasthenia gravis (MG) presented at 10 weeks’ gestation with well-
controlled symptoms of MG for routine clinical care. She reported only
mild intermittent right-sided ptosis. She was on a stable dose of
azathioprine, which she had been taking for several years. Neurologic
examination demonstrated a manual muscle test score of 1 for mild right
ptosis.
She had initially presented with MG 5 years ago with intermittent
diplopia and ptosis, as well as intermittent dysarthria, dysphagia, and
mild proximal limb weakness. Her initial diagnosis had been confirmed
with positive acetylcholine receptor (AChR) binding antibodies and
significant electrophysiologic decrement on repetitive stimulation
testing. She initially had been started on pyridostigmine 60 mg 3 times a
day and prednisone 60 mg/d after five sessions of plasma exchange.
Despite repeated efforts, she was unable to taper the prednisone to less
than 30 mg/d without return of symptoms, so 150 mg/d azathioprine was
initiated 4 years before presentation, and prednisone was slowly tapered
completely approximately 3 years before this presentation.
Pyridostigmine had also been discontinued.
As she presented while pregnant with well-controlled MG on a stable
dose of azathioprine, she continued azathioprine throughout her
pregnancy. She delivered a healthy baby vaginally with spinal epidural
anesthesia without complications.
COMMENT This case illustrates the relative safety of azathioprine in pregnancy. In

recent years, published data and long-standing experience of treating
patients with MG with azathioprine as noted in the 2016 International
Consensus Guidance for Management of Myasthenia Gravis support this
recommendation.42 As in this case, the risk of stopping or starting a
steroid-sparing agent during pregnancy outweighs the benefit.
64 FEBRUARY 2022

Management During Pregnancy KEY POINTS
Preconception counseling should ideally help guide management throughout the
● It is typically advised not
pregnancy. As noted, some medications can affect fertility and potentially will to initiate or stop steroid-
have already been discontinued before conception. The severity of symptoms of sparing agents during
MG can fluctuate throughout pregnancy and will determine how to continue and pregnancy, except in unique
adjust treatment options. It is ideal if symptoms can be controlled with circumstances, because of
the potential risk of
pyridostigmine or corticosteroids, or a combination of both. Azathioprine and
myasthenic exacerbations.
cyclosporine are considered relatively safe to use during pregnancy if the patient
is already on these medications. However, the renal effects of cyclosporine in ● It is recommended to use
patients with diabetes may prompt a change in medication.42 It is not antiseizure medications
recommended to stop steroid-sparing agents or other treatments during rather than magnesium in
the treatment of eclampsia
pregnancy because of the potential risk of myasthenic exacerbations (CASE 3-3). in women with myasthenia
Additionally, there is little benefit to starting a steroid-sparing agent during gravis.
pregnancy because of the length of time needed for steroid-sparing agents to take
effect, which can be up to 6 to 9 months. In a 2018 case series of rituximab use
within 6 months of conception, all completed pregnancies resulted in full-term
live births of healthy newborns.43 One case series of 74 pregnancies in women
with multiple sclerosis with last rituximab exposure before conception did not
demonstrate an increased risk of adverse pregnancy outcomes.15 Another case
series of 19 women reported no pattern of structural abnormalities or other
adverse outcomes noted even with rituximab treatment during pregnancy or
close to the time of conception.44 No major safety signals were observed.
Although, ideally, more data should be collected before initiating treatment with
rituximab, patients can be counseled about the data available if they happen to
conceive or be pregnant while receiving rituximab. Eculizumab appears to be
safe to use based on two case series reports.41,45 For treatment of myasthenic
crisis, IVIg or plasma exchange can be used.
Labor and Delivery

The function of the smooth muscle of the uterus is not affected by MG, which
only affects striated muscle. However, in the second stage of labor, when striated
muscle begins to become more involved, some assistance may be needed if
fatigability becomes an issue. Regional anesthesia with spinal-epidural anesthesia
is considered safe; however, nondepolarizing agents for anesthesia should be
avoided because of impairment of neuromuscular junction transmission related
to these drugs. General anesthesia, narcotics, and any type of neuromuscular
blocking agents should be avoided if possible and vaginal delivery encouraged.
During pregnancy, preeclampsia and eclampsia can develop. These conditions
are often typically treated with calcium channel blockers, beta-blockers, or IV
magnesium in patients without MG. However, treatment with magnesium
inhibits acetylcholine release and impairs neuromuscular junction transmission
and should be avoided in patients with MG as much as possible. Beta-blockers
and calcium channel blockers also provide a relative risk for exacerbation of MG
and should be avoided, if possible. Hydralazine is a safer option for an
antihypertensive for these patients. Phenytoin has historically been suggested in
emergent settings for very short-term use at the end of pregnancy in eclampsia
for seizure prevention and control; however, newer antiseizure medications,
such as levetiracetam, may be preferred. For any type of infection that is
common during pregnancy (eg, a urinary tract infection), antibiotics should be
chosen carefully to avoid any that could contribute to exacerbation of MG

symptoms, particularly fluoroquinolones.46,47 TABLE 3-1 lists medications that

could contribute to worsening symptoms of MG.
Management After Delivery

After delivery, specific counseling about treatment and management should be
discussed if the mother is breastfeeding. Corticosteroid use while breastfeeding is
considered safe if the mother is on a dose of 20 mg/d or less. Other treatments
considered relatively safe to use while breastfeeding include pyridostigmine,
IVIg, and plasma exchange. Azathioprine and cyclosporine can also be
continued; although data are scarce for effects on lactation, no significant
evidence of toxicity was seen.48,49 It is recommended that women not breastfeed
while on methotrexate or mycophenolate mofetil. Recent literature reports a
minimal amount of transfer of rituximab into mature breast milk.50 After
delivery, if a mother was treated with rituximab, neonatal B-cell monitoring is
recommended because B-cell depletion was found in nine of the 23 pregnancies
in which B-cell counts were measured and reported. B-cell counts had recovered
at 6 months postdelivery, and none of the neonates experienced infectious
complications.43 One study evaluated 25 infants following maternal eculizumab
treatment, and 10 mothers provided breast milk samples, in which no
eculizumab was detected.51 Although these results are reassuring, not enough
information is yet available to definitively determine the safety of breastfeeding
while on treatment with eculizumab.
All infants of mothers with MG, even if the MG is well controlled, should be
examined for any evidence of transient neonatal myasthenic weakness. Supportive
care should be provided with monitoring at least for the first 48 hours.37
MYOPATHIES
Autoimmune myopathies and genetic myopathies each present with their own
requirements for management and treatment recommendations during the
course of pregnancy.
Inflammatory Myopathies
Acquired autoimmune myopathies, such as idiopathic inflammatory myopathies
(of which polymyositis and dermatomyositis are the most common forms),
often present later in life. Approximately 14% of patients present in childbearing
TABLE 3-1 Medications That May Exacerbate Myasthenia Gravis
◆ Selected antibiotics, including fluoroquinolones, aminoglycosides, and macrolides

◆ Beta-blockers, calcium channel blockers
◆ Quinine, quinidine, or procainamide
◆ D-penicillamine
◆ Interferons
◆ Magnesium salts
◆ Curare and related drugs
◆ Botulinum toxins
66 FEBRUARY 2022

years. In a comprehensive evaluation of 102 pregnancies in 51 patients with KEY POINTS
inflammatory myopathy, no evidence of significant disease exacerbations during
● It is recommended that
pregnancy was seen. In fact, nearly 50% of patients actually had an improved women do not breastfeed
disease course during pregnancy, with a relapse after delivery.52 Corticosteroids while taking methotrexate
and IVIg are options for treatment during pregnancy. or mycophenolate mofetil.
● Women with muscular

Myotonic Dystrophy
dystrophies generally have
Myotonic dystrophy type 1 (DM1) is inherited in an autosomal dominant fashion good pregnancy outcomes.
due to an expansion of a CTG repeat in the DM1 protein kinase (DMPK) gene.
Maternal transmission can result in anticipation of the repeat and may result in the
most severe form, congenital myotonic dystrophy, which occurs in approximately
one-third of infants with DM1. Polyhydramnios is a known complication of
congenital myotonic dystrophy.36 Myotonic dystrophy type 2 (DM2) is due to an
expansion of a CCTG repeat in the CNBP gene. Congenital forms of DM2 have not
been reported, and genetic anticipation is not as apparent as in DM1. Ideally,
preconception counseling should take place to discuss potential complications of
pregnancy. Women with DM1 have a higher rate of spontaneous abortions, ectopic
pregnancies, preterm labor, peripartum hemorrhage, and placenta previa. DM1
also affects smooth muscle, which can result in an increased rate of complications.
Women with DM2 have a higher rate of preterm labor and urinary tract infections
during pregnancy. Both men and women with myotonic dystrophy may
experience reduced fertility. Thus, in vitro fertilization, genetic testing, and
selective implantation can be used to reduce or prevent the transmission of
myotonic dystrophy. Epidural and spinal block procedures during labor and
delivery are considered relatively safe, whereas general anesthesia is best avoided.53
Muscular Dystrophies and Congenital Myopathies

Women with limb-girdle muscular dystrophies, congenital myopathies, and
facioscapulohumeral dystrophy have overall good pregnancy outcomes, with no
increase in miscarriage rate or preterm labor and overall good infant outcomes.
However, one large review of women with neuromuscular disorders found
worsening of weakness that can persist after delivery in over half of patients with
limb-girdle muscular dystrophy and 12% of patients with facioscapulohumeral
dystrophy. This could just be secondary to weight gain related to pregnancy or
deconditioning. Because of the proximal pattern of weakness in these patients,
the need for assisted delivery can be increased.54
Mitochondrial Myopathy and Metabolic Myopathy

Mitochondrial disease has significant phenotypic variability in patients, with
multiple organ system involvement and limited evidence base on which to make
decisions; this can make counseling for mitochondrial disease in pregnancy
challenging. Mitochondrial disease in pregnancy was studied in a case series of 10
patients, which showed an increased incidence of preeclampsia, threatened
preterm labor, and magnesium sulfate toxicity.55 Mitochondrial myopathies
specifically can be associated with defects in ATP production, which can result in
increased metabolic demands and increased symptoms. Exercise intolerance and
muscle weakness were also reported during pregnancy and resolved after
delivery.55 Regional anesthesia may be helpful during labor and delivery.
McArdle disease is a genetic type of myopathy due to myophosphorylase
deficiency and is the most common glycogen storage myopathy. Creatine kinase

levels often increase during labor but not to the degree of rhabdomyolysis. Some
experts recommend IV glucose loading during labor and delivery to improve
exercise tolerance during this time.39
Pompe disease results from a deficiency of the lysosomal enzyme acid
α-glucosidase. Late-onset Pompe disease results in proximal muscle weakness
and can manifest with significant respiratory involvement. In one study of
20 patients, pregnancy was noted to worsen symptoms or lead to an initial
diagnosis, whereas fertility was not affected. The rate of stillbirths was increased
compared to the national average, although this was a small study. Enzyme
replacement therapy is a disease-specific treatment for Pompe disease; however,
only limited case reports of what appears to be safe use in pregnancy are
available.56 A European consensus panel recommended continuing use of
enzyme replacement therapy throughout pregnancy.57
MOTOR NEURON DISEASE

Pregnancy in patients with motor neuron disease bears special mention with a
specific focus on spinal muscular atrophy and amyotrophic lateral sclerosis.
Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is caused by an autosomal recessive genetic
condition with a mutation in the survival motor neuron 1 (SMN1) gene, which
results clinically in progressive limb weakness of varying phenotypic severity
depending on how many copies of SMN2 a patient has. Fertility does not
appear to be affected. Miscarriages do not appear to occur at a higher
frequency than in the general population, nor does the incidence of gestational
diabetes, hypertension, preeclampsia, or fetal complications appear to be
increased. Depending on the degree of pulmonary dysfunction, which is
typically restrictive in nature, transient worsening of pulmonary function
may occur, which improves after delivery. The incidence of preterm
delivery and the need for operative interventions for delivery appear to be
increased.58 However, neonatal outcomes are favorable.59 Regional anesthesia
is preferred to general anesthesia, as with most neuromuscular disorders.
Nusinersen was approved for the treatment of SMA by the FDA in December
2016. Nusinersen is an antisense oligonucleotide that increases production of
full-length SMN protein. The European Medicines Agency recommends
avoiding the use of nusinersen during pregnancy as a precautionary measure
because the effects on the fetus are unknown.58,59 Risdiplam is an orally
administered medication that increases SMN protein levels. It is
recommended that this drug not be used in pregnant women because of
animal data that suggest fetal harm.60
Amyotrophic Lateral Sclerosis

Because of the typical age of onset of sporadic amyotrophic lateral sclerosis, it
rarely occurs in a woman of childbearing age. Genetic types of amyotrophic
lateral sclerosis, however, can manifest at a younger age. Primary issues of
concern involve limitations secondary to the degree of weakness and respiratory
insufficiency. Successful deliveries have been reported via vaginal or cesarean
delivery depending on the degree of muscle weakness. Riluzole has no reported
negative fetal effects. Edaravone has less evidence-based data for analysis and
68 FEBRUARY 2022

reports exist of adverse animal outcomes, so it is not recommended for use KEY POINTS
in pregnancy.61
● Rhabdomyolysis has not
been reported during labor
in patients with McArdle
CONCLUSION disease.
Neuromuscular disorders vary widely, from autoimmune to genetic in nature,
● Neonatal outcomes for
and require focused expertise for effective management. Generally speaking, if
babies born to women with
preconception counseling can be performed, an ideal management strategy can spinal muscular atrophy are
be formulated for the duration of the pregnancy and after delivery. Many generally good.
treatment options are available for neuromuscular disorders, and with the proper
support, outcomes are relatively good.
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REVIEW ARTICLE
Headache in Pregnancy
and Lactation

CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Melissa Rayhill, MD, FAHS
ABSTRACT
Downloaded from http://journals.lww.com/continuum by dk0DVdnDV+fUlnl1Ul6LIOKG9b/NnbZSXSsgz6LbMijmA29e3msQ7A8r2fAzgSo/H2Nb9wN89d9MJGM/4JnjwKQoWw37vi+9LBO50DUrg9viSIgyryVQ+ksyNnYGQk4t on 02/13/2022
PURPOSE OF REVIEW: This article discusses the many tools available for the
treatment of pregnant and postpartum patients with headache. Adequate
treatment of headache is an essential part of good prenatal and
postnatal care.
RECENT FINDINGS: New therapies such as the calcitonin gene-related peptide

monoclonal antibodies, lasmiditan, direct calcitonin gene-related
peptide antagonists, and neuromodulation devices are available for the
treatment of headache. This article contextualizes these new therapies in
practice as they relate to the treatment of migraine in pregnancy and
lactation.
SUMMARY: Headache is common in pregnancy, and neurologists should be

prepared to care for pregnant patients with headache. Preconception
counseling is an important part of providing safe care to patients of
childbearing potential with headache. Identifying potentially dangerous
secondary headache syndromes during pregnancy and the puerperium is
CITE AS: also essential. The repertoire of available acute and preventive headache
CONTINUUM (MINNEAP MINN) treatments is expanding. It is important to discuss the effectiveness and
PREGNANCY):72–92.
safety of these therapies in the context of individual patient circumstances
during pregnancy and lactation in coordination with the patient’s
Address correspondence to obstetric team.
Dr Melissa Rayhill, 1010 Main St,
2nd Floor, Buffalo, NY 14202,
mrayhill@buffalo.edu.
RELATIONSHIP DISCLOSURE: INTRODUCTION
C
Dr Rayhill has served as an aring for pregnant women who present with headache is often
associate editor of Headache:
The Journal of Head and
perceived as a nerve-racking endeavor by many clinicians. As a
Face Pain. result, many women are inappropriately told to forgo treatment for
the safety of their unborn babies. The purpose of this article is to
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL assure readers that with a better understanding of the tools
USE DISCLOSURE: available, treating headache well in pregnancy is not only possible but can be a
Dr Rayhill discusses the use of
gratifying part of neurologic practice. This article also reviews potentially
various medications for the
treatment of headache in dangerous secondary headache syndromes during pregnancy and the
pregnancy and lactation, none of puerperium, as their risk increases significantly during this time,1 and prompt
which are approved by the US
Food and Drug Administration for
identification of these syndromes is essential.
use in pregnancy/lactation. Although tension-type headache may be the most common headache type, it
does not commonly cause patients to seek medical attention. The most common
© 2022 American Academy type of severe headache seen in clinical practice is migraine, which affects
of Neurology. 1 billion people worldwide. Migraine is a genetically driven condition in which,
72 FEBRUARY 2022

under certain circumstances, people can be more prone to activation of the KEY POINTS
trigeminocervical complex, which then produces headache and other associated
● In women between the
symptoms. This process may be modulated by hypothalamic activity and other ages of 30 and 39, the
peripheral and central provocations. prevalence of migraine can
Migraine seems to cause the most disruption during the reproductive years be as high as 27%, which is
and is much more common in women than in men. In women between the ages about 3 times higher than
the prevalence in men in the
of 30 and 39, the prevalence of migraine can be as high as 27%, which is about 3
same age range.
times higher than the prevalence in men in the same age range.2 The prevalence
of migraine in boys and girls is similar until menarche, at which point migraine ● It is prudent to discuss
prevalence starts to increase in girls. The subsequent increase in migraine any potential teratogenicity
prevalence for women over the next few decades of life is thought to be related to of medications at the time
they are prescribed,
fluctuations in estrogen, which might contribute to cellular excitability.3 regardless of the patient’s
current reproductive plan,
PRECONCEPTION PLANNING as plans may unexpectedly
Many pregnancies are unplanned. In the United States in 2008, 51% of change with time.
pregnancies were unplanned. By 2011, the percentage of unintended pregnancies
declined to 45%, although 75% of pregnancies were still unintended among teens
aged 15 to 19 years.4 Preconception planning is valuable to allow patients and
clinicians to minimize risks to the developing baby while also enabling clinicians
to provide anticipatory guidance, reassurance, and hope that patients can still
manage the symptoms of headache if they become pregnant. Unfortunately, 20%
of patients may avoid pregnancy because of their diagnosis of migraine. In a
study by Ishii and colleagues,5 women who avoided pregnancy because of
migraine believed (often erroneously) that migraine would worsen during
pregnancy, make their pregnancy difficult, and have negative effects on
their child.
The fear of worse pregnancy outcomes in patients with migraine is not
completely unsubstantiated, however. In a 2019 Danish population-based study,
more than 20,000 women with migraine were studied with age-matched
controls. Migraine was associated with an increased prevalence ratio of 1.50 for
pregnancy-associated hypertensive disorders, including preeclampsia (95%
confidence interval, 1.39 to 1.61), and a slightly increased risk of miscarriage, low
birth weight, preterm birth, and cesarean delivery (with adjusted prevalence
ratios on the order of 1.10 to 1.20).6 Still, the decision of whether to have children
is highly personal, and clinicians should be prepared to support and treat patients
however they may choose to proceed.
Every woman of reproductive potential should be asked whether they plan to
conceive in the coming months to years, while acknowledging that not all
patients of reproductive age have the desire or ability to conceive. Contraceptives
can often be omitted from patient-reported medication lists. It is prudent to
discuss any potential teratogenicity of medications at the time they are
prescribed, regardless of the patient’s current reproductive plan, as plans may
unexpectedly change with time.
Although no clear guideline has been established for preconception
management of migraine, most oral preventive headache therapies can be
stopped sometime between the patient’s last menstrual period and ovulation,
although more advanced planning may be prudent if a slower taper is warranted.
If ovulation is being tracked in a carefully selected patient, the use of some oral
preventive therapies can be considered at a low dose preovulation, stopped
postovulation, and restarted again preovulation if the patient does not become

HEADACHE IN PREGNANCY AND LACTATION
pregnant (CASE 4-1). This strategy is based on expert opinion and should not be
used with medications with particularly long half-lives; very-low-dose tricyclics
may work well in this context. In contrast to oral therapies, patients taking
monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) activity
should be advised to stop injections approximately 5 to 6 months before
conception. This recommendation is based on the long half-lives of the
monoclonal antibodies and the lack of sufficient safety data in pregnancy with
theoretical risk of harm.
The use of onabotulinumtoxinA injections in pregnancy remains controversial.
In the absence of high-quality evidence for their use during pregnancy, most
clinicians elect to stop injections before conception. However, some clinicians elect
to continue onabotulinumtoxinA injections up until a positive pregnancy test or
even through the duration of pregnancy. The safety of onabotulinumtoxinA
injections in pregnancy is discussed in more detail later in this article.
DIAGNOSIS
The diagnosis of headache is guided by the International Classification of Headache
Disorders, Third Edition (ICHD-3).7 As helpful as the criteria are, a detailed
CASE 4-1 A 27-year-old woman presented for a routine neurologic follow-up visit
for her migraine and expressed a desire to become pregnant soon. She
was taking amitriptyline 10 mg every evening and receiving
fremanezumab-vfrm injections 225 mg monthly and onabotulinumtoxinA
injections every 12 weeks for headache prevention. For acute therapy,
she was using sumatriptan 100 mg as needed for severe headache and
metoclopramide 10 mg as needed for nausea or headache rescue.
After discussion with her neurologist, she elected to immediately stop
fremanezumab-vfrm injections. She continued amitriptyline for another
6 months, but after discontinuing her oral contraceptive pill, she stopped
amitriptyline completely. After a discussion with her obstetrician, she
decided to stop onabotulinumtoxinA injections also, with her last set of
injections just before she stopped taking her oral contraceptive pill.
She returned for another neurologic follow-up visit 8 weeks after two
consecutive negative pregnancy tests, and her headaches were much
more frequent and severe. She restarted amitriptyline, but only took it
before ovulation for two menstrual cycles. During this time, she needed
to use her acute therapies a little more often than usual. After these two
cycles, she became pregnant and stopped sumatriptan use as well. She
started to use metoclopramide as needed for headache acutely with
good effect when acetaminophen was unhelpful, and her headache
frequency and intensity gradually improved by week 10 of her pregnancy.
COMMENT Preconception counseling is imperative, especially when patients are using

long-acting preventive therapies for headache. Additional acute therapies
and other preventive therapies could have been considered once this
patient became pregnant had her headache pattern not improved.
74 FEBRUARY 2022

history of the course of headache is essential, including eliciting the susceptibility KEY POINTS
to headache in childhood and before pregnancy. One of the first clinical decisions
● Patients taking
during a consultation for headache is determining whether the headache is monoclonal antibodies
secondary to another underlying cause (eg, dissection, preeclampsia, intracranial targeting calcitonin gene-
hypertension) or a primary headache disorder (presumably an inherited related peptide (CGRP)
condition without another underlying cause, eg, tension-type headache or activity should be advised to
stop injections
migraine). A history of hormonally influenced headache (eg, menstrual
approximately 5 to 6 months
association, effect of hormonal contraceptives on headache) may suggest a before conception.
degree of an underlying primary headache disorder and may provide some clues
about how headache could behave in pregnancy. However, even in the same ● The diagnosis of
patient, every pregnancy is different. headache is guided by the
International Classification
of Headache Disorders,
Primary Headache Third Edition.
The most common severe headache disorder is migraine. Although tension-type
headache is the most common headache type worldwide, it is usually mild to ● Women with migraine
with aura may be less likely
moderate in intensity (some headache specialists question whether tension-type to improve in pregnancy,
headache is even mechanistically distinct from migraine at a lower pain intensity). and aura can present for the
The diagnosis of migraine is often missed because of an incorrect notion that all first time during pregnancy.
patients with migraine will be vomiting in a dark room at some point for the
● One study showed that
diagnosis to be correct, but photophobia and phonophobia can be much subtler in
the most common
description (eg, a preference to avoid screaming children or parties when secondary headache
headache is present, a preference to avoid fluorescent lighting, reluctance to go to syndromes in patients who
the gym or grocery store when headache is present). A careful review of the presented to acute care with
ICHD-3 criteria shows that migraine may be much more common than expected severe headache were
caused by hypertensive
in clinical practice (TABLE 4-1); tension-type headache and true cervicogenic disorders of pregnancy. In
headache are actually much less common in most headache medicine practices. this study, a lack of
Cluster headache is characterized by very severe short-duration attacks of headache history was
unilateral side-locked headache with autonomic features. The condition is associated with a nearly
fivefold risk of secondary
uncommon (approximately 1 in 500 people) and affects mostly men.8 As such, it headache, and elevated
is not very common during pregnancy, and data about changes in its frequency blood pressure was
during pregnancy are limited. associated with a 17-fold risk
When discussing the course of primary headache disorders in pregnancy, it is of secondary headache.
crucial to remember that not all patients will have a similar course. Although 50%
of women improve by the end of the first trimester and more than 80% improve
by the end of the second trimester,9 women with aura may be less likely to
improve in pregnancy and aura can present for the first time during pregnancy.10
Still, given the natural improvement that occurs for most pregnant women, some
optimism is warranted.
The challenge in headache diagnosis during pregnancy is determining when to
initiate further testing for secondary headache syndromes. Although most
headache in pregnancy is due to a primary headache disorder, the incidence of
dangerous secondary causes of headache is high, especially at the later stages of
pregnancy. For example, preeclampsia does not occur until after 20 weeks of
gestation, and the risks of venous sinus thrombosis and dissection are highest in
the third trimester and postpartum. Robbins and colleagues11 found that 35% of
140 women presenting to acute care with severe headache who required
inpatient neurologic consultation ended up being diagnosed with a secondary
headache syndrome. The most common secondary headache syndromes in this
group were caused by hypertensive disorders of pregnancy. Preeclampsia was
the most commonly diagnosed disorder, but other related conditions included

posterior reversible encephalopathy syndrome (PRES, which is the radiographic

correlate of preeclampsia), eclampsia, acute arterial hypertension, and reversible
cerebral vasoconstriction syndrome (RCVS, which has a pathophysiologic
mechanism similar to that of preeclampsia). A lack of headache history was
associated with a nearly fivefold risk of secondary headache, and elevated blood
pressure was associated with a 17-fold risk of secondary headache.11 Other
warning signs for secondary headache include fever, papilledema or other
abnormal neurologic examination findings, thunderclap headache onset,
postural provocation, and a history of immunosuppression (TABLE 4-2).
A history of primary headache or migraine is not necessarily reassuring when a
pregnant woman presents with headache. In fact, compared to women without a
history of migraine, women with a history of migraine are more likely to have a
secondary cause of headache, such as cerebral venous thrombosis, pregnancy-
associated stroke, or preeclampsia.12 Therefore, clinicians should have a low
threshold to test for secondary headache syndromes in their pregnant patients
with headache.
TABLE 4-1 ICHD-3 Diagnostic Criteria for Migraine Without Auraa
Description
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics
of the headache are unilateral location, pulsating quality, moderate or severe intensity,
aggravation by routine physical activity, and association with nausea and/or photophobia and
phonophobia.
Diagnostic criteria
A At least five attacksb fulfilling criteria B-D
B Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)c,d
C Headache has at least two of the following four characteristics:
1 Unilateral location
2 Pulsating quality
3 Moderate or severe pain intensity
4 Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing
stairs)
D During headache at least one of the following:
1 Nausea and/or vomiting
2 Photophobia and phonophobia
E Not better accounted for by another ICHD-3 diagnosis
ICHD-3 = International Classification of Headache Disorders, Third Edition.

a
Reprinted with permission from Headache Classification Committee of the International Headache
Society, Cephalalgia.7 © 2018 International Headache Society.
b
One or a few migraine attacks may be difficult to distinguish from symptomatic migrainelike attacks.
Furthermore, the nature of a single or a few attacks may be difficult to understand. Therefore, at least five
attacks are required. Individuals who otherwise meet criteria for migraine without aura but have had fewer
than five attacks should be coded probable migraine without aura.
c
When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned
until the time of awakening.
d
In children and adolescents (aged under 18 years), attacks may last 2-72 hours (the evidence for untreated
durations of less than 2 hours in children has not been substantiated).
76 FEBRUARY 2022

The use of MRI is strongly preferred over CT as it avoids ionizing radiation
exposure to the developing fetus. However, during emergency situations and
when CT is diagnostically advantageous over MRI, the benefits of CT and CT
angiography may outweigh the potential risks to the fetus. No known adverse
effects to human fetuses have been reported when clinically recommended
dosages of gadolinium-based contrast have been given to pregnant women.
However, good quality data studying the teratogenic effects of gadolinium in
pregnant patients are lacking. The American College of Radiology recommends
that gadolinium only be used if it is considered critical and the potential benefits
justify the potential unknown risk to the fetus.13
Secondary Headache
A variety of secondary headache syndromes should be considered when
evaluating pregnant patients. Possibilities include several important
vascular and hypertensive disorders, CSF pressure disorders (intracranial
hypertension and hypotension), infection, endocrine dysfunction (including
hypothyroidism and pituitary apoplexy), anemia, and sleep apnea. Clinicians
should be especially wary of headache with a thunderclap onset in which the
maximum intensity of headache occurs within seconds. The secondary
headache syndromes that are not to be missed during pregnancy and the
puerperium are discussed below.
Cerebral venous thrombosis occurs in 1 in 2500 to 1 in 10,000 pregnancies and
is more likely to occur in patients with a comorbid hypercoagulable disorder. It is
most likely to occur during the third trimester or the postpartum period. In
nonpregnant patients, cerebral venous thrombosis is also associated with the use
of combined hormonal contraceptives. It is thought that the rising levels of
estrogen in late pregnancy may create a relative hypercoagulable state. Shifting
coagulation dynamics in the puerperium may also play a role.14 Patients can
present with headache, seizures, focal neurologic deficits, and signs and
symptoms of increased intracranial pressure such as papilledema and cranial
neuropathies. In one study, almost 90% of patients had associated headache, and
the headache tended to be acute in onset with progressive worsening.15 Venous
hemorrhage may occur in up to 39% of patients.15 Magnetic resonance
venography (MRV) is preferred in pregnancy to avoid the radiation exposure of
CT venography, and treatment usually requires anticoagulation with enoxaparin
sodium injection since it is preferred in pregnancy.16
Characteristics Concerning for Secondary Headache TABLE 4-2
◆ Thunderclap headache onset

◆ Papilledema
◆ Postural provocation/time of day preference
◆ Fever
◆ Systemic hypertension
◆ Cranial neuropathies or other examination abnormalities
◆ History of immunosuppression

Preeclampsia is a condition of widespread endothelial dysfunction during

pregnancy that can impact multiple organ systems. Although the exact
mechanism is still somewhat in question, chronic placental ischemia and
immunologic changes may impact this process. The diagnosis of preeclampsia
should be highly suspected with development of an acute headache in
pregnancy, especially when it occurs with hypertension and proteinuria. In the
absence of proteinuria, women should be diagnosed with preeclampsia if they
present with any of the following severe features: thrombocytopenia, transaminitis,
otherwise unexplained severe persistent right upper quadrant or epigastric
pain, renal insufficiency, pulmonary edema, new-onset headache, or visual
disturbances.17 Preeclampsia is quite common, occurring in 3% to 5% of
pregnancies.18 It most often occurs in the second half of pregnancy, but it can also
first present in the postpartum period. A progressively worsening severe headache
can signal an impending seizure (eclampsia). Treatment includes magnesium
sulfate infusion and blood pressure control. The definitive treatment is delivery;
however, preeclampsia can occur postpartum due to the major endothelial and
physiologic changes that have begun before delivery.
PRES is the radiographic correlate to preeclampsia, and the imaging findings
are a result of failed cerebral autoregulation in the setting of increased
hydrostatic pressure and endothelial cell dysfunction.19 Patients with these
imaging findings can present with headache, confusion, seizures, and cortical
blindness. It is not fully understood why PRES preferentially affects the occipital
lobes; one hypothesis invokes a relatively poor adrenergic innervation in the
posterior circulation territory.20 PRES is best visualized with MRI. It can be seen
in other medical conditions outside of pregnancy, such as malignant
hypertension, and can also be provoked by some medications.
RCVS (also sometimes referred to as postpartum angiopathy) can often
present with focal deficits and a thunderclap headache onset. The majority of
patients have a good outcome, but complications can include ischemic stroke,
subarachnoid hemorrhage, and intraparenchymal hemorrhage.21 RCVS may
have some overlapping pathophysiology and may co-occur with preeclampsia.
Hemorrhagic stroke has an increased frequency during pregnancy, and headache
is often a prominent presenting symptom. Using data from the Canadian Institute
of Health Information, a 2019 study evaluated all antepartum, peripartum, and
postpartum hospitalizations in Canada (excluding Quebec) from 2003 to 2016. The
authors identified 524 cases of stroke among 3,907,262 deliveries (13.4 per 100,000),
and hemorrhagic strokes made up 58.6% of these cases. Furthermore, just over half
of hemorrhagic strokes occurred in the postpartum period. A significant increase in
stroke was associated with hypertensive disorders of pregnancy, emphasizing the
importance of close monitoring of these patients with headache.22 Ischemic stroke is
a less common cause of headache in pregnancy. For more information on stroke in
pregnancy, refer to the article “Maternal Stroke Associated With Pregnancy” by
Eliza C. Miller, MD, MS,23 in this issue of Continuum.
Cervical artery dissection can present with acute headache or neck pain as well
as other neurologic signs (CASE 4-2). In carotid artery dissection, patients may
present with Horner syndrome because of disruption of sympathetic fibers
wrapped around the carotid artery, and patients with vertebral artery dissection
may present with neck pain and other sequelae of posterior circulation ischemia.
Pituitary apoplexy is the result of hemorrhagic infarction of the pituitary
gland. Although it is a rare cause of headache, pregnant women are most
78 FEBRUARY 2022

susceptible in the peripartum period given the physiologic enlargement and KEY POINTS
hyperemia of the gland that occurs during pregnancy; not surprisingly, having a
● Warning signs for
pituitary macroadenoma also increases the risk of apoplexy. It can be best secondary headache include
detected using MRI with thin cuts through the pituitary. Pituitary apoplexy fever, papilledema or other
characteristically presents with acute or thunderclap headache, and it can lead to abnormal neurologic
bitemporal hemianopia and hypotension. In addition to neurosurgical examination findings,
thunderclap headache
consultation, patients may need to be supported with hydrocortisone and thyroid
onset, postural provocation,
hormone and other hormonal therapy as appropriate.24 and a history of
CSF pressure disorders are secondary headache disorders that commonly immunosuppression.
occur in pregnant and postpartum women. Post–dural puncture headache and
spontaneous intracranial hypotension can be quite disabling as they often limit ● Compared to women
without a history of
the ability to even sit upright. Intracranial hypotension usually presents with migraine, women with a
postpartum headache that progressively worsens throughout the day and usually history of migraine are more
worsens with upright posture as gravity exerts downward traction on the likely to have a secondary
well-innervated meninges that remain attached to the skull. Most patients cause of headache, such as
cerebral venous thrombosis,
improve with conservative therapy and rest over a few days. Some with pregnancy-associated
protracted or particularly severe symptoms may be helped with an autologous stroke, or preeclampsia.
blood patch. Although many patients can still have normal imaging, some may
show diffuse pachymeningeal enhancement and other signs of intracranial ● Preeclampsia is quite
common, occurring in 3% to
hypotension, such as acquired cerebellar tonsillar ectopia, decreased
5% of pregnancies.
mamillopontine distance, and, rarely, subdural hematomas. For more
information on post–dural puncture headache, refer to the article “Neurologic ● Pituitary apoplexy
Complications of Obstetric Anesthesia” by Janet F. R. Waters, MD, MBA, characteristically presents
FAAN,25 in this issue of Continuum. with acute or thunderclap
headache, and it can lead to
Idiopathic intracranial hypertension is an important condition to identify in bitemporal hemianopia and
pregnancy as it can lead to potentially permanent visual loss from malignant hypotension.
papilledema if left unchecked. Idiopathic intracranial hypertension can present
with intractable headache, pulsatile tinnitus, and, sometimes, abducens palsy. ● Intracranial hypotension
usually presents with
Lumbar puncture shows increased intracranial pressure (usually above 25 cm postpartum headache that
H2O), but CSF studies are otherwise normal. Optimization of nutrition should be progressively worsens
prioritized, and medical management with acetazolamide can be considered in throughout the day and
consultation with the patient’s obstetrician.26 Surgical interventions such as optic usually worsens with upright
posture.
nerve sheath fenestration and shunt placement are sometimes required. Given
the possibility of permanent visual loss, it is imperative that patients with this
condition be followed by a neuro-ophthalmologist or ophthalmologist in addition
to a neurologist. For more information on idiopathic intracranial hypertension,
refer to the article “Neuro-ophthalmology and Pregnancy” by Heather E. Moss,
MD, PhD, FAAN,27 in this issue of Continuum. The increased intracranial
pressure that occurs during labor is transient and unlikely to affect the safety of
the mother or baby. Therefore, a cesarean delivery is not routinely required,
neuraxial anesthesia can be offered, and the mode of delivery should be
determined by obstetric factors only.28
TREATMENT OF MIGRAINE DURING PREGNANCY

The treatment of migraine during pregnancy seemed more straightforward
several years ago. The US Food and Drug Administration (FDA) previously
categorized medications based on a hierarchical scale from A (safest) to X
(contraindicated in pregnancy), but these categories were discontinued in 2015.
The previous safety categories provided a simple way to stratify the potential
risks of medications during pregnancy; this stratification helped to facilitate

otherwise more complex patient discussions and medical decision making.

However, the convenience of categorization could lead to oversimplification and an
inadequate understanding of why each medication carried risk. Since then,
clinicians and patients have had to wade through the available data themselves to
make informed decisions about medication use in pregnancy. Although the previous
categories are still sometimes used for the sake of simplicity, they are increasingly
outdated. Other sources available for use include the ReproTox and IBM
Micromedex websites, although these services usually require subscriptions.
The United States Department of Health and Human Services Agency for
Healthcare Research and Quality recently performed a systematic review on the
CASE 4-2 A 36-year-old woman developed a headache that started 2 days after a
normal spontaneous vaginal delivery of her third child with epidural
anesthesia. In her late teenage years, she had experienced headaches
that could sometimes be severe about once per month. She had
experienced no headaches during any of her three pregnancies; however,
2 days after the birth of her third child, she developed daily headache.
She did not remember the headache as starting abruptly, and the pain
was constant. She was seen in the emergency department after she
noticed that she had swelling around her right eye to the point that it was
difficult to see. A lumbar puncture showed a normal opening pressure of
14 cm H2O, and brain MRI and magnetic resonance venography (MRV)
were also normal. On examination in the emergency department, her
systolic blood pressure was between 140 mm Hg and 160 mm Hg, and her
diastolic blood pressure was between 80 mm Hg and 98 mm Hg. She was
then discharged home. She was also treated for a urinary tract infection,
but her headaches did not improve.
Three weeks later, she was seen in clinic for outpatient neurologic
headache consultation. Her headache was located around the right eye,
with pain radiation that was holocephalic and into the neck. The pain was
throbbing and associated with photophobia, phonophobia, osmophobia,
and cutaneous allodynia but not nausea. She had no history of aura. The
headache was associated with rhinorrhea and nasal congestion on the
right and ocular injection of the right eye as well as periorbital swelling on
the right. The headache was not positional, and she had no clear history
of trauma.
On physical examination, she had no ptosis or periorbital edema. She
had right miosis in dim lighting at rest. Her pupils were both reactive in
dim light from 5 mm to 3 mm in the left eye and 4 mm to 3 mm in the right
eye. She had no papilledema, and her visual fields were full. The
remainder of her cranial nerve findings were normal, including facial
sensation to light touch and pinprick. Her mental status, motor, sensory,
gait, and reflex examinations were normal. On magnetic resonance
angiography (MRA), she was found to have a right carotid dissection
(FIGURE 4-1). She was sent back to the emergency department, where she
was started on antiplatelet therapy.
80 FEBRUARY 2022

management of primary headache disorders in pregnancy.29 Based on limited
available evidence, this review surprisingly concluded that calcium channel blockers
and antihistamines might be considered first-line preventive therapies for headache
in pregnancy, and that metoclopramide, diphenhydramine, and triptans might
actually be better first-line acute options than acetaminophen. In clinical practice,
however, calcium channel blockers and antihistamines are not considered to be the
most efficacious in treating headache.30 The discussion in this article aims to provide
some guidance and clarity on which therapies should be considered first, which
therapies can possibly be considered when initial therapies have failed, and which
therapies should be avoided in pregnant patients with migraine.
FIGURE 4-1
Imaging of the patient in CASE 4-2. Axial T1-weighted MRI with fat saturation shows a
hyperintense crescent (A, arrow; B) representing subacute thrombus in the false lumen of
the dissected internal carotid artery. The true lumen, which appears hypointense, is
posterior to the thrombus and is compressed by the false lumen. Coronal time-of-flight
magnetic resonance angiography (MRA) shows a filling defect of the cervical segment of
the right internal carotid artery extending just inferior to the petrous segment (C, arrows).
Secondary headache syndromes commonly present in the puerperium, and COMMENT

detailed testing is often warranted. Pupillary examination should be
performed in both dim and bright lighting; dim lighting will make any
disruption to sympathetic function more obvious. This patient was found to
have a carotid artery dissection, with symptoms likely starting 2 days after
her delivery. Arterial dissection risk increases in the puerperium, and
arterial imaging should be considered in postpartum patients presenting
with headache.

Preventive Therapy
Preventive therapies for primary headache disorders aim to decrease the overall
frequency and intensity of headache over time. These therapies often take at least
several weeks to start impacting the headache pattern, and anticipatory guidance
with discussion of expectations of treatment is essential from the beginning.
Many patients (pregnant or not) choose to forgo preventive therapy if headache
frequency is generally low (usually less than 1 to 2 headache days per week), but
preventive therapy can still be considered to reduce the frequency of particularly
disabling attacks. To make an accurate assessment of headache burden, it is
essential to ask patients about days of complete headache freedom. Many patients
prioritize discussion of their most severe attacks and minimize days with mild
headache. Particularly in pregnant patients, the choice to pursue preventive
therapy should be tailored to individual patient circumstances and values. The
discussion is important because of the inherent dissonance between selecting
treatment that is safe and simultaneously selecting treatment that will actually work.
Given the natural improvement in headache that many patients experience
with pregnancy, it may be reasonable to monitor their headaches without
TABLE 4-3 Safety and Effectiveness of Preventive Treatments in Pregnancy
Medication Safetya Effectivenessa
Propranolol More safe Most effective
Magnesium More safe Least effective
Memantine More safe Moderately effective
Coenzyme Q10 More safe Least effective
Venlafaxine Moderate safety Moderately effective
OnabotulinumtoxinA Moderate safety Most effective
Amitriptyline/nortriptyline Moderate safety Most effective
Riboflavin Moderate safety Least effective
Verapamil Moderate safety Least effectiveb
Gabapentin Moderate safety Least effective
Calcitonin gene-related peptide targeting treatments (erenumab, Least safe Most effective
fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant)
Topiramate Least safe Most effective
Lisinopril Least safe Moderately effective
Candesartan Least safe Moderately effective
Valproic acid Least safe Most effective
Feverfew Least safe Least effective
a
Relative safety and effectiveness judged by the opinion of the author of this article combining tolerability in clinical practice and review of the
available evidence29,33 and expert consensus,34 not based on direct comparisons among therapies in clinical trials.
b
May have a specific role in the prevention of migraine with aura.
82 FEBRUARY 2022

preventive therapy early on to see if preventive therapy is indeed required. All KEY POINTS
patients with primary headache disorders may benefit from a discussion of
● The US Food and Drug
lifestyle modifications, such as sleep optimization, stress management, adequate Administration previously
hydration, and regular healthy meals. Patients should also be screened for categorized medications
medication-overuse headache. It is reasonable to consider physical therapy, based on a hierarchical scale
medical massage, cognitive-behavioral therapy, and relaxation techniques in the from A (safest) to X
(contraindicated in
interested patient as well, although the evidence for these nonpharmacologic
pregnancy), but these
interventions is mixed and limitations may include cost and time.29,31 In addition, categories were
intermittent peripheral (usually occipital) nerve blocks can be used safely for the discontinued in 2015.
treatment of severe headache during pregnancy.32
Preventive therapies graded by relative safety and relative effectiveness by the ● To make an accurate
assessment of headache
author of this article are listed in TABLE 4-3.33,34 Effectiveness was judged by the burden, it is essential to ask
opinion of the author of this article, combining tolerability in clinical practice and patients about days of
review of the available evidence29,33,34; it was not based on direct comparisons complete headache
among therapies in clinical trials. If pharmacotherapy is indicated for headache freedom.
prevention, it may be most prudent to start with one of the following preferred ● Given the natural
medications: propranolol (effective; long history of use in pregnancy, although improvement in headache
observational studies show some concern with intrauterine growth restriction, that many patients
neonatal bradycardia, hypoglycemia, and possible multicystic renal dysplasia experience with pregnancy,
it may be reasonable to
risk),35 cyclobenzaprine36 or memantine37 (both less effective than propranolol
monitor their headaches
but likely safe based on animal studies), or oral magnesium (less effective than without preventive therapy
propranolol; safety is likely good, but this is controversial, as discussed below). early on to see if preventive
Cyclobenzaprine can also be used as a sedating rescue therapy.33 therapy is indeed required.
Magnesium therapy was long thought to be one of the safest available options
● All patients with
for migraine prevention in pregnancy. Today, IV magnesium therapy is still headache may benefit from
standard care for the treatment of eclampsia and preeclampsia, in which the a discussion of lifestyle
benefits of treatment clearly outweigh the risks. However, 1 year before the modifications, such as sleep
discontinuation of the FDA safety categories, IV magnesium sulfate was demoted optimization, stress
management, adequate
from Category A to Category D for tocolytic therapy.38 This change was in hydration, and regular
response to concerns about fetal skeletal abnormalities after more than 5 days of healthy meals.
treatment, theoretically from altered calcium physiology during bone
development. Therefore, single doses of IV magnesium sulfate are still used by
many clinicians for status migrainosus, although this remains an area of
controversy. After the FDA’s change, clinicians were left to wonder whether oral
magnesium therapy still remained safe at the previous Category A/B or if this
new warning about IV magnesium should be extrapolated to oral doses as well.
When a physician contacted the FDA for clarification on this point years later,
the FDA simply said that the categories were no longer in use and provided no
further comment.33 Still, most headache specialists continue to believe that oral
magnesium remains one of the safer available preventive options in pregnancy.
Whatever the correct interpretation of the category change may be, it is clear that
a detailed informed consent is warranted when recommending magnesium
therapies to pregnant patients.
If other options are needed, the benefits of some second-line therapies may
outweigh the potential risks in some patients. Consultation with the patient’s
obstetrician is imperative. Second-line therapies that could be considered include
onabotulinumtoxinA injections (effective, although safety is not established;
because it takes a long time to provide any benefit, it is difficult to measure its
effect over natural improvements during pregnancy), CoQ10 (less effective;
likely safe based on a single randomized trial),39 venlafaxine (moderate

effectiveness; possible increased risk of pregnancy loss, neonatal seizures/

abstinence syndrome with use late in pregnancy),40 riboflavin (less effective;
unknown safety of supraphysiologic doses),41 amitriptyline/nortriptyline
(effective; possible increased risk of pregnancy loss, neonatal seizures/abstinence
syndrome with use in late pregnancy, cardiac malformations),42,43 verapamil
(low to moderate effectiveness for migraine; risk of fetal bradycardia, heart
block),44 and gabapentin (less effective; possible cardiac malformations, preterm
birth, small for gestational age).45
The FDA’s official stance is that administration of onabotulinumtoxinA is not
recommended during pregnancy given the absence of well-controlled studies.
When pregnant mice and rats were injected intramuscularly during the period of
organogenesis, the developmental no observed effect level (NOEL) was 4 U/kg.
Higher doses (8 U/kg or 16 U/kg) were associated with reductions in fetal body
weight or delayed ossification, or both. More serious concerns were seen when
onabotulinumtoxinA was given to rabbits, although the FDA noted that rabbits
appear to be very sensitive to onabotulinumtoxinA.46 In humans, a very limited
amount of data from just over 200 pregnancies reported no increased
teratogenicity and no increased risk of pregnancy loss compared to the general
population, but the amount of available data is insufficient to make any solid
conclusions about the safety of onabotulinumtoxinA.47
Despite this, wide variability exists in clinical practice regarding the use of
onabotulinumtoxinA in pregnancy. Some clinicians continue to inject
throughout pregnancy, some continue to inject up until a positive pregnancy test,
and some avoid injections entirely before conception. More than a dozen cases of
systemic botulism in pregnant women have been reported, and all suggest
onabotulinumtoxinA may be too large to cross the placental circulation but may
have led to preterm delivery in at least six cases.48 Being mindful of these
concerns, this therapeutic option can occasionally be considered during
pregnancy for women with particularly intractable and disabling chronic
migraine. In these cases, it may be prudent to avoid starting onabotulinumtoxinA
injections in toxin-naïve patients during pregnancy and only consider restarting
the therapy in patients with significant worsening of primary headache after
stopping injections at the start of pregnancy.
More consensus exists on what to avoid in pregnancy, although some newer
available therapies are largely avoided because of theoretical risks in the absence
of good data. Although human data on the use of CGRP monoclonal antibodies in
pregnancy are lacking, animal studies did not show evidence of teratogenicity.49-51
However, given the lower levels of CGRP in patients with preeclampsia compared
to normotensive individuals, most headache specialists believe avoidance of
CGRP monoclonal antibodies in pregnancy is warranted.52 Consequently, it
bears repeating that clinicians should be mindful of the long half-life of these
medications that are dosed once monthly or quarterly. Despite its efficacy,
topiramate should be avoided given the known risks of cleft palate and lip,
intrauterine growth restriction, and metabolic acidosis.53 Angiotensin-converting
enzyme inhibitors and angiotensin II receptor blockers, such as lisinopril and
candesartan, have low to moderate effectiveness but are associated with fetal and
neonatal death with second- and third-trimester exposure, oligohydramnios, fetal
lung hypoplasia, renal failure, skeletal deformations, and hyperkalemia.54
Some preventive headache treatments are absolutely contraindicated in
pregnancy. Valproic acid was previously in FDA Category X as a contraindication
84 FEBRUARY 2022

for migraine prevention. Valproic acid should always be avoided given the risk of KEY POINTS
neural tube defects, craniofacial defects, cardiovascular malformations, autism,
● Given the lower levels of
and decreased IQ.55 Similarly, feverfew is contraindicated for migraine CGRP in patients with
prevention in pregnancy; although it is an over-the-counter supplement that preeclampsia compared to
may be perceived as benign, it can have dangerous consequences, such as uterine normotensive individuals,
contractions and spontaneous miscarriage.33 Reviewing prescription medications most headache specialists
believe avoidance of CGRP
for safety in pregnancy is routine, but clinicians must not forget to specifically
monoclonal antibodies in
ask about over-the-counter medication and supplement use. pregnancy is warranted.
Acute Therapy ● Despite its efficacy,

Regardless of headache frequency, everyone deserves to have a reliable acute topiramate should be
avoided during pregnancy
therapy for an exacerbation of headache. The goal of acute therapy is to restore given the known risks of
function and resolve pain and other associated symptoms within 2 hours. If a cleft palate and lip,
treatment does not reliably help within 2 hours, other options should be explored. intrauterine growth
No medication is totally devoid of risk to the developing fetus, and risks should restriction, and metabolic
acidosis.
be discussed thoroughly among the patient, the patient’s neurologist, and
the patient’s obstetrician. Still, for particularly severe or disabling attacks, ● Feverfew is
infrequent use of some therapies may result in more benefit than risk. contraindicated for migraine
Inadequate treatment of headache in pregnant women results in work prevention in pregnancy as it
can provoke uterine
absenteeism and presenteeism (still present at work, but with decreased
contractions and
productivity), and pregnant women already face personal and career challenges. spontaneous miscarriage.
Similar to the preventive therapies in TABLE 4-3, the acute therapies listed in
TABLE 4-4 are graded by relative safety and relative effectiveness. Effectiveness was ● Reviewing prescription
judged by the opinion of the author of this article, combining tolerability in clinical medications for safety in
pregnancy is routine, but
practice and review of the available evidence29,33,34 and was not based on direct clinicians must not forget to
comparisons among therapies in clinical trials. specifically ask about over-
Acute medications historically viewed as preferred first-line agents include the-counter medication and
acetaminophen (moderate effectiveness; long history of use but safety is supplement use.
controversial after Agency for Healthcare Research and Quality [AHRQ] ● The goal of acute therapy
systematic review,29 as discussed below), metoclopramide (effective; many for headache is to restore
studies demonstrate good safety; caution with use around delivery given function and resolve pain
extrapyramidal side effects),56 and lidocaine (effective and can be used and other associated
symptoms within 2 hours. If
subcutaneously or with intranasal instillation for nerve blocks; limited data in
a treatment does not
humans but frequently used; no teratogenicity in animal studies).57,58 reliably help within 2 hours,
Certainly, acetaminophen has been considered first-line therapy for the other options should be
acute treatment of headache and pain in pregnancy for many years. Most explored.
headache specialists believe it is likely safe. However, given reports of premature
closure of the ductus arteriosus with use in the third trimester, increased risk of
early childhood respiratory disorders with frequent use, and reports of prolonged
use and third-trimester use leading to an association with attention-deficit/
hyperactivity disorder (ADHD) based on the AHRQ review,29 a more thoughtful
discussion of benefits and risks may be warranted. The data suggest that more
frequent use may increase these associated risks, so it would be reasonable to
continue occasional use when needed during pregnancy.
Along with the first-line agents mentioned above, diphenhydramine and
ondansetron are safe adjunct therapies that may be useful in treating pregnant
patients with migraine. Although neither of these medications is particularly
good at decreasing the pain of headache, diphenhydramine may play a useful
indirect role via its sedating properties, and ondansetron may be useful in
preventing severe nausea and vomiting if other therapies are insufficient

(although safety data are mixed, with some concern for cleft palate and
renal agenesis/dysgenesis).59
Second-line agents to consider for acute treatment of migraine include
triptans (effective; accumulating evidence that they are relatively safe),
ibuprofen (effective; avoid in the first trimester because of a risk of spontaneous
miscarriage and avoid in the third trimester given risk of premature closure of
the ductus arteriosus), prednisone/methylprednisolone (variable effectiveness
but often used clinically for status migrainosus; increased risk of cleft lip/palate
and possibly low birth weight more with chronic use),60 and prochlorperazine
(moderately effective; no known risks aside from neonatal extrapyramidal
symptoms, although metoclopramide preferred).33
Traditionally, triptans have been avoided during pregnancy because of
concern for potential impacts to placental circulation. However, given how
commonly these medications are used and given the accumulated information on
exposures during pregnancy over the years,29,61,62 more and more headache
specialists are adding triptans back to the list of possible therapies offered to
pregnant patients with migraine. With that being said, most headache specialists
TABLE 4-4 Safety and Effectiveness of Acute Medications in Pregnancy
Medication Safetya Effectivenessa
Metoclopramide More safe Moderately effective
Lidocaine (subcutaneous, intranasal) More safe Moderately effective
Acetaminophen More safe Moderately effective
Cyclobenzaprine More safe Moderately effective
Diphenhydramine (adjunct for sedation) More safe Least effective
Ondansetron (adjunct for nausea) Between safest and moderate Most effective
safety categories
Triptans Between safest and moderate Most effective

safety categories
Ibuprofen (only for use during second trimester) Moderate safety Moderately effective
Prednisone Moderate safety Moderately effective
Prochlorperazine Moderate safety Moderately effective
Oxycodone (generally not recommended for migraine) Moderate safety Least effective
Butalbital (generally not recommended for migraine) Moderate safety Least effective
Lasmiditan Least safe Most effective
Gepants (rimegepant, ubrogepant) Least safe Most effective
Magnesium sulfate (IV) Least safe Least effective
Ergots Least safe Moderately effective
a
86 FEBRUARY 2022

would agree that triptans should still probably not be used as first-line therapy. KEY POINTS
Butalbital-containing medications and opiates are not recommended for the
● Butalbital-containing
treatment of migraine in general, and the same applies to pregnant patients.63 medications and opiates are
Given the relative limitation in acute therapy options during pregnancy, it is not recommended for the
reasonable to consider using these medications sparingly in pregnant patients, treatment of migraine in the
although triptans are likely a safer option. Butalbital and opiates should only be general population; this
applies to both pregnant
used as a last resort, and clinicians should be mindful of neonatal withdrawal
and nonpregnant patients.
syndromes with more frequent use.
The new direct CGRP receptor antagonists ubrogepant and rimegepant and ● The new direct CGRP
the new serotonin-1F agonist lasmiditan should be avoided in pregnancy given receptor antagonists
the paucity of available evidence about their safety in pregnancy. Aspirin is often ubrogepant and rimegepant
and the new serotonin-1F
used for the prevention of preeclampsia in patients who are at high risk,64 agonist lasmiditan should be
although most headache specialists avoid this, if possible, when the indication is avoided in pregnancy given
for treatment of migraine given the risk of premature closure of the ductus the paucity of available
arteriosus in late pregnancy, fetal/neonatal hemorrhage, perinatal mortality, and evidence about their safety
in pregnancy.
intrauterine growth restriction with chronic higher doses.33 Ergot derivatives,
including dihydroergotamine, are absolutely contraindicated for use during ● Neuromodulation devices
pregnancy given the oxytocic effects and intrauterine growth restriction.65 should be theoretically safe
to use in pregnant women
with migraine or cluster
Medical Devices
headache, but data are
Neuromodulation devices should be theoretically safe to use in pregnant women limited.
with migraine or cluster headache, but data are limited. Options include single-
pulse transcranial magnetic stimulation, vagus nerve stimulation, trigeminal ● If headache improved
nerve stimulation, remote electrical neuromodulation, and occipital nerve during pregnancy, some
women enjoy a continued
stimulation. Many headache specialists feel the use of these devices during improvement during
pregnancy may be preferable to oral medications with established or unknown lactation and may not
teratogenic potential. However, adequately sham-controlled trials are difficult to require immediate
implement, device effectiveness in clinical practice is moderate at best, and— resumption of their prior
preventive therapies.
perhaps most important—cost continues to be a major barrier to these treatments
for many patients. Still, neuromodulation remains an important tool in the
toolbox when options may otherwise be limited.
TREATMENT OF MIGRAINE DURING LACTATION AND THE PUERPERIUM

Once secondary headache has been excluded, many therapeutic options are
available for the treatment of postpartum headache. If headache improved
during pregnancy, some patients enjoy a continued improvement during
lactation and may not require immediate resumption of their prior preventive
therapies. Similarly, the return of the menstrual cycle and cessation of lactation
can sometimes prompt the return of a prepregnancy headache pattern in some
women. Breastfeeding an infant requires significant effort and time, but it can
also be an incredibly gratifying bonding experience. Many treatments pose more
risk to preterm and newborn infants, so some safety concerns may lessen as the
baby grows older. Unfortunately, patients are often routinely told to just “pump
and dump” after medication use. This practice can be incredibly disruptive and
may sometimes lead to the early cessation of breastfeeding altogether, although
occasionally it can be necessary. These hardships should always be considered
when discussing the benefits and risks of treatments during lactation. Clinicians
should familiarize themselves with evidence-based tools to guide discussions
about the safety of medications during lactation, such as LactMed66 and Hale’s
Medications & Mother’s Milk, the latter of which uses a L1 to L5 safety scale with

TABLE 4-5 Safety and Effectiveness of Medications During Lactation
Medication Hale’s risk categorya,66 Safetya Effectivenessa,b
Acute therapies
Acetaminophen/ibuprofen L1 More safe Moderately effective
Triptans (eletriptan/sumatriptan preferred) L2/L3 More safe Most effective
Lidocaine (subcutaneous/intranasal) L2 More safe Moderately effective
Prednisone (short term) L2 More safe Moderately effective
Ondansetron (adjunct for nausea) L2 More safe Most effective
Antiemetics L2/L3 Moderate safety Moderately effective
Lasmiditan Not rated Least safe Most effective
Gepants (ubrogepant, rimegepant) Not rated Least safe Most effective
Ergots L4 Least safe Most effective
Preventive therapiesc
Amitriptyline/nortriptyline L2 More safe Most effective
Candesartan L3 Moderate safety Moderately effective
Gepants (atogepant, rimegepant) Not rated Least safe Most effective
Propranolol L2 More safe Most effective
Topiramate L3 Moderate safety Most effective
OnabotulinumtoxinA L3 Moderate safety Most effective
Riboflavin/magnesium L1 More safe Least effective
Valproic acid L2 Moderate safety Most effective
Venlafaxine L3 Moderate safety Moderately effective
Verapamil L2 More safe Moderately effective

d
Calcitonin gene-related peptide Not rated Least safe Most effective
targeting treatments (erenumab,
fremanezumab, galcanezumab,
eptinezumab)
a
b
Hale’s risk categories:
L1 Safest: Drug has been taken by many breastfeeding women without evidence of adverse effects in nursing infants OR controlled studies have
failed to show evidence of risk.
L2 Safer: Drug has been studied in a limited number of breastfeeding women without evidence of adverse effects in nursing infants.
L3 Moderately Safe: Studies in breastfeeding have shown evidence for mild nonthreatening adverse effects OR there are no studies in
breastfeeding for a drug with possible adverse effects.
L4 Possibly Hazardous: Studies have shown evidence for risk to a nursing infant, but in some circumstances the drug may be used during
breastfeeding.
L5 Contraindicated: Studies have shown significant risk to nursing infants. The drug should NOT be used during breastfeeding.
c
Lactation for a premature baby may require caution for any preventive treatment that is a central nervous system depressant.
d
The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this
has not been adequately studied.68
88 FEBRUARY 2022

L1 being the safest.67 TABLE 4-5 summarizes this author’s opinion about safety KEY POINTS
and effectiveness of common headache treatments when used during lactation.68
● Eletriptan has the lowest
For acute treatments, acetaminophen and ibuprofen are relatively safe first- milk to plasma ratio of the
line options. The triptans are also commonly used. Although it is sometimes triptans, and sumatriptan
difficult to get insurers to cover it, eletriptan has the lowest milk to plasma ratio has the most safety data
of the triptans, and sumatriptan has the most safety data available for breastfeeding. available for breastfeeding.
Antiemetics can be used, although caution should be used because of their sedating
● Ubrogepant, rimegepant,
effects. Metoclopramide has been known to increase milk supply, and promethazine and lasmiditan should be
can interfere with the establishment of lactation. Similar to the recommendations avoided during lactation
for their use in pregnancy, ubrogepant, rimegepant, and lasmiditan should be given the absence of
avoided during lactation given the absence of available data. available data.
Although patients and clinicians should continue to use caution when deciding ● The CGRP monoclonal
on use of preventive therapy during lactation, arguably more therapeutic options antibodies have not been
are available as compared to during pregnancy. Amitriptyline and nortriptyline studied in lactation.
have limited drug excreted in breast milk (although they can cause sedation in However, given their large
size, it is unlikely that they
sleep-deprived parents). Propranolol, riboflavin, and magnesium can also be will pass through into breast
used. Topiramate should be used at lower doses and with caution given the milk, and some headache
possibility of lethargy and diarrhea in the infant, and avoidance of the drug is specialists are now
prudent if the child is preterm or a newborn66; however, levels measured in considering their use when
treating particularly
breast milk were only between 3% to 23% of the mother’s weight-adjusted dose in
disabling and intractable
published studies.69 OnabotulinumtoxinA is probably compatible with migraine.
breastfeeding given its peripheral administration and large molecular size,
although it has not been well studied.24 Verapamil is also likely safe.70 The CGRP
monoclonal antibodies have not been studied in lactation. However, given their
large size, it is unlikely that they will pass through into breast milk, and some
headache specialists are now considering their use when treating particularly
disabling and intractable migraine in patients who are breastfeeding.
CONCLUSION
A variety of treatment options exist for primary headache disorders in pregnancy
and lactation, including oral medications, medical devices, and other
nonpharmacologic therapy. Newer emerging therapies should generally be
avoided until more data are available. A prior history of migraine is not
necessarily reassuring when new headache presents during pregnancy or the
puerperium, and secondary headache is quite common. Close coordination with
the patient’s obstetric team is essential, and preconception planning is ideal.
Neurologists should be prepared to provide evidence-based care for pregnant
and lactating patients with headaches.
USEFUL WEBSITES
REPROTOX AGENCY FOR HEALTHCARE RESEARCH AND QUALITY 2020
The REPROTOX database includes summaries of the SYSTEMATIC REVIEW ON MANAGEMENT OF PRIMARY
effects of medications, chemicals, infections, and HEADACHES IN PREGNANCY
physical agents on pregnancy, reproduction, and This webpage provides the results of a systematic
development (requires subscription, free for review of the management of primary headaches in
trainees). pregnancy and a summary of the main points of the
reprotox.org review.
effectivehealthcare.ahrq.gov/products/
headaches-pregnancy/research

DRUGS AND LACTATION DATABASE (LACTMED)

This database contains information on drugs and
other chemicals to which breastfeeding mothers
may be exposed and includes the possible adverse
effects in the nursing infant.
ncbi.nlm.nih.gov/books/NBK501922
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products-contraindicated-migraine- 65 Migranal. Prescribing information. Valeant
prevention#:~:text=%5B05%2D06%2D2013%5D, Pharmaceuticals North America LLC; 2019.
the%20prevention%20of%20migraine% Accessed December 1, 2021. www.accessdata.
20headaches fda.gov/drugsatfda_docs/label/2019/
020148Orig1s025lbl.pdf
56 Pasternak B, Svanström H, Mølgaard-Nielsen D,
et al. Metoclopramide in pregnancy and risk of 66 Drugs and Lactation Database (LactMed).
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jama.2013.278343
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92 FEBRUARY 2022

Maternal Stroke REVIEW ARTICLE

Associated With C O N T I N U UM A U D I O
ONLINE
Pregnancy 
VIDEO CONTENT
By Eliza C. Miller, MD, MS A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: This article summarizes current knowledge of the
epidemiology, pathophysiology, prevention, and treatment of
cerebrovascular disease in pregnant and postpartum women.
CITE AS:
RECENT FINDINGS: Stroke is a leading cause of maternal morbidity and CONTINUUM (MINNEAP MINN)
mortality, and most fatal strokes are preventable. Adaptive physiologic P R E G N A N C Y ) : 93–121.
changes of pregnancy, including hemodynamic changes, venous stasis,
hypercoagulability, and immunomodulation, contribute to increased Address correspondence to
maternal stroke risk. The highest-risk time period for maternal stroke is the Dr Eliza C. Miller, Neurological
Institute of New York, 710 West
immediate postpartum period. Migraine and hypertensive disorders of 168th St, 6th Floor, New York,
pregnancy, including gestational hypertension and preeclampsia, are NY 10032, ecm2137@cumc.
columbia.edu.
major risk factors for maternal stroke. Adverse pregnancy outcomes,
including gestational hypertension, preeclampsia, preterm delivery, and RELATIONSHIP DISCLOSURE:
fetal growth restriction, are important risk factors for cerebrovascular Dr Miller serves as a section
editor for Stroke and receives
disease later in life. research/grant support from
the Gerstner Family Foundation,
SUMMARY: Many catastrophic maternal strokes could be avoided with the National Institutes of
Health/National Institute of
targeted prevention efforts, early recognition of warning signs, and rapid Neurological Disorders and
evaluation of neurologic symptoms. Neurologists play a central role in the Stroke (K23NS107645,
1R01NS122815), and the National
care of pregnant patients with cerebrovascular disease, whether acute or
Institutes of Health/National
chronic, and should be familiar with the unique and complex physiology of Institute on Aging (R21AG069111).
pregnancy and its complications, particularly hypertensive disorders of Dr Miller has served as an expert
consultant for Argionis &
pregnancy. Associates, LLC; Finch
McCranie LLP; Grower,
Ketcham, Edie, Telan & Meltz,
PA; and Heyl, Royster, Voelker &
INTRODUCTION Allen, PC.
S
troke is a major cause of severe maternal morbidity and mortality in
UNLABELED USE OF
the United States, accounting for 1 in 12 deaths in women who are PRODUCTS/INVESTIGATIONAL
pregnant and postpartum.1 Even nonfatal strokes, including those USE DISCLOSURE:
considered “minor,” can result in significant disability and have long- Dr Miller discusses the
unlabeled/investigational use of
term physical, emotional, and financial consequences for maternal recombinant tissue
stroke survivors. The unique physiology and pathophysiology of pregnancy plasminogen activator for the
treatment of acute ischemic
contribute to maternal stroke risk and can result in unusual stroke mechanisms stroke in pregnant women.
and presentations. Neurologists must be familiar with the risk factors,
pathophysiology, and mechanisms of maternal stroke to prevent, recognize, and
effectively treat this potentially devastating group of diseases. The neurologist © 2022 American Academy
can play a key role both in acute recognition and treatment of maternal stroke of Neurology.

MATERNAL STROKE ASSOCIATED WITH PREGNANCY
TABLE 5-1 Reported Risk Factors for Maternal Stroke
Non–pregnancy-related
◆ Antiphospholipid syndrome
◆ Arteriovenous malformation
◆ Cardiac disease (congenital or acquired)
◆ Chronic hypertension
◆ Chronic kidney disease
◆ Genetic stroke syndromes (eg, moyamoya syndrome)
◆ Health disparities
◆ Infection
◆ Migraine
◆ Obesity
◆ Older age
◆ Pregestational diabetes
◆ Primary hypercoagulable states
◆ Sickle cell disease
◆ Smoking
◆ Systemic lupus erythematosus
Pregnancy-related
◆ Assisted reproductive technologya
◆ Cesarean deliveryb
◆ Hypertensive disorders of pregnancyc: gestational hypertension, preeclampsia/eclampsia,
or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome (severe form of
preeclampsia)
◆ Metastatic choriocarcinomad
◆ Peripartum cardiomyopathye
a
Assisted reproductive technology, such as in vitro fertilization, has been associated with an increased risk
of maternal complications, including stroke. This may be because of maternal factors such as older age and
increased risk for multiple gestation; however, complications of hormonal induction, such as ovarian
hyperstimulation syndrome, are associated with up to a 10% risk of thrombotic events.15
b
Cesarean delivery has been associated with a higher risk of postpartum maternal stroke. This may be
confounded by indication as cesarean delivery may be performed because of maternal high-risk conditions,
including obesity or preeclampsia. In addition, cesarean delivery is major surgery and carries a risk of
postsurgical complications, such as deep venous thrombosis and infection, both of which increase stroke
risk.
c
Hypertensive disorders of pregnancy are a major risk factor for maternal stroke; refer to the section on
conditions leading to special risk.
d
Postpartum choriocarcinoma is associated with a high risk of thrombotic events due to hypercoagulability
as well as hemorrhagic metastases; in addition, stroke due to direct invasion of cerebral vessels has been
reported.16
e
Peripartum cardiomyopathy, defined as new-onset heart failure within 1 month before to 5 months after
delivery without another explanation, may lead to cardioembolic maternal stroke; in some reported cases,
stroke was the presenting symptom.17,18
94 FEBRUARY 2022

and in primary and secondary prevention. This article summarizes the current KEY POINTS
understanding of the epidemiology, pathophysiology, and treatment of maternal
● The incidence of stroke in
stroke, with an emphasis on recent developments in the field. women during pregnancy
and the postpartum period
EPIDEMIOLOGY OF MATERNAL STROKE is approximately triple the
Historically, epidemiologic studies of maternal stroke have been hampered by a incidence of stroke in
nonpregnant women of
lack of high-quality data, variable definitions of stroke, and differing definitions
similar age.
of the postpartum period. Existing data regarding incidence, timing, risk factors
and outcomes after maternal stroke are summarized below. ● The majority of maternal
strokes occur postpartum,
Incidence often after discharge home
following delivery, and up to
A systematic review of maternal stroke found that the overall incidence was half are hemorrhagic.
approximately 30 per 100,000 deliveries, approximately triple the incidence of
stroke in nonpregnant women of similar age.2 Among pregnant women with ● Migraine and
high-risk comorbidities such as hypertensive disorders of pregnancy, stroke hypertensive disorders of
pregnancy, including
incidence may be as high as 1 in 500 deliveries.3 Unlike the general population, in gestational hypertension
whom 87% of strokes are ischemic,4 approximately half of maternal strokes are and preeclampsia, are
hemorrhagic, including subarachnoid hemorrhage, intracerebral hemorrhage, important risk factors for
and hemorrhagic venous infarction.5 In contrast to the overall incidence of stroke maternal stroke.
in the US population, which has been declining, most studies show a steady
increase in the incidence of maternal stroke over the past 30 years in both US and
non-US populations.5-7 Although one study suggested a decrease in incidence of
stroke during delivery admissions,8 postpartum stroke incidence is on the rise,
leading to an overall higher incidence.5,9 This increased incidence has been
attributed to an increase in underlying maternal risk factors, including older age
at delivery, obesity, and an increasing incidence of hypertensive disorders
of pregnancy.
Timing
The highest risk of maternal stroke occurs in the peripartum and immediate
postpartum periods, from approximately 1 day before to 2 weeks after delivery.2
Many strokes occur after patients have been discharged home from the hospital
following delivery; in a nationally representative US sample, the median time to
readmission for postpartum stroke was 8 days.10 However, the timing of stroke
also depends on the stroke mechanism; for example, most hemorrhages due to
rupture of vascular lesions have been reported during pregnancy, whereas
ischemic strokes and hypertensive hemorrhages are most common in the
postpartum period.11 The risk of maternal thromboembolic events and
intracerebral hemorrhage remains elevated up to 12 weeks after delivery12,13; a
Taiwanese population-based study showed an increased risk of stroke up to a
year after delivery.14
Risk Factors
Risk factors for maternal stroke include older age, hypertensive disorders of
pregnancy, migraine, cardiac disease, primary hypercoagulable states, and
smoking (TABLE 5-115-18).3,6,19 In addition, as with overall maternal morbidity and
mortality, social determinants of health and exposure to the impact of systemic,
institutionalized, and structural racism result in significant disparities in rates
and outcome of maternal stroke. Pregnant and postpartum patients who are
Black experience disproportionately high rates of stroke and mortality regardless

of socioeconomic status and medical comorbidities.19,20 Other racial and

ethnic groups, such as Asians or Hispanics, also experience higher rates of
maternal stroke.20
Outcomes After Maternal Stroke

Overall, approximately 7.4% of maternal strokes are fatal.5 One-third of pregnant
or postpartum patients with ischemic strokes and half of those with hemorrhagic
strokes will have residual deficits.21 A study using data from the American
Heart Association’s Get with the Guidelines stroke registry found that despite
having higher stroke severity, pregnant or postpartum patients with acute
ischemic stroke who were treated with acute reperfusion therapies (thrombolysis
or thrombectomy) had similarly good outcomes compared with patients with
stroke who were not pregnant.22 However, among patients with pregnancy-
associated hemorrhagic stroke, up to 50% are fatal,23,24 and stroke is associated
with an overall 100-fold increase in maternal mortality.8,9
PATHOPHYSIOLOGY OF MATERNAL STROKE

Profound adaptive physiologic changes occur in pregnancy,25 some of which can
contribute to increased stroke risk even in healthy pregnancies. In other cases,
placental dysfunction and its associated disorders (eg, preeclampsia) or failure of
the maternal cardiovascular system to adequately handle the physiologic
demands of pregnancy may lead to a far greater risk of stroke. Maternal
physiologic and pathophysiologic mechanisms contributing to stroke risk are
briefly summarized below.
Cardiovascular Adaptation
Cardiac output increases by up to 50% during pregnancy to meet the demands
of the developing fetus, with associated cardiac remodeling.26 This can increase
the risk of arrhythmias, particularly in patients with underlying cardiac
conditions.26 Elevated progesterone and relaxin during pregnancy contribute to
systemic vasodilation, increased vascular compliance, and increased venous
capacitance.25 This leads to venous stasis and increases the risk of venous
thromboembolism, particularly in late pregnancy when the gravid uterus
compresses pelvic veins. In addition, sympathetic vasomotor activation is
increased in normal pregnancy and even more in hypertensive pregnancy,27
possibly contributing to the increased risk of reversible cerebral
vasoconstriction syndrome (RCVS).
Hematologic Adaptation
Volume expansion occurs throughout pregnancy, resulting in physiologic
dilutional anemia and decreased levels of some clotting factors, such as protein S.
In addition, pregnancy produces an adaptive shift to a procoagulant state, with
increased levels of von Willebrand factor, factor V, factor VIII, and fibrinogen, as
well as acquired resistance to activated protein C. Furthermore, the placenta
produces antifibrinolytics (plasminogen activator inhibitors 1 and 2). Thus,
even healthy pregnancy is associated with the Virchow triad (venous stasis,
hypercoagulability, and delivery-associated vascular damage), contributing to an
increased risk of thromboembolic events.28 This risk is further magnified in
pregnant women with obesity, infections, or underlying hypercoagulable
states.28,29
96 FEBRUARY 2022

Immunomodulation and Inflammatory Changes KEY POINT
Immunologic changes of pregnancy and the postpartum period may contribute
● The adaptive physiologic
to increased stroke risk, particularly changes in inflammatory cytokines that play changes of pregnancy,
crucial roles in implantation and parturition.30 In fact, although pregnancy has including hemodynamic
been classically considered an immune-suppressed state, immunomodulation is a changes, venous stasis,
better descriptor of the complex changes seen during pregnancy and hypercoagulability, and
immunomodulation, can
postpartum.31,32 For example, during the first trimester, a highly inflammatory
contribute to increased
milieu predominates, with high levels of proinflammatory T-helper (TH) 1 stroke risk.
activity, along with increases in IL-6, C-reactive protein, and tumor necrosis
factor-α, all of which affect endothelial function and can increase the risk of
thrombus formation and ischemic stroke in patients who are susceptible.33,34 The
second trimester is a relatively immune-quiescent state, with hormonally
induced downregulation of the immunologic transcription factor nuclear factor
kappa B (NF-κB), but closer to delivery, a proinflammatory state returns, with
upregulation of NF-κB leading to a robust cytokine response and induction of
labor.31 Dysregulation of the immunomodulatory response during pregnancy and
postpartum has been implicated in the pathophysiology of preterm birth,35
preeclampsia,36 and peripartum cardiomyopathy,37 all of which are risk factors
for maternal stroke.8 In addition, maternal infections are associated with higher
risk for peripartum stroke, likely due to increased induction of inflammatory
pathways.
Arterial Remodeling and the Blood-Brain Barrier

Although the effects of pregnancy on cardiac output and venous capacitance are
well described, arterial remodeling in normal pregnancy is less well understood.
One study using pulse wave velocity found significant increases in carotid
stiffness in healthy women in their third trimester compared to nonpregnant
controls.38 These increases correlated with increases in systolic blood pressure
and resolved by 20 months postpartum. Greater increases in maternal arterial
stiffness during pregnancy have been shown to predict placental disorders such
as preeclampsia and fetal growth restriction.39 In contrast, the cerebral
vasculature undergoes significant adaptations during pregnancy to compensate
for the enormous cardiovascular physiologic changes in order to maintain
constant brain perfusion.40,41 These include adaptive remodeling of cerebral
arterioles and resistance to systemic vasoconstrictors40 and permeability
factors.41 Failure of this physiologic cerebrovascular adaptation may account for
some of the acute cerebrovascular complications seen in preeclampsia, including
vasogenic edema and cerebral vasoconstriction. Several studies using animal
models of preeclampsia have demonstrated increased blood-brain barrier
permeability.42,43
COMMON STROKE MECHANISMS DURING PREGNANCY AND

POSTPARTUM
As with stroke in nonpregnant young adults, stroke mechanisms in pregnancy
and postpartum tend to be unusual. Common mechanisms of pregnancy-
associated stroke are summarized below.
Arterial Ischemic Stroke

Arterial ischemic stroke during pregnancy and postpartum is most commonly
due to cardioembolism, caused by paradoxical embolism in the setting of patent

CASE 5-1 A 21-year-old woman, gravida 1, para 0, presented to labor triage 3 days
after delivery, reporting severe headache and blurred vision. She reported
the headache was different from her usual migraine attacks, which were
typically unilateral and throbbing with nausea and photosensitivity; this
headache was unrelenting, holocephalic, and squeezing in quality and
unrelieved by ibuprofen or acetaminophen.
Her blood pressure was 182/110 mm Hg, nearly double her typical
baseline of 100/60 mm Hg. She was drowsy but oriented, and a basic
neurologic examination by the on-call obstetrician was normal. Blood
work, including urinalysis, complete blood cell count, and metabolic
profile, was normal. She was diagnosed with preeclampsia with severe
features based on severely elevated blood pressure (>160/110 mm Hg) with
cerebral symptoms (severe headache and blurred vision). While waiting to
be transported to the high-risk maternal unit to start IV magnesium, she
vomited, then lost consciousness and had a generalized convulsive
seizure. A rapid response was activated,
and she was sedated, paralyzed, and
intubated for airway protection, then
immediately started on 24 hours of IV
magnesium for treatment of eclampsia.
The next morning, her intensive
care nurse noticed her pupils were
dilated and unreactive, so she activated
the acute stroke response team. A head
CT without contrast revealed diffuse
cerebral edema along with a left basal
ganglia intraparenchymal hematoma
with intraventricular extension and
obstructive hydrocephalus (FIGURE 5-1).
CT angiography showed no sign of an
underlying vascular malformation. She FIGURE 5-1
was treated with hyperosmolar therapy Imaging of the patient in CASE 5-1 with
and underwent external ventricular eclampsia and fatal intracerebral
drain placement, but her condition did hemorrhage. Axial noncontrast head CT
shows global cerebral edema with
not improve, and she was declared
intracerebral and intraventricular
brain dead the next day. hemorrhage.
COMMENT This case illustrates some important points. Although new-onset seizures in
the setting of preeclampsia are diagnostic of eclampsia, this does not
obviate the need for emergent neurologic evaluation, including brain
imaging. Preeclampsia and eclampsia can result in catastrophic
complications, including cerebral edema, intracerebral hemorrhage,
herniation, and death. Thus, preeclampsia with severe features, including
cerebral symptoms, should be considered a neurologic emergency.
98 FEBRUARY 2022

foramen ovale or pulmonary shunt,44 preexisting cardiac disease,5 or peripartum KEY POINT
cardiomyopathy.45 Other causes of arterial ischemic stroke include cervical
● Common pregnancy-
artery dissections (discussed further below), arterial vasospasm in association associated stroke
with RCVS, arterial thrombosis due to thrombophilias, or rarer conditions such mechanisms include
as moyamoya vasculopathy. cardioembolism, cervical
artery dissection, cerebral
venous thrombosis, cerebral
Cervical Artery Dissection
vasospasm or subarachnoid
Pregnancy-associated cervical artery dissections have been reported, often in hemorrhage due to
association with hypertensive disorders of pregnancy or postpartum RCVS, or reversible cerebral
both.46 A case control study using administrative data from New York and vasoconstriction syndrome,
and hypertensive
Florida found that pregnancy increased the risk of cervical artery dissection more
intracerebral hemorrhage,
than fivefold; this increased risk was seen in the postpartum period and not seen often in association with
in the antepartum period.47 Of women who had dissections, nearly half had posterior reversible
hypertensive disorders of pregnancy, and all events occurred after hospital encephalopathy syndrome.
discharge for delivery (VIDEO 5-1).47 Trauma is also a frequent cause of cervical
artery dissection, and clinicians should bear in mind that intimate partner
violence is common in both pregnancy and the postpartum period.48
Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) in pregnancy is most commonly seen in the
setting of hypertensive disorders of pregnancy,13 and autopsy series have found
ICH to be the direct cause of death in approximately one-third of preeclampsia-
associated deaths (CASE 5-1).49,50 ICH is frequently seen in the setting of posterior
reversible encephalopathy syndrome (PRES), a syndrome of posterior-
predominant vasogenic brain edema, endothelial dysfunction, and hypertension,
seen both within and outside the context of pregnancy.51 In pregnant or
postpartum patients, PRES is highly associated with eclampsia, and nearly 100%
of patients with eclampsia show signs of PRES on MRI.52 Although PRES can be
reversible, it can also be associated with devastating complications, including
ICH and cerebral edema, and should be monitored closely. ICH may also be due
to rupture of preexisting vascular lesions, such as brain arteriovenous
malformations,53 cerebral aneurysms, or cerebral cavernous malformations, or
rupture of fragile moyamoya collaterals (refer to the section on conditions
leading to special risk below).
Subarachnoid Hemorrhage
In the nonpregnant population, subarachnoid hemorrhage (SAH) is most
commonly due to rupture of intracranial aneurysms and can result in severe
disability or death, depending on the severity of the initial bleed.54 Pregnancy-
associated SAH is more often seen in the setting of RCVS, as discussed below, and
tends to occur over the cerebral convexities, with a substantially better prognosis
compared to aneurysmal SAH.55,56
Reversible Cerebral Vasoconstriction Syndrome

RCVS is a syndrome of transient, multifocal, segmental nonvasculitic vasospasm
of the large and medium-sized cerebral arteries, typically presenting with
recurrent thunderclap headaches with or without associated neurologic
deficits.57 RCVS is typically triggered by an event or drug such as orgasm,
sympathomimetic or serotonergic medications (eg, cocaine, antidepressants), or
the postpartum state, which accounts for up to 20% of cases.57,58 Like PRES,

although RCVS vasculopathy is by definition reversible, the sequelae may not be;
severe and fulminant RCVS may lead to ischemic stroke, SAH, and/or ICH, with
devastating consequences (CASE 5-2).59 Both PRES and RCVS are more common
in patients with preeclampsia, and the two often overlap, possibly because of a
shared common pathophysiology of preeclampsia-associated endothelial
dysfunction, inflammation, and sympathetic hyperactivity.60
CASE 5-2 A 40-year-old woman was admitted for treatment of preeclampsia with
severe features, including unremitting headache and blurred vision, on
postpartum day 5. Her symptoms persisted after treatment with
magnesium, and neurology was consulted. She was found to have a right
superior quadrantanopia. MRI revealed diffuse left-sided convexity
subarachnoid hemorrhage (FIGURE 5-2A) and a left occipital intracerebral
hemorrhage (FIGURE 5-2B). Transcranial Doppler showed vasospasm in the
left middle cerebral artery and left posterior cerebral artery. A diagnostic
cerebral angiogram and follow-up MRI showed no evidence of an
underlying vascular lesion. She was treated with oral verapamil, and her
transcranial Doppler velocities gradually normalized over several weeks;
however, she continued to have a mild residual visual field cut.
FIGURE 5-2
Imaging of the patient in CASE 5-2 with preeclampsia and reversible cerebral vasoconstriction
syndrome. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows a diffuse left-
sided convexity subarachnoid hemorrhage (circled). B, Axial susceptibility-weighted
imaging (SWI) shows a left occipital intracerebral hemorrhage (circled ).
COMMENT This patient developed postpartum reversible cerebral vasocontriction

syndrome (RCVS) in the setting of preeclampsia. Despite the term
reversible, RCVS can result in permanent neurologic deficits if it is
complicated by stroke, as seen in this case.
100 FEBRUARY 2022

Cerebral Venous Thrombosis KEY POINTS
Cerebral venous thrombosis occurs because of clot formation in the cerebral
● Despite the term
venous system or dural sinuses, resulting in venous congestion, cerebral edema, reversible in their names,
and, in severe cases, venous infarction or ICH. Cerebral venous thrombosis reversible cerebral
accounts for approximately one-third of pregnancy-related strokes2 and occurs vasoconstriction syndrome
postpartum in 75% of cases.61 Cerebral venous thrombosis risk factors include and posterior reversible
encephalopathy syndrome
obesity, preeclampsia, infection, dehydration (as seen with hyperemesis
can lead to severe disability
gravidarum), and underlying thrombophilias.62 Patients typically present with or death if complicated by
progressive positional headache (worse lying down), sometimes with blurred ischemic stroke or
vision, seizures, or focal neurologic deficits. Treatment of cerebral venous intracerebral hemorrhage.
thrombosis typically consists of therapeutic anticoagulation for 3 to 12 months or
● Pregnant or postpartum
until recanalization,63 although the optimal duration of anticoagulation is not women who develop
clear. The safety of specific anticoagulant medications in pregnancy and lactation cerebral venous thrombosis
is detailed in TABLE 5-2.64-68 The pregnant state should not be assumed to be should be evaluated for
the sole cause of the thrombus; patients with pregnancy-associated cerebral underlying hypercoagulable
disorders; pregnancy should
venous thrombosis should be evaluated for underlying hypercoagulable not be assumed as the sole
disorders, such as antiphospholipid syndrome and inherited thrombophilias. cause.
A hematology consultation can be helpful to decide on the length of
anticoagulation and whether additional evaluation is needed. Pregnancy is not ● Migraine is associated
with increased risk of
contraindicated in women with a history of prior cerebral venous thrombosis,
preeclampsia and a 15-fold
whether in or outside of pregnancy; however, prophylactic anticoagulation increase in risk of maternal
during subsequent pregnancies and in the postpartum period is probably stroke.
warranted.63
CONDITIONS LEADING TO SPECIAL RISK

Although maternal stroke is rare, certain conditions confer additional risk.
Patients with these conditions may warrant closer monitoring and, in some cases,
involvement of a multidisciplinary team of care providers during pregnancy and
the postpartum period.
Migraine
Migraine has been associated with a 15-fold increase in risk of maternal stroke
in multiple studies,6,69 an alarming statistic given that up to 28% of women in
their childbearing years have migraine.70 Migraine has also been consistently
associated with higher risk of preeclampsia, with odds ratios ranging from 1.08 to
3.5 in a systematic review, so the observed risk of maternal stroke in women with
migraine may be partially mediated by preeclampsia.69 The pathophysiologic
connection between migraine, hypertensive disorders of pregnancy, and
maternal stroke remains elusive71 and is beyond the scope of this article;
however, migraine is also associated with increased risk of ischemic stroke and
cervical artery dissection outside of pregnancy.72 Given the consistency of
epidemiologic studies, patients with migraine who are planning a pregnancy
should aim to minimize other stroke risk factors, such as smoking, obesity, and
hypertension. In addition, patients with migraine should be counseled on red flag
features of headache and signs and symptoms of stroke (CASE 5-3).
Hypertensive Disorders of Pregnancy

Hypertensive disorders of pregnancy, including gestational hypertension,
preeclampsia/eclampsia, HELLP (hemolysis, elevated liver enzymes, and low
platelets) syndrome, and chronic hypertension with or without superimposed

TABLE 5-2 Safety of Common Secondary Stroke Prevention Medications in Pregnancy

and Lactationa
During pregnancy64–66 During lactation67
Low-dose aspirin Safe after 12 weeks of pregnancy; reasonable Safe

before this when used for secondary stroke
prevention
Clopidogrel Insufficient evidence of safety; consider on Insufficient evidence of safety; consider on

case-by-case basis depending on indication case-by-case basis depending on indication
and monitor infant for bruising/bleeding
Ticagrelor Insufficient evidence of safety Insufficient evidence of safety
Low-molecular-weight Safe Safe

heparin
Unfractionated heparin Safe Safe
Warfarin Teratogenic, particularly between 6 and Safe

12 weeks gestation; can consider in rare cases
(eg, mechanical heart valve) after week 12, at
doses <5 mg/d68
Dabigatran Insufficient evidence of safety Limited evidence of safety
Apixaban Insufficient evidence of safety Alternative drug preferred
Rivaroxaban Insufficient evidence of safety Limited evidence of safety
Cholesterol-lowering Insufficient evidence of safety Insufficient evidence of safety

agents (statins)
Labetalol Safe Safe
Propranolol Alternative drug preferred Safe
Metoprolol Alternative drug preferred Safe
Atenolol Contraindicated Not recommended
Long-acting nifedipine Safe Safe
Verapamil Safe Safe
Methyldopa Safe Safe
Clonidine Safe Alternative drug preferred
Hydrochlorothiazide Safe in chronic hypertension Alternative drug preferred
Hydralazine Safe Safe
Angiotensin-converting Contraindicated (teratogenic) Safe: benazepril, captopril, enalapril,

enzyme (ACE) inhibitors quinapril; all others: alternative therapy
preferred
Angiotensin II receptor Contraindicated (teratogenic) Limited evidence of safety for candesartan;

blockers (ARBs) for all others, alternative therapy preferred
a
Risks and benefits of medications may vary depending on an individual patient’s circumstances. All medications should be discussed with the
patient’s obstetrician or maternal-fetal medicine specialist, ideally before conception.
102 FEBRUARY 2022

A 35-year-old primiparous patient with obesity and migraine with aura CASE 5-3
presented to their neurologist because of increased headache frequency
and intensity in the late first trimester. The headaches were similar in
quality to their usual migraines but had become more frequent,
prolonged, and intense. Their blood pressure was 110/70 mm Hg, and
neurologic examination was normal, including funduscopic examination.
After discussion of migraine management, the neurologist brought up the
increased risk of maternal stroke in people with these risk factors
(migraine and obesity), the need for blood pressure monitoring, and the
recommendation to consider low-dose aspirin for prevention of
preeclampsia in pregnant people at high risk. Signs and symptoms of
stroke were discussed, as were the highest-risk periods for stroke and
red flag features of headache to look out for. The patient appreciated the
discussion and obtained a home blood pressure monitor. The neurologist
contacted the patient’s obstetrician, who agreed that low-dose aspirin
was reasonable because of the patient’s risk factors of primiparity, age
(35 or older), and obesity, all three of which are considered moderate-
risk factors for preeclampsia. The patient’s headaches improved in the
second trimester, and the baby was born by cesarean delivery at
39 weeks because of failure to progress in labor.
Five days after delivery, the patient developed a severe unremitting
headache, different in quality from their usual migraine attacks. Their
blood pressure as measured at home was 150/95 mm Hg. Based on the
first-trimester discussion with the neurologist, the patient called their
obstetrician, who advised them to come immediately to the hospital
labor triage area, where they were readmitted and treated for
preeclampsia with severe features. They were discharged home 2 days
later and continued on antihypertensive medication for several more
weeks until their blood pressure returned to normal.
This case illustrates the role a neurologist can play in the prevention of COMMENT
primary stroke associated with pregnancy. Although stroke associated with
pregnancy is rare, this patient had characteristics that put them at higher
risk, including older age, obesity, and migraine. In addition, they had
multiple moderate-risk factors for preeclampsia (nulliparity, obesity, and
age ≥35). The use of low-dose aspirin starting at 12 weeks of gestation is
recommended in those with one or more high-risk factors or two or more
moderate-risk factors for preeclampsia and should be considered in
those with one or more moderate-risk factors, according to current
guidelines.64,73,74 Most people are unaware of the risk of stroke in
pregnancy and particularly in the postpartum period. Migraine is also a risk
factor for preeclampsia, particularly in people with obesity.69 In this
patient’s case, the early discussion with the neurologist led them to pay
close attention to postpartum symptoms and monitor blood pressure,
resulting in early recognition of postpartum preeclampsia and avoidance of
potential complications, including stroke.

preeclampsia, collectively constitute the most significant risk factor for maternal
stroke, increasing the risk of stroke at least fivefold.75 Preeclampsia is defined as
new-onset hypertension after 20 weeks of gestation together with evidence of
organ dysfunction, such as renal, hematologic, liver, or neurologic dysfunction.
Proteinuria is no longer required for the diagnosis, and new severe headache or
neurologic symptoms are considered disease-defining in the presence of new
hypertension.76 Currently accepted definitions of preeclampsia are summarized
in TABLE 5-3. Of note, preeclampsia and eclampsia (preeclampsia with new-onset
generalized seizures) can and does occur postpartum, and neurologic
manifestations such as headache may be the first sign of the incipient disorder.77
Preeclampsia and related hypertensive disorders of pregnancy are far from
rare, affecting nearly 1 in 10 pregnancies in the United States.78 Rates are even
TABLE 5-3 Defining Characteristics of Preeclampsia and Related Disordersa,b
ACOG (2019 revision) ISSHP (2018 revision)
Preeclampsia
New-onset, persistent Systolic blood pressure ≥140 mm Hg or Systolic blood pressure ≥140 mm Hg or
hypertension at or after 20 weeks diastolic blood pressure ≥90 mm Hg on diastolic blood pressure ≥90 mm Hg on
of pregnancy in a woman with two occasions at least 4 hours apart two occasions at least 4 hours apart
previously normal blood pressure
OR OR
AND
Systolic blood pressure of ≥160 mm Hg or Systolic blood pressure of ≥160 mm Hg or
diastolic blood pressure ≥110 mm Hg diastolic blood pressure ≥110 mm Hg
confirmed within a short interval (minutes) confirmed within a short interval (minutes)
Proteinuria ≥300 mg per 24-hour urine collection ≥300 mg per 24-hour urine collection
OR OR
Protein to creatinine ratio of 0.3 mg/mg or Protein to creatinine ratio of 0.3 mg/mg
more or more
OR OR
Urine dipstick reading of 2+ (if other Urine dipstick reading of 2+ (if other
quantitative methods unavailable) quantitative methods unavailable)
OR
In absence of proteinuria New onset of any of the following: Acute kidney injury
Thrombocytopenia Liver involvement
Renal insufficiency Hematologic complications
(thrombocytopenia, disseminated
Impaired liver function
intravascular coagulation, or hemolysis)
Pulmonary edema
Uteroplacental dysfunction (fetal growth
New-onset headache unresponsive to restriction, abnormal umbilical artery
medication and not accounted for by Doppler waveform analysis, or stillbirth)
alternative diagnoses, or visual symptoms
Neurologic complications (eclampsia,
altered mental status, blindness, stroke,
clonus, severe headaches, persistent
visual scotomata)
104 FEBRUARY 2022

higher in low- and middle-income countries, where access to prenatal care may
be limited.79 Pregnant women with chronic hypertension represent an extremely
high-risk group, with up to half developing superimposed preeclampsia.64
The pathophysiology of preeclampsia and related hypertensive disorders of
pregnancy is highly complex and incompletely understood. In brief, the
syndrome is, at least in part, mediated by placental dysfunction, either as a
result of poor implantation of the trophoblast or inability of the maternal
cardiovascular system to adapt to the increased demands of the pregnancy and
adequately supply the placenta. The resulting cascade of effects results in
widespread maternal endothelial dysfunction as well as a procoagulant,
proinflammatory, and hyperreactive sympathetic state, all of which contribute to
maternal stroke risk.80
ACOG (2019 revision) ISSHP (2018 revision)
Preeclampsia variants and related

disorders
Preeclampsia superimposed on Preeclampsia in a woman diagnosed with New-onset proteinuria or other maternal
chronic hypertension chronic essential hypertension organ dysfunction in a woman with a
diagnosis of chronic essential
New-onset thrombocytopenia, elevated
hypertension
liver transaminases, sudden development
of symptoms suggestive of preeclampsia,
or elevated uric acid levels suggest
superimposed preeclampsia
HELLP (hemolysis, elevated liver Lactate dehydrogenase ≥600 IU/L ISSHP does not define this as a separate
enzymes, and low platelets) condition and considers this condition to
Aspartate aminotransferase and alanine
syndrome be part of the preeclampsia spectrum
aminotransferase more than twice the
upper limit of normal
Platelet count <100,000/mm3
Eclampsia New-onset tonic-clonic, focal, or ISSHP does not define this as a separate
multifocal seizures in absence of other condition and considers it a neurologic
causative conditions (eg, epilepsy, complication of preeclampsia
cerebral ischemia, intracranial
hemorrhage, drug use)
ACOG = American College of Obstetricians and Gynecologists; ISSHP = International Society for the Study of Hypertension in Pregnancy.
a
Modified with permission from Miller EC, Vollbracht S, Curr Pain Headache Rep.71 © The Authors, under exclusive license to Springer Science
Business Media, LLC, a part of Springer Nature.
b
Precise definitions of preeclampsia have been debated for decades. Note that important differences exist between the ACOG and ISSHP
definitions, but both organizations consider severe headache or visual symptoms to be preeclampsia-defining in the setting of hypertension.
ACOG notes that women may not exhibit other signs of preeclampsia (eg, hypertension, proteinuria) before presenting with seizures. Of note,
ISSHP also considers other neurologic complications, including eclamptic seizures, stroke, altered mental status, and clonus, to be preeclampsia-
defining in the setting of hypertension.

Preeclampsia is associated with numerous cerebrovascular complications,71

including RCVS, PRES, spontaneous cervical artery dissection, cerebral
venous thrombosis, arterial ischemic stroke, SAH, and ICH. The most
devastating of these, ICH, is a leading cause of preeclampsia-related maternal
mortality.13 Preeclampsia-associated hemorrhagic strokes can occur
because of rupture of vascular lesions,11,81,82 but frequently no underlying
vascular lesion is identified.13 Preeclampsia is also highly associated with
peripartum cardiomyopathy,83 which, in turn, can lead to acute
cardioembolic strokes.17,84
Cerebrovascular Malformations
Studies conflict on whether pregnancy increases the risk of rupture for
vascular malformations such as cerebral cavernous malformations,
arteriovenous malformations (AVMs), and unruptured intracranial
aneurysms. Most studies have been flawed by selection bias since
asymptomatic vascular lesions are less likely to be detected. Increased plasma
volume and increased cardiac output, as well as hormonally mediated vascular
changes, have been hypothesized to increase hemorrhagic stroke risk from
vascular lesions during pregnancy and the puerperium. Some studies have
suggested an up to sevenfold to eightfold increased risk of first-time AVM
rupture during pregnancy/postpartum; however, other studies did not show
increased risk.85 A 2021 study of more than 4 million women in the United
States using data from three state administrative datasets found that AVMs
accounted for 5.8% of ICH during pregnancy or the puerperium.11 The same
study noted that in the 568 women with a known AVM, the risk of rupture
more than tripled during pregnancy and the puerperium compared to the
cohort’s baseline rate during the nonpregnant period. The annual rate of
cerebral cavernous malformation hemorrhage is up to 4.5% in patients with a
previous cerebral cavernous malformation–related hemorrhage.86 Lesions in
the brainstem have even higher risk, with a 5-year risk of 30.8% for brainstem
lesions with prior presentation of ICH.87 However, no study has found a
relationship between cerebral cavernous malformation hemorrhage and
pregnancy. One study of 186 women of childbearing age with cerebral
cavernous malformations who had a total of 349 pregnancies found no
increased risk of ICH during pregnancy, delivery, or postpartum periods
compared to nonpregnant periods.88 Similarly, data are limited and conflict
regarding the risk of unruptured intracranial aneurysm rupture during
pregnancy. Some authors have found an increased risk for aneurysm rupture
during pregnancy.89 However, a 2019 systematic review of 20 studies found a
similar risk of aneurysm rupture in pregnant women compared to the general
population. Most ruptured aneurysms in pregnancy occurred during the third
trimester.81 Another observational study showed that four of five aneurysms
did not change or grow during pregnancy; the fifth did increase in size but then
returned to its original size after delivery.90
Regardless of the type of vascular lesion, hypertension is likely to increase the
risk of rupture and should be carefully monitored, detected early, and treated.
Preemptive interventional treatment of unruptured asymptomatic vascular
lesions during pregnancy is not typically recommended but should be decided on
a case-by-case basis. No evidence shows that cesarean delivery decreases the risk
of rupture of vascular lesions in pregnancy.
106 FEBRUARY 2022

Moyamoya Disease and Syndrome KEY POINTS
Pregnant women with moyamoya disease, a progressive stenoocclusive
● Proteinuria is no longer
cerebrovascular disorder affecting the terminal internal carotid arteries and their required for the diagnosis of
intracranial branches, are at increased risk of both ischemic stroke due to preeclampsia; new severe
hypoperfusion and hemorrhagic stroke due to rupture of fragile moyamoya headache or neurologic
collaterals. Idiopathic primary moyamoya disease is most common in East Asian symptoms are considered
disease-defining in the
populations, and multiple genetic variants have been identified contributing to
presence of new or
its pathogenesis.91 In addition, patients with trisomy 21, sickle cell disease, a worsening hypertension.
history of brain radiation, neurofibromatosis type 1, or severe intracranial
atherosclerotic disease can develop secondary moyamoya syndrome.91 ● Hypertensive disorders of
Moyamoya disease is more common in women and often presents in early pregnancy, including
gestational hypertension,
adulthood during the childbearing years. In a systematic review of 54 articles, preeclampsia, and chronic
more than 95% of women diagnosed with moyamoya disease before pregnancy hypertension with
had good pregnancy outcomes.92 However, among patients diagnosed with superimposed preeclampsia,
moyamoya disease during pregnancy, more than two-thirds presented with affect up to 1 in 10
pregnancies.
ICH, with a high rate of maternal and fetal morbidity and mortality. In
contrast, the majority of moyamoya-associated postpartum strokes were ● Intracerebral hemorrhage
ischemic.92 Patients with moyamoya with recurrent prior transient ischemic is a leading cause of
attacks (TIAs) or strokes and severely reduced regional blood flow on imaging maternal mortality in
patients with preeclampsia,
have higher risk of pregnancy-associated neurologic complications.93 No
and frequently, no underlying
evidence suggests that cesarean delivery should be preferred over vaginal vascular lesion is identified.
delivery.93 In some patients, surgical revascularization before pregnancy may
be beneficial.93 A retrospective single-center study of 56 women with ● No evidence shows that
moyamoya disease with 71 pregnancies found no MRI-confirmed strokes or cesarean delivery decreases
the risk of rupture of
strokes with residual deficits in postbypass pregnancies, although 8% had cerebrovascular lesions in
peripartum TIAs.94 Prepregnancy cerebral revascularization was associated pregnancy.
with lower odds of peripartum stroke or TIA (odds ratio, 0.15; 95% confidence
interval, 0.04-0.56). Another single-center 30-year retrospective study found ● In selected patients with
moyamoya, particularly
a similarly low complication rate of two ischemic strokes out of 77 total those with recurrent
pregnancies in women with moyamoya, both of which occurred postpartum; transient ischemic attacks or
however, 19% of patients developed preeclampsia or another hypertensive decreased regional flow on
disorder of pregnancy,95 suggesting that patients with moyamoya may be at brain imaging, surgical
revascularization before
high risk for these disorders.
pregnancy may decrease the
risk of peripartum
Antiphospholipid Syndrome and Other Hypercoagulable Disorders neurologic complications.
Autoimmune conditions such as antiphospholipid syndrome and systemic
lupus erythematosus are associated with high pregnancy morbidity, increasing
the risk of miscarriage, arterial and venous thrombosis, infections, preeclampsia,
and stroke.96,97 Women with antiphospholipid syndrome, systemic lupus
erythematosus, or other autoimmune disorders are considered high risk and
should be on aspirin starting after 12 weeks of pregnancy for preeclampsia
prevention.74,76
Pregnant women with thrombophilias (inherited or acquired hematologic
disorders associated with abnormal coagulation and thrombosis) have an up to
16-fold higher risk of stroke compared to those without these disorders.19 In
women with conditions predisposing to venous thrombosis (eg, Factor V Leiden;
prothrombin G20210A mutation; or antithrombin, protein C, or protein S
deficiency), maternal stroke may occur as a result of either cerebral venous
thrombosis or paradoxical embolism in women with patent foramen ovale or
pulmonary shunt. Most events occur postpartum when pregnancy-associated

hypercoagulability peaks,98 and the increased risk may continue for up to

12 weeks after delivery.12
Sickle cell disease, another genetic hematologic disorder, is associated with
high risk of both arterial and venous clots as well as hemorrhagic stroke. Pregnant
women with sickle cell disease have high maternal and fetal morbidity, including
pregnancy loss, preterm delivery, preeclampsia/eclampsia, and stroke.99
Prophylactic red blood cell transfusion based on transcranial Doppler velocity is
standard for stroke prevention in children with sickle cell disease and may have
some benefit for pregnant women but is not standard.100 Of note, neither sickle
cell disease nor pregnancy is a contraindication to IV thrombolysis, and it may
benefit appropriately selected patients presenting with acute ischemic stroke.101
It is not known whether patients with acquired or hereditary thrombophilias
should be treated with prophylactic anticoagulation during or after pregnancy to
prevent thromboembolic events. A recently published Cochrane systematic review
and meta-analysis of 29 trials found no evidence to support this practice but noted
the low quality of evidence and significant heterogeneity between trials.102
Fibromuscular Dysplasia
Fibromuscular dysplasia is a nonatherosclerotic fibrotic segmental disorder of
small to medium-sized arteries, typically involving the extracranial cervical
(carotid and vertebral) and renal arteries and affecting women more than men.
Fibromuscular dysplasia can result in stroke because of arterial stenosis,
occlusion, thrombus formation (particularly if fibrous webs are present),
aneurysm, or dissection.103 Data are limited on pregnancy outcomes in patients
with fibromuscular dysplasia. A registry-based review of 534 pregnancies in 237
patients with fibromuscular dysplasia found that 40% experienced pregnancy-
related complications, including gestational hypertension (25%), preterm birth
(20%), and preeclampsia (7.5%). Patients who experienced pregnancy
complications were younger at fibromuscular dysplasia diagnosis and had lower
prevalence of cerebrovascular fibromuscular dysplasia (30% versus 52%;
P=.003). Two patients had acute cerebrovascular events: one multifocal cervical
arterial dissection 19 days after delivery and one SAH due to intracranial
aneurysm rupture at 24 weeks gestation.104 One case of a woman with
fibromuscular dysplasia and prior carotid dissection with ischemic stroke who
had a spontaneous forceps-assisted vaginal delivery at 34 weeks’ gestation
without maternal or fetal complications has been reported.105 No evidence
suggests that cesarean delivery is safer than vaginal delivery in women with a
history of cervical artery dissection.106
PREVENTION, RECOGNITION, AND TREATMENT OF MATERNAL STROKE

Neurologists have an important role in prevention, early recognition, and prompt
treatment of maternal stroke to minimize maternal morbidity and mortality.
Primary Prevention of Maternal Stroke

Prevention of maternal stroke is critically important, particularly in the case of
ICH, in which treatment options are limited. Unfortunately, maternal stroke is
difficult to predict because of its rarity. However, some patients are at increased
risk and may benefit from targeted prevention strategies, which can be as
simple as a brief review of stroke signs and symptoms and a discussion of the
highest-risk time periods (CASE 5-3). Patients with known risk factors, such as
108 FEBRUARY 2022

frequent migraine headaches, hypertensive disorders, thrombophilias, or known KEY POINTS
cerebrovascular lesions, should be targeted for risk reduction that includes close
● Women with elevated risk
monitoring of blood pressure, particularly in the postpartum period. Patients for maternal stroke should
should also be counseled on red flag features of headache, such as sudden onset, be counseled on stroke
change in quality from usual headache, positionality, elevated blood pressure, or signs and symptoms and
presence of focal neurologic deficits. warned that the postpartum
period is the highest-risk
time point for stroke.
Secondary Stroke Prevention
Data are very limited regarding the risk of pregnancy-related stroke in women ● A history of stroke or
with a history of prior stroke, either during or outside of pregnancy. A 2019 cerebrovascular disease is
systematic review found that in 55 pregnancies in women with a prior history of not, in itself, an indication
for cesarean delivery.
pregnancy-related stroke, the risk of recurrent stroke was 2%.107 However, the Delivery planning should be
risk varies considerably depending on the mechanism of the initial stroke. A based on obstetric
study of 373 women with prior arterial ischemic stroke found 13 recurrent strokes considerations in most
over 5 years, two of which were pregnancy related.108 In the FUTURE (Follow- cases.
Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk
Factor Evaluation) study of stroke in young adults, women with prior stroke had
higher rates of adverse pregnancy outcomes but no recurrent strokes during
pregnancy.109 A systematic review found the risk of recurrent cerebral venous
thrombosis in future pregnancies to be 2.2% per pregnancy.110 In an
observational study of 53 women with history of cervical artery dissections
outside of pregnancy, 11 women had a total of 13 pregnancies after their first
dissection. None of the pregnancies were complicated by recurrent dissection,
and 6 of the 13 pregnancies resulted in a successful vaginal delivery.111
A 2020 study was the first to describe the risk of postpartum RCVS in women
with prior RCVS, whether pregnancy related or not. The authors described the
characteristics of 60 premenopausal women with a history of RCVS; pregnancy
was the initial trigger in 14 cases. Eleven of the 60 women went on to have a total
of 16 new pregnancies, of which five were electively terminated, in several cases
out of fear of recurrence of RCVS. One episode of recurrent RCVS occurred
among the remaining 11 deliveries (9%).112 The authors note that pregnancy
avoidance in women with a history of postpartum RCVS was likely a
confounding factor.
Current expert consensus guidelines from the Heart and Stroke Foundation of
Canada recommend giving appropriate secondary prevention based on stroke
mechanism, together with aggressive management of additional stroke risk
factors such as hypertensive disorders of pregnancy.65 The safety of stroke
preventive medications in pregnancy and lactation is detailed in TABLE 5-2.
Delivery Planning and the Multidisciplinary Care Model

An individualized approach is recommended when caring for pregnant patients
with high-risk cerebrovascular conditions (CASE 5-4). These patients need close
monitoring during pregnancy and postpartum and should be followed by a
multidisciplinary team of specialists whenever possible. Delivery planning
should take into account the pregnant patient’s risks and, in most cases, should
be based on obstetric considerations. A history of stroke or cerebrovascular
disease is not in itself an indication for cesarean delivery.65 In patients with recent
acute stroke with elevated intracranial pressure or high risk of hemorrhagic
conversion, cesarean delivery should be considered. The need for antithrombotic
agents following maternal stroke may affect decisions about timing and mode

CASE 5-4 A 36-year-old woman with a history of migraine, fibromuscular dysplasia,

and multiple cervical artery dissections, including one complicated by a
cerebellar stroke while on dual antiplatelet therapy, presented to her
neurologist for preconception counseling. She had been told in the past
by another physician that she should avoid pregnancy, but she very much
desired it. Her neurologist counseled her on the potential risks of the
pregnancy, including an increased risk for maternal complications such as
preeclampsia and stroke, and summarized the existing medical literature
for the patient so she could make an informed choice about whether to
pursue pregnancy.
The patient elected to proceed with pregnancy and was followed
closely throughout her pregnancy by a multidisciplinary team of
specialists, including vascular neurology, neurosurgery, hematology,
maternal-fetal medicine, and obstetric anesthesiology. After discussion
among all services, the decision was made to treat her with therapeutic
anticoagulation with enoxaparin during the pregnancy, with close
monitoring of her blood pressure. She strongly preferred to avoid
cesarean delivery, although concerns were raised regarding the possible
risk of recurrent dissection with Valsalva. After multidisciplinary
discussion of her birth plan, which included the patient and her partner in
the decision-making process, she elected to undergo induction of labor
at 39 weeks’ gestation with early epidural placement followed by
assisted second-stage (forceps) delivery to minimize Valsalva, with
planned conversion to cesarean delivery if second-stage labor became
prolonged. Anticoagulation was discontinued the week before delivery,
and she was switched to aspirin. She successfully delivered a healthy
infant vaginally with no intrapartum complications and was restarted on
anticoagulation. Her postpartum course was complicated by mild
hypertension and migraine headaches, for which she was treated with
antihypertensives and gabapentin, after discussion of potential
breastfeeding-related risks. She was continued on therapeutic
anticoagulation for 12 weeks after delivery and then switched back to
low-dose aspirin for secondary stroke prevention.
COMMENT This case illustrates a multidisciplinary approach to the care of a high-risk

patient with an extensive neurovascular history and little high-quality
evidence to guide the treatment plan. The approach begins with
preconception counseling and a frank discussion of risks, including areas of
uncertainty. An individualized and shared decision-making approach is
adopted throughout the course of the pregnancy, with every effort to
address the patient’s concerns and honor her wishes when possible, while
clearly delineating the potential risks. A multidisciplinary team with close
communication between team members and a well-defined birth plan
helps to minimize uncertainty and facilitate transitions of care.
110 FEBRUARY 2022

of delivery, and obstetric anesthesiology should be involved in delivery KEY POINTS
planning.
● Red flag headache
features in a pregnant or
Recognition of Stroke and the Role of the Neurologist postpartum woman, such as
Most fatal maternal strokes could be prevented by earlier recognition of warning lack of headache history,
signs, such as severe hypertension and headache,113 and more aggressive blood elevated blood pressure,
very severe pain, or focal
pressure management. Neurologists can play a key role in educating colleagues in
neurologic deficits, should
obstetrics, emergency medicine, and obstetric anesthesiology on features of prompt urgent neurologic
headache that warrant further evaluation, particularly in the postpartum period. evaluation.
Red flags such as lack of prior headache history, elevated blood pressure, prior
history of a secondary headache disorder, fever, very severe pain, or an abnormal ● When a pregnant woman
presents with acute
neurologic examination should prompt neurologic consultation as well as disabling neurologic
neuroimaging and laboratory evaluation.114 deficits, CT is usually the
fastest and most accessible
Treatment of Acute Ischemic Stroke in the Pregnant or Postpartum Patient imaging modality and thus is
preferred. CT angiography
As soon as acute focal neurologic deficits are identified in a pregnant or should be performed in
postpartum patient, stroke assessment should be performed rapidly in pregnant patients with
accordance with current guidelines.101,115 Brain imaging is critical to decision symptoms concerning for
making regarding acute stroke interventions. In most cases, CT is the fastest and large vessel occlusion.
most accessible imaging modality and thus is preferred when hyperacute treatment
● Current guidelines for
decisions are needed.115 The dose of ionizing radiation to the fetus from a acute ischemic stroke do not
noncontrast head CT is 0.001 mGy to 0.01 mGy, far below the 50 mGy threshold consider pregnancy to be a
above which adverse fetal effects become a concern.116 CT angiography should be contraindication to IV
thrombolysis if the deficits
obtained when large vessel occlusion or rupture of a vascular lesion is suspected,
are disabling and the
since these conditions are life-threatening, despite a theoretical risk of neonatal bleeding risks are
hypothyroidism (never demonstrated in human studies). Similarly, mechanical acceptable.
thrombectomy should not be withheld because of fears of contrast toxicity to the
fetus.115 If immediately available, MRI is reasonable but in most cases would result in
unacceptable treatment delays.115 Gadolinium contrast is not recommended in
pregnancy but is not needed for most acute stroke treatment decisions.115
Breastfeeding should not be interrupted and breast milk need not be discarded after
the administration of either iodinated or gadolinium contrast.117
IV thrombolysis and mechanical thrombectomy have been performed in
pregnant and postpartum patients successfully.22,118 Alteplase and tenecteplase
both have a molecular weight of approximately 59 kilodaltons (kDa) and do not
cross the placenta; however, an obstetrician should be involved in the decision
making to assess pregnancy-related bleeding risks. Current American Heart
Association/American Stroke Association guidelines do not consider pregnancy
to be a contraindication to thrombolysis, if the deficits are disabling and the
bleeding risks are acceptable.101 Fewer data support the use of thrombolytics in
the postpartum period, but it may be considered on a case-by-case basis.101
Whenever possible, a multidisciplinary team of specialists, including vascular
neurology, obstetrics or maternal-fetal medicine, obstetric anesthesiology, and
neonatology, is recommended when making hyperacute decisions regarding
stroke care in pregnant patients.115
Treatment of Acute Hemorrhagic Stroke in the Pregnant or Postpartum

Patient
Hemorrhagic stroke (SAH or ICH) must be ruled out immediately in any patient
presenting with acute neurologic deficits, thunderclap headache, or loss of

consciousness. Pregnancy is no exception to this rule. The treatment of SAH or

ICH during pregnancy requires close collaboration between neurologists,
neurocritical care specialists, neurosurgeons, interventional neuroradiologists,
obstetric anesthesiologists, and obstetricians. In some cases, concurrent cesarean
delivery and neurosurgical procedures may be required.115
In addition to control of the bleeding source through neurosurgical or
endovascular interventions, the treatment of hemorrhagic stroke typically
includes blood pressure management, reversal of coagulopathy, and avoidance of
complications such as vasospasm, intracranial hypertension, hydrocephalus, and
seizures. Pregnant or postpartum patients with acute hemorrhagic stroke should
be cared for in a neurocritical care unit whenever possible.119
SUBARACHNOID HEMORRHAGE. All patients with SAH must undergo emergent

cerebrovascular imaging to help determine the etiology. When a ruptured
aneurysm is identified, interventional treatment should not be delayed because
of pregnancy. Tranexamic acid may be safely used as an antifibrinolytic during
pregnancy and postpartum.120
First-line agents for blood pressure control in pregnancy are labetalol,
methyldopa, and long-acting nifedipine.115 If necessary, nimodipine and
nicardipine can also be used in pregnancy and during lactation.121-123 Lowering
of blood pressure to below a threshold of 140/90 mm Hg is reasonable in
pregnancy; fetal monitoring should be used to monitor for signs of placental
hypoperfusion.
INTRACEREBRAL HEMORRHAGE. As with SAH, standard blood pressure targets after

ICH apply during pregnancy and postpartum. Hypertensive ICH typically occurs
in the setting of preeclampsia, eclampsia, or HELLP syndrome, and emergent
delivery of the fetus may be needed. Magnesium is standard therapy for seizure
prevention in patients with preeclampsia, based on the results of the large
randomized Magpie (A Randomised Trial Comparing Magnesium Sulphate With
Placebo for Pre-eclampsia) trial.124 For patients with ICH related to rupture of
arteriovenous malformations or other vascular lesions, source control through
surgical or endovascular intervention should not be delayed because of
pregnancy status, but every effort should be made to minimize fetal risk.115
CONSIDERATIONS FOR MANAGEMENT OF INCREASED INTRACRANIAL PRESSURE.

Elevated ICP can occur in the setting of PRES, ICH, or SAH; cerebral venous
sinus thrombosis; or large hemispheric or cerebellar infarctions. First-line
treatment of acutely elevated ICP in pregnancy begins with elevation of the head
of the bed with placement of the head in a neutral (midline) position, keeping in
mind that left lateral displacement of the uterus is needed to avoid inferior vena
cava compression. Hemodynamic management should focus on optimizing
cerebral perfusion pressure and avoiding hypotension. Pain must be controlled,
and sedation or endotracheal intubation may be required. Hyperosmolar therapy
with low doses (0.25 g/kg to 0.5 g/kg) of mannitol is considered safe in
pregnancy; IV hypertonic saline can also be considered, although its safety in
pregnancy is not well established. Brief hyperventilation can also be used as a
temporizing measure in cases of imminent herniation, but stringent fetal
monitoring is recommended.125 This author recommends involvement of an
obstetric anesthesiologist in care of all critically ill pregnant patients, if possible.
112 FEBRUARY 2022

Stroke Recovery in the Pregnant or Postpartum Patient KEY POINTS
Pregnancy presents unique recovery challenges after a stroke. Poststroke
● Poststroke depression
recovery is often complicated by depression, which may be exacerbated by the may be exacerbated by the
pregnant or postpartum state, particularly if preeclampsia occurred.126 The pregnant or postpartum
author favors early involvement of psychiatry when patients exhibit signs of state, particularly if the
depression or anxiety. For pregnant patients recovering from stroke, maternal- pregnancy had an adverse
outcome, and early
fetal medicine should be consulted, and fetal monitoring may be needed while
involvement of psychiatry is
the patient is admitted to the stroke or neurocritical care unit. Patients with stroke recommended.
who are lactating may need special accommodations and additional assistance
from physical and occupational therapy or rehabilitation medicine for pumping ● Adverse pregnancy
breast milk and breastfeeding the infant. The author recommends consulting a outcomes, including
hypertensive disorders of
lactation specialist, and breastfeeding status should be considered in decisions pregnancy, preterm
regarding secondary prevention medications. For postpartum patients, efforts delivery, and fetal growth
should be made to facilitate visitation between mother and infant, when possible. restriction, are associated
with higher risk for future
cerebrovascular disease,
LONG-TERM CEREBROVASCULAR DISEASE AFTER ADVERSE including stroke and
PREGNANCY OUTCOMES vascular cognitive
Stroke is a leading cause of death and disability in women in the United States, impairment.
and stroke and its risk factors in younger and middle-aged women are on the
● Neurologists who treat
rise in the United States.127 Adverse pregnancy outcomes, including preterm
young women should screen
delivery, gestational hypertension, preeclampsia, and fetal growth restriction, are them for a history of
associated with increased risk of future stroke,128 and some evidence supports an pregnancy complications;
association between hypertensive disorders of pregnancy and future vascular for women who have
experienced pregnancy
cognitive impairment.129,130 The American Heart Association recommends close
complications, how to
follow-up and early risk factor modification for patients with a history of these reduce future stroke risk and
complications to prevent future cardiovascular disease, including stroke.131 Similar optimize brain health should
to the poststroke recovery period, the postpartum period offers a unique be discussed.
opportunity to intervene and change the trajectory of future cerebrovascular
disease in women who are at higher risk. As part of standard history taking,
neurologists should obtain an obstetric history with every consultation,
particularly consultations for headache, cerebrovascular disorders, or cognitive
symptoms (CASE 5-5). Neurologists who treat young women have an opportunity
to screen them for a history of pregnancy complications; for patients who have
experienced pregnancy complications, how to reduce future stroke risk and
optimize brain health should be discussed. Although this may seem more the
province of the primary care physician, many patients fear stroke and dementia
and may take recommendations more seriously when coming from a
brain specialist.
CONCLUSION
Stroke is a devastating complication of pregnancy and a leading cause of
maternal morbidity and mortality. Many catastrophic strokes could be avoided
with targeted prevention efforts, early recognition of warning signs, and rapid
evaluation of neurologic symptoms. Neurologists play a central role in the care of
pregnant patients with cerebrovascular disease, whether acute or chronic, and
should be familiar with the unique and complex physiology of pregnancy and its
complications, particularly hypertensive disorders of pregnancy. In addition,
adverse pregnancy outcomes are associated with long-term risk for
cerebrovascular disease, making the obstetric history highly relevant in the

evaluation for patients with stroke, transient ischemic attack, or vascular

cognitive impairment. Future research should explore whether primary
prevention of stroke with aspirin or other medications is warranted in patients
with a history of adverse pregnancy outcomes. In the meantime, the author
advocates for close collaboration between neurologists and obstetricians in the
care of pregnant patients at high risk for stroke.
ACKNOWLEDGMENT
This article was supported by a grant from the National Institutes of Health/
National Institute of Neurological Disorders and Stroke (K23NS107645).
CASE 5-5 A 49-year-old woman presented to a neurologist for evaluation of

cognitive symptoms. She had a history of three pregnancies, all more
than 20 years earlier; the first two were complicated by gestational
hypertension and the third by preeclampsia with preterm delivery. She
had reported low back pain for years, chronic daily headaches, and
“brain fog” impairing her ability to work at her job as a school
administrator. She also reported a “bad leg” for the past few years but
had not thought much of it and assumed it was due to her back problems.
She saw her gynecologist occasionally for a pelvic examination but had
no other primary care provider.
Her blood pressure was 154/95 mm Hg. Her mental status examination
was notable for poor three-word recall but no other deficits. Motor
examination showed slight increased tone and brisker reflexes in the left
leg and mild left hemiparesis with right arm orbiting the left. MRI revealed
multiple chronic lacunar infarcts and diffuse patchy white matter
hyperintensities consistent with cerebral small vessel disease (FIGURE 5-3).
She was started on aspirin, antihypertensives, and a high-intensity statin
for secondary stroke prevention and underwent a comprehensive
cardiovascular evaluation, which revealed severe obstructive sleep
apnea with nocturnal hypertension, elevated cholesterol, and left
ventricular hypertrophy on echocardiography. Her headaches, cognitive
symptoms, and hypertension all improved significantly after treatment of
her sleep apnea with continuous positive airway pressure (CPAP).
114 FEBRUARY 2022

VIDEO LEGEND
VIDEO 5-1
Gestational hypertension with spontaneous
postpartum cervical artery dissection. Video
shows CT angiogram of a woman who presented on
postpartum day 8 with severe headache, neck pain,
and elevated blood pressure of 145/90 mm Hg. Her
pregnancy had been complicated by gestational
hypertension. She had no neurologic deficits and no
history of recent neck trauma. She was found to
have extensive right vertebral artery dissection in
the V2-V3 segment. She was treated with warfarin
and followed with serial imaging until the dissection
healed. No underlying connective tissue disorder
was identified after extensive evaluation, including
genetic testing.
FIGURE 5-3
Imaging of the patient in CASE 5-5. Axial
fluid-attenuated inversion recovery
(FLAIR) MRI shows patchy white matter
hyperintensities and subcortical
lacunar infarcts consistent with
cerebral small vessel disease.
This case illustrates the importance of close follow-up, primary prevention, COMMENT
and aggressive cardiovascular risk reduction in patients with a history of
adverse pregnancy outcomes. This patient’s appointment with a neurologist
for vague cognitive symptoms was her first comprehensive medical
encounter in many years. She was found to have multiple uncontrolled
vascular risk factors, including undetected and untreated hypertension, and
undiagnosed obstructive sleep apnea which was affecting her blood
pressure, headaches, and cognition. Her brain imaging revealed evidence of
cerebral small vessel disease, including lacunar infarcts, at least one of
which was symptomatic. This patient’s neurologist played a critical role in
recognizing and intervening on the patient’s cerebrovascular disease and
improving her long-term heart and brain health.

USEFUL WEBSITES
NATIONAL LIBRARY OF MEDICINE DRUGS AND LACTATION CANADIAN STROKE BEST PRACTICE RECOMMENDATIONS,
DATABASE (LACTMED) PART TWO: ACUTE STROKE MANAGEMENT DURING
This database contains information on drugs and PREGNANCY
other chemicals to which breastfeeding mothers This website is a part two of a consensus statement
may be exposed and includes the possible adverse on best practices published by the Heart and Stroke
effects in the nursing infant. Foundation of Canada.
ncbi.nlm.nih.gov/books/NBK501922 heartandstroke.ca/-/media/1-stroke-best-
practices/csbpr-2018-acute-sip-module-final-
CANADIAN STROKE BEST PRACTICE RECOMMENDATIONS, 10jul18-en-(1).ashx?rev=
PART ONE: PREVENTION OF RECURRENT STROKE IN 7eaf0c2fa9e744ca9905644b3dd24f62
PREGNANT WOMEN AND WOMEN PLANNING A PREGNANCY
This website is a part one of a consensus statement
on best practices published by the Heart and Stroke
Foundation of Canada.
heartandstroke.ca/-/media/1-stroke-best-
practices/csbpr6-2017-sip-prevention-module-
final-english-24nov2017.ashx?rev=
0f007df497ae4ee0853d8d55d91c511d
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risk during pregnancy and the early postnatal doi:10.1097/01.AOG.0000151116.84113.56
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6736(02)08778-0

REVIEW ARTICLE

Managing Central
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Nervous System Tumors
During Pregnancy
By Na Tosha N. Gatson, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article discusses current recommendations and
special considerations for the management of central nervous system
(CNS) tumors in pregnant women and provides case vignettes to emphasize
important clinical concepts.
RECENT FINDINGS:Given that nearly 60% of all intracranial and spinal cord
tumors, including both primary and metastatic tumor types, malignant or
benign, are diagnosed in women, it is equitable to bring attention to the
unique management considerations that pertain to women during specific
phases of their lifespan, such as pregnancy. The pregnancy phase is
marked by changes in hormonal, immunologic, and other physiologic
responses. Although substantial evidence supports a pregnancy influence
on tumor oncogenicity, the cumulative effect of the pregnancy state on
brain tumor biology remains elusive. Furthermore, as innovative cancer
treatments and surveillance technologies expand, providers must consider
potential new risks to safe pregnancy maintenance. This article reviews
pregnancy considerations in CNS tumor care and offers best practice
approaches and considerations.
CITE AS:
2022;28(1, NEUROLOGY OF SUMMARY: Informed neuro-oncology practices on safer surgical, radiation,
P R E G N A N C Y ): 1 2 2 – 1 4 6 . medical, device, and imaging techniques is of critical importance to
pregnancy and fertility maintenance in cancer survivors. Expanding this
Dr Na Tosha N. Gatson, Banner
knowledge relies on advocacy and a commitment to develop equitable and
MD Anderson Cancer Center, multidisciplinary research within the field. This also requires a focus on
Neuro-Oncology Division, 925 E patient-reported outcomes and patient-centered conversations to best
McDowell Rd, Phoenix, AZ
85006, natosha.gatson@ care for pregnant women with CNS tumors.
bannerhealth.com.
Dr Gatson has served as an INTRODUCTION
T
advisory board consultant for
his article presents key considerations and recommendations to
Novocure GmbH.
support effective management of central nervous system (CNS)
UNLABELED USE OF tumors in pregnant women and offers complementary case-based
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
vignettes to emphasize important concepts. Nearly 60% of all
Dr Gatson reports no disclosure. intracranial and spinal cord tumors, including both primary and
metastatic tumor types, malignant or benign, are diagnosed in women.1 A
© 2022 American Academy considerable proportion of these tumors are diagnosed during the female
of Neurology. reproductive years (approximately ages 15 to 44).1 The pregnancy and
122 FEBRUARY 2022

postpartum periods are characterized by significant physical, biochemical, KEY POINTS
hormonal, physiologic, immunologic, and psychological changes that can
● Nearly 60% of all
influence tumor behavior and treatment decision making.2-4 The diagnosis of intracranial and spinal cord
cancer during pregnancy is uncommon; however, when the two coexist, routine tumors, including both
approaches to cancer diagnosis and treatment could jeopardize fetal or maternal primary and metastatic
outcomes.4 For the purposes of this article, the term fetus will refer to the tumor types, malignant or
benign, are diagnosed in
conceptus at any time during pregnancy from embryo (typically before 13 weeks
women.
gestation) to fetus (typically beyond 13 weeks gestation).
Brain cancer is among the rarest malignancies found during pregnancy, with a ● Brain cancer is among the
reported incidence comparable to the incidence in nonpregnant age-matched rarest malignancies found
females.2,3 However, these data are referenced from population-based studies during pregnancy, with a
reported incidence
from 40 years ago, bringing into question the statistical relevance to present-day comparable to the incidence
knowledge. Irrespective of current rates, compelling data support comorbid in nonpregnant age-
pregnancy influences on brain tumor pathophysiology.4 The goal of this article is matched females.
fourfold: (1) to provide a brief description of common CNS tumors reported
● Meningiomas account for
during pregnancy, (2) to outline some of the proposed pregnancy-related almost 55% of all
influences on tumor biology, (3) to list important recommendations and nonmalignant primary brain
considerations for managing CNS tumors during pregnancy, and (4) to increase tumors and make up about
awareness around the need for more women’s research in neuro-oncology to best 38% of all central nervous
system tumors.
support clinical decision making.
MOST REPORTED CENTRAL NERVOUS SYSTEM TUMORS

DURING PREGNANCY
Several CNS tumor types are more commonly reported during pregnancy:
meningioma, astrocytoma, schwannoma, pituitary adenoma, and breast
cancer metastasis.4,5 Below is a brief description of each tumor, followed by
epidemiology, common presenting symptoms, initial diagnostic testing,
and common treatment approaches. It is important to note that the various
diagnostic and treatment modalities can potentially impact pregnancy
outcomes.
Meningioma
Meningiomas arise from arachnoid cap cells within the meningeal tissue layers
covering the brain and spinal cord. Meningiomas account for almost 55% of all
nonmalignant primary brain tumors and make up about 38% of all CNS tumors.1
These extraaxial tumors have a female predominance and typically express
progesterone receptors. Meningiomas have been shown to become more
aggressive in response to exogenous sex hormones and during pregnancy and
menstrual cycles (CASE 6-1).1,6
According to the 2021 World Health Organization (WHO) Classification of
CNS tumors, meningiomas can be graded as benign (WHO grade 1), atypical
(WHO grade 2), or malignant (WHO grade 3).7 Meningiomas are typically slow
growing and are commonly found incidentally; however, they can present with
headaches and other symptoms that warrant brain imaging.8 Treatment of
meningiomas is guided by symptomatology, tumor location, grade, extent of
resection, and recurrence status. Treatment typically includes observation,
neurosurgery, and/or radiation therapy.8 More recently, chemotherapeutic and
targeted agents have been used to treat recurrent or high-grade meningiomas.9
Other reports have demonstrated a tumor response to hormone-blocking
therapies.10

MANAGING CNS TUMORS DURING PREGNANCY
CASE 6-1 A 50-year-old woman, gravida 3, para 3, presented for multidisciplinary

neuro-oncology follow-up for her history of a recurrent right petroclival
World Health Organization (WHO) grade 1 meningioma. At age 34, she
experienced postpartum headaches, and a brain MRI revealed a right
17.6 mm × 11.3 mm mass (FIGURE 6-1A), which was initially observed until
further progression at age 36. At progression, the mass was
25.8 mm × 22.3 mm (FIGURE 6-1B), and she underwent surgical resection of a
benign meningioma WHO grade 1 with minimal residual (FIGURE 6-1C).
The patient moved away, and for the next 10 years she was treated with
surgery and stereotactic radiosurgery at an outside facility for two
additional recurrences. After 10 years, she returned to the original facility
with deficits of right cranial nerves V, VII, VIII, and XII. A brain MRI
confirmed further progression (FIGURE 6-1D), and she underwent a fourth
surgical resection (FIGURE 6-1E) followed by 6 weeks of involved-field
radiation therapy. The patient was followed, with recurrence
(44.0 mm × 28.8 mm) and some component of radiation necrosis noted
2 years later (FIGURE 6-1F), so she was referred to neuro-oncology. In
consultation with her gynecologist, the patient was taken off hormone
replacement therapy and started on systemic therapy based on results of
a molecular analysis. The patient was followed every 12 months with MRI
with and without contrast. Three years later, the primary tumor was
smaller at 43.2 mm × 26.3 mm (FIGURE 6-1G), and 1 year after that, the tumor
measured 41.9 mm × 26.2 mm (FIGURE 6-1H). The patient remained clinically
and radiographically stable.
She had been on oral contraceptive pills from age 22 to age 26, then
had three normal vaginal deliveries before going back on oral
contraceptive pills at age 35. After 10 more years on the oral
contraceptive, she had an abdominal hysterectomy and was started on
hormone replacement therapy, which she was still on at the time of her
current visit to neuro-oncology clinic.
COMMENT This case emphasizes the potential tumor oncogenic impacts of pregnancy
and exogenous sex-hormone exposure.
124 FEBRUARY 2022

FIGURE 6-1
Imaging of the patient in CASE 6-1. A, Coronal and axial postcontrast T1-weighted images show a right inferior temporal lobe
mass adjacent to the midbrain and brainstem (arrows). B, Coronal and axial postcontrast T1-weighted follow-up images
2 years later show tumor progression (arrows). C, Coronal postcontrast T1-weighted postoperative image shows minimal
residual tumor after resection (arrow). D, Coronal and axial postcontrast T1-weighted images 10 years later confirm further
tumor progression (arrows). E, Coronal and axial postcontrast T1-weighted postoperative images show results of resection
(arrows). F, Coronal and axial postcontrast T1-weighted images 2 years later show tumor recurrence and radiation necrosis
(arrows). Coronal and axial postcontrast T1-weighted follow-up images 3 years (G) and 4 years (H) after systemic
therapy show reduction in tumor size (G, H, arrows).
Images courtesy of Michel Lacroix, MD; Gino Mongelluzzo, MD; and Syed A. J. Kazmi, MD.

Glioma (Astrocytoma Type)

Astrocytomas are the most common adult glial tumor and arise from astrocytes,
the gluelike supportive cells of the CNS.1,7 Astrocytomas can range from low-
grade (WHO grades 1 and 2) to high-grade (WHO grades 3 and 4).7 The WHO
classification and grading of astrocytic tumors evaluates microscopic, histologic,
molecular, and morphologic features, which guide prognostication and clinical
decision making.1,7,8 In adults, glioblastoma (WHO grade 4) is the deadliest and
most common primary brain malignancy (49%), comprising 14.5% of all primary
brain tumors.1 Pregnancy influences on low-grade astrocytic tumor oncogenicity
remain controversial11; however, convincing evidence exists to support this
relationship in high-grade astrocytoma.12-17 Several case series have reported
either an increased rate of diagnosis or worsening of astrocytomas during late
pregnancy.12-17 CASE 6-2 illustrates clinical concepts in late pregnancy and
postpartum immunologic and physiologic changes and how each may influence
tumor outcomes.
Whereas infiltrative gliomas can be asymptomatic or present with seizures,
higher-grade gliomas more commonly present with progressive symptoms of
increased intracranial pressure.16,17 These symptoms are most common in
glioblastomas and should prompt brain imaging. In adults, standard treatment
for glioblastoma has been maximal safe surgical resection followed by radiation
and temozolomide chemotherapy.18 This recommendation has been revised to
include the adjuvant use of tumor treating fields (a wearable device discussed
later in this article) as part of a Category 1 recommendation by the National
Comprehensive Cancer Network.19 This recommendation is based on the EF-14
(Effect of NovoTTF- 100A Together With Temozolomide in Newly Diagnosed
Glioblastoma Multiforme) phase 3 trial, which demonstrated a significant
improvement in 5-year survival.19
Schwannoma
Schwannomas are peripheral nerve sheath tumors that arise from Schwann cells.7
They are typically benign slow-growing tumors that are commonly diagnosed
between the second and fifth decades of life1 and have been associated with more
aggressive tumor behavior in response to sex hormones (progesterone and
estrogen) and during pregnancy.20 Overall, schwannomas do not have a known
sex predilection1,21; however, vestibular schwannomas are more common in
women.21 A pregnancy influence on vestibular schwannoma was first reported in
1917,21 and contemporary studies continue to support vestibular schwannoma
susceptibility to progression or initial diagnosis during pregnancy.22,23 CASE 6-3
illustrates the need for surveillance planning for schwannomas during pregnancy
and potential pregnancy and hormonal influences on tumor oncogenicity.
Schwannoma symptoms are location dependent.21 For example, vestibular
schwannomas arise from the vestibular portion of cranial nerve VIII and are
often associated with hearing loss, tinnitus, and vertiginous symptoms.21,23 In
these cases, audiology and brain imaging assessments are diagnostic. Treatment
of schwannomas varies based on the goal to preserve the patient’s functional
hearing weighed against the rate of tumor growth.24 Observation and audiology
monitoring could be elected for small stable tumors in patients with functional
hearing, whereas radiation or surgical resection are options for aggressive tumors
or for patients with significant functional hearing loss.24 Chemotherapy and
targeted/biologic therapies are not commonly used up front; however, studies
126 FEBRUARY 2022

support their use in malignant transformation or refractory tumors and in KEY POINTS
patients with genetic predisposition for tumors expressing targetable markers.25,26
● In adults, glioblastoma
(World Health Organization
Pituitary Adenoma grade 4) is the deadliest and
Several types of pituitary tumors exist. These tumors arise from the pituitary most common primary brain
gland and range in aggressiveness from benign to invasive to carcinomatous.27 malignancy (49%),
comprising 14.5% of all
The adenoma type is the most reported pituitary tumor concurrent with
primary brain tumors.
pregnancy and is characterized by size as either microadenoma (<1 cm) or
macroadenoma (≥1 cm). Adenomas are further subclassified as hormone ● Overall, schwannomas do
secreting or nonsecreting.27 Females often harbor prolactin-secreting, not have a known sex
adrenocorticotropic hormone (ACTH)–secreting, or thyrotrophin-secreting predilection; however,
vestibular schwannomas are
adenomas, whereas males more often present with growth hormone–secreting or more common in women.
endocrine-inactive adenomas.27 Prolactinomas are the most common hormone-
secreting pituitary tumor and are 4.5 times more likely to occur in women,28,29 ● Prolactinomas are the
raising concern for more optimized surveillance in lactating women. Diagnosis most common hormone-
secreting pituitary tumor
involves dedicated head imaging and serum endocrine studies.27-29 These tumors and are 4.5 times more likely
can be associated with headache, galactorrhea, infertility, vision changes, or to occur in women.
abnormal hormone production based on size, growth pattern, and secreting
status. Pituitary apoplexy is a rare emergency that involves sudden hemorrhage ● Breast cancer brain
metastases have increased
or infarct of the pituitary gland and risks the life of the mother and fetus.27,28
in incidence secondary to
Clinical symptoms of pituitary apoplexy involve rapid onset of headache, vision improved diagnostic and
loss, altered mentation, nausea, and vomiting.27,28 surveillance technologies as
Treatment of pituitary tumors generally involves any combination of well as to innovative cancer
supportive care and observation, drug therapy (eg, dopamine agonists, therapies that extend
patient survival.
corticosteroids), surgical intervention, and radiation.27-29 Growing data support
the use of alkylating chemotherapeutics for refractory or carcinomatous pituitary
tumors.30 The treatment of prolactin-secreting tumors, specifically, is a bit more
complex and important to consider during pregnancy. Prolactinoma treatment
standards involve the use of dopamine agonists (mimicking the effects of
dopamine) with the goal to normalize prolactin levels and reduce the tumor
size.29 Importantly, abnormal prolactin levels may halt ovulation and therefore
limit fertility.29 During normal pregnancy, the pituitary gland enlarges because
of estrogen overproduction and risks expanding the tumor and worsening
clinical symptoms because of compression of adjacent structures.28,29 The risk
of tumor enlargement is 3% in microprolactinomas and as high as 32% in
untreated macroprolactinomas.29 Bromocriptine is a commonly used dopamine
agonist with some evidence for use during early pregnancy without an increased
risk for spontaneous abortion over that of the general population (9.9%).29
However, not enough safety data are available to support the use of dopamine
agonists during pregnancy. Current clinical practice guidelines from the
Endocrine Society recommend discontinuation of dopamine agonists upon
confirmation of pregnancy, except for women with invasive
macroprolactinomas, for whom therapy should be continued.29 Refractory
macroprolactinomas in pregnant women may require transsphenoidal surgery,
preferably in the second trimester, or consideration for preterm delivery of
viable fetuses before surgery.29
Metastatic Breast Cancer

Breast cancer brain metastases have increased in incidence secondary to
improved diagnostic and surveillance technologies as well as to innovative cancer

CASE 6-2 A 34-year-old woman, gravida 2, para 1, at 31 weeks’ gestation presented

to the emergency department with headache, nausea, altered mentation,
and seizurelike activity. A noncontrast brain MRI demonstrated a
bifrontal mass crossing the corpus callosum, with restricted diffusion,
intrinsic T1 hyperintensity (suggestive of blood), and prominent T2
prolongation concerning for a high-grade glioma (butterfly glioblastoma)
rather than a lymphoproliferative process (FIGURE 6-2A). Neurosurgery
obtained consent from her spouse for a brain MRI with contrast,
recognizing the unknown risks to the fetus but a clear benefit for
emergent preoperative tumor localization. The MRI showed bifrontal
heterogeneous enhancement of the ependymal lining of the ventricles
and crossing the corpus callosum (FIGURE 6-2B).
After a multidisciplinary discussion that included an ethicist and
maternal-fetal medicine, her spouse consented to surgical intervention.
The fetus demonstrated healthy vital signs and imaging, and it was
determined that a delay of cesarean delivery might be maternally fatal.
The patient was started on steroids and antiseizure medication
perioperatively. With no option for a gross total resection, the primary
surgical goal was for tissue diagnosis and to limit anesthesia time. The
surgeon elected for stereotactic biopsy followed by image-guided
bifrontal laser interstitial thermal therapy with cavity suction. The
postoperative brain MRI for planning radiation therapy is shown
(FIGURE 6-2C).
Pathology confirmed a World Health Organization (WHO) grade 4
glioblastoma, with tumor markers supporting the use of standard
chemotherapy. After consenting, the patient underwent 6 weeks of
standard-dose radiation therapy with abdominal shielding (no concurrent
chemotherapy was used because of pregnancy and poor functional
status). Radiation was completed around 38 weeks’ gestation, and the
patient delivered a healthy infant via term cesarean delivery. MRI
obtained 4 weeks post–radiation therapy (2 weeks postpartum and
12 weeks after laser interstitial thermal therapy) showed areas of
enhancement likely reflecting treatment-related changes
(FIGURE 6-2D). Sequential adjuvant chemotherapy was initiated. The patient
improved clinically, with mild behavioral impulsiveness and expressive
aphasia, and was ambulating independently.
Approximately 3 months postpartum, the patient experienced
progressive clinical decline, with breakthrough seizures, headaches,
somnolence, and mutism. A brain MRI with perfusion demonstrated
stable to improved areas of enhancement, minimal restricted diffusion,
and no increased relative cerebral blood volume (more suggestive of
radiation necrosis and less likely of tumor progression). However, a large
volume of vasogenic edema (hyperintense areas on fluid-attenuated
inversion recovery [FLAIR] images) was seen that was refractory to
multiple anti-inflammatory agents (FIGURE 6-2E). The patient’s spouse
elected comfort measures, and the patient died 13 weeks after delivery,
presumed secondary to postpartum proinflammatory central nervous
system immune flare-up.
128 FEBRUARY 2022

FIGURE 6-2
Imaging of the patient in CASE 6-2. A, Preoperative axial noncontrast T1-weighted, diffusion-
weighted (DWI), and fluid-attenuated inversion recovery (FLAIR) images show superior (higher
up) brain images of a bifrontal mass (arrows). B, Axial and coronal postcontrast T1-weighted
images show more inferior slices of the same bifrontal tumor with heterogeneous enhancement
involving the ependymal lining of the ventricles and crossing the corpus callosum (arrows). C,
Laser interstitial thermal therapy postoperative postcontrast T1-weighted axial and sagittal
images and axial diffusion-weighted and FLAIR images show areas of enhancement likely
reflecting treatment related changes (arrows) (cannot rule out residual tumor, however). D,
Post–radiation therapy axial and sagittal postcontrast T1-weighted and axial diffusion-weighted
and FLAIR images showing areas of increased cellular density and edema (arrows), respectively.
E, Axial postcontrast T1-weighted, diffusion-weighted, FLAIR, and perfusion images show
minimal restricted diffusion (arrows) and no increased relative cerebral blood volume (arrows)
on follow-up imaging, but with a large volume of vasogenic edema noted on FLAIR.
Images courtesy of Michel Lacroix, MD; Gino Mongelluzzo, MD; and Syed A. J. Kazmi, MD. CONTINUED ON
PAGE 130

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COMMENT This case emphasizes the pregnancy and immediate postpartum systemic
immunologic profile changes that influence the tumor microenvironment,
leading to inflammatory responses and vasogenic edema.
therapies that extend patient survival.31,32 A comprehensive review of 106 studies

on breast cancer brain metastases included 14,599 women over a 35-year
follow-up period.31 The review reported a breast cancer brain metastasis
incidence rate of 24%, and among these, a multifocal brain metastasis rate of
54%.31 Another large systematic review of 96 studies across 28 countries listed
risk factors for breast cancer brain metastases (TABLE 6-1) as well as time to
brain metastases.31,32
Depending on the metastatic volume (number and size of lesions) and their
anatomic location, breast cancer brain metastases can present with a host of
symptoms, including seizures, headaches, and cognitive changes.32 Treating
oncologists typically have a low threshold to order brain tumor imaging in
patients who are symptomatic. Breast cancer is the most reported cancer
concurrent with pregnancy,2-4 and pregnant patients with an established breast
cancer history who are symptomatic should be carefully assessed for cancer
progression. CASE 6-4 illustrates the need for appropriate surveillance and
multidisciplinary care for pregnant patients with cancer.
Treatment of breast cancer brain metastases is multimodal and may
potentially require neurosurgical resection for symptomatic lesions or for
tissue confirmation and molecular recharacterization.32,33 After surgical
considerations, brain radiation and systemic therapy (preferably therapy that
crosses the blood-brain barrier and blood-CSF barrier) are commonly used.32,33
Patients with rare leptomeningeal metastasis of breast cancer may also require
intrathecal chemotherapy for additional control.31,32 Of note, no studies
have examined the potential risks of intrathecal chemotherapy during
pregnancy; however, this therapeutic approach has limited leakage of the
delivered agents into the periphery and therefore potentially carries reduced
risks to the fetus.
PROPOSED PREGNANCY INFLUENCES ON INTRACRANIAL TUMORS

Pregnancy is characterized by the production and regulation of various
hormones and serum immune and growth factors as well as by vascular,
hemodynamic, and structural body changes.4,16 Multiple patient case series
have reported that although pregnancy does not confer a higher risk for
incidence of brain tumors, pregnancy is associated with worsening aggressive
tumor behavior.4,12-17 Clarifying the impact of the full pregnancy state on brain
tumor oncogenicity remains a challenge. The most commonly proposed
pregnancy-related causes for brain tumor exacerbation are (1) hormones and
growth factors, (2) immune tolerance and exhaustion, and (3) vascular and
hemodynamic changes.
130 FEBRUARY 2022

Hormones and Growth Factors KEY POINTS
Commonly proposed pregnancy-associated hormones and growth factors that
● Breast cancer is the most
influence aggressive brain tumor behavior include vascular endothelial growth reported cancer concurrent
factor (VEGF), placental growth hormone, brain-derived neurotrophic factor with pregnancy.
(BDNF), the luteal phase hormones (luteinizing hormone [LH] and follicle-
stimulating hormone [FSH]), and sex-specific hormones (progesterone ● Multiple patient case
series have reported that
and estrogen).14,34-38
although pregnancy does
VEGF is an angiogenic growth factor essential in the vascularization of the not confer a higher risk for
corpus luteum (a temporary endocrine structure housed in the ovary that incidence of brain tumor,
supports ovulation and the production of progesterone during early pregnancy is associated with
pregnancy).14,34,37 VEGF is also highly expressed by specific brain tumors and worsening aggressive tumor
behavior.
regulates neoangiogenesis and vascular permeability; it is often targeted to limit
brain tumor growth and complications such as vasogenic edema.26,39 ● Vascular endothelial
Placental growth hormone is a placental-derived growth hormone variant growth factor is highly
expressed into the maternal circulation that acts in concert with insulinlike expressed by specific brain
tumors and regulates
growth factor 1 to increase nutrient flow to the placenta.14,40 An abnormal neoangiogenesis and
placental growth hormone level is an important biomarker of pregnancy vascular permeability; it is
pathology.40 Potential exists for cross-reactivity of these hormones with multiple often targeted to limit brain
growth hormone variants expressed intracranially.41,42 tumor growth and
complications such as
BDNF increases cellular proliferation and accelerates the rate of the cell cycle.
vasogenic edema.
This factor is overexpressed during pregnancy and potentially contributes to
progressive pituitary tumors based on preclinical research models.27,42 ● Follicle-stimulating
Fluctuations in hormone expression patterns over the course of the menstrual hormone and luteinizing
cycle are well known. Hormones such as the luteal phase hormones (FSH and hormone are tumor
inhibitory hormones,
LH) and estrogen undergo a brief preovulatory surge but rapidly wane after whereas progesterone has
ovulation.41 Conversely, an increase in progesterone levels is seen in the been implicated in
postovulatory phase.6,41 Interestingly, FSH and LH are tumor-inhibitory worsening oncogenicity of
hormones,6,38,41 whereas progesterone has been implicated in worsening several cancer types based
on its role in regulating cell
oncogenicity of several cancer types based on its role in regulating cell apoptosis, apoptosis, proliferation, and
proliferation, and tumor metastasis.6,38 The second and third pregnancy tumor metastasis.
trimesters have negligible levels of LH and FSH, whereas progesterone
expression is 5 to 10 times higher in the second and third trimesters than in the ● The human immune
response is more
first trimester.38,41 Taken together, tumor hormone and growth factor
specialized in four vital
responsiveness may partially explain the risk for more aggressive tumor compartments within the
behaviors during pregnancy.6,38,41,42 human body: the eyeball,
the testis, the brain, and the
gravid uterus.
Immune Exhaustion, Tolerance, and Neoantigens
The major role of the human immune response is to distinguish “self” from ● Tolerance of neoantigens
“nonself” antigens to protect the host from foreign pathogenic invaders. Although is a hallmark characteristic
this is generally true, the immune response is more specialized in four vital of immune-specialized
compartments within the human body: the eyeball, the testis, the brain, and the compartments.
gravid uterus.43-46 These compartments uniquely produce immunoregulatory
factors that act on local and distant tissues to dampen destructive inflammatory
responses and provide a more tolerogenic microenvironment.45
Tolerance of neoantigens is a hallmark characteristic of immune-specialized
compartments and is essential for placentation and fetal development during
pregnancy.47 The immunologic relationship between the pregnant host (mother)
and the fetal allograft (unborn child) is critical for pregnancy maintenance as
well as for maternal, fetal, and future pregnancy outcomes.45-48 Fetal-derived
neoantigens are present at the maternal-fetal interface and can be identified in

CASE 6-3 A 29-year-old woman, gravida 1, para 1, had a 2-year prior history of
benign left vestibular schwannoma (FIGURE 6-3A) with near gross total
resection (FIGURE 6-3B) and classic benign tumor pathology (FIGURE 6-3C).
Clinically, she had stable left-sided hearing loss, facial droop, and mild
swallowing difficulty unchanged from the time of surgery. After 2 years of
stability, the patient decided to conceive. She had an uneventful
pregnancy, during which she was seen once in the neuro-oncology clinic
without brain tumor imaging. After vaginal delivery of a healthy infant, she
elected to start oral contraceptive pills for pregnancy prevention.
At 6 months postpartum, she presented to the emergency department
with worsening neurologic deficits and suspected aspiration pneumonia.
A postcontrast brain MRI revealed local recurrence (FIGURE 6-4A), and the
patient underwent repeat surgical resection (FIGURE 6-4B). Surprisingly, the
pathology revealed a malignant peripheral nerve sheath tumor with rare
divergent glandular (epithelial) differentiation and histone mutation
H3K27me3 loss (FIGURE 6-4C), an exceedingly rare and aggressive
morphologic occurrence. The patient underwent stereotactic radiation
therapy to the cavity and was preparing to start systemic chemotherapy
when she again presented to the emergency department with aspiration
pneumonia, weakness and numbness in both arms (worse on the right),
double vision, and severe fatigue. Postcontrast MRI of the entire neuraxis
was significant for a third local recurrence, with new nodular cervical
spine involvement and diffuse epidural enhancement
(FIGURE 6-4D). A lumbar puncture confirmed CSF dissemination of her
malignancy. Because of the patient’s poor performance status, she was
unable to tolerate further therapies aimed to control this rapidly
progressive tumor, and she died during this final hospitalization.
132 FEBRUARY 2022

FIGURE 6-3
Imaging of the patient in CASE 6-3. Coronal and axial images show a left vestibular
schwannoma before (A, arrows) and after (B) near gross total resection. C, Histopathology
shows classic benign tumor pathology. Sections demonstrate spindle cell tumor composed
of cellular (Antoni A) and myxoid (Antoni B) areas. Mitoses are difficult to see. There are
foci of cellular clusters composed of epithelioid and chondromyxoid cells with vacuolated
cytoplasm and irregular hyperchromatic nuclei. Well-formed Verocay bodies are not seen.
Hyalinized vessels are seen. Immunostains show neoplastic cells diffusely positive for S100
and focally high MIB-1 labeling index (approximately 20%). Immunostains for keratin AE1/AE3
and epithelial membrane antigen (EMA) are positive in a small cluster of epithelioid
cells (not shown).
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134 FEBRUARY 2022

FIGURE 6-4
Imaging of the patient in CASE 6-3. Coronal postcontrast T1-weighted image shows local
recurrence of the tumor (A, arrow), which was again resected (B). C, Tissue specimens show a
malignant peripheral nerve sheath tumor with rare divergent glandular (epithelial)
differentiation and histone mutation H3K27me3 loss. Sections show a hypercellular tumor
composed mostly of small round cells and a minor spindle cell component. Mitoses are easy
to see. There is geographic necrosis as well as Homer-Wright rosettes and epithelioid
tubulelike structures. Immunostains show round cell component is diffusely positive for
synaptophysin, CD99 and tubulelike epithelial component is positive for keratin (AE1/AE3).
Both tumor components show loss of H3K27M expression and intact expression of ATRX and
INI-1 (not shown). Immunostaining was negative for S100, as well as for mIDH [R132H], p53,
GFAP, and Olig-2 (not shown). Immunostain for FLI-1 show focal nonspecific staining. The
MIB-1 labeling is very high (70% to 80%). Coronal (D, left panel) and axial (D, middle panel)
postcontrast T1-weighted brain images show a third local recurrence (arrows). Sagittal
postcontrast T1-weighted cervical spine image (D, right panel) shows new nodular
involvement with diffuse epidural cord enhancement (arrows).
This case emphasizes the late pregnancy and postpartum tumoral oncogenic COMMENT
influences potentially leading to transformation of benign schwannoma to a
malignant tumor with dissemination to the CSF.

the serum of the mother as early as 5 weeks after placentation.49-51 These fetal-
derived serum factors persist throughout pregnancy and have been reported to
be present in the serum and brains of parous women more than 40 years
postpartum.49-51 The maternal-fetal interface becomes a site for reeducation of
immune cells to the new foreign fetal antigens.49,51,52 This reeducation induces
T-cell anergy and immune tolerance, which confers protection to the developing
fetus within this specialized compartment.48,49,52
Since brain tumors develop within an immune-specialized compartment, the
CNS is another presumed sanctuary for circulating pregnancy serum factors and
may influence tumor pathogenesis.50-52 Immune tolerance and anergy due to
T-cell dysfunction are well evidenced in glioblastoma and permit tumor
oncogenesis.53,54 During glioblastoma development, tumor-driven processes
promote an immunosuppressive microenvironment, thereby exhausting the
protective immune cells and contributing to tumor immune evasion.53,54 Both
fetal and brain tumor development induce immunosuppressive host immune
microenvironments, potentially explaining tumor progression during
concurrent pregnancy.
Vasculature and Hemodynamics

The previously discussed pregnancy hormones and growth factors that promote
vascular proliferation during fetal and placental development may also support
angiogenesis within existing brain tumors. Pregnancy-associated hemodynamic
changes include increased maternal blood volume, hypertension, vascular
resistance, vessel engorgement, and oxygen consumption.55,56 These factors have
been linked to increased tumor aggressiveness, such as increased tumor size
TABLE 6-1 Assessment of Independent Risk Factors Associated With Breast Cancer
Brain Metastases
Breast cancer brain Time to brain HER2+ breast cancer

Independent risk factors (higher risk) metastases metastases brain metastases
Age (>40 years) + +
Estrogen receptor (estrogen receptor negative) + +
Human epidermal factor (overexpression) +
Stage at diagnosis (high, stage III) + +
Histologic grade (high, grade 3) + +
Tumor size (>2 cm) + +
Ki-67 labeling index (high) +
Nodal involvement (positive) + + +
Triple-negative cancer +
Liver metastases (positive) +
+ = Denotes positive association with risk factor for this patient category; HER2+ = human epidermal growth factor receptor 2 positive.
a
Data from Koniali L, et al, Oncotarget.32
136 FEBRUARY 2022

and hemorrhagic outcomes.55 Studies suggest that routine hemodynamic and KEY POINTS
cardiac monitoring of the mother and fetus over the course of the pregnancy may
● The maternal-fetal
help prevent adverse pregnancy outcomes.55 Furthermore, assessment of these interface becomes a site for
vascular and hemodynamic changes is relevant when considering brain reeducation of immune cells
imaging, surgery, and anesthesia, as discussed later in this article. to the new foreign fetal
antigens.
PREGNANCY RECOMMENDATIONS AND CONSIDERATIONS IN
● Routine hemodynamic
CENTRAL NERVOUS SYSTEM TUMORS and cardiac monitoring of
With the expanding diversity of cancer therapies and advanced technologies for the mother and fetus over
tumor diagnosis and surveillance, providers must be cognizant of potential risks the course of the pregnancy
to safe pregnancy maintenance in patients with cancer. Interest in defining the may help prevent adverse
pregnancy outcomes.
relative contraindications and developing guidelines to inform multidisciplinary
care of pregnant women with brain tumors is growing. ● Noncontrast MRI with a
lower than 3T magnet is the
Diagnostic and Surveillance Brain Tumor Imaging best modality for brain
tumor imaging in pregnant
Based on expert opinion by the Committee on Obstetric Practice, guided by the women.
American College of Obstetricians and Gynecologists and the American College
of Radiology, noncontrast MRI with a lower than 3T magnet is the best modality ● Head CT for brain tumor
for brain tumor imaging in pregnant women.5,57 MRI does not involve radiation, imaging during pregnancy is
contraindicated as it uses
and the use of this modality poses no significant risk to the mother or fetus.5,58
ionizing radiation, a
The use of gadolinium MRI contrast dye is important to obtain the most accurate carcinogen, and is reserved
brain tumor images for surgical and radiation planning. However, gadolinium for emergent scenarios (eg,
crosses the placenta and poses a potential risk to the developing fetus and would hemorrhage or acute stroke)
be acceptable (with appropriate informed consent) in the setting where the in which the benefit to the
mother outweighs the risk to
expected benefit to the mother outweighs the undefined risk to the fetus.5,57 the fetus.
Head CT for brain tumor imaging during pregnancy is contraindicated as it
uses ionizing radiation, a carcinogen, and is reserved for emergent scenarios ● Tumor grade, anatomic
(eg, hemorrhage or acute stroke) in which the benefit to the mother outweighs location, and tumor rate of
growth are important for
the risk to the fetus.5,48 In these cases, shielding the gravid uterus during head CT neuroclinical
offers some reassurance. As a reference, an adult head CT delivers about 75 mGy prognostication.
to the mother.59 Intrauterine exposure to ionizing radiation is estimated to be
one-third the dose of that entering the mother, and the guideline limits fetal
exposure to up to 50 mGy.60 However, studies have shown no impact on
neurocognitive function for in utero exposures lower than 100 mGy at any point
during pregnancy.59,60 Cumulative in utero exposure at or exceeding 150 mGy
has evidence for high-risk gross congenital malformations and a 3% lifetime risk
for cancer.60 In these cases, pregnancy counseling and the potential for elective
termination should be discussed.59
Neurosurgical Intervention and Anesthesia

In pregnant patients with brain tumors, clinical decision making for sedation and
neurosurgical intervention depends on several tumor, fetal, and maternal
factors.4,5,56 Often, the decision involves physical, hemodynamic, and
pharmacodynamic properties that are influenced by the pregnancy state and
impact safe surgical positioning and administration of anesthesia.5,56,61
Tumor grade, anatomic location, and tumor rate of growth are important for
neuroclinical prognostication.4,59 For example, high-grade or rapidly growing
tumors risk brain herniation, worsening neurologic deficit, or death and would
therefore be prioritized for neurosurgery. Fetal viability is the gestational age at
which a fetus could survive outside of the uterus and is generally considered to

CASE 6-4 A 43-year-old woman, gravida 2, para 2, with a diagnosis of widely

metastatic triple positive breast cancer (ie, harboring all three types of
cell surface receptors: estrogen, progesterone, and human epithelial
growth factor receptor 20) diagnosed on body positron emission
tomography (PET) CT (FIGURE 6-5A), was treated with systemic therapy with
an excellent response (FIGURE 6-5B). Baseline postcontrast brain MRI was
normal (FIGURE 6-5C).
She continued systemic chemotherapy and reported 6 months of
amenorrhea, attributed to her therapy. The patient began noting weight
gain, increased fatigue, nausea, and lower limb numbness. She had a
positive urine home pregnancy test, which was confirmed by her primary
oncologist via serum qualitative human chorionic gonadotropin (HCG)
test. The patient was referred to a maternal-fetal medicine specialist and
determined by ultrasound to be at 14 weeks’ gestation. Systemic therapy
was held while the patient considered options for treatment and
pregnancy maintenance.
While off therapy, the patient developed lightheadedness, headaches,
blurred vision, and tinnitus, all initially attributed to vascular and
metabolic changes of pregnancy. By 17 weeks’ gestation, the patient was
experiencing falls, seizurelike events, and cognitive status changes and
presented to the emergency department. A postcontrast brain MRI
demonstrated miliary parenchymal metastases and diffuse
leptomeningeal enhancement with a burden of disease within the
posterior fossa (FIGURES 6-5D through 6-5F), also shown in a three-
dimensional rendering of the MRI (FIGURE 6-5G). CSF studies confirmed the
presence of malignant cells.
After a multidisciplinary discussion, the patient underwent an elective
abortion at 19 weeks’ gestation, and antiseizure and steroid therapies
were initiated. The patient had evidence of systemic oligometastatic
disease recurrence, and she underwent whole-brain radiation therapy,
restarted systemic chemotherapy, and had an Ommaya reservoir placed
for intrathecal chemotherapy (FIGURE 6-5H). She experienced clinical
improvement, and a repeat postcontrast MRI brain demonstrated an
objective response with improved areas of parenchymal and
leptomeningeal enhancing lesions (FIGURES 6-5I and 6-5J). A three-
dimensional rendering of the MRI showed the Ommaya placement and
interval resolution of leptomeningeal enhancement (FIGURE 6-5K). The two
remaining nodular cerebellar lesions were treated with stereotactic
radiosurgery.
COMMENT This case emphasizes the importance of clinical hypervigilance and

maintaining a low threshold for suspicion of tumor progression in pregnant
patients with cancer.
138 FEBRUARY 2022

FIGURE 6-5
Imaging of the patient in CASE 6-4. Positron emission tomography (PET) CT shows widely
metastatic breast cancer before (A) and after (B) systemic therapy. C, Baseline axial
postcontrast T1-weighted MRI is normal. Axial (D, E) and coronal (F) postcontrast
T1-weighted images show miliary parenchymal metastases and diffuse leptomeningeal
enhancement, with a burden of disease within the posterior fossa, also shown in three-
dimensional rendering of the MRI (G), with areas of tumor indicated in pink. H, Coronal
postcontrast T1-weighted image shows placement of an Ommaya reservoir. I, J,
Repeat axial postcontrast T1-weighted images show improved areas of parenchymal and
leptomeningeal enhancing lesions. K, Three-dimensional rendering shows placement of the
Ommaya reservoir and interval resolution of leptomeningeal enhancement.
Images courtesy of Andrew Conger, MD; Gino Mongelluzzo, MD; and Syed A. J. Kazmi, MD.

begin at 24 weeks’ gestation.45 Discussing fetal viability is important when

tumor progression or surgical complications may require preterm delivery or
otherwise risk safe pregnancy maintenance.45,59 Maternal clinical status and
current pregnancy trimester are also considerations for urgency and safety
of neurosurgery.5,59 The second trimester presents the optimal hemodynamic
status for surgical body positioning, with a goal to preserve uterine blood
perfusion and limit fetal anesthetic exposure.56,61 It is important to discuss risks
for pregnancy maintenance and to involve multidisciplinary experts to ensure
the patient understands options for pregnancy termination and risks to future
fertility.4,5,16 Of course, with routine clinical monitoring, stable patients could
undergo elective neurosurgery or defer surgery until after delivery.56
Radiation Oncology Therapy

As noted above, ionizing radiation at specific doses is a known teratogen, and
use of radiation therapy during pregnancy is reserved for benefits to the mother
that outweigh the known risks to the fetus. Radiation therapy for brain tumors
typically involves up to 600 mGy (60 cGy), and fetal exposure is similar for both
targeted radiosurgery and external beam radiation.59,60 The risk for neurocognitive
dysfunction was shown to be higher in fetal exposures between 100 mGy and
500 mGy during the first trimester (6%) as compared to the second trimester
(2%).62 The fetal dose is calculable based on radiation scatter, and specialized
shielding has been shown to limit the fetal dose by 25% to 50%.59,62
Medical Therapeutics
Use of chemotherapy during pregnancy has been discouraged; however, over the
past 2 decades, multiple targeted and immunotherapeutic agents have been
developed to fight cancer. Unfortunately, aside from limited prospective studies
and case reports, a paucity of evidence remains to support clinical decision making
for use of these agents during pregnancy.59,63 Many targeted therapies and standard
chemotherapies cross the placenta and may result in spontaneous abortion or other
risks to the developing fetus, especially during the first trimester.59,63 Ideally, the
initiation of medical cancer therapies is delayed until delivery; however, if
treatment is necessary during pregnancy, a general rule for initiation is after the
first trimester when fetal organ development is largely completed.4,59
Medical treatment of primary brain tumors commonly involves alkylating
agents, tyrosine kinase inhibitors, platinum-based agents, and biologic and
other targeted therapies.4,16 Many of these have cautionary labeling for use
during pregnancy for known or suspected risk to the fetus.4,5,16 Although multiple
animal studies have demonstrated embryo-lethal outcomes using many of these
agents, no controlled studies in human pregnancy have been reported.4
Furthermore, the optimal time for systemic clearance of these therapies before
conception is controversial, and current recommendations vary between 4
and 6 months.5,16
The use of immune-directed therapies in atopic illnesses during pregnancy
was evaluated as early as the 1970s, and these therapies were reported to have
limited negative effects on fetal outcomes.64 Promising newer immunotherapies,
specifically the immune checkpoint inhibitors, are currently being evaluated for
use in newly diagnosed or recurrent CNS tumors as part of several ongoing
clinical trials65-67; however, pregnancy remains an exclusion criterion for
enrollment in these trials.
140 FEBRUARY 2022

Approved/Cleared Device-Based Therapies in Adult Brain Tumors KEY POINTS
US Food and Drug Administration (FDA) approval is granted for drugs, whereas
● When considering
FDA clearance is granted for devices and instruments. Device-based therapies in neurosurgery for pregnant
CNS tumor treatment are typically designed to deliver regional or tumor- patients with central
directed therapy. The following is a brief summary of commonly used and nervous system tumors, it is
promising next-line therapies available to patients with brain tumors in clinics, in important to involve
multidisciplinary experts to
clinical trials, or for compassionate use.
discuss the patient’s options
for pregnancy maintenance
TUMOR TREATING FIELDS. Tumor treating fields are created by an externally placed or termination as well as any
scalp device categorized as an antimitotic therapy that delivers low-intensity risks for future fertility.
alternating electric fields. Tumor treating fields therapy has demonstrated
● The risk of neurocognitive
effectiveness to extend patient survival when used in combination with standard dysfunction resulting from
chemotherapy and received FDA clearance for both recurrent and newly radiation therapy was higher
diagnosed glioblastoma.19,68,69 In 2015, the use of tumor treating fields was added in fetal exposures between
to the National Comprehensive Cancer Network Clinical Practice Guidelines in 100 mGy and 500 mGy during
the first trimester (6%) as
Oncology for CNS cancers.19 No studies for this device that specifically included compared to the second
pregnant women have been reported. Use of this device is specifically trimester (2%).
contraindicated for use during pregnancy.
● Targeted therapies and
standard chemotherapies
INTRAOPERATIVELY IMPLANTED CHEMOTHERAPY-INFUSED DEVICE. In 1997, the FDA
cross the placenta and may
approved a biodegradable polymer containing 1,3-bis[2-chloroethyl]-1- result in spontaneous
nitrosourea (BCNU), an alkylating agent, to be introduced inside the resection abortion or other risks to the
cavity of recurrent glioblastomas; approval was extended to include newly developing fetus, especially
during the first trimester.
diagnosed glioblastoma in 2003.70 No studies for this device that specifically
included pregnant women have been reported. Use of this device is ● Tumor treating fields
contraindicated for use during pregnancy. therapy has been
demonstrated to be
INTRAOPERATIVE BRACHYTHERAPY DEVICE. In 2018, the FDA cleared the use effective in extending
patient survival when used in
of a device that delivers a surgically targeted calculated dose of radiation to combination with standard
brain tumors using cesium (131Cs) radiation-emitting seeds housed in a chemotherapy and has
collagen-based carrier tile.71,72 This therapy delivers 90% of the radiation dose received US Food and Drug
within 33 days, and the tiles are radiation free after 100 days.72 Pregnancy Administration clearance for
both recurrent and newly
indications for this device are unclear as it is not addressed on the consumer- diagnosed glioblastoma.
facing home page. Appropriate and safe use is therefore left to the surgical
provider and remains a device-based option for pregnant patients with brain
tumors. Pregnant women are excluded from the ongoing brain tumor
registry73 as well as from the newly diagnosed CNS metastases study74 using
this device. The risks for use of this device during pregnancy are not clearly
defined.
NEUROSURGICAL ABLATIVE DEVICES. Use of this FDA-cleared approach offers a

minimally invasive MRI-guided neurosurgical option to deliver targeted
ablative thermal therapy as a cytoreductive treatment for brain tumors.75,76 This
approach is also known as laser interstitial thermal therapy, stereotactic laser
ablation, and MRI-guided laser ablation.75,76 A 2021 review of the literature for
effectiveness of this approach in newly diagnosed glioblastoma was inconclusive
and noted the need for more well-designed prospective studies to generate
conclusions.76 No studies for this device that specifically included pregnant
women have been reported. However, use during pregnancy is not absolutely
contraindicated.

Supportive Care Issues

Supportive care issues often arise in patients with brain tumors secondary to
tumor treatment or tumor progression. Pregnant patients with CNS tumors have
added indications for supportive care approaches, often secondary to the normal
physiologic changes of pregnancy.4,5,16 Common issues include cerebral edema,
seizures, headache pain, and fatigue.
Glucocorticoids commonly used during pregnancy include prednisone,
prednisolone, betamethasone, and dexamethasone. Steroids may be used during
pregnancy for a variety of reasons, ranging from facilitation of fetal lung
maturity in high-risk pregnancies to providing a safer alternative to anti-
inflammatory or immunosuppressive therapies during pregnancy.77 Newly
diagnosed and recurrent brain tumors are frequently associated with vasogenic
edema causing significant morbidity and require steroids as a temporary supportive
care measure.78 Symptoms of swelling of brain tumors include pain; seizures;
weakness; nausea; vomiting; and changes in cognition, vision, speech, and
gait.78,79 To minimize pregnancy risks, antenatal steroids should be used
sparingly and preferably after completion of the first trimester.80,81 However,
treatment may vary based on the patient’s tolerance and disease severity.
The most recent brain tumor guideline from the Congress of Neurological
Surgeons addressed the prophylactic use of antiseizure medications.78 Although
pregnancy is not specifically referred to in the guideline, the guideline does not
recommend antiseizure medication prophylaxis in patients with brain tumors.78
The general principles of use of antiseizure medications during pregnancy for
patients with seizures/epilepsy should apply similarly in the setting of brain
tumors. For more information, refer to the article “Epilepsy and Pregnancy” by
Yi Li, MD, PhD, and Kimford J. Meador, MD, FAAN, FAES, FRCPE,82 in this
issue of Continuum. Safe implementation of antiseizure medications and steroids
in pregnant patients with CNS tumors should be discussed with the
multidisciplinary care team and consider gestational timing, dose, and duration
of therapy.
NEURO-ONCOLOGY OF WOMEN
Although studies on the outcomes of women with brain tumors have long been
addressed as an important topic, the author’s team has worked to formally
establish the neuro-oncology of women as a subfield within neuro-oncology. The
neuro-oncology of women is defined as “the study of the neuro-biological and
psychosocial impact of brain tumors in women, paired with the academic
movement to encourage female-focused clinical and translational CNS tumor
research.”5 The pregnancy state is widely understudied in CNS tumors, and
multiple additional considerations exist central to the neuro-oncology of women,
which are not addressed in this article. For example, other special pregnancy
considerations for prepubertal, pregnant, and reproductive-aged patients with
CNS tumors include fertility preservation, pregnancy prevention, pregnancy
maintenance, pregnancy termination, chemotherapy in body-fluid exposure
risks (sexual intercourse, lactation, toileting), mood disorders, transgender
health and cross-sex hormone exposure, and brain tumor impacts on sex and
sexuality in women. Another interesting consideration not addressed in this
article is the potential influence of pregnancy on various treatments. Very little is
known about the potential for pregnancy to impact treatment tolerance,
pharmacokinetics, efficacy, and, ultimately, treatment outcomes.
142 FEBRUARY 2022

As patients with CNS tumors live longer, the demand for evidence-based KEY POINTS
research to support clinical decision making for the diagnosis, treatment, and
● Supportive care issues
management of brain tumors during pregnancy will be growing. Opportunities often arise in patients with
should be expanded to develop more multidisciplinary research that includes brain tumors secondary to
negligible to low risks for informed patients with CNS tumors during pregnancy. tumor treatment or tumor
progression.
● Steroids may be used

CONCLUSION during pregnancy for a
CNS tumors during pregnancy are rare but present a significant challenge for variety of reasons, ranging
treating clinicians. The most common CNS tumors diagnosed during pregnancy from facilitation of fetal lung
have multifactorial risks that may influence aggressive tumor behaviors. maturity in high-risk
pregnancies to providing a
Diagnosis, treatment, and management of CNS tumors during pregnancy can be safer alternative to anti-
complicated by risks to the safe maintenance of pregnancy and thereby require inflammatory or
multidisciplinary care. Research to support clinical decision making for patients immunosuppressive
with CNS tumors during pregnancy is lacking. As such, most of the newer therapies during pregnancy.
innovative and promising brain tumor therapies have specifically excluded or ● Newly diagnosed and
failed to include pregnant patients in their indications for use protocols. More recurrent brain tumors are
attention must be paid to the growing number of special considerations for frequently associated with
treating pregnant women with CNS tumors. The neuro-oncology of women vasogenic edema causing
significant morbidity and
subfield of neuro-oncology emphasizes these and other issues in neuro-oncology
require steroids as a
as they pertain to women over their lifespan. temporary supportive care
measure.
● Although pregnancy is not

USEFUL WEBSITES
specifically addressed in the
NATIONAL VITAL STATISTICS REPORT BRAIN CANCER: GLIOMAS
guideline by the Congress of
This Centers for Disease Control and Prevention This National Comprehensive Cancer Network
report provides demographic information on 2019 Guidelines for Patients report provides an overview Neurological Surgeons, the
birth data in the United States. of gliomas and includes information on testing, recommending body, in
treatments, and recurrent disease. general, does not
Cdc.gov/nchs/data/nvsr/nvsr70/nvsr70-02-
508.pdf Nccn.org/patients/guidelines/content/PDF/brain- recommend prophylactic
gliomas-patient.pdf
use of antiseizure
CANCER DURING PREGNANCY
medications in patients with
This Cancer.Net website provides information on brain tumors.
the types of cancer that occur in pregnancy and
their diagnosis and treatment. The site includes
questions patients should ask their providers and
related resources.
Cancer.net/navigating-cancer-care/dating-sex-
and-reproduction/cancer-during-pregnancy
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146 FEBRUARY 2022

Neuro-ophthalmology REVIEW ARTICLE

and Pregnancy C O N T I N U UM A U D I O
ONLINE
By Heather E. Moss, MD, PhD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article summarizes the impact of pregnancy on

neuro-ophthalmic pathways and presents an approach to the evaluation of
pregnant women who have neuro-ophthalmic symptoms or signs.
CITE AS:
Advances in noninvasive ophthalmic imaging have
RECENT FINDINGS: 2022;2 8 ( 1 , N E U R O L O G Y O F
P R E G N A N C Y ): 1 4 7 – 1 6 1 .
increased knowledge of the impact of pregnancy on ocular blood flow,
which may have relevance for understanding the impact of preeclampsia Address correspondence to
and eclampsia on the eye. Dr Heather E. Moss, Spencer
Center for Vision Research,
Stanford Department of
SUMMARY: The framework for approaching neuro-ophthalmic symptoms and
Ophthalmology, 2370 Watson
signs in pregnant women is similar to the general approach for people who Ct, Palo Alto, CA 94303,
are not pregnant. Visual symptoms are common in preeclampsia and hemoss@stanford.edu.
eclampsia. Some diseases that impact the neuro-ophthalmic pathways are RELATIONSHIP DISCLOSURE:
more common in pregnant women. Pregnancy should be considered when Dr Moss has served on the
editorial board of the Journal of
recommending the workup and treatment for neuro-ophthalmic symptoms
Neuro-Ophthalmology and as an
and signs. associate editor for Frontiers in
Neurology and MedLink
Neurology, an assistant editor
for Frontiers in Ophthalmology,
a review editor for Current Eye
Research, a guest editor for
Current Opinion in Neurology
INTRODUCTION and Current Neurology and
P
Neuroscience Reports, and a
regnancy induces changes throughout the body, including in the eyes
special issue editor for Life.
and brain. This article begins with a discussion of pregnancy- Dr Moss has served as a
associated changes in visual pathway structures that occur consultant for Twenty/Twenty
Therapeutics and Verana Health
physiologically and pathophysiologically in states of preeclampsia and and on an advisory board for
eclampsia. The remainder of the article provides a clinical approach to Genentech, Inc; has received
pregnant women who present with neuro-ophthalmic symptoms (eg, blurry personal compensation for
speaking engagements for
vision, double vision) or signs (eg, papilledema, ptosis). Although the focus is on Vindico Medical Education; and
neuro-ophthalmic pathways, including the optic nerve, central visual pathways, receives research/grant
and eye movements, common ophthalmic conditions with increased prevalence support from the Department of
Defense, the National Institutes
during pregnancy are also reviewed. of Health (P30 EY 026 877, R21
For the most part, the approach to pregnant patients with visual symptoms or EY 031 726), and Research to
Prevent Blindness.
signs is similar to the approach to nonpregnant patients, including
comanagement with an eye care provider for conditions necessitating UNLABELED USE OF
monitoring of vision or ophthalmic structures. The treating neurologist should be PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
aware of mechanisms and etiologies of visual pathway disease that are more Dr Moss reports no disclosure.
common in pregnant women and consider the risk to both the patient and fetus
when recommending testing or treatment.
© 2022 American Academy
of Neurology.

NEURO-OPHTHALMOLOGY AND PREGNANCY
THE EYE IN PREGNANCY

Pregnancy induces physiologic changes in many, if not all, maternal organ systems,
including in the eye. Although many of these changes are benign, they can cause
visual symptoms, and patients accordingly present for medical assessment. Other
pregnancy-associated changes in the eyes and visual pathway are pathologic.
Physiologic Changes in the Eye

Pregnancy can be associated with shifts in refraction, which may cause blur at
near or distance because of the need for new glasses or contact lenses.1,2 This can
be attributed to hormonal effects on the lens and cornea that alter their optical
properties. Impaired accommodation can lead to blur at near. Dry eye disease
related to decreased tear production increases during the third trimester,3 which
may contribute to eye discomfort, blur, and contact lens intolerance.4 Although
intraocular pressure generally decreases in pregnancy,5 this is not universal, and
some people with glaucoma experience worsening during the course of
pregnancy. Thus, close ophthalmologic monitoring of any pregnant woman with
glaucoma is important.6
Blood flow to the retina is altered during normal pregnancy. Optical coherence
tomography (OCT) is a noninvasive ophthalmic imaging technology with which
FIGURE 7-1
Retinal causes of acute vision loss in pregnancy. Inferior temporal branch retinal artery
occlusion of the right eye (A, arrows) causing temporal visual field loss (B). Lack of retinal
whitening is consistent with either a hyperacute or chronic state. Central retinal vein occlusion
of the right eye shows optic nerve head swelling, enlarged tortuous venules, and retinal
hemorrhages (C) compared to baseline (D). Optical coherence tomography of central serous
chorioretinopathy shows retinal pigment epithelial detachment pushing up the fovea (E, arrow)
compared to the normal foveal contour (F).
Panels A and B courtesy of Kathleen Digre, MD; panels C and D courtesy of Huy Nguyen, MD; panels E and
F courtesy of Ted Leng, MD.
148 FEBRUARY 2022

cross-sectional images of the retina can be obtained with 5-micron resolution KEY POINTS
without dilating the pupils. OCT angiography obtains noncontrast images of the
● Ocular surface and
retinal microvasculature by detecting movement, similar to time-of-flight MRI. cornea changes in
Multiple studies using OCT angiography have shown that the outer retina pregnancy can cause blur,
vascular density (a measure of perfusion) in the macula increases during eye pain, refractive shift,
pregnancy.7-9 One study also showed an increase in perfusion of and around the and contact lens
discomfort.
optic nerve.9 Reports of vascular density changes in the inner retina have been
conflicting. No differences in perfusion or thickness of the choroid, a high-flow ● Branch retinal vein
vascular bed between the retina and the sclera, were seen in subjects with occlusions, branch retinal
uncomplicated pregnancy compared with control subjects in a single study.10 artery occlusions, and
central serous
chorioretinopathy are retinal
Pathophysiologic Changes in the Eye causes of acute partial vision
Central serous chorioretinopathy is an idiopathic local detachment of the retinal loss in pregnancy.
pigment epithelium that is typically more common in men but can cause focal
vision disturbance in pregnant women.11 The same mechanisms responsible for ● Visual symptoms occur in
more than one-fourth of
cerebral infarct in pregnant women (eg, amniotic fluid emboli, hematologic patients with preeclampsia
emboli, vasculitis) can cause central retinal artery and branch retinal arterial and almost half of patients
occlusion presenting as sudden (partial) vision loss in one eye. Central and with eclampsia.
branch retinal vein occlusions also occur in association with hypercoagulable
states in pregnancy and also present with sudden (partial) vision loss in one eye.
Purtscher-like retinopathy is a rare cause of vision loss in the immediate
postpartum setting because of patchy retinal infarction postulated to be due to
amniotic fluid activation of complement causing leukocyte aggregates
blocking arterioles.12
Diabetic retinopathy can worsen in pregnant women with risk factors such as
longer duration of diabetes prepregnancy, higher baseline level of diabetic
retinopathy during pregnancy, and worse glycemic control.13 Diabetic
retinopathy is generally not an issue in those with solely gestational diabetes.
Vision-impacting retinal disease is typically apparent via examination by a
qualified eye care provider, with the exception of central serous
chorioretinopathy, for which OCT can aid in diagnosis (FIGURE 7-1). For a
comprehensive review of ophthalmic changes during pregnancy, refer to
excellent reviews by Grant and Chung14 and Kalogeropoulos and colleagues.15
THE VISUAL SYSTEM IN PREECLAMPSIA AND ECLAMPSIA

Visual symptoms are common in people with preeclampsia and eclampsia, with
one study reporting prevalence of almost 30% in preeclampsia and almost 70% in
eclampsia among patients who reported neurologic symptoms.16 This is likely an
overestimate as patients without neurologic symptoms were not included in this
study. In another study, 45% of patients reported visual disturbance before an
eclampsia-defining seizure.17 The most common symptoms are “spots” (in
approximately 35% of patients with preeclampsia/eclampsia) and color vision
disturbances (in approximately 25%), with blurred vision and reduced visual
acuity seen in a minority of patients with severe preeclampsia/eclampsia.18
Blindness can rarely occur.19
The etiologies of visual symptoms are myriad and include changes to the
retina and brain as well as sporadic involvement of the optic nerve and cranial
nerves. Retinal changes are similar to those seen in non–pregnancy-related
hypertension, including arteriolar narrowing, focal retinal ischemia (cotton wool
spots), hemorrhages, and, in severe cases, optic disc edema. Preeclampsia can

cause focal occlusion of the choroidal circulation leading to changes in the

overlying retina, including color changes (Elschnig spots) and serous retinal
detachments (FIGURE 7-2).20 Retinal and choroidal thickness measured using OCT
have been reported to be increased in severe preeclampsia21 and may be a marker
for this given that choroid thickness is not generally increased in pregnancy.10
Although not common, cranial nerve involvement can occur in association
with preeclampsia/eclampsia and contribute to visual symptoms. Optic nerve
swelling and dysfunction can occur in association with hypertensive retinopathy,
elevated intracranial pressure (ICP), or ischemic optic neuropathy.22 Both single
and multiple cranial nerve palsies impacting extraocular motility have been
described in association with preeclampsia.23
Posterior reversible encephalopathy syndrome (PRES) associated with
preeclampsia/eclampsia can cause visual disturbance on a cerebral basis
(FIGURE 7-3). Visual symptoms are more common in patients with preeclampsia/
eclampsia and PRES, occurring in 50% compared to in 25% of those without PRES
in one study.16 The same study found visual disturbances to be more common in
patients with cytotoxic edema than in patients with vasogenic edema on MRI.
Blindness from any cause has been estimated to occur in 15% of patients with
eclampsia, with over 80% of these attributable to PRES.19 Other symptoms of
PRES include visual processing disturbances (eg, simultagnosia, optic ataxia,
alexia).12
Magnesium, which is used to treat preeclampsia, can impair accommodation
and cause blur.24 This can be diagnosed using a pinhole occluder. Although
recovery of visual deficits from preeclampsia/eclampsia is typically excellent,
permanent visual impairment can persist. Interestingly, reduced vision-specific
quality of life was reported in patients with eclampsia an average of 10 years
postpartum despite normal visual field testing.25
APPROACH TO VISUAL SYMPTOMS IN PREGNANCY

As in nonpregnant patients, localization of the cause of blur is the first step in
evaluation of pregnant patients with blurry vision. Asking if the symptoms are
present when using both eyes, the right eye alone, or the left eye alone guides
localization. If the patient does not know, they can be talked through the exercise
in the office or during a telehealth visit. A symptom that is present only when
both eyes are open but not with either eye alone suggests ocular misalignment as
the cause of the symptom. A symptom present when using one eye in isolation
FIGURE 7-2
Retinal findings in preeclampsia/eclampsia. Cotton wool spots (A, arrows), indicating retinal
ischemia; retinal hemorrhages (B, arrows); hypopigmented areas caused by choroidal
infarction beneath the neurosensory retina (C, arrows); serous retinal detachment (D, arrows).
Figure courtesy of Kathleen Digre, MD.
150 FEBRUARY 2022

FIGURE 7-3
MRI changes characteristic of posterior reversible encephalopathy syndrome (PRES)
associated with preeclampsia/eclampsia. Axial fluid-attenuated inversion recovery (FLAIR)
slices show hyperintensity of parietal and occipital white matter, which can be associated
with vision loss and visual processing disturbances.
Figure courtesy of Nancy Fischbein, MD.
but not when using the other suggests a problem anterior to the chiasm on the
affected side. A symptom that is similar with each eye used in isolation and with
both eyes used together suggests a retrochiasmal cause. Dysfunction of the
chiasm or structures anterior to the chiasm on both sides will typically cause
dissimilar symptoms when comparing each eye used in isolation.
Examination should include visual acuity with each eye at the distance at which
the patient is symptomatic (ie, near or far). If visual acuity is abnormal despite
the patient’s usual corrective lenses, acuity should be rechecked using a pinhole
occluder, which will correct for most refractive and ocular surface causes of blur.
Confrontation visual fields are sensitive and specific for severe vision loss. Formal
perimetry, available in most ophthalmology offices, should be obtained if concern
exists for peripheral vision loss and confrontation visual field testing is normal.
Pupil examination should assess for anisocoria in light versus dark and relative
afferent pupillary defect. Anisocoria worse in light suggests that the large pupil has
trouble constricting (eg, because of parasympathetic impairment). Anisocoria
worse in dark suggests that the small pupil has trouble dilating (eg, because of
sympathetic impairment). A relative afferent pupillary defect demonstrates lower
direct than indirect pupillary response and suggests impaired perception of light in
that eye (eg, because of optic neuropathy). Extraocular motility examination
should be complemented by assessment of ocular alignment using techniques such
as Maddox rod or alternating cover testing.
Funduscopic examination is necessary to assess the optic nerve head and
vascular changes in the retina. If visualization is difficult, options include dilating
the pupils with topical mydriatic medications, which is regarded to be safe during
pregnancy,26 and the use of nonmydriatric funduscopic photography. OCT,
which is nonmydriatic, can also be helpful to visualize the shape of the retina and
optic nerve head. Referral to an eye care provider may be necessary to obtain a
dilated funduscopic examination, fundus photography, or OCT imaging.
BLURRY VISION IN ONE EYE (CAN IMPACT BOTH EYES)

Central serous chorioretinopathy in the retina can cause local loss of vision or
metamorphopsia (FIGURE 7-1), seen as focal waviness of straight lines when

viewing an Amsler grid, which is a grid of horizontal and vertical lines used to
test the central 20 degrees of vision. Although central serous chorioretinopathy
can be challenging to observe on funduscopic examination, it is readily visible
using OCT. Acute vision loss in one eye is concerning for ischemia (arterial or
venous) of the retina (FIGURE 7-1) or optic nerve. Ischemia of the retina is the
equivalent of cerebral stroke and should be managed similarly. For more
information on stroke in pregnancy, refer to the article “Maternal Stroke
Associated With Pregnancy” by Eliza C. Miller, MD, MS,27 in this issue
of Continuum.
A common consideration for unilateral vision loss in women of childbearing
age regardless of pregnancy status is optic neuritis. A typical history is
progressive loss of vision in one eye over days associated with pain on eye
movements. Examination findings include loss of visual acuity, visual field loss,
and relative afferent pupillary defect. The optic nerve head can appear normal or
mildly swollen in the acute setting. Women with multiple sclerosis generally
experience fewer attacks of optic neuritis during pregnancy, thought to relate to
a relative immunosuppressed state during pregnancy; however, this relative
remission is less pronounced in patients with neuromyelitis optica (NMO). Both
multiple sclerosis and NMO often have more activity in the postpartum period.28
Two case series examined relapses of anti–myelin oligodendrocyte glycoprotein
(MOG)–associated disorder during pregnancy, reporting 10% to 20% of patients
CASE 7-1 A 29-year-old woman at 35 weeks’ gestation presented with

headaches and blurry vision worsening over 2 weeks. Her visual
acuity was 20/20 with each eye, and confrontation visual fields were
normal. Ophthalmoscopic examination
was normal. Humphrey visual field
testing showed mild temporal visual
field constriction in both eyes. This
prompted MRI of the sellar region,
which showed an enlarged pituitary
gland abutting the optic chiasm
(FIGURE 7-4). Shortly after completion
of the MRI, she spontaneously
delivered a healthy baby boy.
Transsphenoidal biopsy of the lesion
performed postpartum showed
inflammatory infiltrates of B cells and
T cells without abnormal morphology FIGURE 7-4
diagnostic of lymphocytic hypophysitis. Imaging of the patient in CASE 7-1.
Coronal noncontrast T1-weighted MRI
She was treated with corticosteroids,
shows enlargement of the pituitary
and her vision normalized. Endocrine gland abutting the optic chiasm (arrow).
evaluation was unrevealing. Figure courtesy of Nancy Fischbein, MD.
COMMENT This case exemplifies one of the suprasellar pathologies that can grow
during pregnancy to compress the chiasm and cause peripheral vision loss.
152 FEBRUARY 2022

with attacks (mostly optic neuritis) during pregnancy, 40% with postpartum KEY POINTS
attacks, and 50% to 70% with no attacks during gestation or postpartum.28,29 For
● The approach to visual
more information on multiple sclerosis and NMO spectrum disorder (NMOSD) symptoms in pregnant
and pregnancy, refer to the article “Pregnancy Management in Multiple Sclerosis patients is similar to the
and Other Demyelinating Diseases” by Riley M. Bove, MD, and Maria K. approach to visual
Houtchens, MD,30 in this issue of Continuum. symptoms in other patients.
Meningiomas, particularly of the skull base or optic nerve sheath, can grow
● Dilating the pupils with
during pregnancy to cause accelerated visual symptoms due to optic nerve eye drops is regarded to be
compression. This accelerated growth is thought to be related to increased safe during pregnancy.
estrogen, progesterone, prolactin, and, possibly, vascular endothelial growth
factor (VEGF).31 In a large case series of pregnancy-related meningiomas, skull ● Optic neuritis related to
multiple sclerosis,
base location and presentation with visual symptoms were more common than in neuromyelitis optica, or
non–pregnancy-related meningiomas.32 For more information on meningiomas myelin oligodendrocyte
and pregnancy, refer to the article “Managing Central Nervous System Tumors glycoprotein–associated
During Pregnancy” by Na Tosha N. Gatson, MD, PhD, FAAN,33 in this issue disorder is less common
during pregnancy and has
of Continuum. increased frequency
postpartum.
BLURRY VISION IN BOTH EYES
If pregnant patients have blurry vision in both eyes, consideration should be
given to refractive error or accommodation impairment (which both generally
differ in near versus distance viewing and improve with pinhole) and ocular
surface dryness; the symptoms of ocular surface dryness are usually variable and
respond to topical artificial tears, which can be obtained without prescription.
In addition to bilateral presentation of the unilateral conditions discussed
above, symptoms in both eyes should prompt consideration of chiasmal or
retrochiasmal disease. Chiasm-impacting diseases with increased incidence in
pregnant women include enlargement of pituitary tumors, Sheehan syndrome
due to hemorrhage into an infarcted pituitary tumor, lymphocytic hypophysitis,
and, rarely, physiologic pituitary enlargement.34 For more information on
pituitary tumors, refer to the article “Managing Central Nervous System Tumors
During Pregnancy” by Na Tosha N. Gatson, MD, PhD, FAAN,33 in this issue of
Continuum. All of these can cause classic bitemporal visual field loss but also
unilateral vision loss as well as cranial nerve III, IV, V, or VI palsy due to
cavernous sinus extension. Lymphocytic hypophysitis is an inflammatory
condition of the pituitary thought to be autoimmune in etiology that is clinically
and radiologically heterogeneous. The most common symptoms are
hypopituitarism, headaches, and vision loss. Half of all cases of lymphocytic
hypophysitis occur in association with pregnancy (CASE 7-1).35 For pregnant
women with known pituitary adenomas, monitoring with formal visual fields
during pregnancy can be helpful to detect chiasmal dysfunction. Acute onset of
symptoms localizing to the chiasm suggests Sheehan syndrome or pituitary
apoplexy. Acute-onset vision loss localizing to retrochiasmal dysfunction
suggests stroke or PRES associated with preeclampsia/eclampsia.
Migraine with aura is less likely to remit during pregnancy than migraine without
aura, and migraine with aura can also occur de novo during pregnancy.36 Migraine
with aura may also worsen during the postpartum period because of interrupted
sleep. Typical symptoms of auras are positive visual phenomena that evolve over
10 to 20 minutes and feature movement of the image that occurs before or without
headache. Sudden onset of visual symptoms suggests ischemia. For more
information on migraine and pregnancy, refer to the article “Headache in

Pregnancy and Lactation” by Melissa Rayhill, MD, FAHS,37 in this issue

of Continuum.
PAPILLEDEMA
Although papilledema due to elevated ICP does cause visual symptoms,
including peripheral vision loss, general blur, and transient visual obscurations,
up to 50% of individuals with papilledema do not have visual symptoms.38
Evaluation for papilledema in pregnant patients with headache or other
symptoms suggestive of high ICP, such as pulsatile tinnitus, is imperative to
prompt evaluation for both primary and secondary causes of high ICP. Some
secondary causes of ICP, such as cerebral venous sinus thrombosis (diagnosed
using neuroimaging), may be more common in the third trimester and
postpartum because of the associated hypercoagulable state. If no secondary
cause is found on MRI of the brain and magnetic resonance venography (MRV)
of the brain, lumbar puncture is important to measure opening pressure and
evaluate CSF for secondary causes of high ICP. Even if a secondary cause is found
on neuroimaging, lumbar puncture may provide temporary lowering of pressure
to provide symptom relief and mitigate the short-term risk of vision loss.
Regardless of the cause of high ICP, any patient with papilledema due to high
ICP must be monitored regularly by an ophthalmologist or neuro-
ophthalmologist to assess the optic nerve appearance and peripheral visual
function so that the risk of vision loss can be appropriately managed. Because
CASE 7-2 A 35-year-old woman with a 1-year history of idiopathic intracranial

hypertension managed on acetazolamide sought prenatal consultation
regarding medication management. She had no visual symptoms and no
headaches. Visual acuity was 20/20 with each eye, and Humphrey visual
field testing was normal. She had mild fullness of both optic nerves.
Optical coherence tomography showed mild optic nerve elevation
without ganglion cell injury.
Given her lack of symptoms, she was weaned off acetazolamide over
2 months without development of symptoms or change in optic nerve
appearance. Following conception, she was monitored by her neuro-
ophthalmologist every 6 to 8 weeks. In the second trimester, her optic
nerves became more elevated, but she did not develop headaches, visual
field loss, or ganglion cell injury; therefore, no medication was started.
This remained stable throughout the remainder of her pregnancy. She had
consultations with maternal-fetal medicine and anesthesia regarding her
delivery plan. Given the lack of vision loss or signs of optic nerve injury on
examination and ophthalmic imaging, plans were made to proceed with a
vaginal delivery. This occurred spontaneously at 37 weeks with no
complications.
COMMENT This case exemplifies the medication, monitoring, and delivery planning
considerations in a pregnant woman with preexisting idiopathic intracranial
hypertension.
154 FEBRUARY 2022

vision loss from papilledema can be difficult to detect on bedside examination, KEY POINTS
formal visual field testing with automated perimetry is preferred.
● Bilateral optic disc edema
from increased intracranial
Idiopathic Intracranial Hypertension pressure does not cause
Although some people develop idiopathic intracranial hypertension (IIH) during visual symptoms in up to half
pregnancy, it is more common that women with preexisting IIH become of affected patients.
pregnant than that women without IIH prepregnancy develop it during
● Regular formal perimetry
pregnancy. (CASE 7-2). Despite the well-established association between IIH and to monitor visual fields of
weight gain, pregnancy does not typically exacerbate IIH, nor are outcomes patients with papilledema
different than in nonpregnant women with IIH.39 IIH in pregnancy was recently from primary or secondary
reviewed by Park and colleagues.40 high intracranial pressure is
important to detect vision
The goals of treatment of IIH in a pregnant woman are to prevent permanent loss so that intracranial
vision loss due to optic nerve damage and manage symptoms. Accordingly, it pressure–lowering therapy
may be appropriate not to treat IIH in a patient with mild papilledema, without can be advanced to prevent
vision loss, and no or minimal headaches. Weight loss, which is effective for further worsening.
treatment of IIH in nonpregnant people, should be undertaken with caution in
those who are pregnant. Restricted weight gain (eg, with a salt-restricted diet)
has been reported to reduce visual dysfunction.41 Oral acetazolamide, which has
Level I evidence for IIH treatment in the nonpregnant population, is classified as
Category C by the US Food and Drug Administration (FDA) using the pre-2015
classifications. Although case reports exist of fetal malformations born to people
exposed to acetazolamide, studies of 113 pregnant women who were exposed to
acetazolamide, including 59 in the first trimester, did not identify adverse
outcomes as a result of acetazolamide use.42,43 Topiramate, classified as Category
D by the FDA using the pre-2015 classifications, is associated with oral clefts.44 In
patients with no evidence of vision loss or ganglion cell injury, symptomatic
management of headache is an option. For more information about symptomatic
management of headaches in pregnant women, refer to the article “Headache in
Pregnancy and Lactation” by Melissa Rayhill, MD, FAHS,37 in this issue
of Continuum.
Lumbar puncture transiently lowers ICP and can provide longer than
expected relief in some patients. In pregnant patients with severe vision loss
associated with papilledema, surgical intervention with optic nerve sheath
fenestration or CSF diversion can be considered if the risk of vision loss
outweighs the risks of surgery and anesthesia.
Uterine contractions are associated with a rise in ICP of 3.4 cm H2O, whereas
Valsalva during delivery caused an increase of 10.8 cm H2O in a study of pregnant
women without IIH.45 Another study estimated higher increases to 70 cm H2O
during labor. Furthermore, lumbar epidural anesthesia may elevate ICP, and this
elevation may be more pronounced when baseline ICP is elevated, based on an
animal model.46 Although this increase could theoretically put additional stress
on an optic nerve with dysfunction, many people with IIH have had successful
vaginal deliveries with the aid of obstetrical anesthesia without maternal or fetal
morbidity.47 Ultimately, the decision is best made by the patient’s
multidisciplinary care team.
DIPLOPIA
If a person presents with diplopia, the first thing to check is whether it resolves
with covering either eye. Resolution with covering either eye suggests that the
person is experiencing binocular diplopia (one image coming from each eye) due

to ocular misalignment. If the diplopia persists when one eye is covered, it is

monocular diplopia attributable to an optical cause in the eye (refer to the
discussion on refractive error and dry eye above). Lack of diplopia does not
exclude ocular misalignment (eg, in people with poor vision in one eye or
poor binocularity).
Careful examination of eye movements and ocular alignment in different
directions of gaze is helpful to localize the underlying cause of binocular diplopia
or ocular misalignment. Other clues can be gathered from the symptoms: vertical
or oblique diplopia suggests involvement of the superior oblique or vertical
rectus muscles, horizontal diplopia worse at distance suggests esotropia, and
horizontal diplopia worse at near suggests exotropia. For example, horizontal
diplopia worse at distance that resolves when looking to the left suggests a right
sixth nerve palsy. Symptom patterns and measurable misalignment may be
apparent before obvious extraocular motility deficits manifest.
Idiopathic cranial nerve palsies can occur during pregnancy but are diagnoses
of exclusion. Sixth nerve palsies are associated with gestational hypertension and
preeclampsia. They can also result from intracranial hypertension and may be a
presenting sign of cerebral venous sinus thrombosis. Intracranial hypotension
(eg, after lumbar puncture or inadvertent dural puncture during obstetric
anesthesia) can also cause sixth nerve palsy.48
Cavernous sinus invasion because of pituitary tumor growth, pituitary
apoplexy, Sheehan syndrome, or lymphocytic hypophysitis can cause diplopia
through dysfunction of cranial nerves III, IV, and VI, with cranial nerve VI being
the most commonly affected. Numbness in the forehead and cheek suggestive of
involvement of the V1 and V2 divisions of the trigeminal nerve and Horner
syndrome can also occur in cavernous sinus disease. Skull base meningiomas can
grow during pregnancy to impact cranial nerves and have been reported to
recover after delivery.49
CASE 7-3 A 27-year-old woman at 15 weeks’ gestation presented with blurry vision
and fatigue. She described excessive vomiting for the past 7 weeks, with
a weight loss of 12 kg (26.5 lb), for which she had not received care. On
examination, she had upbeat nystagmus, and her extraocular movements
were full without diplopia. Her gait was unsteady. Thiamine deficiency
causing partial Wernicke encephalopathy was suspected, and she was
empirically treated with IV thiamine and IV fluids while blood test results
were pending. Over the ensuing days, her fatigue and blurry vision
resolved. Following treatment with antiemetics, she was able to tolerate
an oral diet.
COMMENT This case exemplifies the clinical presentation of thiamine deficiency

induced by malnutrition due to hyperemesis gravidarum. Maintaining a high
clinical suspicion for malnutrition in patients with hyperemesis gravidarum
is critically important to allow for prompt diagnosis and treatment as
delayed treatment is associated with permanent sequelae, including
Korsakoff syndrome characterized by memory loss.
156 FEBRUARY 2022

As in nonpregnant people, an expanding posterior communicating artery KEY POINTS
aneurysm in pregnant women is a cause of cranial nerve III palsy, necessitating
● Sixth nerve palsies in
emergent treatment. Parenchymal disease due to multiple sclerosis, strokes, or pregnancy can result from
tumors can cause diplopia because of internuclear ophthalmoplegia and intracranial hypertension
skew deviation. (eg, due to cerebral venous
Diplopia, ophthalmoplegia, and/or nystagmus can occur because of thiamine sinus thrombosis) and
hypotension (eg, due to
deficiency as part of Wernicke encephalopathy (CASE 7-3). Other symptoms
dural puncture during
include ataxia and confusion. The funduscopic examination can show anesthesia).
hemorrhages. Wernicke encephalopathy can be provoked by hyperemesis
gravidarum, and urgent repletion with IV thiamine should be instituted.50 ● Growth of sellar and
Ocular myasthenia gravis and thyroid eye disease are autoimmune diseases suprasellar structures during
pregnancy can cause vision
impacting the neuromuscular junction and extraocular muscles that can cause loss, diplopia, facial
diplopia. Ocular myasthenia gravis can improve, worsen, or stabilize during numbness, and Horner
pregnancy. Because ptosis and diplopia are not life-threatening symptoms, syndrome.
conservative management with patching one eye (applying translucent tape to
● Eye movement
glasses is often effective) and cosmetic lid tape can be offered if medications are abnormalities can be caused
being avoided. For more information on myasthenia gravis and pregnancy, refer by thiamine deficiency
to the article “Neuromuscular Disorders and Pregnancy” by Janice M. Massey, provoked by hyperemesis
MD, FAAN, and Karissa Gable, MD,51 in this issue of Continuum. Preexisting gravidarum, which requires
urgent treatment.
thyroid eye disease has a variable course during pregnancy and can cause
worsening of orbital signs, diplopia, and lid retraction in some people.52 Although ● Facial nerve palsy is the
conservative management is generally appropriate, severe cases may need orbital most common cranial nerve
decompression to reverse compressive optic neuropathy.53 Detection and palsy in pregnancy.
treatment of associated thyroid hormone dysregulation is important for the
health of the pregnancy.
OTHER EYE AND FACIAL SYMPTOMS

Symptoms involving the eyelids, facial muscles, and pupils, as well as pain in the
eyes and face, can occur in association with pregnancy.
Eyelid and Facial Abnormalities

The palpebral fissure can appear smaller because of ptosis and larger because
of lid retraction or proptosis. Isolated Horner syndrome causing a small
pupil and mild ipsilateral ptosis can occur because of migration of spinal
anesthetic,54 but carotid dissection should also be considered (CASE 7-4).
Myasthenia gravis can cause fluctuating ptosis, often with variable diplopia.
Ptosis in association with extraocular motility limitations suggests third cranial
nerve palsy. Aponeurotic ptosis due to hormonal effects on the levator
palpebrae muscle can manifest during pregnancy.55 The eye can appear
prominent, with sclera visible superior or inferior to the iris in the relaxed state
because of orbicularis oculi weakness from cranial nerve VII palsy, lid
retraction from thyroid eye disease, or proptosis because of increased orbital
volume due to mass or inflammation.
Cranial nerve VII palsy is approximately 3 times more common in pregnant
women than in nonpregnant women of similar age, typically developing
during the third trimester, and may be associated with worse long-term
outcomes.57 Perineural edema causing compression, hypercoagulability, and
viral reactivation may contribute.58 Some experts advocate for treatment with
steroids, as in non–pregnancy-associated cranial nerve VII palsy, citing safe
use of steroids for other conditions in pregnancy along with the association

with better outcomes in nonpregnant people.58 Cranial nerve VII palsy has
been reported in association with spinal and epidural anesthesia.48 If the eyelid
does not close completely, protection of the ocular surface with frequent
application of ocular lubricant and taping the lid shut overnight is important.
Surgical tarsorrhaphy can be performed if patients have ocular surface
damage.
An enlarged palpebral fissure due to mild proptosis can appear similar to
cranial nerve VII palsy. One cause of this is orbital varices, which can become
symptomatic in pregnancy because of changes in hemodynamics that cause
orbital fullness that is worse with bending over or Valsalva.59
Pupil Abnormalities
The pupil can be large because of impaired parasympathetic response or small
because of impaired sympathetic response. Comparison of pupil asymmetry in
light and dark environments helps to determine which is the abnormal pupil. As
in nonpregnant people, the most concerning cause of a large pupil with
anisocoria more pronounced in light is a posterior communicating artery
aneurysm, and careful examination should be pursued to detect ipsilateral ptosis
and ocular motility limitations to suggest third nerve palsy. A small pupil with
anisocoria worse in dark is concerning for Horner syndrome, as discussed above.
Impaired accommodation can occur in association with migraine or
idiopathically to cause bilateral large pupils with blurry vision at near that
resolves with pinhole or reading glasses. A relative afferent pupillary defect
suggests optic nerve dysfunction.
CASE 7-4 A 30-year-old woman was noted to have left ptosis following vaginal
delivery of a healthy baby. She had no other symptoms. During delivery,
she had received epidural analgesia with a T8 sensory level. On
examination, she had 1 mm of relative ptosis of the left eye with
symmetric levator function. In dark, the right pupil was 4 mm and the left
pupil was 1 mm. In light, the right pupil was 2 mm and the left pupil was
1 mm. A diagnosis of a left Horner syndrome was made. Magnetic
resonance angiography (MRA) of the neck with fat saturation did not
show carotid dissection, and her symptoms were presumed to be due to
upward spread of anesthetic in the epidural space to impact the
sympathetic fibers at their site of origination in the lower cervical and
upper thoracic spinal cord. The ptosis and miosis resolved within
24 hours.
COMMENT This case demonstrates Horner syndrome developing from anesthetic

migration. As this is a diagnosis of exclusion, neuroimaging was performed
to exclude alternative causes. For more information on spread of
anesthetic in pregnant women, refer to the article “Neurologic
Complications of Obstetric Anesthesia” by Janet F. R. Waters, MD, MBA,
FAAN,56 in this issue of Continuum.
158 FEBRUARY 2022

Eye Pain KEY POINT
If patients have localized eye pain, an ophthalmologic examination is advised to
● Artificial tears are the
exclude eye disease (eg, uveitis, corneal abrasion) as a cause of the pain. Dry eye, first-line treatment for
which increases during pregnancy, can cause eye pain that may worsen at the end management of eye pain and
of the day or after screen use. Initial treatment is with nonprescription artificial blur due to dry eye.
tears 3 to 4 times daily to improve the ocular surface and prevent dryness from
developing. Primary headache syndromes are commonly associated with eye
pain that is not necessarily temporally coincident with the headache. This can be
managed together with the eye pain.
CONCLUSION
The approach to neuro-ophthalmic symptoms and signs in a pregnant patient is
similar to that for people who are not pregnant, including obtaining a thorough
history and careful examination. The differential diagnosis should consider any
preexisting disease; the physiologic changes of pregnancy; the pathophysiologic
changes of pregnancy, particularly eclampsia; and disease processes that are
more prevalent during pregnancy. Evaluation and management should consider
risks and benefits to both the parent and the fetus.
ACKNOWLEDGMENT
This work was supported by a grant from the National Institutes of Health
(P30 EY 026 877) and an unrestricted grant from Research to Prevent Blindness.
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628-632. doi:10.1136/bjo.55.9.628

REVIEW ARTICLE

Neurologic
ONLINE
Complications of
Obstetric Anesthesia
By Janet F. R. Waters, MD, MBA, FAAN
Downloaded from http://journals.lww.com/continuum by dk0DVdnDV+fUlnl1Ul6LIOKG9b/NnbZSXSsgz6LbMijmA29e3msQ7A8r2fAzgSo/H2Nb9wN89d9MJGM/4JnjwKQoWw37vi+9LBO50DUrg9viSIgyryVQ+ksyNnYGQk4t on 02/13/2022
ABSTRACT
PURPOSE OF REVIEW: The advantages of neuraxial anesthesia over general
anesthesia in the obstetric population are well established. Some
neurologic conditions have the potential to lower the safety threshold for
administration of neuraxial anesthesia, whereas others require special
consideration before using general anesthesia. The aim of this article is to
help neurologists determine when neuraxial anesthesia can be safely
administered and when it is inadvisable.
RECENT FINDINGS: Neuraxial anesthesia can usually be given safely in most

pregnant patients with neurologic disease. Patients with mass lesions
causing increased intracranial pressure or spinal tumors at the site of
neuraxial needle placement and patients on anticoagulant medication are
the exceptions. Post–dural puncture headaches and obstetric nerve
injuries are the most common complications of neuraxial anesthesia and
resolve in most patients. Other complications, including epidural
hematoma, meningitis, and epidural abscess, are rare but devastating.
SUMMARY: This article provides a review of neurologic diseases that may

affect the decision-making process for anesthesia during delivery. It
discusses the neurologic complications that can occur because of
obstetric anesthesia and how to recognize them and describes obstetric
CITE AS:
nerve injuries and how to distinguish these relatively benign injuries from
2022;2 8 (1 , N E U R O L O G Y O F more serious complications.
PREGNANCY):162–179.
Dr Janet F. R. Waters, Kaufman INTRODUCTION
T
Medical Building, 3471 Fifth Ave, he advantages of neuraxial anesthesia (epidural and spinal anesthesia)
Ste 810, Pittsburgh, PA 15232,
watersjf@upmc.edu. over general anesthesia in pregnant women are well established.1-4
The incidence of failed intubation is 8 times higher in pregnant
women than among nonpregnant women,5 and the incidence of fatal
Dr Waters reports no disclosure.
failed intubation is 13 times higher.4,6 This is related to edema and
UNLABELED USE OF capillary engorgement of the airway that occur with pregnancy and can be
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
exacerbated in women who have preeclampsia. Pregnant women desaturate
Dr Waters reports no disclosure. more quickly when difficulty in intubating is encountered because of decreased
lung capacity from the uterus pressing up against the diaphragm. This reduction
© 2022 American Academy is even greater in a patient who is obese. Medications used in general anesthesia,
of Neurology. such as isoflurane and sevoflurane, prevent the uterus from contracting and can
162 FEBRUARY 2022

lead to increased bleeding after delivery. General anesthetic agents cross the KEY POINTS
placenta, and the newborn may be drowsy and have difficulty taking their first
● Women with multiple
breath. Epidural and spinal anesthesia are clearly preferable when they can be sclerosis who are pregnant
safely administered. Some neurologic conditions have the potential to lower the often have less frequent
safety threshold for administration of neuraxial anesthesia, and others require exacerbations than women
special consideration before using general anesthesia. The aim of this article is to with multiple sclerosis who
are not pregnant. Flare-ups
help neurologists determine when neuraxial anesthesia can be safely
increase in the postpartum
administered and when it is inadvisable. Neurologic complications that can occur period.
as a result of obstetric anesthesia and how to recognize them are also discussed.
Finally, the article describes obstetric nerve injuries and how to distinguish these ● Neuraxial anesthesia may
relatively benign injuries from more serious complications such as epidural be given safely in women
with multiple sclerosis.
hematoma, cauda equina syndrome, and spinal cord injuries.
● Studies show that the use
ANESTHESIA CONSIDERATIONS FOR PATIENTS WITH of neuraxial anesthesia
NEUROLOGIC DISEASE poses no risk to women with
Chiari malformation type I in
It is not uncommon for obstetricians and obstetric anesthesiologists to consult a the absence of increased
neurologist to help determine the safest way to provide anesthesia to pregnant intracranial pressure. Spinal
women with preexisting neurologic disease. This section reviews some of the and epidural anesthesia may
common and less common neurologic illnesses seen in pregnant women and be given safely in pregnant
women with syringomyelia.
discusses safety issues in anesthesia management.
● Although elevated
Multiple Sclerosis intracranial hypertension
Multiple sclerosis (MS) is one of the most common diseases of the central due to a mass lesion is a
nervous system, affecting 400,000 people in the United States.7 It is contraindication to neuraxial
anesthesia because of the
characterized by focal central nervous system demyelination. It is twice as risk of herniation, it is safe in
common in women than men and is often diagnosed in the childbearing years.8 patients with idiopathic
Pregnancy is not uncommon in women with MS. It has been observed that intracranial hypertension
women with MS who are pregnant have less frequent exacerbations than women and may be therapeutic in
these patients.
with MS who are not pregnant. However, the rate of exacerbation is increased by
as much as 50% in the 3 months following delivery.7 In the past, this observation ● General anesthesia
left many anesthesiologists reluctant to administer neuraxial anesthesia in should be avoided, if
women with MS because of concern that neurotoxicity of analgesic agents could possible, in patients with
idiopathic intracranial
play a role in postpartum flare-ups. The PRIMS (Pregnancy in Multiple Sclerosis)
hypertension because of the
study published in 2004 put this notion to rest.9 The study followed 277 women risk of increased intracranial
for up to 2 years following delivery. No difference in relapse rate was seen pressure during intubation.
between women who received neuraxial anesthesia and those who did not. A Obesity puts these patients
at increased risk for difficult
prospective study that followed 423 pregnancies in 415 women for 1 year
intubation and aspiration.
postpartum found no increase in MS-related disease or disability in women who
received neuraxial anesthesia.10 Therefore, MS is no longer considered a ● Epidural and spinal
contraindication to neuraxial anesthesia. anesthesia is preferable in
pregnant women with
myasthenia gravis. When
Chiari Malformation general anesthesia is used,
Chiari malformations types I through IV are a group of congenital posterior fossa extubation can be
abnormalities affecting the structural relationships between the bony cranial challenging. If general
base, cerebellum, brainstem, and cervical cord.11 Chiari malformation type I is anesthesia is used,
depolarizing agents
defined as a descent of the cerebellar tonsils below the foramen magnum by (including succinylcholine)
5 mm or more.12 Patients may have an associated cervical syrinx.13 In patients should be avoided because
with Chiari malformation type II, both the cerebellum and brainstem tissue of the risk of neuromuscular
protrude into the foramen magnum. Abnormalities of the cerebellum are also blockade.
seen, and the malformation is often accompanied by a myelomeningocele, a form

NEUROLOGIC COMPLICATIONS OF OBSTETRIC ANESTHESIA
of spina bifida that occurs when the spinal canal and backbone do not close
before birth. In Chiari malformation type III, patients have herniation of the
cerebellum with or without the brainstem through a posterior encephalocele.
Chiari malformation type IV is defined as cerebellar hypoplasia or aplasia with
normal posterior fossa and no hindbrain herniation. Chiari malformation types
III and IV are rare and generally lethal.14,15
Chiari malformation type 1 is common and can be found in 0.6 percent of the
population. Patients with Chiari malformation type I can be asymptomatic or
may present with a constellation of symptoms, including headaches that are
exacerbated by coughing, Valsalva maneuvers, or positional changes. Patients
who are more severely affected may present with cerebellar symptoms,
quadriparesis, lower cranial nerve palsies, and central cord signs. As the use of
brain imaging has become more common, Chiari malformation type I is more
frequently discovered, often as an incidental finding.
In the past, anesthesiologists have been reluctant to offer neuraxial anesthesia
to women with Chiari malformation type I because of concerns for changes in
pressure gradients associated with dural puncture. It has been well established
that neuraxial anesthesia poses no risk to women with decompressed Chiari
malformation type I.15 In 2017, a retrospective review was carried out for 97
deliveries of women with untreated Chiari malformation type I over a 5-year
period. Neuraxial anesthesia was administered to 62 of the deliveries without
adverse effect.15 The study concluded that in women with Chiari malformation
type I who had no signs or symptoms of increased intracranial pressure,
neuraxial anesthesia can safely be administered. A number of smaller studies also
support the safety of spinal and epidural anesthesia in women with Chiari
malformation type I.4,14-18
Syringomyelia
Syringomyelia refers to a fluid-filled column within the spinal cord. It can be seen
in 40% to 60% of patients with Chiari malformation type I. It can also be
associated with tethered cord syndrome, arachnoiditis, and trauma. Patients with
a small syrinx are often asymptomatic. Some concern exists about the risk of
extension of a syrinx with rapid epidural bolus injection; however, the literature
does not support this theoretical complication.19,20 In 2017, Garvey and
colleagues19 identified 21 women with Chiari malformation type I with an
associated syrinx. No anesthesia-related adverse events occurred in the 17
patients who received neuraxial anesthesia. If a syrinx becomes progressively
symptomatic during pregnancy, some clinicians advocate administration of
epidural boluses slowly.
Idiopathic Increased Intracranial Pressure

Idiopathic increased intracranial pressure is characterized by an elevated CSF
pressure without a structural etiology, such as a space-occupying lesion or
venous sinus thrombosis. The mechanism is not well understood, but some
experts have postulated that insufficient reabsorption of CSF may be the cause. It
occurs most often in women of childbearing age who are obese. Symptoms
include severe headache that worsens with lying flat, visual loss, and pulsatile
tinnitus. It is often, but not always, accompanied by papilledema. Diagnosis is
confirmed by lumbar puncture with CSF pressure exceeding 250 mm H2O in the
absence of a mass lesion on MRI or venous thrombosis on magnetic resonance
164 FEBRUARY 2022

venography (MRV). Treatment is with carbonic anhydrase inhibitors. Although KEY POINTS
the teratogenicity of carbonic anhydrase inhibitors in humans has not been well
● Meningiomas,
studied, the absence of reported adverse fetal outcomes in the human population schwannomas, and gliomas
suggests they are safe to use in pregnancy.21 Idiopathic increased intracranial may all have accelerated
pressure is not a contraindication to vaginal delivery, and neuraxial anesthesia growth in pregnancy. If
may be safer than general anesthesia in this patient population.22 Although increased intracranial
pressure is demonstrated,
elevated intracranial pressure due to a mass lesion is a contraindication to
neuraxial anesthesia should
neuraxial anesthesia because of the risk of herniation, patients with idiopathic be avoided because of the
increased intracranial pressure do not have a pressure differential or obstruction risk of herniation.
to communication between the cranial and spinal CSF compartments.23 Dural
puncture is safe and may be therapeutic in these patients.23,24 General anesthesia ● General anesthesia
presents risk in pregnant
should be avoided, if possible, because of the risk of increased intracranial women with brain tumors.
pressure during intubation.14 Obesity also puts these patients at increased risk for An increase in intracranial
difficult intubation and aspiration. If general anesthesia becomes necessary, pressure can occur during
succinylcholine is relatively contraindicated because of transient intracranial induction and intubation.
pressure elevation. Use of rocuronium may be preferable.14 ● In most pregnant women
with brain tumors without
Myasthenia Gravis mass effect and increased
Myasthenia gravis is a chronic autoimmune disorder in which antibodies to the intracranial pressure,
neuraxial anesthesia can be
postsynaptic neuromuscular junction cause impairment of striated muscle
safely administered. A
function. It occurs at a case rate of 20 per 100,000 individuals and is more case-by-case assessment of
common in women than men, with a ratio of 3:2.25 It is unmasked or exacerbated these patients is indicated.
in one-third of pregnant women, with worsening symptoms occurring most
commonly during the first trimester, the last 4 weeks of gestation, during ● In patients with
neurofibromatosis, the
delivery, and in the postpartum period. Patients with this disorder experience presence of lumbar tumors
fluctuating weakness in voluntary muscles, leading to ptosis, diplopia, dysphagia, can increase the risk of
dysarthria, and proximal limb weakness. Diagnosis is confirmed by elevated epidural hematoma during
serum levels of acetylcholine receptor (AChR) or muscle-specific tyrosine kinase spinal and epidural needle
placement. Pregnant
(MuSK) antibodies. Patients who are seronegative may undergo EMG studies women with
with repetitive nerve stimulation and single-fiber studies for confirmation. neurofibromatosis should
Epidural and spinal anesthesia may be used safely in these patients. Regional undergo noncontrast MRI of
anesthesia is recommended in patients undergoing cesarean delivery. Extubation the lumbar spine before
undergoing neuraxial
after general anesthesia can present challenges in these patients. If general anesthesia.
anesthesia is used, depolarizing agents (including succinylcholine) should be
avoided. Nondepolarizing agents, such as vecuronium and rocuronium, are an ● Patients with
option; however, reversal should be with sugammadex, which is a binding agent Guillain-Barré syndrome are
at no increased risk with the
that envelops the nondepolarizing agents.25
use of neuraxial anesthesia
but should be monitored
Brain Tumors carefully for the
Meningiomas, schwannomas, and gliomas may all have accelerated growth in development of
pregnancy. Rising estrogen and progesterone levels are thought to be responsible. hypotension due to
autonomic dysfunction and
Treatment of less aggressive tumors is usually delayed until after delivery. Rapid exaggerated vasovagal
growth and mass effect may necessitate immediate treatment and early delivery. response. If general
A multidisciplinary team should be involved in delivery planning for pregnant anesthesia is used,
women with brain tumors, including neurology, neurosurgery, obstetrics, and succinylcholine is
contraindicated because of
obstetric anesthesiology. Neurologic examination and neuroimaging should be the potential for
reviewed to assess for mass effect and increased intracranial pressure. life-threatening
If increased intracranial pressure is demonstrated, neuraxial anesthesia should hyperkalemia.
be avoided because of the risk of herniation. Even in the hands of experienced
anesthesiologists, epidural placement can result in inadvertent dural puncture.

Concern of further elevation of intracranial pressure also exists following

large-volume or bolus epidural catheter dosing.
General anesthesia also presents risk. An increase in intracranial pressure can
occur during induction and intubation. Hypercarbia should always be avoided in
patients with increased intracranial pressure. Hyperventilation and hypocarbia
should be reserved for emergent need to reduce intracranial pressure.
Hyperventilation can lead to vasoconstriction, cerebral hypoperfusion, uterine
artery vasoconstriction, and decreased blood flow to the fetus.26 In most patients
with brain tumors without mass effect and increase in intracranial pressure,
neuraxial anesthesia can be safely administered. A case-by-case assessment of
these patients is indicated.
Neurofibromatosis
Neurofibromatosis is an autosomal dominant hereditary disorder that causes
tumor formation on nerve tissue. Neurofibromatosis type 1 is characterized by
café au lait spots and tumor growth along nerves in the skin, brain, and spine.
Neurofibromatosis type 2 is associated with vestibular schwannomas and hearing
loss. Pregnancy can increase tumor growth in both types. The presence of lumbar
tumors can increase the risk of epidural hematoma during spinal and epidural
needle placement. Pregnant women with neurofibromatosis should undergo
noncontrast MRI of the lumbar spine before undergoing neuraxial anesthesia.
Consultation with a neurologist and an obstetric anesthesiologist should take
place before delivery to determine whether patients are candidates for
neuraxial anesthesia.
Guillain-Barré Syndrome
Guillain-Barré syndrome, the most common form of which is acute
inflammatory demyelinating polyradiculoneuropathy (AIDP), is an
immune-mediated monophasic disorder that manifests as a rapidly progressive
neuropathy that can result in weakness and sensory loss. It typically causes an
ascending pattern of weakness that can involve the muscles of respiration.
Cranial nerve involvement and autonomic dysfunction may also occur. It
sometimes develops following a viral illness or vaccine and may occur at
increased frequency in the postpartum period.17 Patients with Guillain-Barré
syndrome are at no increased risk with the use of neuraxial anesthesia but should
be monitored carefully for the development of hypotension due to autonomic
dysfunction and exaggerated vasovagal response. If general anesthesia is used,
succinylcholine is contraindicated because of the potential for life-threatening
hyperkalemia.27
Ventriculoperitoneal and Lumboperitoneal Shunts

Epidural or spinal anesthesia is not contraindicated in women with
ventriculoperitoneal shunts. Most women with lumboperitoneal shunts are also
able to undergo neuraxial anesthesia; however, imaging may be needed before
delivery to ascertain the position of the shunt. The point of needle entry can then
be adjusted as needed to avoid disruption or entanglement of the spinal portion
of the shunt. Spinal anesthesia may be unpredictable and of shorter duration if
local anesthetic leaks via the shunt into the peritoneal cavity, which can lead to an
inadequate block.28
166 FEBRUARY 2022

Myotonic Dystrophy KEY POINTS
Myotonic dystrophy is the most common adult muscular dystrophy, occurring in
● Most women with
1 to 2 of 8000 patients.14 It is an autosomal dominant inherited disease with lumboperitoneal shunts are
progressive but variable severity of symptoms. It is divided into two subtypes, able to undergo neuraxial
type 1 (DM1) and type 2 (DM2). DM1 is the more severe of the two and presents anesthesia; however,
earlier in life with myotonia, muscle weakness and atrophy, intellectual imaging may be needed
before delivery to ascertain
disability, premature cataracts, impaired intestinal motility, hypogonadism,
the position of the shunt.
insulin resistance, and cardiac conduction abnormalities. Although DM2 shares Spinal anesthesia may be
many of the same features as DM1, the average age of onset is 30 to 50, and it unpredictable and of
tends to be limited to proximal muscle involvement. Myotonic dystrophy is shorter duration if local
anesthetic leaks via the
associated with infertility, but those who achieve pregnancy are at a higher risk
shunt into the peritoneal
of complications, with a significantly higher risk of placenta previa and preterm cavity, which can lead to an
delivery.29 Delivery may be difficult in some patients because of uterine smooth inadequate block.
muscle abnormality, which can affect all stages of labor. The second stage of
labor may be prolonged because of skeletal muscle weakness. The need for ● In pregnant women with
myotonic dystrophy,
cesarean or instrumental delivery is higher in women with myotonic dystrophy delivery may be difficult
than in the general population.30 General anesthesia should be avoided in because of uterine smooth
patients with myotonic dystrophy, if possible, as they are at high risk for muscle abnormality, which
aspiration because of pharyngeal muscle weakness and gastric immotility.31 can affect all stages of
labor. The second stage of
Triggers for myotonia should be avoided, including hypothermia and shivering. labor may be prolonged
Respiratory complications can occur in the postoperative period, and opioid use because of skeletal muscle
should be minimized. No neurologic contraindications to neuraxial anesthesia weakness.
have been identified in patients with myotonic dystrophy.
● General anesthesia
should be avoided in
Spinal Muscular Atrophy patients with myotonic
Spinal muscular atrophy (SMA) occurs in 1 in 10,000 births and is the leading dystrophy, if possible, as
inherited cause of infant mortality, most often due to respiratory failure.32 The they are at high risk for
disease causes degeneration of the spinal anterior motor neurons, resulting in aspiration because of
pharyngeal muscle
skeletal muscle weakness and atrophy, scoliosis, dysphagia, and autonomic weakness and gastric
dysfunction. SMA has four types. SMA types 3 and 4 are rare milder forms of the immotility. Triggers for
disease and do not seem to affect labor and delivery. Obstetric issues are seen myotonia should be
most often in women with SMA type 2 and occur at a rate of 80%.33 avoided, including
hypothermia and shivering.
Complications include preterm labor, increased muscle weakness, and restrictive Respiratory complications
lung disease related to uterine expansion.29 Worsened neurologic deficits persist can occur in the
after delivery in half of these patients. Anesthetic concerns for pregnant women postoperative period, and
with SMA are considerable. Pulmonary complications are the leading cause of opioid use should be
minimized.
morbidity and mortality in patients with this disorder, and pulmonary
consultation to assess respiratory status before delivery is advisable.34 Intubation
is difficult in this population, as many have limited jaw opening because of
mandibular joint ankylosis and cervical immobility. Nondepolarizing
neuromuscular blockers have a prolonged effect on patients with SMA even after
reversal, but with the use of sugammadex, these agents should be safe.35 If
nondepolarizing neuromuscular blockers are used, direct transfer to an intensive
care unit setting after delivery is advisable.36 Neuraxial anesthesia is preferable to
general anesthesia but may not be feasible in some patients with severe scoliosis.
Imaging before placement of epidural or spinal anesthesia can be helpful.37
NEURAXIAL ANESTHESIA
TABLE 8-1 summarizes recommendations for the use of neuraxial anesthesia in
patients with neurologic illness. Neuraxial anesthesia may be achieved through

epidural or spinal injection. The level of injection for both is at the L2-L3, L3-L4,
or L4-L5 interspaces. Spinal anesthesia is generally used for elective cesarean
deliveries. In spinal anesthesia, a single shot of bupivacaine and morphine is
injected into the intrathecal space. The goal is to provide anesthesia from T4
caudally. Epidural anesthesia is used for labor analgesia and for cesarean delivery
when the duration of surgery is longer than routine. A catheter is threaded into
the epidural space for continuous analgesia over a prolonged period. A combined
spinal-epidural technique can be used for prolonged periods of analgesia both
before and after delivery, and it can be used for prolonged complex cesarean
deliveries or cesarean hysterectomy. The onset of analgesia for spinal anesthesia
is faster (2 to 5 minutes) than with epidural anesthesia (10 to 15 minutes). When
implementing a combined spinal-epidural technique, an epidural needle is placed
first, followed by the advancement of a spinal needle into the intrathecal space
TABLE 8-1 Recommendations on the Use of Neuraxial Anesthesia in Patients With

Neurologic Illness
Neurologic conditions that do not pose increased risk for women undergoing neuraxial
anesthesia
◆ Epilepsy
◆ Preeclampsia and eclampsia
◆ Chiari malformation in absence of increased intracranial pressure
◆ Syringomyelia
◆ Guillain-Barré syndrome
◆ Multiple sclerosis
◆ Idiopathic increased intracranial pressure
◆ Aneurysm
◆ Arteriovenous malformation
◆ Ventricular shunt
◆ Aspirin use
Neurologic conditions that should be reviewed on a case-by-case basis before neuraxial
anesthesia
◆ Brain tumor
◆ Neurofibromatosis
◆ Lumboperitoneal shunt
◆ Spinal muscular atrophy
◆ Spina bifida
Contraindications to neuraxial anesthesia
◆ International normalized ratio (INR) greater than 1.6
◆ Anticoagulant medications
◆ Platelet inhibitors (eg, clopidogrel)
◆ Brain tumors with mass effect and increased intracranial pressure
168 FEBRUARY 2022

through the epidural needle. Medicine is injected intrathecally followed by the
withdrawal of the spinal needle. A catheter is then threaded into the epidural
space through the epidural needle. The catheter will allow redosing of medication
as needed.
Neurologic Complications of Neuraxial Anesthesia

Neurologic deficits during or following labor and delivery can occur because
of obstetric trauma. Neuraxial anesthesia may also cause neurologic injury.
Differentiation between the two mechanisms can present a diagnostic
challenge. A sound understanding of the kinds of neurologic injury that can
occur and the mechanism of these injuries is instrumental in caring for
these patients.
POST–DURAL PUNCTURE HEADACHE. Post–dural puncture headache is the most

common complication of neuraxial anesthesia. It occurs in 1.5% to 11.2% of
patients who receive spinal anesthesia, depending on the size of the needle
used.38 The use of a pencil-point spinal needle reduces the risk of a dural
puncture headache closer to the lower end of the range.
In patients receiving epidural anesthesia, the rate of accidental dural puncture
is 0.04% to 6%39-41; of those, 45% to 80% experience a low CSF pressure headache.42
Post–dural puncture headache is thought to be due to CSF leakage through the hole
in the dural sac. Symptoms usually occur 24 to 48 hours after dural puncture,
although it may occur as late as 5 days after dural puncture. The headache
resulting from CSF leak is bilateral and frontooccipital, radiates to the neck, and
worsens on standing or sitting upright. It may be associated with hyperacusis,
double vision, photophobia, and nausea. It can be distinguished from migraine
and other types of headache by its postural nature, occurring within 15 minutes
of standing or sitting and resolving within 15 minutes of lying down (CASE 8-1).
A 26-year-old woman underwent epidural placement before an CASE 8-1

unremarkable delivery. During placement, a dural puncture occurred.
The following day when the patient stood to walk, she noted a severe
bifrontal headache and a change in her hearing, with ringing in the ears.
She also had some neck pain but no fever. Her symptoms improved after
she lay down. The postural headache persisted the following day but
then improved, and she was discharged to home.
The patient returned to the emergency department the next day,
reporting the headache was worse and did not improve when supine. She
underwent CT of the head, which revealed a subdural hematoma. The
hematoma was not large enough to require surgical intervention and
resolved spontaneously. The patient recovered well.
This patient experienced a low CSF pressure headache and then COMMENT
subsequently developed a subdural hematoma because of stretching of
bridging meningeal veins. When post–dural puncture headaches persist or
change, other causes for the headache should be sought.

Risk factors for post–dural puncture headache include young age, small body
habitus, history of headaches, female sex, and pregnancy.4 Treatment starts with
conservative management, including bed rest for patients who cannot tolerate
ambulation, adequate hydration, and analgesics.43 Although some clinicians
advocate the use of caffeine, this has not been supported by the literature.44 If
conservative management fails, an epidural blood patch can be placed after
24 hours. An epidural blood patch is performed by placing 15 mL to 20 mL of
autologous blood into the epidural space. The blood acts as a patch over the dura
hole. The volume of the blood is thought to push CSF back into the cranium, thus
resolving intracerebral hypotension. The effect occurs almost immediately upon
placing the blood patch.
An epidural blood patch should be done with the same strict aseptic conditions
that are used with placement of a neuraxial anesthetic. Placement at a level lower
than the initial neuraxial block is recommended as up to 70% of the blood
injected will spread cephalad. For unknown reasons, a blood patch that is placed
less than 24 hours after the inadvertent dural puncture is often ineffective. An
epidural blood patch performed 24 hours after dural puncture has success rate of
70% to 97%.42 In some circumstances, a second blood patch is needed for
complete resolution of the headache.
If two epidural blood patches have been performed and the patient still reports
a headache, neuroimaging should be considered. A rare consequence of
intracranial hypotension from dural puncture is the development of a subdural
hematoma.45 When the CSF pressure is low, the bridging veins that cross the
subdural space may tear and leak blood into the subdural space. Although most of
these hematomas will resolve without intervention, some can increase
intracerebral pressure and become life-threatening.
TABLE 8-2 Anticoagulant/Antiplatelet Agents and Waiting Period Before Neuraxial

Procedure
Medication Waiting period before neuraxial procedure
Fondaparinux 72 h
Clopidogrel 48 h
Abciximab 48 h
Enoxaparin high dose 24 h
Enoxaparin low dose 12 h
Eptifibatide 8h
Tirofiban 8h
Unfractionated heparin, high dose, IV When partial thromboplastin time (PTT)

continuous <40 s
Unfractionated heparin, low dose No time restrictions
IV = intravenous.
170 FEBRUARY 2022

In obstetrics, rare circumstances may arise following delivery that would KEY POINTS
contraindicate an epidural blood patch. Most practitioners consider the
● Intubation may be
presence of sepsis, cellulitis at the skin site, and any coagulation abnormality as difficult in patients with
reasons not to proceed with an epidural blood patch. With these precautions, spinal muscular atrophy as
the potential for complications of infection or epidural hematoma may many have limited jaw
be avoided. opening because of
mandibular joint ankylosis
and cervical immobility.
SPINAL EPIDURAL HEMATOMA. Spinal epidural hematoma formation is a rare but Depolarizing neuromuscular
serious complication of epidural anesthesia. It occurs in 1 in 500,000 to 1 in blockers have a prolonged
700,000 women who receive epidural anesthesia in pregnancy.46 Spinal epidural effect on patients with
spinal muscular atrophy
hematoma should be suspected in patients who experience anesthesia persisting
even after reversal and
for greater than the expected time of duration of action of the local anesthetic should be avoided.
used, unusual back pain and tenderness, persistent motor weakness, sensory loss, Neuraxial anesthesia is
and sphincter dysfunction. Risk factors include traumatic needle or catheter preferable to general
placement, intrinsic or iatrogenic clotting dysfunction, gestational anesthesia but may not be
feasible in some patients
thrombocytopenia, preeclampsia/eclampsia/HELLP (hemolysis, elevated liver with severe scoliosis.
enzymes, and low platelets) syndrome, and spinal cord and nerve root tumors Imaging before placement
(neurofibromatosis). The most common factor associated with the formation of epidural or spinal
of spinal epidural hematoma is the use of anticoagulant or antiplatelet agents. anesthesia can be helpful.
Patients receiving these drugs should not undergo neuraxial anesthesia until the ● Post–dural puncture
effect of the drug has subsided (TABLE 8-2). Relevant laboratory investigations, headache is the most
including coagulation profile and platelet counts, should be carried out in common complication of
patients with risk factors.42 Timely diagnosis and treatment of a spinal epidural neuraxial anesthesia. It may
be associated with
hematoma is essential to prevent permanent neurologic injury. MRI may be done
hyperacusis, double vision,
on an urgent basis to confirm the diagnosis of a spinal epidural hematoma. photophobia, and nausea. It
Emergency surgical decompression is recommended to avoid permanent can be distinguished from
neurologic dysfunction. migraine and other types of
headaches by its postural
nature.
SPINAL INJURY. Direct conus and cord injury can occur if the lower end of the
spinal cord is not accurately determined before needle insertion. In ● Treatment of post–dural
approximately 80% of adults, the spinal cord ends at the level of first lumbar puncture headache starts
vertebra; the remaining 20% have spinal cords that extend to the level of the with conservative
management, including bed
second lumbar vertebra.47 Placing the neuraxial block at the level below the rest, adequate hydration,
second lumbar vertebra reduces the risk of direct spinal cord injury.46,48,49 and analgesics. Although
When spinal cord trauma occurs, it is most often a result of direct catheter or some clinicians advocate
needle injury to the conus medullaris, spinal cord, or spinal nerve roots. It may the use of caffeine, this has
not been supported by the
also occur if local anesthetics are injected intraneurally.50,51 Trauma may present literature.
with paresthesia or pain in the lower limbs, which can be transient or persistent.
If the symptoms are transient, the anesthesiologist may go forward with the ● If conservative
procedure. If the paresthesia or pain persists in one or both lower extremities, it is management of post–dural
puncture headache fails, an
prudent to stop and reposition the needle or catheter. Local anesthetic injection into
epidural blood patch can be
the intrathecal or epidural space should be avoided in a patient who reports persistent placed. A blood patch done
neurologic symptoms, as a sensory-motor block related to the local anesthetics may less than 24 hours after the
mask the recognition of signs and symptoms of nerve or spinal cord injury. dural puncture has a high
failure rate. An epidural
blood patch performed
CAUDA EQUINA SYNDROME. Cauda equina syndrome was first described as a after 24 hours after dural
complication of anesthesia in the 1990s in the setting of the use of lidocaine for puncture has a success rate
spinal anesthesia. Continuous intrathecal microcatheters were introduced, and of 70% to 97%.
reports of cauda equina syndrome followed.52,53 Cauda equina syndrome is a
dysfunction of the L2 through S5 nerve roots. It manifests as burning low back

pain, sphincter dysfunction, lower extremity weakness, and saddle anesthesia.

Neurotoxicity caused by pooling of local anesthetic was determined to be the
source. Residual neurologic deficits can occur in some patients. Lidocaine and
tetracaine have the greatest potential for neurotoxicity. Patients with diabetic
neuropathy have a higher risk of this complication. Lidocaine is no longer
favored as a spinal anesthetic agent.42
SPINAL EPIDURAL ABSCESS. The incidence of spinal epidural abscess in women who
receive neuraxial anesthesia is rare, occurring in 1 in 200,000 to 1 in 500,000
procedures.43 Skin flora is usually the source of infection, and Staphylococcus
aureus is the most common underlying organism.54 The risk of developing an
abscess increases with prolonged duration of epidural catheterization; most
practitioners will limit the duration of catheter use to 3 days. Failure to adhere to
aseptic conditions while performing neuraxial block raises the risk of spinal
epidural abscess formation. Immunosuppression, traumatic placement, and
maternal sepsis may also contribute to a higher incidence of spinal epidural
abscess. Clinical presentation includes local back tenderness, fever, headache,
and malaise. Nerve root pain develops within 3 to 5 days of the onset of back pain,
and leg weakness, sensory loss, and bladder or bowel dysfunction may follow.
Urgent MRI with gadolinium should be done to confirm the diagnosis of spinal
epidural abscess in patients who are postpartum. Aggressive antimicrobial
therapy is the mainstay of treatment for spinal epidural abscess. Surgical
decompression may be necessary if features of nerve root or spinal cord
compression are present.
MENINGITIS. Meningeal infection is a complication of neuraxial anesthesia in 1 in

39,000 procedures.55 The incidence decreases with adherence to strict aseptic
conditions (face mask, sterile gloves, and cap). Microbial contamination from
CASE 8-2 A 32-year-old woman presented in labor at 40 weeks’ gestation. Her

blood pressure was 130/80 mm Hg and pulse was 85 beats/min. She had a
history of obesity. Epidural anesthesia was planned before vaginal
delivery, but placement was challenging. A test dose of 3 mL 1.5%
lidocaine plus epinephrine was given, immediately followed by 10 mL
0.25% bupivacaine. About 3 minutes later, the patient reported inability
to feel or move her legs. She was noted to have a third cranial nerve palsy
bilaterally with pupil dilatation. She then developed shortness of breath,
followed by marked hypotension with systolic blood pressure of 60 mm
Hg and heart rate of 40 beats/min. She required intubation and pressors
and was transferred to the intensive care unit for supportive care. She
ultimately recovered.
COMMENT This patient has a classic presentation of a total spinal block. It occurs
when the large dose of anesthetic used for epidural anesthesia is
inadvertently injected into the subarachnoid space.
172 FEBRUARY 2022

the mouth and nose of the practitioner is the most common source. The most KEY POINTS
common causative organism is Streptococcus viridans. Patients present with fever,
● A rare consequence of
headache, confusion, and neck stiffness. Confirmation is obtained with CSF intracranial hypotension
analysis, and treatment is aggressive antimicrobial therapy. Chemical meningitis from dural puncture is the
may also complicate spinal anesthesia. It occurs when lidocaine is injected into development of a subdural
the subarachnoid space. Use of lidocaine in neuraxial anesthesia is currently hematoma.
limited to epidural procedures. Chemical arachnoiditis can also occur if traces of
● Spinal epidural hematoma
chlorhexidine found in skin preparations are inadvertently introduced into the should be suspected in
subarachnoid space. Clinical features are difficult to differentiate from infective patients who experience
meningitis. Chemical meningitis resolves spontaneously; however, antimicrobial anesthesia persisting for
therapy is advisable until infection is ruled out.42 greater than the expected
duration, unusual back pain,
persistent motor weakness,
TOTAL SPINAL BLOCK. When an epidural catheter is placed, it may be inadvertently sensory loss, and sphincter
threaded into the subarachnoid space rather than the intended epidural space. To dysfunction.
assess for this complication, a test dose is given before injection of the full dose of
● Risk factors for spinal
epidural anesthesia. A test dose is a small amount of local anesthetic with epidural hematoma include
epinephrine. If the catheter has been placed into a vein, the patient will intrinsic or iatrogenic
experience tachycardia from the epinephrine and lightheadedness from local clotting dysfunction and
anesthetic neurotoxicity. If the catheter is placed into the subarachnoid space, the spinal tumors.
patient will develop lower extremity paralysis; however, because of the small
● Early diagnosis and
dose, the block does not spread beyond the umbilicus. Following administration management of a spinal
of a test dose, larger doses of local anesthetic should not be administered for 3 to epidural hematoma is
5 minutes. If this time is not given, a total spinal block may occur when the full essential to prevent
epidural dose is administered. If the test dose is not performed or if inadequate permanent neurologic
injury.
time is allowed between the test dose and the full epidural dose, accidental
placement of the epidural catheter into the subarachnoid space may go ● Direct conus and cord
unrecognized. A total spinal block will occur if a large volume of local anesthetic, injury can result if the lower
intended for the epidural space, is injected into the subarachnoid space. end of the spinal cord is not
accurately determined
A total spinal block can produce anesthesia involving the entire spinal cord, before needle placement.
nerve roots, and brainstem. When this occurs, patients develop weakness of Placement of neuraxial
lower and sometimes upper extremities. Cranial nerve findings, including block, especially spinal
pupillary dilatation, may occur (CASE 8-2). Respiratory insufficiency ensues, anesthesia, at the level
below the second lumbar
followed by cardiovascular collapse with profound hypotension and bradycardia.
vertebra reduces the risk.
Instant recognition and supportive treatment are needed to prevent maternal
and fetal demise. Treatment is primarily supportive. Patients may be placed in ● Cauda equina syndrome
the reverse Trendelenburg position to prevent further cephalad spread of the manifests as burning low
anesthetic agent. Intubation and positive pressure ventilation can be performed back pain, sphincter
dysfunction, lower
to manage respiratory insufficiency. Hypotension may be managed with extremity weakness, and
vasopressors, such as epinephrine, norepinephrine, ephedrine, or phenylephrine. saddle anesthesia. It can
Bradycardia can be treated with atropine or glycopyrrolate. Urgent cesarean develop because of
delivery may be indicated if fetal bradycardia ensues. neurotoxicity caused by
pooling of local anesthetic.
Factors that may predispose a patient to a total spinal block include obesity,
pregnancy, and the pharmacology of the anesthetic agent. Patients who are obese
often have a reduced subarachnoid space, which may favor cephalad spread of
local anesthetics. Obesity also increases intraabdominal pressure, which can
further increase risk of high block. Pregnancy may also cause increased
intraabdominal pressure.
The pharmacologic properties of the local anesthetic can play a role in the
distribution of the drug. Baricity of an anesthetic agent refers to the specific
gravity of the drug in relation to the CSF. Drugs that are hyperbaric will sink

lower in the subarachnoid space as the heavier agent displaces the lighter CSF.
Conversely, hypobaric drugs will rise higher than the CSF within the
subarachnoid space. Most local anesthetics that are used for spinal anesthesia are
hyperbaric. In contrast, local anesthetics used for administration of epidural
anesthesia are isobaric. Their density is similar to that of CSF, allowing them to
stay close to the location of their injection.42
SEIZURE FROM SYSTEMIC TOXICITY OF LOCAL ANESTHETICS. Seizures may occur when
local anesthetic is accidentally injected intravascularly. It rarely occurs after
spinal anesthesia because of the small dose of local anesthetic required to achieve
a surgical block. Systemic toxicity is more likely to occur after obstetric epidural
anesthesia because larger volumes of local anesthetics are used. When injected
into the vasculature, these drugs can have a profound effect on the central
nervous system and can produce seizures. Bupivacaine is the most seizurogenic,
followed by ropivacaine, levobupivacaine, lidocaine, and chloroprocaine.42 The
rate of the injection dictates the peak serum level, and subsequently a faster
injection will result in a quicker onset of systemic toxicity.
CASE 8-3 A 33-year-old woman delivered her first child. She received epidural
anesthesia for a prolonged period of labor. Her newborn weighed 4 kg
(9 lb). The following day she attempted to stand, but her legs buckled
beneath her. She reported no back pain and had no bowel or bladder
symptoms but reported a pins-and-needles sensation in her thighs
bilaterally. An urgent neurology consult was requested.
Motor examination revealed normal bulk and tone throughout. Upper
extremity power was normal bilaterally. Right lower extremity power was
4/5 at the iliopsoas; 3/5 quadriceps; and 5/5 hamstrings, tibialis anterior,
gastrocnemius, and extensor hallucis longus. Left lower extremity power
was 4/5 at the iliopsoas; 2+/5 quadriceps; and 5/5 hamstrings, tibialis
anterior, gastrocnemius, and extensor hallucis longus. Sensory
examination revealed decreased pinprick in the anterior medial thighs.
Reflexes were 2+ at biceps, triceps, and brachioradialis; 0 patella; and
2+ Achilles bilaterally. Toes were downgoing bilaterally. Gait could not
be assessed because of leg weakness.
MRI of the lumbosacral spine was normal. CT of the pelvis revealed no
evidence of retroperitoneal hematoma. Weakness improved but was still
present after 3 weeks. EMG confirmed bilateral femoral neuropathy. Her
symptoms continued to improve with physical therapy, and total
recovery occurred.
COMMENT This patient had classic signs and symptoms of femoral neuropathy, which
occurs when the fetal head compresses the femoral nerve at the pelvic
brim during delivery. The large size of the baby likely contributed. Femoral
nerve injury related to childbirth is bilateral in 25% of patients.
Case modified from Waters JFR.59 © 2019 Springer Nature Switzerland AG.
174 FEBRUARY 2022

OBSTETRIC NERVE INJURIES KEY POINTS
The most common lower extremity nerve injuries associated with pregnancy and
● Skin flora is the most
delivery include, in descending order, the lateral femoral cutaneous nerve, common source of infection
femoral nerve, fibular (peroneal) nerve, lumbosacral plexus, sciatic nerve, and in women who develop
obturator nerve.56-58 Use of epidural anesthesia in the management of labor pain spinal epidural abscess, and
may prolong the second stage of labor and increase the risk of nerve injury. Staphylococcus aureus is
the most common
Absence of sensation can prevent women from sensing pressure or pain so that
underlying organism. The
they are less likely to adjust their position. Other risk factors for obstetric nerve risk of developing an
injury include the following: abscess increases with
prolonged duration of
u Excessive weight gain epidural catheterization.
Urgent MRI with gadolinium
u Large fetus should be done to confirm
u Short stature the diagnosis.
u Nulliparity ● Microbial contamination

u Instrumental delivery from the mouth and nose of
the practitioner are the most
u Epidural anesthesia59 common source of
meningitis as a complication
The most common obstetric neuropathy in pregnancy involves the lateral of neuraxial anesthesia. The
most common causative
cutaneous femoral nerve, otherwise known as meralgia paresthetica.60 During organism is Streptococcus
pregnancy, the nerve may be stretched or compressed by the enlargement of the viridans. Confirmation is
abdomen. Women with this neuropathy report paresthesia in the lateral thigh. As obtained with CSF analysis,
in the general population, meralgia paresthetica in pregnancy may be treated by and treatment is aggressive
antimicrobial therapy.
wearing loose clothing and avoiding positions that aggravate the condition. In
most patients, symptoms resolve after delivery. The nerve has no motor ● A total spinal block will
component, and, unlike the nerve injuries described below, meralgia paresthetica occur if a large volume of
does not cause postpartum leg weakness. local anesthetic intended
Femoral nerve injury is the most common cause of postpartum leg weakness.61 for the epidural space is
injected into the
It occurs in 2.8 per 100,000 deliveries. In 25% of patients, the injury is bilateral subarachnoid space. It can
and causes significant impairment of mobility. The femoral nerve arises from the produce anesthesia
lumbar plexus where nerve roots L2 through L4 are joined. It passes between the involving the entire spinal
iliacus and psoas muscles, then courses under the inguinal ligament. During cord, nerve roots, and
brainstem. Cranial nerve
vaginal delivery, the femoral nerve can be compressed by the fetal head. It may findings, including pupillary
also undergo a stretch injury during hip abduction and external rotation. Patients dilatation, may occur. It can
who spend a prolonged period in the lithotomy position are at increased risk of lead to respiratory
femoral nerve injury. insufficiency and profound
hypotension and
Postpartum patients with femoral nerve injury experience weakness in the bradycardia. Treatment is
quadriceps femoris and the iliopsoas muscle (CASE 8-3). Sensory loss often is supportive.
noted in the anteromedial thigh, and the knee jerk is diminished or absent.
Diagnosis of femoral neuropathy can usually be made at the bedside by obtaining ● Seizures may occur when
local anesthetic is
a thorough history and neurologic examination. Most injuries are compression
accidentally injected
injuries with demyelination and improve within days to weeks. Axonal injuries intravascularly. Systemic
may take up to 6 to 12 months to improve, and recovery may be incomplete. toxicity is more likely to
Treatment includes a supportive knee brace and a course of physical therapy. occur after obstetric
Fibular (peroneal) neuropathy occurs when the nerve is compressed at the epidural anesthesia than
spinal anesthesia because
fibular head. In pregnant patients, it can occur in the setting of prolonged knee larger volumes of local
flexion while in the lithotomy position or while squatting or by the exertion of anesthetics are used.
pressure on the fibular head with stirrups during delivery. Patients with this
nerve injury develop footdrop due to weakness in the tibialis anterior and
extensor hallucis longus and weakness in foot eversion. Patients may experience

decreased sensation to pain and temperature on the dorsum of the foot, most
pronounced between the first and second toes.62 Awareness of the vulnerability
of the fibular (peroneal) nerve to injury has led to attention to positioning and
subsequent decreased frequency of injury.
Injuries to the lumbosacral plexus can occur during delivery if compressed by
forceps or the fetal head at the pelvic brim. Symptoms depend upon which nerve
roots are involved. Muscles innervated by L4 and L5 nerve roots are commonly
affected and cause weakness in ankle dorsiflexion, inversion, and eversion.
Sensory impairment may occur in the distribution of the L5 dermatome. The
Achilles reflex is usually preserved. Risk factors include large fetal head size,
small maternal pelvis, and instrumental delivery.
Postpartum obturator neuropathy is a rare cause of postpartum leg weakness.
It comprises less than 4.7% of postpartum neuropathies. Patients experience
sensory loss of the upper one-third of the medial thigh and weakness of thigh
adduction. Wide-based gait with circumduction is seen on examination. Risk
factors include instrumental vaginal delivery and cephalopelvic disproportion.
Treatment is supportive with physical therapy.63
Sciatic nerve injuries in the obstetric setting are rare in the United States. They
occur more frequently in less developed countries where IM injections of pain
medication in the gluteal region are used for pain control during labor and
delivery. Sciatic nerve injury can cause a wide array of symptoms, from minor
sensory changes to disabling paralysis of the muscles of the ankle and foot. Sciatic
nerve injury may produce weakness in the tibialis anterior muscle, gastrocnemius
muscles, hamstrings, foot invertors and evertors, and extensor hallucis longus.
Paresthesia and sensory loss on the dorsal and plantar surfaces of the foot and
lateral calf may occur. Achilles tendon reflex will be absent on examination.
When assessing a woman with postpartum leg weakness, a careful neurologic
examination is crucial and should include a detailed examination of muscle
strength, reflexes, and the distribution of sensory loss. Diagnosis of peripheral
nerve injuries can often be made at the bedside. Most patients improve in a
matter of days to weeks. If symptoms persist beyond 3 weeks, EMG can be
helpful in localization and prognosis. If the examination reveals any evidence of
TABLE 8-3 Differential Diagnosis for Postpartum Leg Weakness
◆ Femoral nerve injury

◆ Fibular (peroneal) nerve injury
◆ Lumbosacral plexopathy
◆ Sciatic nerve injury
◆ Obturator nerve injury
◆ Retroperitoneal hematoma
◆ Epidural hematoma
◆ Direct spinal cord/cauda equina injury
◆ Anterior spinal artery syndrome
a
Reprinted with permission from Waters JFR.59 © 2019 Springer Nature Switzerland AG.
176 FEBRUARY 2022

spinal cord, conus, or cauda equina injury, imaging with MRI is recommended on
an urgent basis. If spinal epidural hematoma or abscess is present, immediate
surgical decompression may be indicated.
If patients have abdominal pain or bruising, CT of the pelvis can be obtained to
rule out retroperitoneal hematoma. The differential diagnosis for postpartum leg
weakness is listed in TABLE 8-3.
CONCLUSION
The advantages of neuraxial anesthesia over general anesthesia in pregnant
women are well established, and neuraxial anesthesia can usually be
administered safely in most patients with neurologic disease. Patients with mass
lesions causing increased intracranial pressure or spinal tumors at the site of
neuraxial needle placement and patients on anticoagulant medication are the
exceptions. Post–dural puncture headaches and obstetric nerve injuries are the
most common complications of neuraxial anesthesia and resolve in most patients.
Other complications, although rare, can be devastating. The simple tools of a
reflex hammer, tuning fork, and safety pin will allow a neurologist to localize the
problem, distinguish serious complications from more benign problems, and
determine whether confirmation with appropriate imaging is indicated.
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MEDICOLEGAL ISSUES

Legal and Ethical
ONLINE
Challenges in the Care of
the Pregnant Patient
After Brain Death
By Joseph S. Kass, MD, JD, FAAN; Rachel V. Rose, JD, MBA
ABSTRACT
Using two scenarios based on real-life cases reported in the media, this
article examines the ethical and legal controversies that arise when a
pregnant woman dies based on neurologic criteria while her fetus remains
alive. In the first scenario, all parties agreed to maintain physiologic
support until a safe delivery could be achieved, whereas in the second
CITE AS:
CONTINUUM (MINNEAP MINN) scenario the woman’s family sought a legal remedy to stop the hospital
2022;2 8 (1 , N E U R O L O G Y O F from continuing to provide physiologic support for the patient and her
PREGNANCY):180–185.
neurologically devastated fetus.
Dr Joseph S. Kass, Baylor
College of Medicine, One Baylor CASE 1
Plaza M-210, Houston, TX 77030,
kass@bcm.edu.
When she was 19 weeks pregnant, a 26-year-old woman sustained an
asthma-related anoxic brain injury. She was transported to a hospital in
RELATIONSHIP DISCLOSURE: Porto, Portugal, where she quickly progressed to death by neurologic
Dr Kass serves as associate
editor of medicolegal issues for
criteria. With the agreement of her family and the father of the unborn
Continuum, as a neurology child, the hospital ethics committee ordered continued maternal
section editor of Ferri’s Clinical physiologic support after brain death until 32 weeks of gestation. At
Advisor for Elsevier, and as
co-editor of Neurology Secrets, 31 weeks and 6 days, the woman’s body’s hemodynamic instability
Sixth Edition and has served necessitated a cesarean delivery. Physiologic support for the mother was
as an associate editor for
withdrawn the next day.1,2
Continuum Audio. Dr Kass
serves as a principal investigator
for clinical trials for Alzheimer
disease from Biogen; Eisai Co, CASE 2
Ltd; Lilly; the National Institutes
of Health; Novartis AG; and When she was 14 weeks pregnant, a 33-year-old woman sustained an
Roche Diagnostics. Ms Rose anoxic brain injury due to a pulmonary embolism–induced cardiac arrest.
serves on the editorial board of
BC Advantage and receives She was transported to a hospital in Fort Worth, Texas, where she was
book royalties from the declared dead based on neurologic criteria soon after hospital admission.
American Bar Association.
Despite objections from her husband and parents, the hospital continued
UNLABELED USE OF maternal physiologic support after brain death based on its interpretation
PRODUCTS/INVESTIGATIONAL of the state’s advance directive law. Physiologic support did not cease
USE DISCLOSURE:
Dr Kass and Ms Rose report no
until 2 months later, when a state district court ruled that the hospital had
disclosures. misinterpreted the statute and ordered cessation of physiologic support.
The fetus had hydrocephalus as well as other deformities and was judged
© 2022 American Academy not to be viable. Therefore, the fetus was not delivered and died with the
of Neurology. cessation of maternal physiologic support.3,4
180 FEBRUARY 2022

DISCUSSION
Maternal brain death in pregnancy with continued fetal survival occurs very
rarely. The catastrophic injury leading to maternal brain death during pregnancy
typically results in fetal demise.3 In a 2021 review, Dodaro and colleagues5
identified only 35 cases published in the medical literature of maternal
physiologic support after brain death for the benefit of a developing fetus. They
found that in over two-thirds of cases, maternal brain death resulted from some
type of intracranial hemorrhage and typically occurred during the second
trimester of pregnancy. Common maternal complications of physiologic support
after brain death were infection, circulatory instability, diabetes insipidus,
temperature dysregulation, and panhypopituitarism. Maternal physiologic
support after brain death lasted for a mean of 7 weeks and resulted in live births
in just over three-fourths of pregnancies, with the majority of the infants who
were followed after delivery experiencing good outcomes.
Given the rarity of maternal brain death with fetal survival, physicians, ethics
committees, hospital administrators, and judges confronting this scenario are
unlikely to have experience with the ethical and legal issues these tragedies raise.
This lack of preparedness is reflected in the findings of Lewis and colleagues,6
who in 2016 examined whether the brain death policies of US hospitals include
specific mention of maternal brain death during pregnancy. Of 317 unique brain
death protocols reviewed, eight protocols prohibited evaluation of maternal
brain death in cases where fetal life could be preserved. Of the other 309
protocols, 289 lacked specific guidance about maternal physiologic support after
brain death, and all but three protocols failed to identify the individual
responsible for making decisions on the fetus’s behalf.
Whereas hospital policies typically do not address maternal physiologic
support after brain death explicitly, the ethics committees of both the American
College of Obstetricians and Gynecologists (ACOG) and the International
Federation of Gynecology and Obstetrics (FIGO) have issued policy statements
that clearly maintain focus on the autonomy rights of the mother.7,8 ACOG states
that pregnant women have the right to make medical decisions for themselves
without considering the effects of these interventions on the fetus. FIGO has
published a guide to the management of maternal physiologic support after
brain death but reminds health care providers to respect maternal rights,
establishing the maternal body as the primary patient.3,6 By holding maternal
interests front and center, the statements from both organizations can be
interpreted as recognizing situations where maternal physiologic support after
brain death may be deemed inappropriate, such as when the intensive medical
interventions at the core of maternal physiologic support after brain death
contravene the woman’s previously expressed wishes to forgo extraordinary
measures in the face of devastating irreversible neurologic injury.
Analysis of Case 1
CASE 1 appears noncontroversial because the pregnant woman’s family and the
hospital ethics committee agreed on maternal physiologic support after brain
death for the benefit of the fetus. Although this case did not raise a legal
challenge, the decision to pursue maternal physiologic support after brain death,
even if the decedent’s previously expressed values align with the goals of
maternal physiologic support after brain death, raises many unique ethical
questions and should sustain ethical inquiry.

LEGAL AND ETHICAL CHALLENGES AFTER BRAIN DEATH
Ethical challenges arising in obstetric practice are particularly difficult because

physicians must understand whether they are treating one patient or two.
Although the values of the pregnant patient typically align with promoting a
positive health outcome for the fetus, at times the pregnant patient and her
physicians must face a vexing conundrum in which a management decision
about one member of the mother-fetus dyad has the potential to harm the other
member. A further complication to decision making in the face of maternal-fetal
conflict is the politically and ethically charged atmosphere around reproductive
rights. Therefore, Chervenak and McCullough’s9 professional responsibility
model of obstetric ethics is particularly appealing because it allows for an
ethical consensus to be reached without broaching the thorny topic of fetal
personhood. The professional responsibility model is derived from a
physician’s professional responsibilities to patients. Professional
responsibility includes a commitment to clinical competence, the protection
and promotion of patients’ health-related interests, and the preservation and
strengthening of medicine as a public trust. The application of this
professional responsibility model to obstetrics creates for the physician a dual
beneficence- and autonomy-based obligation to the pregnant patient but
solely a beneficence-based obligation to the fetus. This obligation, however,
accrues to the fetus only once the pregnant patient has presented the fetus to
the physician for care. Thus, the pregnant woman’s choice to seek medical
management of her ongoing pregnancy endows both the pregnant woman and
her fetus with the status of a patient.
Beneficence-based obligations to the pregnant patient require the physician
to provide the pregnant woman with care options that in the physician’s clinical
judgment offer the patient more benefit than harm. Autonomy-based obligations
require the physician to support the pregnant patient’s decision making and to
help the patient reach a decision aligned with her personal perspective about her
health-related interests in the context of her own values and beliefs.
Once a fetus becomes a patient, the physician assumes a beneficence-based
obligation to the fetus. A fetus becomes a patient “when the fetus is presented
(by the pregnant patient) for medical interventions, whether diagnostic or
therapeutic, that reasonably can be expected to result in a greater balance of
goods over harms for the child and person the fetus can later become during early
childhood.”9 Typically, the pregnant patient’s goals for the pregnancy align with
a positive health outcome for the fetus, but when they do not, the physician has
a beneficence-based obligation to express an opinion about the impact of a
particular medical decision on fetal health. Importantly, this professional
obligation model does not ground the physician’s obligation to the fetus in fetal
autonomy rights since a fetus cannot have values or beliefs about its own
interests and therefore lacks rights-based interests.
Applying this model to the ethics of maternal physiologic support after brain
death presupposes that the pregnant woman knew she was pregnant before her
cardiac arrest. It appears likely that the pregnant patient had sought prenatal
care, signaling her intention to optimize health outcomes for both herself and her
unborn child. This analysis also assumes that the brain dead but still pregnant
body should be afforded the moral status equivalent to a living incapacitated
patient, despite the body’s legal status as a corpse. For practical and ethical
purposes, the physicians managing the care of the pregnant woman who is brain
dead will be providing the same type of critical care they would provide a
182 FEBRUARY 2022

pregnant patient who is comatose. Therefore, turning to the patient’s surrogate
decision maker for medical decisions is the ethically appropriate way to honor the
autonomy obligation to the pregnant patient. The surrogate decision maker
should employ substituted judgment in making medical decisions, acting how
the pregnant patient would have acted in this situation. The beneficence
obligation to a patient who is brain dead is more challenging to articulate because
the reality of the body’s legal status as a corpse is difficult to avoid. However,
respect for the dignity of a corpse is a deeply enriched cultural, religious, and
legal tenet and is the most appropriate manifestation of beneficence to the
pregnant patient who is brain dead. Respecting the dignity of the decedent’s
body may manifest as supporting that body as a vessel for fetal maturation.
However, depending on the woman’s previously expressed values, which may
consider the health status of the fetus and the types of interventions and length of
time required for maternal physiologic support after brain death, beneficence
may be best served by eschewing maternal physiologic support after brain death.
Beneficence to the fetus is generally thought of as taking action to support
healthy fetal development and delivery. However, the health status of the fetus
after the catastrophic injury that led to maternal brain death should be
considered when determining the contours of the beneficence obligation to
the fetus.
Analysis of Case 2
CASE 2 came into the national spotlight because the Fort Worth, Texas, hospital
caring for the patient interpreted the “pregnancy exclusion” to the Texas
Advance Directives Act10 as requiring maternal physiologic support after brain
death. The Texas “pregnancy exclusion” has two parts: “[a] person may not
withdraw or withhold life-sustaining treatment…from a pregnant patient,” and
“[a] person may not withhold cardiopulmonary resuscitation or certain other
life-sustaining treatment… from a person known by the responding health care
professionals to be pregnant.” However, the Texas Health and Safety Code
recognizes death when “there is irreversible cessation of all spontaneous brain
function. Death occurs when the relevant functions cease.”11 Therefore, the court
concluded that the Advance Directives Act does not apply when a patient,
including a pregnant patient, has been declared dead. Two months of physiologic
support for the patient and her nonviable fetus ended when the court ruled in
favor of the patient’s family and physiologic support of the pregnant woman’s
body was discontinued. Another important aspect of the family’s argument
was that at the time of the initial diagnosis of brain death, the pregnancy was
sufficiently early so as to fall within the legally sanctioned time frame for
termination of pregnancy in Texas. Thus, although the court did not have to
broach the effect of laws regulating the termination of pregnancy in this case
where the hospital admitted that the fetus was not viable, there is no guarantee
that such considerations would not have arisen had the facts differed and the
fetus was deemed potentially viable.
Texas is not unique in its restrictive handling of advance directives during
pregnancy. As of 2015, 12 states had statutes similar to the Texas pregnancy
exclusion, automatically invalidating a woman’s advance directive when she is
pregnant. Fourteen states require ongoing cardiopulmonary support of the
pregnant patient if fetal live birth is probable, with four carving out exceptions
when the critical care interventions will be exceptionally painful or dangerous to

LEGAL AND ETHICAL CHALLENGES AFTER BRAIN DEATH
the woman. Five states allow women to write in pregnancy-specific instructions

in their advance directives. Fourteen states and the District of Columbia have no
special provision for pregnancy in their advance directive statutes.3 On one hand,
all states recognize brain death as death, so presumably even the most restrictive
states would interpret their advance directive law as inapplicable to a mother
who is brain dead. Yet in jurisdictions with laws that prioritize the state’s interest
in sustaining fetal life over a pregnant woman’s autonomous interest in her own
body, it may very well turn out that courts will interpret these scenarios in the
context of laws regulating the termination of pregnancy. Therefore, if the mother
who is brain dead is carrying a potentially viable fetus, courts may decide to
discount the premorbid choices of the woman and determine that a legitimate
state interest in fetal life requires ongoing maternal physiologic support after
brain death, even over the objections of a surrogate decision maker that are
grounded in the woman’s previously expressed values and wishes. A court’s
interpretation of state law regulating termination of pregnancy will likely
influence whether a court will favor sustaining physiologic support to the fetus
over legitimate objections of the family or health care team.
CONCLUSION
When a pregnant woman experiences a health catastrophe that results in her
death by neurologic criteria but spares the life of her fetus, a grieving family,
the medical team caring for the woman and her fetus, and the health care
institution where care is taking place may be thrust into a legal, ethical, and
cultural conflict for which they are neither emotionally nor intellectually
prepared. When all parties reach consensus that the pregnant woman would
have chosen to continue the pregnancy to optimize a viable fetus’s health
outcome, physiologic support can continue free of ethical or legal conflict. By
proceeding in alignment with the pregnant woman’s previously expressed
values, the health care team demonstrates its respect for the woman’s autonomy
and treats the decedent and her fetus with beneficence. However, in the absence
of such a consensus, the final decision about the medical management of the
pregnancy will likely rest with the legal system. Although restrictions pertaining
to the advance directives of pregnant patients would not apply to an already dead
individual, a court could determine that the jurisdiction’s laws regulating the
termination of pregnancy should govern when a potentially viable fetus is
gestating within the deceased mother’s body. The outcome of such an analysis
would vary from jurisdiction to jurisdiction based on the statutory language as
well as a court’s interpretation of the legislative intent behind the statutory
language.
REFERENCES
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s-0036-1582445

NEUROLOGY OF PREGNANCY
ARTICLE 1: PREGNANCY MANAGEMENT

IN MULTIPLE SCLEROSIS AND OTHER
DEMYELINATING DISEASES
Riley M. Bove, MD; Maria K. Houtchens, MD. Continuum (Minneap Minn).
February 2022; 28 (1 Neurology of Pregnancy):12–33.
ABSTRACT
PURPOSE OF REVIEW:
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs) are chronic
autoimmune demyelinating conditions of the central nervous system often diagnosed in women
of childbearing age. Therefore, safe family planning, pregnancy, and postpartum management
are important considerations for many patients with MS or NMOSD.
RECENT FINDINGS:
Many patients with MS can safely become pregnant and remain well throughout pregnancy
and the postpartum period with guidance from specialists on treatment planning. During
pregnancy, women with NMOSD may face some increased risk of both neurologic and obstetric
complications. Recent attention has focused on evaluating the safety of pharmacologic
agents during pregnancy and breastfeeding. Unfortunately, care disparities remain common
in both MS and NMOSD, and recovery of function is often not optimally managed in the
postpartum period.
SUMMARY:
This article reviews the current state of knowledge on peripartum management in these
neurologic conditions and offers practical considerations and case studies. When caring for
women with MS and NMOSD of childbearing potential, treatment planning is important to
optimize outcomes in both patient and newborn.
KEY POINTS
• Many patients with multiple sclerosis (MS) can safely go through pregnancy and the postpartum period.
• In patients with more serious and active neurologic disease and patients who experience health care
disparities with poor access to neurologic or obstetric care, maternal pregnancy and postpartum outcomes
are at risk.
• In MS, postpartum MRI may reveal elevated inflammatory activity even in women deemed clinically stable
and is a useful evaluation tool to decide on treatment selection.

• Women with neuromyelitis optica spectrum disorder (NMOSD) face elevated risk of inflammatory activity
both during and after pregnancy relative to prepartum and potentially greater pregnancy complications than
the general population.
• For both MS and NMOSD, there is a trend to use anti-CD20 therapies before pregnancy, which can provide
clinical stability before conception, during pregnancy, and, potentially, postpartum.
• Intrapartum and postpartum outcomes in patients with MS or NMOSD are linked to disease stability for a year
preceding pregnancy.
• Asking patients “Would you like to become pregnant in the next year?” allows for a screening assessment of
the patient’s family planning needs to help guide the health care provider’s treatment and care plan.
• Any form of contraception is safe for patients with MS or NMOSD.
• In patients with demyelinating diseases, if pregnancy is not achieved after 3 to 6 months of optimal
conception attempts, referral to a fertility clinic should be considered.
• Many disease-modifying therapies are used in MS. A thorough understanding of prepregnancy washout and
safety in pregnancy exposure recommendations is needed to optimize MS management.
• To ensure complete elimination of products before conception, typically waiting at least 5 maximal half-lives
is recommended (with the exception of teriflunomide, for which an accelerated washout protocol is
recommended).
• If natalizumab is continued into the mid to late third trimester, hematologic screening of the newborn is
necessary because of an increased risk of transient thrombocytopenia and anemia in some newborns.
• MRI without gadolinium can be obtained and compared to the preconception MRI in cases of new neurologic
symptoms in pregnancy.
• Methylprednisolone, prednisone, and prednisolone are preferred in pregnancy as they are inactivated by
placental 11-β-hydroxysteroid dehydrogenase and therefore do not enter the fetal circulation.
• Surveillance neuroimaging should be considered within the first few months postpartum to establish a new
baseline.
• Comprehensive evaluation of women with MS and NMOSD is recommended early postpartum and should
include gait, balance, bladder, bowel, mood, fatigue, cognition, strength, pain, social supports, and
neuroimaging review.
• In MS, exclusive breastfeeding is protective against postpartum inflammatory activity.
• Safety data suggest that both first-line self-injectable therapies (glatiramer and interferon beta)
and IgG monoclonal antibodies (such as ocrelizumab and rituximab) are reasonable to consider during
breastfeeding.
• Women with MS and women with NMOSD may face disparities in their obstetric and neurologic care and
outcomes. Care coordination between the two specialists is important.
ARTICLE 2: EPILEPSY AND PREGNANCY

Yi Li, MD, PhD; Kimford J. Meador, MD, FAAN, FAES, FRCPE. Continuum
(Minneap Minn). February 2022; 28 (1 Neurology of Pregnancy):34–54.
ABSTRACT
PURPOSE OF REVIEW:
Seizure disorders are the most frequent major neurologic complication in pregnancy, affecting
0.3% to 0.8% of all gestations. Women of childbearing age with epilepsy require special care
related to pregnancy. This article provides up-to-date information to guide practitioners in the
management of epilepsy in pregnancy.

RECENT FINDINGS:
Ongoing multicenter pregnancy registries and studies continue to provide important information
on issues related to pregnancy in women with epilepsy. Valproate poses a special risk for
malformations and cognitive/behavioral impairments. A few antiseizure medications pose low
risks (eg, lamotrigine, levetiracetam), but the risks for many antiseizure medications remain
uncertain. Although pregnancy rates differ, a prospective study found no difference in fertility
rates between women with epilepsy who were attempting to get pregnant and healthy controls.
During pregnancy, folic acid supplementation is important, and a dose greater than 400 mcg/d
during early pregnancy (ie, first 12 weeks) is associated with better neurodevelopmental
outcome in children of women with epilepsy. Breastfeeding is not harmful and should be
encouraged in women with epilepsy even when they are on antiseizure medication treatment.
SUMMARY:
Women with epilepsy should be counseled early and regularly about reproductive health.
Practitioners should discuss the risks of various obstetric complications; potential anatomic
teratogenicity and neurodevelopmental dysfunction related to fetal antiseizure medication
exposure; and a plan of care during pregnancy, delivery, and postpartum. Women with epilepsy
should also be reassured that the majority of pregnancies are uneventful.
KEY POINTS
• Although pregnancy rates differ, no difference in fertility rate is seen between women with epilepsy who are
attempting to get pregnant and healthy controls (60.7% compared to 60.2%).
• Certain medications, including valproate and phenobarbital, have been linked to lower fertility, but these
findings require further validation in a larger cohort.
• Patients treated with CYP3A4 enzyme-inducing antiseizure medications should consider alternative methods
of contraception.
• Lamotrigine may require substantial titration when it is used in combination with oral hormonal contraceptives.
• Knowledge is limited regarding the interaction of oral contraceptives and some of the new antiseizure
medications.
• Most women with epilepsy will not experience seizure frequency changes during pregnancy.
• The diagnosis of epilepsy alone should not be considered as an indication for cesarean delivery.
• The risk of gestational hypertension and preeclampsia may be slightly increased in women with epilepsy.
• The majority of women with epilepsy have uneventful pregnancies, and 90% of children born to women with
epilepsy are healthy.
• The risk of major congenital malformations has been associated with first trimester antiseizure medication
exposure, the dose and type of antiseizure medication (especially valproate), polytherapy, low folate
concentrations, and low maternal level of education.
• The teratogenic risks for many antiseizure medications are uncertain. Valproate is the poorest choice of
antiseizure medication based on the higher risk profile of both anatomic and behavioral teratogenicity. If
used, the dose should be as low as possible.
• The impact of neuromodulation therapy on pregnancy outcomes is limited.
• Children born to women with epilepsy may have impaired cognitive development; the contributing factors
include antenatal antiseizure medication exposure, frequent tonic-clonic seizures in pregnancy, low
maternal IQ, and maternal education level.
• Women with epilepsy of childbearing potential should be taking folic acid 0.4 mg/d to 4 mg/d.
• Monitoring of antiseizure medication levels during pregnancy should be considered.
• The most marked decline in serum concentration of antiseizure medications in pregnancy is seen with
lamotrigine, levetiracetam, and oxcarbazepine (decrease ranging from 40% to 70%). Carbamazepine and
valproate have minimal decreases in serum concentration, usually 10% to 20%.
• Breastfeeding while taking antiseizure medication appears to be safe.

ARTICLE 3: NEUROMUSCULAR
DISORDERS AND PREGNANCY
Janice M. Massey, MD, FAAN; Karissa L. Gable, MD. Continuum (Minneap Minn).
February 2022; 28 (1 Neurology of Pregnancy):55–71.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of neuromuscular disorders in pregnancy, with a focus on
diagnosis and management.
RECENT FINDINGS:
Neuromuscular disorders with issues that occur in pregnancy include conditions that are
acquired (including autoimmune) or genetic; each requires a unique approach to management
and treatment prepartum, peripartum, and postpartum. Guidance in the literature regarding
management and treatment options is predominantly from case series and retrospective
reviews. Treatment can be complex, particularly in autoimmune neuromuscular diseases,
because of the risks of side effects of the treatments that may affect the patient and fetus.
SUMMARY:
This article summarizes expectations, diagnosis, and management for a wide range of
neuromuscular disorders in pregnancy.
KEY POINTS
• Treatment of Guillain-Barré syndrome in pregnant women is similar to treatment in nonpregnant patients.
Both IV immunoglobulin (IVIg) and plasma exchange are considered to be safe.
• Accurate diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy relies on clinical history,
examination findings, and electrodiagnostic testing meeting European Federation of Neurological Societies/
Peripheral Nerve Society criteria.
• IVIg, plasma exchange, or corticosteroids can be used in treatment of chronic inflammatory demyelinating
polyradiculoneuropathy during pregnancy, and IVIg is most effective for multifocal motor neuropathy.
• If thiamine deficiency is suspected in pregnant women, treatment with vitamin repletion is recommended
even while awaiting laboratory results for serum levels of vitamins as no significant harm exists in treatment.
Treatment can be stopped if levels are found to be within normal limits.
• Pregnancy outcomes in women with Charcot-Marie-Tooth disease have been found to be similar to women
without the disease.
• Supportive care is often all that is necessary for carpal tunnel syndrome in pregnancy. Resolution has
variable timing.
• Recovery from idiopathic brachial plexopathy may be partial and can take months to years.
• Focal neuropathies associated with pregnancy often improve over time with supportive care.
• Recurrence of facial nerve palsy in future pregnancies is rare.
• Exacerbations of myasthenia gravis occur more often in the first trimester and postpartum.
• Preconception counseling is very important to select the appropriate medications for treatment of
myasthenia gravis.
• It is typically advised not to initiate or stop steroid-sparing agents during pregnancy, except in unique
circumstances, because of the potential risk of myasthenic exacerbations.
• It is recommended to use antiseizure medications rather than magnesium in the treatment of eclampsia in
women with myasthenia gravis.

• It is recommended that women do not breastfeed while taking methotrexate or mycophenolate mofetil.
• Women with muscular dystrophies generally have good pregnancy outcomes.
• Rhabdomyolysis has not been reported during labor in patients with McArdle disease.
• Neonatal outcomes for babies born to women with spinal muscular atrophy are generally good.
ARTICLE 4: HEADACHE IN PREGNANCY

AND LACTATION
Melissa Rayhill, MD, FAHS. Continuum (Minneap Minn). February 2022;
28 (1 Neurology of Pregnancy):72–92.
ABSTRACT
PURPOSE OF REVIEW:
This article discusses the many tools available for the treatment of pregnant and postpartum
patients with headache. Adequate treatment of headache is an essential part of good prenatal
and postnatal care.
RECENT FINDINGS:
New therapies such as the calcitonin gene-related peptide monoclonal antibodies, lasmiditan,
direct calcitonin gene-related peptide antagonists, and neuromodulation devices are available
for the treatment of headache. This article contextualizes these new therapies in practice as
they relate to the treatment of migraine in pregnancy and lactation.
SUMMARY:
Headache is common in pregnancy, and neurologists should be prepared to care for pregnant
patients with headache. Preconception counseling is an important part of providing safe care to
patients of childbearing potential with headache. Identifying potentially dangerous secondary
headache syndromes during pregnancy and the puerperium is also essential. The repertoire of
available acute and preventive headache treatments is expanding. It is important to discuss the
effectiveness and safety of these therapies in the context of individual patient circumstances
during pregnancy and lactation in coordination with the patient’s obstetric team.
KEY POINTS
• In women between the ages of 30 and 39, the prevalence of migraine can be as high as 27%, which is about
3 times higher than the prevalence in men in the same age range.
• It is prudent to discuss any potential teratogenicity of medications at the time they are prescribed, regardless
of the patient’s current reproductive plan, as plans may unexpectedly change with time.
• Patients taking monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) activity should be
advised to stop injections approximately 5 to 6 months before conception.
• The diagnosis of headache is guided by the International Classification of Headache Disorders, Third Edition.
• Women with migraine with aura may be less likely to improve in pregnancy, and aura can present for the first
time during pregnancy.
• One study showed that the most common secondary headache syndromes in patients who presented to
acute care with severe headache were caused by hypertensive disorders of pregnancy. In this study, a lack of
headache history was associated with a nearly fivefold risk of secondary headache, and elevated blood
pressure was associated with a 17-fold risk of secondary headache.
• Warning signs for secondary headache include fever, papilledema or other abnormal neurologic examination
findings, thunderclap headache onset, postural provocation, and a history of immunosuppression.

• Compared to women without a history of migraine, women with a history of migraine are more likely to have a
secondary cause of headache, such as cerebral venous thrombosis, pregnancy-associated stroke, or
preeclampsia.
• Preeclampsia is quite common, occurring in 3% to 5% of pregnancies.
• Pituitary apoplexy characteristically presents with acute or thunderclap headache, and it can lead to
bitemporal hemianopia and hypotension.
• Intracranial hypotension usually presents with postpartum headache that progressively worsens throughout
the day and usually worsens with upright posture.
• The US Food and Drug Administration previously categorized medications based on a hierarchical scale from
A (safest) to X (contraindicated in pregnancy), but these categories were discontinued in 2015.
• To make an accurate assessment of headache burden, it is essential to ask patients about days of complete
headache freedom.
• Given the natural improvement in headache that many patients experience with pregnancy, it may be
reasonable to monitor their headaches without preventive therapy early on to see if preventive therapy is
indeed required.
• All patients with headache may benefit from a discussion of lifestyle modifications, such as sleep
optimization, stress management, adequate hydration, and regular healthy meals.
• Given the lower levels of CGRP in patients with preeclampsia compared to normotensive individuals, most
headache specialists believe avoidance of CGRP monoclonal antibodies in pregnancy is warranted.
• Despite its efficacy, topiramate should be avoided during pregnancy given the known risks of cleft palate and
lip, intrauterine growth restriction, and metabolic acidosis.
• Feverfew is contraindicated for migraine prevention in pregnancy as it can provoke uterine contractions and
spontaneous miscarriage.
• Reviewing prescription medications for safety in pregnancy is routine, but clinicians must not forget to
specifically ask about over-the-counter medication and supplement use.
• The goal of acute therapy for headache is to restore function and resolve pain and other associated
symptoms within 2 hours. If a treatment does not reliably help within 2 hours, other options should
be explored.
• Butalbital-containing medications and opiates are not recommended for the treatment of migraine in the
general population; this applies to both pregnant and nonpregnant patients.
• The new direct CGRP receptor antagonists ubrogepant and rimegepant and the new serotonin-1F agonist
lasmiditan should be avoided in pregnancy given the paucity of available evidence about their safety
in pregnancy.
• Neuromodulation devices should be theoretically safe to use in pregnant women with migraine or cluster
headache, but data are limited.
• If headache improved during pregnancy, some women enjoy a continued improvement during lactation and
may not require immediate resumption of their prior preventive therapies.
• Eletriptan has the lowest milk to plasma ratio of the triptans, and sumatriptan has the most safety data
available for breastfeeding.
• Ubrogepant, rimegepant, and lasmiditan should be avoided during lactation given the absence of
available data.
• The CGRP monoclonal antibodies have not been studied in lactation. However, given their large size, it is
unlikely that they will pass through into breast milk, and some headache specialists are now considering their
use when treating particularly disabling and intractable migraine.

ARTICLE 5: MATERNAL STROKE
ASSOCIATED WITH PREGNANCY
Eliza C. Miller, MD, MS. Continuum (Minneap Minn). February 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article summarizes current knowledge of the epidemiology, pathophysiology, prevention,
and treatment of cerebrovascular disease in pregnant and postpartum women.
RECENT FINDINGS:
Stroke is a leading cause of maternal morbidity and mortality, and most fatal strokes are
preventable. Adaptive physiologic changes of pregnancy, including hemodynamic changes,
venous stasis, hypercoagulability, and immunomodulation, contribute to increased maternal
stroke risk. The highest-risk time period for maternal stroke is the immediate postpartum period.
Migraine and hypertensive disorders of pregnancy, including gestational hypertension and
preeclampsia, are major risk factors for maternal stroke. Adverse pregnancy outcomes,
including gestational hypertension, preeclampsia, preterm delivery, and fetal growth
restriction, are important risk factors for cerebrovascular disease later in life.
SUMMARY:
Many catastrophic maternal strokes could be avoided with targeted prevention efforts, early
recognition of warning signs, and rapid evaluation of neurologic symptoms. Neurologists play a
central role in the care of pregnant patients with cerebrovascular disease, whether acute or
chronic, and should be familiar with the unique and complex physiology of pregnancy and its
complications, particularly hypertensive disorders of pregnancy.
KEY POINTS
• The incidence of stroke in women during pregnancy and the postpartum period is approximately triple the
incidence of stroke in nonpregnant women of similar age.
• The majority of maternal strokes occur postpartum, often after discharge home following delivery, and up to
half are hemorrhagic.
• Migraine and hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, are
important risk factors for maternal stroke.
• The adaptive physiologic changes of pregnancy, including hemodynamic changes, venous stasis,
hypercoagulability, and immunomodulation, can contribute to increased stroke risk.
• Common pregnancy-associated stroke mechanisms include cardioembolism, cervical artery dissection,
cerebral venous thrombosis, cerebral vasospasm or subarachnoid hemorrhage due to reversible cerebral
vasoconstriction syndrome, and hypertensive intracerebral hemorrhage, often in association with posterior
reversible encephalopathy syndrome.
• Despite the term reversible in their names, reversible cerebral vasoconstriction syndrome and posterior
reversible encephalopathy syndrome can lead to severe disability or death if complicated by ischemic stroke
or intracerebral hemorrhage.
• Pregnant or postpartum women who develop cerebral venous thrombosis should be evaluated for underlying
hypercoagulable disorders; pregnancy should not be assumed as the sole cause.
• Migraine is associated with increased risk of preeclampsia and a 15-fold increase in risk of maternal stroke.

• Proteinuria is no longer required for the diagnosis of preeclampsia; new severe headache or neurologic
symptoms are considered disease-defining in the presence of new or worsening hypertension.
• Hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and chronic
hypertension with superimposed preeclampsia, affect up to 1 in 10 pregnancies.
• Intracerebral hemorrhage is a leading cause of maternal mortality in patients with preeclampsia, and
frequently, no underlying vascular lesion is identified.
• No evidence shows that cesarean delivery decreases the risk of rupture of cerebrovascular lesions in
pregnancy.
• In selected patients with moyamoya, particularly those with recurrent transient ischemic attacks or
decreased regional flow on brain imaging, surgical revascularization before pregnancy may decrease the risk
of peripartum neurologic complications.
• Women with elevated risk for maternal stroke should be counseled on stroke signs and symptoms and
warned that the postpartum period is the highest-risk time point for stroke.
• A history of stroke or cerebrovascular disease is not, in itself, an indication for cesarean delivery. Delivery
planning should be based on obstetric considerations in most cases.
• Red flag headache features in a pregnant or postpartum woman, such as lack of headache history, elevated
blood pressure, very severe pain, or focal neurologic deficits, should prompt urgent neurologic evaluation.
• When a pregnant woman presents with acute disabling neurologic deficits, CT is usually the fastest and most
accessible imaging modality and thus is preferred. CT angiography should be performed in pregnant patients
with symptoms concerning for large vessel occlusion.
• Current guidelines for acute ischemic stroke do not consider pregnancy to be a contraindication to IV
thrombolysis if the deficits are disabling and the bleeding risks are acceptable.
• Poststroke depression may be exacerbated by the pregnant or postpartum state, particularly if the
pregnancy had an adverse outcome, and early involvement of psychiatry is recommended.
• Adverse pregnancy outcomes, including hypertensive disorders of pregnancy, preterm delivery, and fetal
growth restriction, are associated with higher risk for future cerebrovascular disease, including stroke and
vascular cognitive impairment.
• Neurologists who treat young women should screen them for a history of pregnancy complications; for
women who have experienced pregnancy complications, how to reduce future stroke risk and optimize brain
health should be discussed.
ARTICLE 6: MANAGING CENTRAL

NERVOUS SYSTEM TUMORS DURING
PREGNANCY
Na Tosha N. Gatson, MD, PhD, FAAN. Continuum (Minneap Minn). February 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article discusses current recommendations and special considerations for the management
of central nervous system (CNS) tumors in pregnant women and provides case vignettes to
emphasize important clinical concepts.

RECENT FINDINGS:
Given that nearly 60% of all intracranial and spinal cord tumors, including both primary and
metastatic tumor types, malignant or benign, are diagnosed in women, it is equitable to bring
attention to the unique management considerations that pertain to women during specific
phases of their lifespan, such as pregnancy. The pregnancy phase is marked by changes in
hormonal, immunologic, and other physiologic responses. Although substantial evidence
supports a pregnancy influence on tumor oncogenicity, the cumulative effect of the pregnancy
state on brain tumor biology remains elusive. Furthermore, as innovative cancer treatments and
surveillance technologies expand, providers must consider potential new risks to safe
pregnancy maintenance. This article reviews pregnancy considerations in CNS tumor care and
offers best practice approaches and considerations.
SUMMARY:
Informed neuro-oncology practices on safer surgical, radiation, medical, device, and imaging
techniques is of critical importance to pregnancy and fertility maintenance in cancer survivors.
Expanding this knowledge relies on advocacy and a commitment to develop equitable and
multidisciplinary research within the field. This also requires a focus on patient-reported
outcomes and patient-centered conversations to best care for pregnant women with
CNS tumors.
KEY POINTS
• Nearly 60% of all intracranial and spinal cord tumors, including both primary and metastatic tumor types,
malignant or benign, are diagnosed in women.
• Brain cancer is among the rarest malignancies found during pregnancy, with a reported incidence
comparable to the incidence in nonpregnant age-matched females.
• Meningiomas account for almost 55% of all nonmalignant primary brain tumors and make up about 38% of all
central nervous system tumors.
• In adults, glioblastoma (World Health Organization grade 4) is the deadliest and most common primary brain
malignancy (49%), comprising 14.5% of all primary brain tumors.
• Overall, schwannomas do not have a known sex predilection; however, vestibular schwannomas are more
common in women.
• Prolactinomas are the most common hormone-secreting pituitary tumor and are 4.5 times more likely to
occur in women.
• Breast cancer brain metastases have increased in incidence secondary to improved diagnostic and
surveillance technologies as well as to innovative cancer therapies that extend patient survival.
• Breast cancer is the most reported cancer concurrent with pregnancy.
• Multiple patient case series have reported that although pregnancy does not confer a higher risk for
incidence of brain tumor, pregnancy is associated with worsening aggressive tumor behavior.
• Vascular endothelial growth factor is highly expressed by specific brain tumors and regulates
neoangiogenesis and vascular permeability; it is often targeted to limit brain tumor growth and complications
such as vasogenic edema.
• Follicle-stimulating hormone and luteinizing hormone are tumor inhibitory hormones, whereas progesterone
has been implicated in worsening oncogenicity of several cancer types based on its role in regulating cell
apoptosis, proliferation, and tumor metastasis.
• The human immune response is more specialized in four vital compartments within the human body: the
eyeball, the testis, the brain, and the gravid uterus.
• Tolerance of neoantigens is a hallmark characteristic of immune-specialized compartments.
• The maternal-fetal interface becomes a site for reeducation of immune cells to the new foreign fetal
antigens.

• Routine hemodynamic and cardiac monitoring of the mother and fetus over the course of the pregnancy may
help prevent adverse pregnancy outcomes.
• Noncontrast MRI with a lower than 3T magnet is the best modality for brain tumor imaging in
pregnant women.
• Head CT for brain tumor imaging during pregnancy is contraindicated as it uses ionizing radiation, a
carcinogen, and is reserved for emergent scenarios (eg, hemorrhage or acute stroke) in which the benefit to
the mother outweighs the risk to the fetus.
• Tumor grade, anatomic location, and tumor rate of growth are important for neuroclinical prognostication.
• When considering neurosurgery for pregnant patients with central nervous system tumors, it is important to
involve multidisciplinary experts to discuss the patients options for pregnancy maintenance or termination
as well as any risks for future fertility.
• The risk of neurocognitive dysfunction resulting from radiation therapy was higher in fetal exposures
between 100 mGy and 500 mGy during the first trimester (6%) as compared to the second trimester (2%).
• Targeted therapies and standard chemotherapies cross the placenta and may result in spontaneous abortion
or other risks to the developing fetus, especially during the first trimester.
• Tumor treating fields therapy has been demonstrated to be effective in extending patient survival when used
in combination with standard chemotherapy and has received US Food and Drug Administration clearance for
both recurrent and newly diagnosed glioblastoma.
• Supportive care issues often arise in patients with brain tumors secondary to tumor treatment or tumor
progression.
• Steroids may be used during pregnancy for a variety of reasons, ranging from facilitation of fetal lung maturity
in high-risk pregnancies to providing a safer alternative to anti-inflammatory or immunosuppressive therapies
during pregnancy.
• Newly diagnosed and recurrent brain tumors are frequently associated with vasogenic edema causing
significant morbidity and require steroids as a temporary supportive care measure.
• Although pregnancy is not specifically addressed in the guideline by the Congress of Neurological Surgeons,
the recommending body, in general, does not recommend prophylactic use of antiseizure medications in
patients with brain tumors.
ARTICLE 7: NEURO-OPHTHALMOLOGY
AND PREGNANCY
Heather E. Moss, MD, PhD, FAAN. Continuum (Minneap Minn). February 2022;
ABSTRACT
PURPOSE OF REVIEW:
This article summarizes the impact of pregnancy on neuro-ophthalmic pathways and presents an
approach to the evaluation of pregnant women who have neuro-ophthalmic symptoms or signs.
RECENT FINDINGS:
Advances in noninvasive ophthalmic imaging have increased knowledge of the impact of
pregnancy on ocular blood flow, which may have relevance for understanding the impact of
preeclampsia and eclampsia on the eye.
SUMMARY:
The framework for approaching neuro-ophthalmic symptoms and signs in pregnant women is
similar to the general approach for people who are not pregnant. Visual symptoms are common

in preeclampsia and eclampsia. Some diseases that impact the neuro-ophthalmic pathways are
more common in pregnant women. Pregnancy should be considered when recommending the
workup and treatment for neuro-ophthalmic symptoms and signs.
KEY POINTS
• Ocular surface and cornea changes in pregnancy can cause blur, eye pain, refractive shift, and contact lens
discomfort.
• Branch retinal vein occlusions, branch retinal artery occlusions, and central serous chorioretinopathy are
retinal causes of acute partial vision loss in pregnancy.
• Visual symptoms occur in more than one-fourth of patients with preeclampsia and almost half of patients
with eclampsia.
• The approach to visual symptoms in pregnant patients is similar to the approach to visual symptoms in
other patients.
• Dilating the pupils with eye drops is regarded to be safe during pregnancy.
• Optic neuritis related to multiple sclerosis, neuromyelitis optica, or myelin oligodendrocyte glycoprotein–
associated disorder is less common during pregnancy and has increased frequency postpartum.
• Bilateral optic disc edema from increased intracranial pressure does not cause visual symptoms in up to half
of affected patients.
• Regular formal perimetry to monitor visual fields of patients with papilledema from primary or secondary
high intracranial pressure is important to detect vision loss so that intracranial pressure–lowering therapy can
be advanced to prevent further worsening.
• Sixth nerve palsies in pregnancy can result from intracranial hypertension (eg, due to cerebral venous sinus
thrombosis) and hypotension (eg, due to dural puncture during anesthesia).
• Growth of sellar and suprasellar structures during pregnancy can cause vision loss, diplopia, facial
numbness, and Horner syndrome.
• Eye movement abnormalities can be caused by thiamine deficiency provoked by hyperemesis gravidarum,
which requires urgent treatment.
• Facial nerve palsy is the most common cranial nerve palsy in pregnancy.
• Artificial tears are the first-line treatment for management of eye pain and blur due to dry eye.
ARTICLE 8: NEUROLOGIC
COMPLICATIONS OF OBSTETRIC
ANESTHESIA
Janet F. R. Waters, MD, MBA, FAAN. Continuum (Minneap Minn). February 2022;
ABSTRACT
PURPOSE OF REVIEW:
The advantages of neuraxial anesthesia over general anesthesia in the obstetric population are
well established. Some neurologic conditions have the potential to lower the safety threshold
for administration of neuraxial anesthesia, whereas others require special consideration before
using general anesthesia. The aim of this article is to help neurologists determine when neuraxial
anesthesia can be safely administered and when it is inadvisable.

RECENT FINDINGS:
Neuraxial anesthesia can usually be given safely in most pregnant patients with neurologic
disease. Patients with mass lesions causing increased intracranial pressure or spinal tumors at
the site of neuraxial needle placement and patients on anticoagulant medication are the
exceptions. Post–dural puncture headaches and obstetric nerve injuries are the most common
complications of neuraxial anesthesia and resolve in most patients. Other complications,
including epidural hematoma, meningitis, and epidural abscess, are rare but devastating.
SUMMARY:
This article provides a review of neurologic diseases that may affect the decision-making
process for anesthesia during delivery. It discusses the neurologic complications that can occur
because of obstetric anesthesia and how to recognize them and describes obstetric nerve
injuries and how to distinguish these relatively benign injuries from more serious complications.
KEY POINTS
• Women with multiple sclerosis who are pregnant often have less frequent exacerbations than women with
multiple sclerosis who are not pregnant. Flare-ups increase in the postpartum period.
• Neuraxial anesthesia may be given safely in women with multiple sclerosis.
• Studies show that the use of neuraxial anesthesia poses no risk to women with Chiari malformation type I in
the absence of increased intracranial pressure. Spinal and epidural anesthesia may be given safely in
pregnant women with syringomyelia.
• Although elevated intracranial hypertension due to a mass lesion is a contraindication to neuraxial anesthesia
because of the risk of herniation, it is safe in patients with idiopathic intracranial hypertension and may be
therapeutic in these patients.
• General anesthesia should be avoided, if possible, in patients with idiopathic intracranial hypertension
because of the risk of increased intracranial pressure during intubation. Obesity puts these patients at
increased risk for difficult intubation and aspiration.
• Epidural and spinal anesthesia is preferable in pregnant women with myasthenia gravis. When general
anesthesia is used, extubation can be challenging. If general anesthesia is used, depolarizing agents
(including succinylcholine) should be avoided because of the risk of neuromuscular blockade.
• Meningiomas, schwannomas, and gliomas may all have accelerated growth in pregnancy. If increased
intracranial pressure is demonstrated, neuraxial anesthesia should be avoided because of the risk of
herniation.
• General anesthesia presents risk in pregnant women with brain tumors. An increase in intracranial pressure
can occur during induction and intubation.
• In most pregnant women with brain tumors without mass effect and increased intracranial pressure,
neuraxial anesthesia can be safely administered. A case-by-case assessment of these patients is indicated.
• In patients with neurofibromatosis, the presence of lumbar tumors can increase the risk of epidural
hematoma during spinal and epidural needle placement. Pregnant women with neurofibromatosis should
undergo noncontrast MRI of the lumbar spine before undergoing neuraxial anesthesia.
• Patients with Guillain-Barré syndrome are at no increased risk with the use of neuraxial anesthesia but should
be monitored carefully for the development of hypotension due to autonomic dysfunction and exaggerated
vasovagal response. If general anesthesia is used, succinylcholine is contraindicated because of the
potential for life-threatening hyperkalemia.
• Most women with lumboperitoneal shunts are able to undergo neuraxial anesthesia; however, imaging may
be needed before delivery to ascertain the position of the shunt. Spinal anesthesia may be unpredictable and
of shorter duration if local anesthetic leaks via the shunt into the peritoneal cavity, which can lead to an
inadequate block.

• In pregnant women with myotonic dystrophy, delivery may be difficult because of uterine smooth muscle
abnormality, which can affect all stages of labor. The second stage of labor may be prolonged because of
skeletal muscle weakness.
• General anesthesia should be avoided in patients with myotonic dystrophy, if possible, as they are at high risk
for aspiration because of pharyngeal muscle weakness and gastric immotility. Triggers for myotonia should
be avoided, including hypothermia and shivering. Respiratory complications can occur in the postoperative
period, and opioid use should be minimized.
• Intubation may be difficult in patients with spinal muscular atrophy as many have limited jaw opening
because of mandibular joint ankylosis and cervical immobility. Depolarizing neuromuscular blockers have a
prolonged effect on patients with spinal muscular atrophy even after reversal and should be avoided.
Neuraxial anesthesia is preferable to general anesthesia but may not be feasible in some patients with severe
scoliosis. Imaging before placement of epidural or spinal anesthesia can be helpful.
• Post–dural puncture headache is the most common complication of neuraxial anesthesia. It may be
associated with hyperacusis, double vision, photophobia, and nausea. It can be distinguished from migraine
and other types of headaches by its postural nature.
• Treatment of post–dural puncture headache starts with conservative management, including bed rest,
adequate hydration, and analgesics. Although some clinicians advocate the use of caffeine, this has not been
supported by the literature.
• If conservative management of post–dural puncture headache fails, an epidural blood patch can be placed.
A blood patch done less than 24 hours after the dural puncture has a high failure rate. An epidural blood
patch performed after 24 hours after dural puncture has a success rate of 70% to 97%.
• A rare consequence of intracranial hypotension from dural puncture is the development of a subdural
hematoma.
• Spinal epidural hematoma should be suspected in patients who experience anesthesia persisting for greater
than the expected duration, unusual back pain, persistent motor weakness, sensory loss, and sphincter
dysfunction.
• Risk factors for spinal epidural hematoma include intrinsic or iatrogenic clotting dysfunction and
spinal tumors.
• Early diagnosis and management of a spinal epidural hematoma is essential to prevent permanent
neurologic injury.
• Direct conus and cord injury can result if the lower end of the spinal cord is not accurately determined before
needle placement. Placement of neuraxial block, especially spinal anesthesia, at the level below the second
lumbar vertebra reduces the risk.
• Cauda equina syndrome manifests as burning low back pain, sphincter dysfunction, lower extremity
weakness, and saddle anesthesia. It can develop because of neurotoxicity caused by pooling of local
anesthetic.
• Skin flora is the most common source of infection in women who develop spinal epidural abscess, and
Staphylococcus aureus is the most common underlying organism. The risk of developing an abscess
increases with prolonged duration of epidural catheterization. Urgent MRI with gadolinium should be done to
confirm the diagnosis.
• Microbial contamination from the mouth and nose of the practitioner are the most common source of
meningitis as a complication of neuraxial anesthesia. The most common causative organism is Streptococcus
viridans. Confirmation is obtained with CSF analysis, and treatment is aggressive antimicrobial therapy.
• A total spinal block will occur if a large volume of local anesthetic intended for the epidural space is injected
into the subarachnoid space. It can produce anesthesia involving the entire spinal cord, nerve roots, and
brainstem. Cranial nerve findings, including pupillary dilatation, may occur. It can lead to respiratory
insufficiency and profound hypotension and bradycardia. Treatment is supportive.
• Seizures may occur when local anesthetic is accidentally injected intravascularly. Systemic toxicity is more
likely to occur after obstetric epidural anesthesia than spinal anesthesia because larger volumes of local
anesthetics are used.

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POSTREADING TEST
ARTICLE 1: PREGNANCY MANAGEMENT IN MULTIPLE SCLEROSIS AND OTHER

1 Which of the following glucocorticoids is least preferred in pregnant

patients with multiple sclerosis to treat relapses?
A dexamethasone
B hydrocortisone
C methylprednisolone
D prednisolone
E prednisone
2 A 32-year-old woman with anti–aquaporin-4 antibody positive

neuromyelitis optica spectrum disorder (NMOSD) who is 16 weeks
pregnant and not on current treatment for her neurologic disease
presents to the emergency department with 2 days of weakness and
numbness in both legs and her right arm. MRI of the cervical spine
shows a longitudinally extensive transverse myelitis from C6 through
T2. The patient receives 5 days of IV steroids without any improvement.
Which of the following would be the best next step in management?
A eculizumab
B fingolimod
C IV immunoglobulin (IVIg)
D plasma exchange
E second course of IV steroids
3 Which of the following statements regarding pregnancy outcomes and

demyelinating disorders is most correct?
A disease activity in the year before pregnancy is not correlated

with disease activity during pregnancy in patients with multiple
sclerosis and neuromyelitis optica spectrum disorder (NMOSD)
B an increased risk of relapses during pregnancy exists in patients
with multiple sclerosis
C an increased risk of relapses during pregnancy exists in patients
with neuromyelitis optica spectrum disorder (NMOSD)
D obstetric complications are rare in patients with neuromyelitis
optica spectrum disorder (NMOSD)
E the risk of postpartum relapses is decreased in patients with
multiple sclerosis and neuromyelitis optica spectrum disorder
(NMOSD)
190 FEBRUARY 2022

4 Which of the following disease-modifying therapies for multiple sclerosis
is associated with rebound activity after the medication is stopped?
A dimethyl fumarate
B fingolimod
C glatiramer acetate
D interferon beta 1a
E ocrelizumab
5 A 23-year-old woman with multiple sclerosis presents shortly after giving

birth. She was diagnosed with multiple sclerosis 4 years ago and has had a
number of relapses before pregnancy despite being on interferons and
dimethyl fumarate. During pregnancy, she elected to be off medication
and had two relapses in the first trimester that were treated with IV
steroids. Three weeks postpartum, she was hospitalized for right arm
weakness and numbness, with MRI of her brain showing a new enhancing
lesion. She is now breastfeeding and would like to continue. She asks what
her options are regarding disease-modifying therapy while breastfeeding.
Which of the following is the most effective option to control this patient’s
disease while allowing her to continue breastfeeding?
A dimethyl fumarate
B fingolimod
C glatiramer acetate
D rituximab
E teriflunomide
6 A 19-year-old woman has a 5-year history of temporal lobe epilepsy that

has been well controlled on carbamazepine for 2 years. She is planning
to start a hormonal contraceptive. Which of the following contraceptive
methods would be the best option for this patient?
A contraceptive patch
B levonorgestrel intrauterine device
C low-dose combination oral contraceptive
D progestin/progesterone implants
E vaginal ring
7 Which of the following pregnancy- and labor-related events occur at

almost double the frequency in women with epilepsy compared to
women without epilepsy?
A cesarean delivery
B eclampsia
C forceps-assisted delivery
D gestational diabetes
E multiple pregnancies

POSTREADING TEST
8 Which of the following characteristics increases the risk of major

congenital malformations?
A antiseizure medication exposure during the last trimester

B antiseizure medication polytherapy
C father with epilepsy
D history of Panayiotopoulos syndrome in the mother
E number of focal seizures during pregnancy
9 What is the earliest point in pregnancy at which a decrease in

lamotrigine levels can be seen?
A 1 week postconception
B 3 weeks postconception
C late first trimester
D late second trimester
E mid third trimester
10 What is the optimal timing of initiation of folic acid supplementation in

women with epilepsy on antiseizure medication?
A as soon as pregnancy is identified

B at the time of active pregnancy planning
C following menarche
D once patients become sexually active
E 1 year before pregnancy
ARTICLE 3: NEUROMUSCULAR DISORDERS AND PREGNANCY
11 Which of the following conditions may worsen during pregnancy

because of the shift in endogenous steroid levels that occurs during
pregnancy?
A Charcot-Marie-Tooth disease
B chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP)
C dermatomyositis
D multifocal motor neuropathy (MMN)
E myasthenia gravis
192 FEBRUARY 2022

12 A 32-year-old woman at 18 weeks’ gestation presents to the emergency
department with 4 weeks of worsening weakness and numbness. Her
pregnancy has been complicated by hyperemesis gravidarum, causing
her to have significant nausea and vomiting over the past 2 months.
Four weeks ago, she noticed numbness in her toes that has moved up to
her knees and now to her hands. For the past few days, she has needed a
walker to ambulate because of weakness. On examination, she has both
distal and proximal weakness in her arms and legs, decreased sensation
to the knees bilaterally, and decreased reflexes. A lumbar puncture is
performed, which is normal, and nerve conduction studies and EMG
demonstrate a severe axonal sensorimotor polyneuropathy. Which of
the following is the most likely cause of her symptoms?
A acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

B amyloidosis
C POEMS (polyneuropathy, organomegaly, endocrinopathy,
monoclonal plasma cell disorder, and skin changes) syndrome
D thiamine deficiency
E vitamin B12 deficiency
13 A 22-year-old woman reports right leg weakness and numbness that

began after prolonged labor. Neurologic examination is notable for 4/5
strength in right hip flexion, hip adduction, knee extension, ankle
dorsiflexion, and ankle eversion; absent right patellar reflex; and
decreased sensation in the right thigh, lateral and medial aspects of the
leg, and dorsum of the foot. Which of the following is the most likely
cause of the patient’s symptoms?
A femoral neuropathy
B fibular (peroneal) neuropathy
C L5 radiculopathy
D lumbosacral plexopathy
E obturator neuropathy
14 Which of the following medications used to treat myasthenia gravis

should be stopped at least 6 weeks before a patient is planning to
conceive?
A azathioprine
B IV immunoglobulin (IVIg)
C mycophenolate mofetil
D prednisone
E pyridostigmine

POSTREADING TEST
15 A 28-year-old woman at 35 weeks’ gestation with myasthenia gravis

well controlled on prednisone and pyridostigmine presents with
symptoms concerning for preeclampsia. In the hospital, the patient is
treated for high blood pressure with hydralazine and given magnesium
to prevent seizures. She is also found to have a urinary tract infection
that is treated with nitrofurantoin. Three days into the hospital course,
the patient’s blood pressure has improved, but she begins to develop
shortness of breath, dysarthria, dysphagia, and ptosis. What is the most
likely cause of her myasthenia gravis exacerbation?
A hydralazine
B magnesium
C nitrofurantoin
D preeclampsia
E urinary tract infection
ARTICLE 4: HEADACHE IN PREGNANCY AND LACTATION
16 A 27-year-old woman has been on erenumab for 1 year with marked

decrease in migraine frequency. She is starting to think about conception
planning, including carefully tracking ovulation once she stops taking
contraception. Which of the following is the most appropriate guidance
on the timing of stopping erenumab and the timing of pregnancy?
A erenumab is safe during pregnancy and does not need to be

stopped
B erenumab should be stopped between her last menstrual period
and start of ovulation
C erenumab should be stopped postovulation, but injections can be
restarted again preovulation if she does not become pregnant
D the last injection of erenumab should be 5 to 6 months before
conception
E no further injections of erenumab should be administered once
pregnancy is confirmed with a positive pregnancy test
17 Which of the following factors increases the risk of a secondary cause

of headache in pregnancy?
A advanced maternal age

B glycosuria
C headache during first pregnancy
D headache during the first trimester
E history of migraine
194 FEBRUARY 2022

18 A 30-year-old woman who is 28 weeks pregnant presents to the
emergency department with 4 days of headache that was acute in onset
and has progressed in intensity daily. On examination, she has bilateral
papilledema. Magnetic resonance venography (MRV) of the head is
obtained and reveals superior sagittal sinus thrombosis. What is the
most appropriate next step in her management?
A anticoagulation with apixaban

B anticoagulation with enoxaparin sodium
C IV magnesium sulfate
D serial imaging and symptomatic management of her headache
E urgent cesarean delivery
19 A 32-year-old woman who is 37 weeks pregnant develops a thunderclap

headache rapidly followed by the onset of bitemporal hemianopia and
hypotension. Which of the following studies is the most appropriate
next step in her workup?
A head CT
B lumbar puncture
C magnetic resonance venography (MRV)
D MRI with gadolinium
E MRI without gadolinium with thin cuts through the pituitary
20 Which of the following best determines the most appropriate mode of

delivery in pregnant patients with idiopathic intracranial hypertension?
A cesarean delivery is indicated in all patients with a diagnosis of

idiopathic intracranial hypertension made during pregnancy
B cesarean delivery is indicated in patients who required emergent
fenestration or shunt placement for management during
pregnancy
C opening pressure on lumbar puncture performed at the time of
epidural anesthesia administration
D opening pressure on lumbar puncture performed a week before
the patient’s scheduled due date
E standard obstetric factors only
21 Which of the following risks should be included in the informed

consent discussion held with patients before initiation of oral magnesium
therapy for preventive headache management during pregnancy?
A fetal bradycardia
B fetal skeletal abnormalities
C premature closure of the ductus arteriosus
D reduction in fetal body weight
E uterine contractions

POSTREADING TEST
ARTICLE 5: MATERNAL STROKE ASSOCIATED WITH PREGNANCY
22 Which time period during pregnancy is associated with the highest risk
of maternal stroke?
A first trimester
B peripartum to 2 weeks postpartum
C second trimester
D third trimester
E 2 weeks to 12 weeks postpartum
23 A 20-year-old woman presents on postpartum day 4 with a severe

sudden-onset headache associated with photophobia, phonophobia,
and vomiting. On examination, the patient is drowsy, although fully
oriented, and answers questions appropriately. Head CT shows
subarachnoid hemorrhage with blood noted over the cerebral
convexities. Which of the following is the most likely etiology of the
patient’s subarachnoid hemorrhage?
A cocaine use
B idiopathic
C intracranial aneurysm rupture
D reversible cerebral vasoconstriction syndrome
E vascular malformation
24 Which of the following is correct regarding preeclampsia?
A it can occur anytime during pregnancy or postpartum

B it is often associated with posterior reversible encephalopathy
syndrome (PRES), although not with ischemic or hemorrhagic strokes
C it is relatively rare and affects about 1 in 500 pregnancies
D neurologic complications are required for diagnosis
E neurologic complications can substitute for proteinuria to
establish a diagnosis
25 A 28-year-old woman who is 24 weeks pregnant presents to the hospital

with acute left-sided weakness and numbness and left-sided neglect,
with last known well time 90 minutes ago. Blood pressure is 135/65 mm Hg,
and glucose is normal. Head CT is normal, but head CT angiography
demonstrates a right M1 thrombus with no distal flow. Which of the
following is the most appropriate treatment for this patient?
A aspirin
B dual antiplatelet therapy with aspirin and clopidogrel
C IV heparin drip
D IV thrombolysis
E IV thrombolysis and thrombectomy
196 FEBRUARY 2022

26 What is the increased risk of maternal stroke in patients with migraine?
A 5-fold
B 10-fold
C 15-fold
D 20-fold
E 25-fold
ARTICLE 6: MANAGING CENTRAL NERVOUS SYSTEM TUMORS DURING

PREGNANCY
27 The impact of pregnancy is less clear for which of the following

tumor types?
A glioblastoma
B low-grade astrocytoma
C meningioma
D pituitary adenoma
E schwannoma
28 A 30-year-old woman had the incidental finding of a small right

vestibular schwannoma on MRI obtained for migraine when she was
23. Audiology testing at that time revealed minimal right-sided hearing
loss, which has not progressed on repeat testing over the years. Annual
MRIs have not shown tumor progression. She is now planning to
conceive. Which of the following is the most appropriate management
of her tumor during her pregnancy?
A initiation of chemotherapy only if she develops subjective hearing

loss or other neurologic symptoms
B MRI with gadolinium contrast once every trimester
C radiation at least 6 months before she becomes pregnant
D routine audiology monitoring and clinical observation throughout
her pregnancy
E surgical resection at least 3 months before she becomes pregnant
29 Per professional society guidelines, which of the following is the most

accurate recommendation for the use of dopamine agonists in pregnant
patients with microprolactinomas?
A continuation throughout the pregnancy at a 50% dose reduction

B continuation throughout the pregnancy, with close monitoring of
drug levels
C continued use throughout the first trimester, with discontinuation
in the later stages of pregnancy
D discontinuation for the first and second trimester, with
resumption of treatment in the third trimester
E discontinuation upon confirmation of pregnancy

POSTREADING TEST
30 Which of the following hormones is tumor inhibitory?
A brain-derived neurotrophic factor

B estrogen
C luteinizing hormone
D placental growth hormone
E progesterone
ARTICLE 7: NEURO-OPHTHALMOLOGY AND PREGNANCY
31 Which of the following is the easiest method to diagnose central serous

chorioretinopathy?
A funduscopic examination
B head CT
C MRI brain
D optical coherence tomography
E visual acuity testing
32 A 34-year-old woman on postpartum day 20 presents to the emergency

department with moderate headaches for the past 5 days. Examination
reveals bitemporal field defects with an otherwise normal examination,
including funduscopy, visual acuity, and extraocular movements. MRI
of her brain demonstrates diffuse pituitary enlargement and postcontrast
enhancement. Laboratory tests indicate low thyroid-stimulating
hormone (TSH) levels. The patient had an uneventful pregnancy with
minimal blood loss. Which of the following is the most likely diagnosis?
A lymphocytic hypophysitis
B migraine with aura
C pituitary apoplexy
D pituitary macroadenoma
E Sheehan syndrome
33 Which of the following treatment options for idiopathic intracranial

hypertension is generally contraindicated during pregnancy because of
risk to the fetus?
A acetazolamide
B mild to moderate weight loss
C optic nerve sheath fenestration
D serial lumbar punctures
E topiramate
198 FEBRUARY 2022

34 A 24-year-old woman who is 37 weeks pregnant presents to the
emergency department with 3 days of oblique diplopia. The diplopia
improves when the patient closes either eye. On examination, she has
ptosis of the right eye and anisocoria with the right pupil larger than
the left that is more prominent in light, and the right eye appears down
and out. Which of the following diagnostic tests should be performed
urgently?
A lumbar puncture
B magnetic resonance angiography (MRA) of the head
C magnetic resonance venography (MRV) of the head
D MRI of the brain
E optical coherence tomography
35 A 40-year-old woman presents with blurry vision and pain in both eyes
that worsen at the end of the day and after looking at a computer screen
for a prolonged period of time. Neurologic and ophthalmologic examination
are normal. Which of the following is the most likely diagnosis?
A dry eye disease

B migraine headaches
C optic neuritis
D posterior reversible encephalopathy syndrome (PRES)
E uveitis
ARTICLE 8: NEUROLOGIC COMPLICATIONS OF OBSTETRIC ANESTHESIA
36 Which of the following complications occurs at a higher incidence in

pregnant patients who receive general anesthesia?
A agitation of the newborn

B desaturation once intubated
C eclampsia
D fatal arrhythmias
E peripartum hemorrhage
37 Repeat MRI is indicated before neuraxial anesthesia in pregnant

women with which of the following neurologic diagnoses?
A Chiari malformation type I

B epilepsy
C multiple sclerosis
D neurofibromatosis
E syringomyelia

POSTREADING TEST
38 Which of the following is a contraindication to neuraxial anesthesia?
A aspirin use
B clopidogrel use
C idiopathic intracranial hypertension
D multiple sclerosis
E syringomyelia
39 A 25-year-old woman at 41 weeks’ gestation with a past medical history

of obesity receives epidural anesthesia for a planned vaginal delivery.
Four minutes following injection of anesthesia, the patient says that
her arms and legs are both numb and she cannot move them, and she
starts to feel short of breath. On examination, the patient’s blood
pressure decreases to 70/40 mm Hg, and her heart rate decreases to
36 beats/min. On neurologic examination, the patient is quadriplegic.
Which of the following diagnoses is most likely?
A chemical meningitis
B direct spinal cord injury
C epidural abscess
D epidural hematoma
E total spinal block
40 A 42-year-old woman receives epidural anesthesia for a planned

vaginal delivery. The delivery is unremarkable. The patient feels well
until the next day, when she starts to notice headaches that are
constant, although worse when standing up; the headaches are
associated with hyperacusis, photophobia, and nausea. Neurology is
consulted, and conservative management is recommended. After 1 day
of no improvement, the patient receives an epidural blood patch; the
epidural blood patch helps, but the patient continues to have a
constant headache that worsens with standing up. A second epidural
blood patch is given, but the patient has no improvement in headaches.
She has no fever. Which of the following is recommended as a
next step?
A caffeine
B head CT
C IV fluids
D lumbar puncture
E a third epidural blood patch
200 FEBRUARY 2022

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
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By Nuri Jacoby, MD; Allison L. Weathers, MD, FAAN
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with each question are intended to encourage independent study.
US PARTICIPANTS: Upon
completion of the Postreading Self-Assessment and
CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS. Thisprogram is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Refer to the CME tab on
ContinuumJournal.com for dates of accreditation. Canadian participants
should visit MAINPORT (mainport.org) to record learning and outcomes.
Canadian participants can claim a maximum of 20 hours per issue (credits
are automatically calculated).
ARTICLE 1: PREGNANCY MANAGEMENT IN MULTIPLE SCLEROSIS AND OTHER

1 The preferred response is A (dexamethasone). Eighty percent of maternal

dexamethasone crosses the placenta and enters the fetal circulation. The
other glucocorticoids, in contrast, are inactivated by placental 11-β
hydroxysteroid dehydrogenase and do not enter the fetal circulation. For
more information, refer to page 23 of the Continuum article, “Pregnancy
Management in Multiple Sclerosis and Other Demyelinating Diseases.”

POSTREADING TEST—PREFERRED RESPONSES
2 The preferred response is C (IV immunoglobulin [IVIg]). First-line

treatment for severe neuromyelitis optica spectrum disorder (NMOSD)
attacks is IV steroids. For steroid-resistant disease in pregnant women,
as in this patient, IVIg is preferred over plasma exchange because of the
risks of hypotension with plasma exchange, which may affect the fetus.
This is in contrast to nonpregnant patients, to whom plasma exchange
is often given. Further stabilization with a disease-modifying therapy
may be considered after treatment for the acute relapse. For more
information, refer to pages 24, 26 of the Continuum article, “Pregnancy
3 The preferred response is C (an increased risk of relapses during

pregnancy exists in patients with neuromyelitis optica spectrum
disorder[NMOSD]). Pregnant women with NMOSD have an increased
risk of relapses during pregnancy, whereas the risk of relapses during
pregnancy is typically reduced in women with multiple sclerosis. In both
multiple sclerosis and aquaporin-4–seropositive NMOSD, the risk of
relapse is increased postpartum. In NMOSD, obstetric complications are
reported to be more common, unlike in multiple sclerosis. In both
conditions, intrapartum and postpartum outcomes are partially linked to
disease stability in the year before pregnancy. For more information,
refer to page 16 of the Continuum article, “Pregnancy Management in
Multiple Sclerosis and Other Demyelinating Diseases.”
4 The preferred response is B (fingolimod). Fingolimod and natalizumab

are the two disease-modifying therapies that are most associated with
rebound multiple sclerosis activity. As fingolimod should not be
continued during pregnancy, women on fingolimod who stop the
medication before pregnancy are at higher risk of rebound relapse
during pregnancy. For more information, refer to pages 18, 21 of the
Continuum article, “Pregnancy Management in Multiple Sclerosis and
Other Demyelinating Diseases.”
5 The preferred response is D (rituximab). Dimethyl fumarate, fingolimod,

and teriflunomide are not recommended in patients who are
breastfeeding. Although glatiramer acetate and rituximab are probably
compatible with breastfeeding and both are reasonable options, given
the patient’s aggressive disease, rituximab is preferred. For more
information, refer to page 28 of the Continuum article, “Pregnancy
202 FEBRUARY 2022

6 The preferred response is B (levonorgestrel intrauterine device).

Efficacy is maintained with the use of levonorgestrel intrauterine devices
in women with epilepsy on enzyme-inducing antiseizure medications.
Efficacy is not maintained with the other options listed because certain
antiseizure medications (eg, carbamazepine) may decrease hormonal
contraception levels for estrogen or progesterone agents. For more
information, refer to page 37 of the Continuum article “Epilepsy and
Pregnancy.”
7 The preferred response is A (cesarean delivery). Studies have found

that the frequency of cesarean delivery in women with epilepsy is nearly
twice that of the general population. This increased risk exists for both
elective cesarean delivery and emergent procedures, without a clear
obstetric indication to explain this increase. The incidence of
preeclampsia is increased in women with epilepsy compared to those
without, but eclampsia does not occur at twice the frequency. For more
information, refer to page 39 of the Continuum article “Epilepsy
and Pregnancy.”
8 The preferred response is B (antiseizure medication polytherapy). The

risk of congenital malformations is increased in children born to women
with epilepsy compared to children born to women without epilepsy.
Characteristics that have been associated with increased risk include
low level of education, early antiseizure medication exposure in the first
trimester, antiseizure medication polytherapy, the dose and type of
antiseizure medication, and low serum folate concentration. The type of
epilepsy and number of seizures has not been found to correlate with
the number of malformations. Exposure to antiseizure medications in the
last trimester has not been found to be associated with an increased risk
of major congenital malformations but may be associated with increased
risk of cognitive impairment. For more information, refer to pages 41-42
of the Continuum article “Epilepsy and Pregnancy.”
9 The preferred response is B (3 weeks postconception). Lamotrigine is

eliminated by glucuronidation and is very susceptible to the rapid
pharmacokinetic changes that occur during pregnancy, increasing the
risk of breakthrough seizures. Although the changes are most
pronounced in the mid third trimester, a decrease in serum
concentration can be seen as early as 3 weeks postconception. For more
information, refer to page 47 of the Continuum article “Epilepsy and
Pregnancy.”

10 The preferred response is D (once patients become sexually active).

Women with epilepsy should be counseled once they are of
childbearing age regarding the impact of epilepsy and its management
on contraception, conception, pregnancy, and delivery. Folic acid
supplementation is recommended once women with epilepsy become
sexually active. Given several factors, including that the unplanned
pregnancy rate is above 50%, the critical role of folate in the development
of the fetal brain, and the detrimental effect of many antiseizure
medications on folate levels, initiation of folic acid supplementation
should not be deferred until the time of active pregnancy planning or
identification of pregnant status. For more information, refer to
page 45 of the Continuum article “Epilepsy and Pregnancy.”
ARTICLE 3: NEUROMUSCULAR DISORDERS AND PREGNANCY
11 The preferred response is D (multifocal motor neuropathy [MMN]). In a

small case series of patients with MMN, all patients had worsening of
symptoms during pregnancy. Unlike a number of other neuromuscular
autoimmune conditions, worsening of symptoms is reported with
corticosteroid treatment in patients with MMN. During pregnancy,
endogenous steroid levels are increased, which may suggest a possible
explanation for the clinical worsening patients with MMN experience
during pregnancy. For more information, refer to page 58 of the
Continuum article “Neuromuscular Disorders and Pregnancy.”
12 The preferred response is D (thiamine deficiency). This patient presents

with an acute axonal sensorimotor polyneuropathy. Acute nutritional
neuropathy can mimic the clinical presentation of Guillain-Barré
syndrome, as in this case. Thiamine deficiency, in particular, can cause
an acute nutritional neuropathy. Pyridoxine deficiency is another cause.
Clues in this case that the patient has a nutritional neuropathy and not
Guillain-Barré syndrome include the absence of albuminocytologic
dissociation seen on lumbar puncture and the history of hyperemesis
gravidarum. Pregnant women who have nausea and vomiting, especially
those who have hyperemesis gravidarum, can be at particularly high risk
of developing a nutritional neuropathy. For more information, refer to
page 58 of the Continuum article “Neuromuscular Disorders and
Pregnancy.”
13 The preferred response is D (lumbosacral plexopathy). The distribution

of weakness and sensory loss on examination involves the femoral,
obturator, and fibular (peroneal) nerves, suggesting a more proximal
localization. The differential includes a lumbosacral plexopathy or a
polyradiculopathy as both the L4 and L5 nerve roots would need to be
affected to explain the patient’s symptoms. Of the answer options, only
204 FEBRUARY 2022

a lumbosacral plexopathy could explain the patient’s examination
findings. The lumbosacral plexus can be compressed during prolonged
labor, especially with fetal macrosomia and malpresentation. For more
information, refer to page 60 of the Continuum article “Neuromuscular
Disorders and Pregnancy.”
14 The preferred response is C (mycophenolate mofetil). Of the answer

options, only mycophenolate mofetil is believed to be unsafe for use
during pregnancy. It is recommended that it be stopped at least 6 weeks
before attempting conception. Pyridostigmine, prednisone, IV
immunoglobulin (IVIg), and azathioprine do not appear to affect fertility
and have all been used safely during pregnancy. Fewer data are
available on rituximab and eculizumab; although case series and reports
suggest they may be safe to use, more data are needed. For more
15 The preferred response is B (magnesium). Magnesium should be

avoided in patients with myasthenia gravis as much as possible as it can
cause exacerbations. This can be an issue in pregnant women who
develop preeclampsia and eclampsia, in which IV magnesium is standard
care. Beta-blockers and calcium channel blockers can also exacerbate
myasthenia gravis, with hydralazine a safer option. Certain antibiotics to
treat urinary tract infections can also exacerbate myasthenia gravis,
especially fluoroquinolones, although nitrofurantoin does not. For more
ARTICLE 4: HEADACHE IN PREGNANCY AND LACTATION
16 The preferred response is D (the last injection of erenumab should be

5 to 6 months before conception). Erenumab is a monoclonal antibody
that targets calcitonin gene-related peptide (CGRP) activity. Human
data for the use of CGRP monoclonal antibodies in pregnancy are
insufficient. Although animal studies did not show teratogenicity,
women with preeclampsia have lower levels of CGRP compared to
people who are normotensive; therefore, this class of drugs is not
recommended during pregnancy. Given this and the long half-life of
CGRP monoclonal antibodies, the current recommendation is to stop
injections 5 to 6 months before conception, in contrast to the
recommendation to stop most oral preventive therapies sometime
between the patient’s last menstrual period and ovulation. For more
information, refer to page 74 of the Continuum article “Headache in
Pregnancy and Lactation.”

17 The preferred response is E (history of migraine). Women with a history

of migraine are more likely to have increased risk of some secondary
causes of pregnancy-related headache, such as cerebral venous sinus
thrombosis, pregnancy-related stroke, and preeclampsia. Lack of
prepregnancy headache history is also associated with increased risk of
secondary headache. Proteinuria, not glycosuria, is associated with
preeclampsia as the etiology of a pregnancy-related headache.
Headache during the third trimester, not the first, is associated with a
higher incidence of secondary causes of headache. For more
information, refer to page 76 of the Continuum article “Headache in
Pregnancy and Lactation.”
18 The preferred response is B (anticoagulation with enoxaparin sodium).

The patient’s presentation is consistent with cerebral venous sinus
thrombosis, which is confirmed on imaging. Treatment with
anticoagulation is warranted, and enoxaparin sodium is preferred in
pregnancy. For more information, refer to page 77 of the Continuum
article “Headache in Pregnancy and Lactation.”
19 The preferred response is E (MRI without gadolinium with thin cuts

through the pituitary). The patient’s presentation is characteristic of
pituitary apoplexy. Because of the enlargement and hyperemia of the
pituitary that can occur during pregnancy, the peripartum period is one
of increased risk, especially in patients with preexisting pituitary
macroadenoma. MRI with thin cuts through the pituitary is the diagnostic
study of choice when this diagnosis is suspected. For more information,
refer to pages 78-79 of the Continuum article “Headache in Pregnancy
and Lactation.”
20 The preferred response is E (standard obstetric factors only). As the

increased intracranial pressure that occurs during labor is transient,
patients with idiopathic intracranial hypertension do not require
cesarean delivery by default. Obstetric factors only should be used to
determine the most appropriate mode of delivery for a patient with
idiopathic intracranial hypertension. For more information, refer to
page 79 of the Continuum article “Headache in Pregnancy and
Lactation.”
21 The preferred response is B (fetal skeletal abnormalities). IV

magnesium sulfate for more than 5 days of treatment has been found to
be associated with fetal skeletal abnormalities. It remains unclear
whether an increased risk for this complication exists with oral
magnesium therapy, and this drug is still considered one of the safer
preventive options. However, a discussion of the potential risks should
be included in the informed consent of the patient before initiation of
206 FEBRUARY 2022

therapy. For more information, refer to page 83 of the Continuum
article “Headache in Pregnancy and Lactation.”
ARTICLE 5: MATERNAL STROKE ASSOCIATED WITH PREGNANCY
22 The preferred response is B (peripartum to 2 weeks postpartum). The

highest risk of maternal stroke occurs approximately 1 day before to
2 weeks after delivery. The median time for postpartum stroke is
8 days, although the risk of maternal thromboembolic events and
intracerebral hemorrhage is higher up to 12 weeks after delivery. When
subclassifying strokes, most hemorrhages due to rupture of vascular
lesions occur during pregnancy, whereas ischemic strokes and
hypertensive hemorrhages most commonly occur during the
postpartum period. For more information, refer to page 95 of the
Continuum article “Maternal Stroke Associated With Pregnancy.”
23 The preferred response is D (reversible cerebral vasoconstriction

syndrome). Subarachnoid hemorrhage in pregnant women is more
commonly caused by reversible cerebral vasoconstriction syndrome,
whereas in nonpregnant patients intracranial aneurysm rupture is the
most common cause. Pregnancy is a significant risk factor for reversible
cerebral vasoconstriction syndrome, with up to 20% of all cases
occurring during the postpartum state. For more information, refer to
page 99 of the Continuum article “Maternal Stroke Associated With
Pregnancy.”
24 The preferred response is E (neurologic complications can substitute

for proteinuria to establish a diagnosis). Preeclampsia is defined as
new-onset hypertension after 20 weeks of gestation together with
evidence of organ dysfunction, which may be renal, hematologic,
hepatic, or neurologic. Unlike prior definitions, proteinuria is no longer
required. Neurologic complications, including visual symptoms and
headaches that do not respond to medications and are not better
explained by an alternative etiology, can substitute for proteinuria to
establish a diagnosis in the presence of new hypertension.
Preeclampsia is relatively common, affecting nearly 1 in 20 pregnancies
in the United States. In addition to its association with posterior
reversible encephalopathy syndrome (PRES), it can also be associated
with reversible cerebral vasoconstriction syndrome, ischemic and
hemorrhagic strokes, subarachnoid hemorrhage, cerebral venous
thrombosis, and cervical artery dissections. For more information, refer
to page 104 of the Continuum article “Maternal Stroke Associated With
Pregnancy.”

25 The preferred response is E (IV thrombolysis and thrombectomy). This

patient is presenting with an acute stroke and is in the time window for
IV thrombolysis and thrombectomy. Pregnancy is not a contraindication
for thrombolysis if deficits are severe, as in this patient, and bleeding
risks are acceptable. Thrombectomies have also been performed safely
in pregnant women. For more information, refer to page 111 of the
Continuum article “Maternal Stroke Associated With Pregnancy.”
26 The preferred response is C (15-fold). A 15-fold increase in risk of

maternal stroke exists in women with migraine, which may be partially
because of the higher risk of preeclampsia in these patients. For more
information, refer to page 101 of the Continuum article “Maternal Stroke
Associated With Pregnancy.”
ARTICLE 6: MANAGING CENTRAL NERVOUS SYSTEM TUMORS DURING

PREGNANCY
27 The preferred response is B (low-grade astrocytoma). Although

pregnancy is known to impact the other tumor types listed, less clear
evidence exists for the influence of pregnancy on low-grade
astrocytoma and an impact cannot be definitively stated. For more
information, refer to page 126 of the Continuum article, “Managing
Central Nervous System Tumors During Pregnancy.”
28 The preferred response is D (routine audiology monitoring and clinical

observation throughout her pregnancy). Although schwannomas
demonstrate more aggressive behavior during pregnancy, audiology
monitoring and observation are sufficient and most appropriate in
patients with small stable tumors without significant functional hearing
loss, especially during pregnancy. For more information, refer to
page 126 of the Continuum article, “Managing Central Nervous System
Tumors During Pregnancy.”
29 The preferred response is E (discontinuation upon confirmation of

pregnancy). Some evidence exists for the use of bromocriptine in early
pregnancy, without increased risk of spontaneous abortion. However,
based on the lack of safety data to support their use, the Endocrine
Society clinical practice guidelines recommend discontinuation of
dopamine agonists when used in the treatment of microprolactinomas
on confirmation of pregnancy. For more information, refer to page 127
of the Continuum article, “Managing Central Nervous System Tumors
During Pregnancy.”
208 FEBRUARY 2022

30 The preferred response is C (luteinizing hormone). Luteinizing hormone
and follicle-stimulating hormone are tumor inhibitory. It has been
theorized that the near absence of these hormones that occurs in the
second and third trimesters, along with the increase in levels of other
hormones that encourage cell growth, may be a factor in the aggressive
growth seen of some tumors during pregnancy. For more information,
refer to page 135 of the Continuum article, “Managing Central Nervous
System Tumors During Pregnancy.”
ARTICLE 7: NEURO-OPHTHALMOLOGY AND PREGNANCY
31 The preferred response is D (optical coherence tomography). Central

serous chorioretinopathy is idiopathic local detachment of the retinal
pigment epithelium that can cause local vision loss or metamorphopsia.
Although it more commonly occurs in men, pregnancy increases the risk
of occurrence. It is easily diagnosed by optical coherence tomography
and can be difficult to see on funduscopic examination. For more
information, refer to page 152 of the Continuum article “Neuro-
ophthalmology and Pregnancy.”
32 The preferred response is A (lymphocytic hypophysitis). Lymphocytic

hypophysitis is felt to be an autoimmune inflammatory condition
characterized by lymphocytic infiltration of the pituitary that is
especially prevalent during late pregnancy and the postpartum period.
It presents with hypopituitarism, headaches, visual field defects, and
diabetes insipidus. The radiologic findings are heterogeneous, although
common findings include diffuse pituitary enlargement and diffuse
homogeneous postcontrast enhancement, as seen in this patient.
Sheehan syndrome would be expected to occur in the setting of
postpartum hemorrhage. The clinical presentation of pituitary apoplexy
would be more acute than this patient’s presentation. In addition, the
imaging findings in this patient are less consistent with pituitary
apoplexy, pituitary macroadenoma, or Sheehan syndrome. For more
information, refer to page 153 of the Continuum article “Neuro-
ophthalmology and Pregnancy.”
33 The preferred response is E (topiramate). Topiramate was classified as

Category D by the US Food and Drug Administration (FDA) using pre-
2015 labeling as its use has been associated with oral clefts.
Acetazolamide was classified as Category C; a 2012 study looking at 158
pregnancies did not find any fetal anomalies associated with its use.
Although significant maternal weight loss can be harmful to the fetus,
mild to moderate weight loss is generally safe and can be helpful to
improve a patient’s symptoms. An optic nerve sheath fenestration
can be done in patients with severe vision loss associated with

papilledema. Lumboperitoneal and ventriculoperitoneal shunts, not an

answer option, are generally avoided during pregnancy because of the
surgical risk. For more information, refer to page 155 of the Continuum
article “Neuro-ophthalmology and Pregnancy.”
34 The preferred response is B (magnetic resonance angiography [MRA]

of the head). This patient’s signs and symptoms are consistent with a
cranial nerve III palsy. Similar to a nonpregnant patient, this patient
needs to be urgently evaluated for a posterior communicating artery
aneurysm, which can be evaluated with an MRA of the head. An
expedient MRA of the head is preferable to CT angiography as the
patient is pregnant. For more information, refer to page 158 of the
Continuum article “Neuro-ophthalmology and Pregnancy.”
35 The preferred response is A (dry eye disease). This patient presents

with classic symptoms of dry eye disease, which often presents with
eye pain and blurry vision that worsen at the end of the day and after
screen use. The incidence of dry eye disease increases during the third
trimester of pregnancy because of reduced tear production. For
more information, refer to page 159 of the Continuum article
“Neuro-ophthalmology and Pregnancy.”
ARTICLE 8: NEUROLOGIC COMPLICATIONS OF OBSTETRIC ANESTHESIA
36 The preferred response is E (peripartum hemorrhage). A number of

increased risks are associated with general anesthesia in pregnant
patients. The medications used in general anesthesia can decrease
uterine contractions, which can result in increased peripartum
bleeding. As general anesthetic agents can cross the placenta, the
newborn may be sedated with respiratory suppression. Pregnant
patients do not desaturate more easily once intubated but can
desaturate more quickly if intubation is difficult or has failed, secondary
to decreased lung capacity. The incidence of failed intubations,
including fatal failed intubation, is higher in pregnant patients. For more
information, refer to page 162 of the Continuum article “Neurologic
Complications of Obstetric Anesthesia.”
37 The preferred response is D (neurofibromatosis). Pregnant women

with neurofibromatosis should have a noncontrast MRI of the lumbar
spine before neuraxial anesthesia as the presence of lumbar tumors
can increase the risk of epidural hematoma with epidural and spinal
needle placement. Repeat MRI before planned neuraxial anesthesia is
not indicated for the other diagnoses listed. For more information, refer
210 FEBRUARY 2022

to page 166 of the Continuum article “Neurologic Complications of
Obstetric Anesthesia.”
38 The preferred response B (clopidogrel use). Brain tumors with mass

effect and increased intracranial pressure, international normalized
ratio (INR) greater than 1.6, anticoagulant medications, and platelet
inhibitors such as clopidogrel are contraindications to the use of
neuraxial anesthesia. The other answer options are not
contraindications to neuraxial anesthesia. Neurologic conditions in
which the decision of neuraxial versus general anesthesia should be
made on a case-by-case basis include neurofibromatosis (if lumbar
tumors are present, the risk of epidural hematoma during needle
placement increases), spina bifida, spinal muscular atrophy (severe
scoliosis may make it unfeasible), brain tumors (in which mass effect is
present), and the presence of a lumboperitoneal shunt (imaging should
be done before neuraxial anesthesia so the point of needle entry can
be adjusted). For more information, refer to page 168 of the Continuum
article “Neurologic Complications of Obstetric Anesthesia.”
39 The preferred response is E (total spinal block). This patient’s

presentation is typical of total spinal block, which can occur during
epidural anesthesia when the anesthetic is accidentally injected into
the subarachnoid space. This does not occur during intraspinal
anesthesia as the dose of anesthetic given is much smaller. The risk of
total spinal block increases if a test dose of a small amount of local
anesthetic is not performed or if not enough time lapses after a test
dose is given to determine whether the needle was accidentally placed
in the subarachnoid space. While direct spinal cord injury may occur
during epidural anesthesia, the injury would likely be to the conus or
lower spinal cord and would not present with hypotension,
bradycardia, and shortness of breath indicating upper spinal cord
pathology. For more information, refer to page 173 of the Continuum
article “Neurologic Complications of Obstetric Anesthesia.”
40 The preferred response is B (head CT). This patient should undergo

head CT to evaluate for a subdural hematoma, a rare complication of
low CSF pressure following epidural anesthesia. Although this patient
has many features of a typical post–dural puncture headache, including
the worsening symptoms on standing, hyperacusis, photophobia, and
nausea, the headache has not completely resolved despite
conservative measures and two epidural blood patches and has a
component that is not positional. Therefore, it is advisable to look for
other causes of a headache, such as a subdural hematoma. For more
information, refer to page 170 of the Continuum article “Neurologic
Complications of Obstetric Anesthesia.”

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives Core Competencies

Upon completion of this Continuum: Lifelong This Continuum: Lifelong Learning in Neurology
Learning in Neurology Neurology of Pregnancy Neurology of Pregnancy issue covers the
issue, participants will be able to: following core competencies:
◆ Discuss the effects of pregnancy on inflammatory ◆ Patient Care

activity in women with demyelinating diseases and the

major principles governing treatment use in relation ◆ Medical Knowledge
to pregnancy
◆ Practice-Based Learning and Improvement
◆ Describe the risks and management of epilepsy in
women preceding pregnancy, during pregnancy, ◆ Interpersonal and Communication Skills
and postpartum
◆ Professionalism
◆ Discuss the diagnosis, management, and treatment
of neuromuscular disorders in pregnancy ◆ Systems-Based Practice
◆ Describe the effectiveness and safety data for both

novel emerging and traditional therapies for the
treatment of headache in pregnancy and lactation
and identify potentially dangerous secondary headache
syndromes that may occur in pregnancy
◆ Describe the risk factors, pathophysiology, evaluation,

and treatment of pregnant and postpartum patients
with acute or chronic cerebrovascular disease
◆ Discuss the most reported central nervous system

tumors during pregnancy and commonly proposed
mechanisms for pregnancy exacerbation of
brain tumors and utilize up-to-date guidelines,
provide recommendations, and recognize special
considerations in the management of pregnant
patients with brain tumors
◆ Describe how the approach to visual symptoms

experienced by pregnant women differs from the
approach for other patients
◆ Discuss the effects of neurologic conditions on

obstetric anesthesia and describe both the
serious and more benign complications of
neuraxial anesthesia
◆ Discuss the complexities that arise from both a legal

and a bioethical standpoint when a patient is brain
dead, but a fetus remains viable
4 F EB R UA R Y 2 0 2 2

LIST OF ABBREVIATIONS
Neurology of Pregnancy ICH Intracerebral hemorrhage

ICHD-3 International Classification of Headache Disorders,
Third Edition
ICP Intracranial pressure
AChR Acetylcholine receptor IIH Idiopathic intracranial hypertension
ACOG American College of Obstetricians and Gynecologists IM Intramuscular
ACTH Adrenocorticotropic hormone INCAT Inflammatory Neuropathy Cause and Treatment
ADEM Acute demyelinating encephalomyelitis [disability score]

AHRQ Agency for Healthcare Research and Quality IQ Intelligence quotient
AIDP Acute inflammatory demyelinating IUD Intrauterine device
polyradiculoneuropathy
IV Intravenous
ATP Adenosine triphosphate
IVIg Intravenous immunoglobulin
AVM Arteriovenous malformation
LH Luteinizing hormone
BDNF Brain-derived neurotrophic factor
LRP4 Lipoprotein receptor-related protein 4
CGRP Calcitonin gene-related peptide
MADSAM Multifocal acquired demyelinating sensory
CIDP Chronic inflammatory demyelinating and motor neuropathy
polyradiculoneuropathy
MG Myasthenia gravis
CMT Charcot-Marie-Tooth disease
MMN Multifocal motor neuropathy
CNS Central nervous system
MOG Myelin oligodendrocyte glycoprotein
CPAP Continuous positive airway pressure
MRA Magnetic resonance angiography
CSF Cerebrospinal fluid
MRI Magnetic resonance imaging
CT Computed tomography
MRV Magnetic resonance venography
DM1 Myotonic dystrophy type 1
MS Multiple sclerosis
DM2 Myotonic dystrophy type 2
MuSK Muscle-specific tyrosine kinase
DMT Disease-modifying therapy
NF-ĸB
NF- B Nuclear factor kappa B
EEG Electroencephalogram; electroencephalography
NMOSD Neuromyelitis optica spectrum disorder
EMA European Medicines Agency
OCT Optical coherence tomography
EMG Electromyography
PET Positron emission tomography
FDA US Food and Drug Administration
PRES Posterior reversible encephalopathy syndrome
FIGO International Federation of Gynecology and Obstetrics
RCVS Reversible cerebral vasoconstriction syndrome
FLAIR Fluid-attenuated inversion recovery
S1P Sphingosine-1-phosphate
FSH Follicle-stimulating hormone
SAH Subarachnoid hemorrhage
GBS Guillain-Barré syndrome
SMA Spinal muscular atrophy
HELLP Hemolysis, elevated liver enzymes, and low platelets
[syndrome] SSRI Selective serotonin reuptake inhibitor
HIV Human immunodeficiency virus TIA Transient ischemic attack
HNPP Hereditary neuropathy with liability to pressure palsies VEGF Vascular endothelial growth factor
I-RODS Inflammatory Rasch-built Overall Disability Scale WHO World Health Organization
© 2022 American Academy of Neurology.

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CONTRIBUTORS

Mary Angela O’Neal, MD, Karissa L. Gable, MD

School; Director, Women’s

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Joseph S. Kass, MD, JD, FAAN

Unlabeled Use of Products/Investigational

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Kimford J. Meador, MD, FAAN, Heather E. Moss, MD,

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Rachel V. Rose, JD, MBA Janet F. R. Waters, MD,

Self-Assessment and CME Test Writers

Nuri Jacoby, MD Allison L. Weathers, MD, FAAN

Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Discuss the effects of pregnancy on inflammatory activity in women with demyelinating

 Discuss the diagnosis, management, and treatment of neuromuscular disorders in

 Practice-Based Learning and Improvement

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Mary Angela O’Neal, MD, FAAN, Guest Editor

Unlabeled Use of Products/Investigational Use Disclosure: Dr O’Neal reports no disclosure.

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Na Tosha N. Gatson, MD, PhD, FAAN

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Joseph S. Kass, MD, JD, FAAN

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12 Pregnancy Management in Multiple Sclerosis and Other

34 Epilepsy and Pregnancy

55 Neuromuscular Disorders and Pregnancy

72 Headache in Pregnancy and Lactation

93 Maternal Stroke Associated With Pregnancy

122 Managing Central Nervous System Tumors During Pregnancy

147 Neuro-ophthalmology and Pregnancy

162 Neurologic Complications of Obstetric Anesthesia

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SELF-ASSESSMENT AND CME

4 Learning Objectives and Core Competencies

187 Instructions for Completing Postreading Self-Assessment and CME

189 Postreading Self-Assessment and CME Test