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ADVANCES IN

Pediatrics
Editor-in-Chief
Carol D. Berkowitz, MD
Division of General Pediatrics,
Department of Pediatrics,
Harbor-University of California Los Angeles Medical Center,
David Geffen School of Medicine at UCLA,
Torrance, CA, USA

ELSEVIER

PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO

Editor-in-Chief
CAROL D. BERKOWITZ, MD, FAAP, FACEP, Chief, Division of General Pediatrics,
Department of Pediatrics, Harbor-UCLA Medical Center, Distinguished Professor
of Pediatrics, David Geffen School of Medicine at UCLA, Torrance, California

Associate Editors
JANE D. CARVER, PhD, MS, Professor Emeritus, University of South Florida Morsani
College of Medicine, Department of Pediatrics, Tampa, Florida

RONALD BRUCE HIRSCHL, MD, Arnold G. Coran Collegiate Professor of Pediatric

Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan

MOIRA SZILAGYI, MD, PhD, FAAP, Professor of Pediatrics, Chief, Division of Devel-
opmental Behavioral Pediatrics, Peter Shapiro Term Chair for Promotion of Child
Developmental and Behavioral Health, UCLA David Geffen School of Medicine,
Mattel Children’s Hospital, Los Angeles, California

SURENDRA VARMA, MD, DSc (Hon), FAAP, FACE, FRCP(London), Grover E. Murray
Professor, Ted Hartman Endowed Chair in Medical Education, Executive Asso-
ciate Dean for GME & Resident Affairs, University Distinguished Professor &
ViceChair, Pediatrics, Texas Tech University Health Sciences Center, School of
Medicine, Lubbock, Texas

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ADVANCES IN
Pediatrics

CONTENTS VOLUME 70 2023

Associate Editors v

Contributors vii

Preface: Is It Over Yet? Did I Miss Anything? xxi

Carol D. Berkowitz

Pediatrics in Disasters: Evolution of a Hybrid Global

Health Training Program During the COVID-19
Pandemic 1
Lisa Umphrey, Joseph Wathen, Amy Chambliss,
Kathryn Kalata, Lucas Morgan, Mary Moua, Alexa Collesides,
and Stephen Berman
This report describes the Pediatrics in Disasters (PEDS)
course during a novel hybrid in-person and virtual format
due to the coronavirus disease 2019 pandemic.
International and local faculty collaborated on 2021
precourse revisions and course facilitation for
multinational in-person and virtual students. Student and
facilitator 2021 surveys and 2019 to 2021 student
feedback reported overall satisfaction with the course
while suggesting needed improvements to maximize
international and virtual student participation. The hybrid
PEDS course structure successfully achieved course goals
and incorporated international faculty. Lessons learned
will guide future course revisions and fellow global health
educators.
Introduction/background 1
Methods 4
Results 5
Course facilitation 5
Short-term revision planning 5
Course organization, participation, and completion 6
Postcourse satisfaction survey 6
2019 to 2021 student course feedback 7
Course debriefing 7

xi
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CONTENTS continued

Discussion 10
International facilitators 10
International participants 10
Incorporating multidisciplinary audiences 11
Course evaluation and improvement 11
Limitations 12
Summary 12
Funding/support 12
Author contributions 13
Acknowledgments 13
Disclosure 13

The Effects of the COVID-19 Pandemic on Violent Injuries

in Children: A Literature Review 17
Christina Georgeades and Katherine T. Flynn-O’Brien
The SARS-CoV-2 (COVID-19) pandemic and
implementation of stay-at-home orders led to changes in
the daily lives of children. Subsequently, there have been
reports of increases in pediatric violent traumatic
injuries. This review summarizes the existing literature
regarding pediatric violent injury temporally related to
the COVID-19 pandemic, including demographic,
injury, and hospital characteristics in addition to
associated factors. Key findings include an increase in
fatal and nonfatal firearm injuries, particularly in
minority and socioeconomically disadvantaged
populations. However, more comprehensive and long-
term data are needed specific to pediatric violent injuries
to fully understand how the COVID-19 pandemic
impacted trends.
Introduction 17
Classifications of violent injury 18
Institution-specific data 18
Early studies 19
Later studies 24
Gun Violence Archive data 24
Databases and information systems 25
Demographic characteristics 28
Relevant factors for consideration 38
Early versus late trends after stay-at-home order initiation 38
Firearm violence 38
Structural inequalities 39
Data source considerations 40
Summary 40
Clinics care points 40
Disclosure 41

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CONTENTS continued

Burns in Children: Accidental or Inflicted? 45

Katherine W. Canty and Catherine A. DeRidder
This article provides a review of burns in childhood with a
focus on the characteristics that help differentiate abusive
from accidental burns. Case presentations are used to
highlight important differences in the way that abusive
versus accidental burns present to medical care.
Introduction 45
Describing burns 46
Thermal burns 46
Scald 46
Case presentations 48
Relationship of liquid type, time, and temperature to burn severity 50
Contact 51
Case presentation 52
Radiant 53
Chemical burns 53
Electrical burns 53
Case presentation 54
Medical mimickers 54
Evaluation 55
Role of a scene investigation 55
Neglect 56
Summary 56
Clinics care points 56
Disclosure 57

Medical Child Abuse: A Review by Subspecialty 59

Melissa K. Egge
Medical child abuse (MCA), formerly called Munchausen
syndrome by proxy (MSP or MSBP), occurs when a
caregiver, usually the mother, falsifies or exaggerates
symptoms resulting in harm to a child through
inappropriate medical care. MCA is underrecognized,
underreported, and results in significant morbidity and
mortality. Pediatrics subspecialists should consider MCA
when unusual disease presentation [THAT] do not
respond to traditional treatments. This article reviews
the more common diagnoses encountered in MCA cases
by specialty.
Background 59
Barriers to identification and reporting 60
Epidemiology 60
Reporting to child protective services 61
Perpetrator profile 61

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CONTENTS continued

Screening and detection: roles of all medical providers 62

Primary care provider’s role 63
Subspecialist’s role 63
Tips for records review 63
Allergy and immunology 64
Cardiology 72
Ear, nose, throat 72
Endocrinology 73
Gastroenterology 73
Genetics 74
Gynecology 75
Hematology 75
Infectious disease 75
Nephrology/urology 75
Neurologist/neurosurgery referrals 76
Pain clinic 76
Pulmonary 77
Rheumatology 77
Treatment of medical child abuse 77
Testifying in court 77
Future directions 78
Clinics care points 78

Challenges in Diagnosing and Treating Myasthenia

Gravis in Infants and Children with Presentation of
Cases 81
Ornella Bricoune, Bailey Hamner, and Maria Gieron-Korthals
Myasthenia gravis (MG) is a rare condition that impairs
function at the neuromuscular junction of skeletal
muscles, seen less commonly in children. Causes include
autoimmune MG, congenital myasthenic syndromes,
and transient neonatal myasthenia gravis. Symptoms of
weakness, hypotonia, and fatigability can be reasonably
explained by more common causes, thus children with
MG disorders commonly experience delays in treatment
with severe consequences. This leads to the progression
of disease and serious complications including
myasthenic crises and exacerbations. We describe 5
cases of MG, which illustrate clinical and genetic
challenges in establishing diagnosis and subsequent
consequences of delayed diagnosis.
Introduction 81
Case description 85
Discussion 87
Summary 88
Clinics care points 89
Acknowledgments 89
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CONTENTS continued

Disclosure 89

Guillain–Barre Syndrome in Children and Adolescents 91

Megan M. Langille
Guillain–Barre syndrome (GBS) is an immune-mediated
disease of the peripheral nerves and cause of acute
flaccid paralysis in children around the world. The most
common type of GBS in North America targets myelin
and leads to demyelinating neuropathy. Often there is a
history of infection in the weeks preceding motor
symptoms. GBS has been associated with different
infections, including COVID. Children usually recover
motor function, but autonomic instability and respiratory
compromise can occur necessitating close observation
and potentially intensive care unit admission.
Overview 91
Epidemiology 92
Diagnosis 92
Presentation and disease course 92
Dysautonomia 94
Atypical presentation 94
Disease course and recovery 94
Triggering events 94
Variants 96
Pathophysiology 96
Immune targets 96
Antibodies 98
Outcomes 98
Differential diagnosis 98
Management 101
Monitoring and preventative care 101
Immunotherapy 101
Prognosis 102
Clinics care points 103
Disclosure 103

Appendicitis in Children 105

Lindsay A. Gil, Katherine J. Deans, and Peter C. Minneci
The management of pediatric appendicitis continues to
advance with the development of evidence-based
treatment algorithms and a recent shift toward patient-
centered treatment approaches. Further research should
focus on development of standardized institution-specific
diagnostic algorithms to minimize rates of missed
diagnosis and appendiceal perforation and refinement of

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CONTENTS continued

evidence-based clinical treatment pathways that reduce

complication rates and minimize health care resource utilization.
Introduction 105
Epidemiology of pediatric appendicitis 106
Pathophysiology of pediatric appendicitis 106
Diagnosis of pediatric appendicitis 106
Clinical presentation 106
Laboratory tests 107
Radiographic imaging studies 107
Pediatric appendicitis risk scores 108
Management of pediatric appendicitis 109
Management strategies for uncomplicated appendicitis 109
Management strategies for complicated appendicitis 115
Summary 116
Clinics care points 116
Disclosure 117

Surgery for Thyroid Disease in Children 123

Steven W. Bruch
Thyroid surgery in children results from three main
etiologies: Medullary thyroid cancer in MEN
syndromes, benign disease most often Graves’ disease,
and thyroid nodules which may harbor differentiated
thyroid cancers. I will discuss the evaluation of these
etiologies, pre-operative preparation, and operative
strategies for each of these pediatric thyroid problems.
MEN 2 123
Grave’s disease 125
Nodular thyroid disease 125
Operative approach 127
Postoperative complications 128
Postoperative care 129
Clinics care points 130
Disclosure 130

Lower Urinary Tract Obstruction in Newborns 131

Jaime Flores-Torres, Amarilis Sanchez-Valle, Jose R. Duncan,
Valerie Panzarino, Jessica Marie Rodriguez, and
Russell S. Kirby
Lower urinary tract obstruction (LUTO) is a rare birth
defect with a prevalence between 1 in 5,000 and 1 in
25,000 pregnancies. LUTO is one of the most common
causes of congenital abnormalities of the renal tract.
Several genetic conditions have been associated with
LUTO. Most common causes of LUTO are posterior

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CONTENTS continued

urethral valves and urethral atresia. Despite available

prenatal and postnatal treatments, LUTO is a significant
cause of morbidity and mortality in newborns causing
significant end stage renal disease and pulmonary hypoplasia.
Introduction 132
Pathophysiology of lower urinary tract obstruction 132
Genetics of lower urinary tract obstruction 134
Prenatal diagnosis and management of lower urinary tract obstruction 136
Prenatal management 136
Aneuploidy testing 136
Detailed anatomy ultrasound 137
Vesicocentesis and biochemical markers 137
Prenatal interventions and staging systems 137
Prognosis and outcomes after prenatal diagnosis of lower urinary
tract obstruction 139
Fetal intervention risks and complications 139
Postnatal management 140
Summary 142
Clinics care points 142
Disclosure 142

Chronic Myeloid Leukemia in Children and Adolescents 145

Moran Gotesman, Sahar Raheel, and Eduard H. Panosyan
Acute leukemia is the most common malignancy in
childhood, while chronic myeloid leukemia is rare,
accounting for only 2% to 3% of all leukemia in
childhood and 9% in adolescents, with an annual
incidence of 1 and 2.2 cases per million in the two
groups. The goal in Pediatrics is remission and cure with
tyrosine kinase inhibitors (TKIs) and monitoring closely
for long-term effects of TKI use.
Introduction 145
History 146
Pathogenesis 146
Clinical manifestations 147
Laboratory investigations 147
Definitions 148
Chronic phase 148
Accelerated phase 148
Blast phase 148
Scoring system 148
Management 148
Hyperleukocytosis 148
Tyrosine kinase inhibitors 149
Response 150
Resistance 151

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CONTENTS continued

Compliance 151
Long-term care 151
Stopping tyrosine kinase inhibitors 152
Transition of care 152
Summary 152
Clinics care points 153

Update on Atopic Dermatitis 157

Caitlyn Kellogg and Jan Smogorzewski
Atopic dermatitis (AD) is a chronic inflammatory skin
disorder with a lifetime prevalence of up to 20% which
can occur at any age but is most common among
children. There is a significant burden of pediatric AD in
the primary care setting; thus, the ability to recognize
and manage AD is of utmost importance to
pediatricians. Treatment of AD requires a multifaceted
approach based on a patient’s severity including
behavioral modifications, topical and systemic
pharmacologic therapies, and phototherapy.
Introduction 157
Epidemiology 158
Pathophysiology 158
Overview 158
Risk factors 160
Presentation and diagnosis (I) clinical features and comorbidities 161
Atopic dermatitis severity 162
Treatment 162
Lifestyle modifications 162
Topicals 163
Systemics 165
Phototherapy 166
Summary 166
Clinics care points 167
Disclosure 167

Chest Pain, Palpitations, and Syncope: Preventing

Sudden Cardiac Death in Children 171
Saar Danon
Sudden cardiac death is defined as an abrupt, unexpected
death of cardiovascular cause with loss of consciousness
within 1 hour of onset of symptoms. In an effort to
prevent these events, clinicians need to recognize
symptoms to identify at risk patients. There is often an
overlap in symptoms of chest pain, palpitations, and
syncope. The workup depends on the characteristics of
these symptoms. The history and physical examination
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CONTENTS continued

often provide adequate information, but additional testing

and referral to pediatric cardiology are sometimes indicated.
Introduction 171
General content 172
Symptoms 173
Chest pain 173
Palpitations 174
Syncope 175
Dyspnea 175
Evaluation and workup 175
Physical examination 175
Echocardiogram 177
Advanced cardiac imaging 177
Home cardiac monitor 179
Exercise studies 180
Cardiac catheterization and electrophysiologic studies 181
Genetic testing 181
Discussion 182
Summary 183
Clinics care points 183
Disclosures 183
Care of Transgender and Gender-Diverse Children and
Adolescents 187
Jennifer K. Yee and Catherine S. Mao
Children and adolescents may present with transgender or
gender diverse (TGD) identity during the course of
development. Pediatricians may be the first health care
providers to whom TGD identity is revealed.
Pediatricians can optimize health care outcomes by
promoting a gender-affirming clinical environment,
initiating the evaluation for gender incongruence,
supporting social transition, and initiating medical
interventions. Clinical practice guidelines are available
from the World Professional Association for
Transgender Health (WPATH, Standards of Care,
version 8, 2022) and the Endocrine Society (2017). This
article outlines a general approach to providing social
and medical affirming care from the pediatrician’s office.
Introduction 187
Mental health outcomes 189
Promotion of a safe and supportive clinic environment 189
Prepubertal children 190
Adolescents 192
Working with parents and family members 196
Summary 196
Clinics care points 196
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Advances in Pediatrics 70 (2023) xxi–xxiii

ADVANCES IN PEDIATRICS

PREFACE

Is It Over Yet? Did I Miss Anything?

Carol D. Berkowitz, MD

S
ince the start of the COVID-19 pandemic, I have focused this preface on
the changes that occurred over the previous year and how the pandemic
affected our lives and medical care. Each year since 2020, Advances in Pe-
diatrics has highlighted articles dealing with the impact of COVID-19 on certain
areas of life or medical care. Sometimes the effect was positive, as described by
Humphrey and colleagues in their article, ‘‘Pediatric Disasters: Evolution of a
Hybrid Health Training Program during the COVID-19 Pandemic.’’ The use
of virtual technology expanded the ability to teach about the management of
pediatric disasters. Of note, this methodology allows for the participation of
multinational faculty and asynchronous learning, and even as the pandemic
wanes, this more global approach to learning through virtual sessions will most
likely persist. On a more somber note, Flynn-O’Brien and Georgeades report
that the incidence of violent injuries in children increased during the initial
phase of Stay-At-Home. Many injuries involved firearms and disproportionally
impacted socially disadvantaged children. While attributing such injuries to the
pandemic is still an area under investigation, understanding other areas of child
maltreatment continues to be refined. Distinguishing between accidental and in-
flicted burns involves obtaining a complete history, including the child’s devel-
opmental progress. As with other areas of child maltreatment investigations,
there needs to be involvement of a multidisciplinary team, often including so-
cial work and law enforcement. A multidisciplinary team is equally integral to
the evaluation of what has come to be called Medical Child Abuse, also called
Munchhausen Syndrome by Proxy. In these cases, a child’s alleged symptoms
may be fabricated or actually induced. Often the symptoms don’t fit into a
classic diagnostic pattern, and physicians feel obligated to search for a cause,
thus subjecting children to multiple, invasive, and unnecessary tests. Often
the parent goes to multiple different medical facilities ‘‘searching for an
answer.’’ While the list of alleged symptoms is lengthy, neurologic complaints,
including seizures, apnea, and altered mental status, are high on the list.
True neurologic conditions in children may also be challenging to both diag-
nose and manage. Myasthenia gravis in infants and children is a rare neuro-
muscular disease that may be on a genetic basis, especially if congenital.
Misdiagnosis or delayed diagnosis can occur when an infant presents with

https://doi.org/10.1016/j.yapd.2023.04.007
0065-3101/23/ª 2023 Published by Elsevier Inc.

atypical features. On the other hand, Guillain-Barre syndrome, though rare in

children under the age of 2 years, affects both children and adults and is the
most common cause of flaccid paralysis. The diagnosis of Guillain-Barre is
based on history and physical findings, but laboratory and electrophysiologic
studies provide supportive evidence.
While much elective surgery was curtailed during the pandemic, emergent
surgery persisted with the evolution of some new approaches. The accuracy
of the diagnosis of appendicitis has been augmented by ultrasonography and
involvement of the family in shared decision making of operative or nonoper-
ative management. The surgical management of thyroid disease in children oc-
curs in three situations: nodular thyroid disease, Grave disease, and multiple
endocrine neoplasia (MEN). Children with MEN 2 develop abnormalities of
the thyroid, parathyroid, and adrenal glands based on the specific mutations
of the RET photo-oncogenes, and the evaluation of the specific mutation deter-
mines the risk for medullary thyroid cancer as well as pheochromocytoma and
hyperthyroidism. Likewise, certain genetic conditions are associated with CA-
KUT (Congenital Anomalies of the Kidney and Urinary Tract). While there
are multiple genes that have been associated with CAKUT, there are specific
genes seen with LUTO (Lower Urinary Tract Obstruction), for example,
Prune Belly Syndrome (CHRM3-autosomal recessive; Filamin A- X-linked).
Prenatal diagnosis and genetic testing can help delineate a management plan.
Impressive advances in the management of a number of medical conditions
have also appeared in the forefront of pediatric care. We are all aware of the
incredible advances made in the management of acute leukemia in childhood.
Chronic myeloid leukemia (CML) is significantly less common, accounting for
only 2% of leukemia in childhood and 9% of leukemia in adolescence. CML
results form a translocation t(9-22). In brief, this translocation generates
messenger RNA, resulting in constitutive kinase activity providing leukemic
cells with a growth advantage. Tyrosine kinase inhibitors target this activity
and have proven to be revolutionary treatment for CML. Equally revolution-
ary has been the augmented therapies for the management of atopic dermatitis.
These modalities target immune modulators (eg, Th2 pathway), which are up-
regulated in atopic dermatitis. These treatments have led to improvement not
only in the skin but also in the quality of life.
Two other conditions are discussed in this issue of Advances in Pediatrics. Sud-
den Cardiac Death is an ever-present concern for the physician assessing a
youngster for chest pain, palpitations, and syncope. While most chest pain is
noncardiac, the physician is challenged with the extent of the workup and
when to refer the patient to a cardiologist. Equally challenging is the care of
transgender and gender-diverse children. It is critical for all pediatric health
care providers to gain the knowledge and the skills of gender development,
to understand the spectrum of gender-affirming care, and to be prepared to
address the disinformation that has appeared, including on social media.
My title for this preface is ‘‘Is it over yet? What did I miss?’’ It is hard to tell if the
COVID-19 pandemic is officially over. Many jurisdictions have declared the

COVID-19 emergency over, which impacts on a multitude of things, personal,

societal, and medical. My sense is that things will continue to slowly normalize,
and hopefully we can retain what has improved things, like the increase in phone
visits and virtual meetings and conferences. I can’t help but be reminded of the
1925 poem, ‘‘The Hollow Men’’ by T.S. Eliot: ‘‘This is the way the world ends,
Not with a bang but a whimper.’’ One morning COVID-19 won’t be on the
forefront.
My next query is ‘‘What did I miss?’’ Hopefully not much. Early on in the
pandemic, it seemed the entirety of medical reports dealt with COVID-19—
epidemiology, prevention, complications, treatment. That has also changed,
but Advances in Pediatrics, even throughout the pandemic, kept its readership
apprised not only on COVID-19–related issues but also on the continued prog-
ress being made across the board in pediatric medicine. My answer to ‘‘What
did I miss?’’—not much!

Carol D. Berkowitz, MD
Division of General Pediatrics
Department of Pediatrics
Harbor-University of California Los Angeles Medical Center
David Geffen School of Medicine at UCLA
1000 West Carson Street
Box 437
Torrance, CA 90509, USA

E-mail address: cberkowitz52@gmail.com

ADVANCES IN PEDIATRICS

Pediatrics in Disasters
Evolution of a Hybrid Global Health
Training Program During the COVID-19 Pandemic

Lisa Umphrey, MDa,b,*, Joseph Wathen, MDa,b,

Amy Chambliss, MDa, Kathryn Kalata, MDa,
Lucas Morgan, MDa, Mary Moua, MSb, Alexa Collesides, BSb,
Stephen Berman, MDa,c
a
Department of Pediatrics, University of Colorado, c/o Center for Global Health, 13199 East
Montview Boulevard, Suite 310, Aurora, CO, USA; bc/o Center for Global Health, Colorado
School of Public Health, 13199 East Montview Boulevard, Suite 310, Aurora, CO, USA; cDe-
partment of Epidemiology, Colorado School of Public Health, c/o Center for Global Health, 13199
East Montview Boulevard, Suite 310, Aurora, CO, USA

Keywords
PEDS in disaster Pediatric disaster education Disaster training program
Global health Virtual global health education
Key points
This report describes the Pediatrics in Disasters (PEDS) course during a hybrid in-
person and virtual pilot due to the coronavirus disease 2019 pandemic.
The hybrid course included multinational faculty and participants, with interna-
tional and local faculty collaborating on needed revisions before the course.
Course activities included synchronous and asynchronous lectures and small
group sessions co-led by in-person and virtual faculty, followed by student
knowledge tests and evaluations.
Continued

INTRODUCTION/BACKGROUND
Man-made or natural disasters—due to armed conflict, environmental catastro-
phes, forced displacements, and epidemics—affect thousands of people world-
wide each year with loss of home, livelihood, or possessions [1]. Complex
humanitarian disasters and emergencies are increasing due to international

*Corresponding author. c/o Center for Global Health, 13199 East Montview Boulevard,
Suite 310, Aurora, CO. E-mail address: lisa.umphrey@childrenscolorado.org

https://doi.org/10.1016/j.yapd.2023.04.004
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

Continued
Student and facilitator 2021 surveys and 2019 to 2021 student feedback reported
overall satisfaction with the course while suggesting needed improvements to maxi-
mize international and virtual student participation.
The hybrid PEDS course structure successfully achieved course goals and incorporated
international faculty; lessons learned will guide future course revisions and fellow
global health educators.

conflict or civil war [1,2]. The coronavirus disease 2019 (COVID-19) pandemic
further highlights the need for efficient and equitable disaster responses, partic-
ularly for those in low- and middle-income countries (LMICs) [3,4].
The need for pediatric-specific considerations and care during disasters,
particularly during humanitarian emergencies [5] and in resource-limited set-
tings with baseline high burdens of preventable illness and poor access to
care [6–10], is an important and sometimes overlooked component of disaster
response [2]. Children make up a disproportionately large percent of the vic-
tims of natural or man-made disasters, largely due to their developmental
and physical vulnerabilities [2]. Children with complex health-care needs or dis-
abilities are especially at risk [11]. Catastrophic consequences for children due
to gaps in preparedness and response have also been demonstrated in high-
income (HIC) settings (ie, Hurricane Katrina)[12]. Previous articles called for
better training for all levels of medical trainees and disaster relief workers to
improve pediatric disaster preparedness [5,12–18].
The Pediatrics in Disasters (PEDS) course is a 1-week, 10 module in-person
or online training program designed for health trainees and professionals. It dif-
fers from other pediatric emergency trainings in that it targets LMICs and in-
cludes a comprehensive curriculum incorporating multiple facets of pediatric
disaster response [2]. The original course content resulted from a multi-
institutional collaboration between the Center for Global Health (Colorado
School of Public Health; CGH), the American Academy of Pediatrics, the
Pan American Health Organization, the United States Military, and the Asso-
ciation for Health Research and Development; course aims and organization
have been described previously [2]. Please see Box 1 for the PEDS course
description [19].
The CGH has coordinated and implemented the PEDS course since its
inception in 2008, and courses have taken various forms over the years. Be-
tween 2008 and 2013, training teams from CGH conducted 19 in-person
courses for 730 participants in 12 LMICs [2]. Internationally, between 2014
and 2018, 292 participants (262 from Kenya and 30 from Ghana) completed
the course. Locally, in 2012, CGH began offering the PEDS course annually
to University of Colorado (CU) graduate medical trainees (residents, fellows,
and health professionals and public health students) and external health profes-
sionals, training 67 people during the 2012 to 2013 academic year.

PEDIATRICS IN DISASTERS
Box 1: Pediatrics in disasters course description [19]
PEDS course aims PEDS course elements PEDS course modules
Aim 1: Motivate pediatric health 3–5-d course Module 1: Disasters and
professionals in LMICs to participate in Lectures with standardized PowerPoint their effect on the
pediatric disaster planning and response presentations population: key concepts
activities for their communities by Facilitator and Student Guide Module 2: Preventative
providing training that they consider useful Small group sessions medicine in humanitarian emergencies
and valuable Pretests/Posttests Module 3: Planning and triage in the disaster
Aim 2: Establish national PEDS training Mass casualty simulation scenario
centers in LMICs to disseminate the Module 4: Pediatric trauma
training throughout the country, especially Module 5: Management of prevalent
in areas prone to natural events infections in children after a disaster
Aim 3: Facilitate collaboration for the Module 6: Diarrhea and dehydration
training among professional societies, Module 7: Delivery and immediate neonatal
hospitals, medical schools, and care
governmental agencies to improve Module 8: Nutrition and malnutrition
coordination related to pediatric disaster Module 9: The emotional impact of disasters
preparedness planning and response in children and their families
Module 10: Toxic exposures

Abbreviations: LMIC, low- to middle-income country; PEDS, pediatrics in disasters course.

Adapted from Pediatric Education in Disasters Manual. https//njaap.org/uploadfiles/documents/2015/Disaster%20Toolkit/peds-full-eng_2012.pdf. Published
2022. Accessed15 March 2022.

3
4 UMPHREY, WATHEN, CHAMBLISS, ET AL

Additionally, since 2014, adapted PEDS course modules and small group ma-
terials have been available online through CGH (http://cgh.mycrowdwisdom.-
com/diweb/start) for asynchronous participation; 147 participants, including
participants from Kenya and the Philippines, participated in the course exclu-
sively online between 2013 and 2021.
Due to a lack of funding, over the years there was a shift away from interna-
tional course iterations and coordination with LMIC partners toward in-person,
USA-based courses. The course also evolved to address changing audiences af-
ter inclusion in the CU medical student curriculum. Global events (such as the
H1N1 pandemic) presented new funding opportunities if new course sub-aims
and objectives were added to course content. These external factors affected
the course over time, shifting away from its original aims (see Box 1).
Due to COVID-19-related disruptions to in-person Global Health Education
(GHE) activities [3,4,20–23], in 2020, the annual in-person CGH PEDS course
occurred completely virtually, with local CU or affiliate faculty leading the
course for local virtual learners. In 2021, the CGH team offered the course
via a novel mixed in-person and virtual hybrid structure, as CU had relaxed
restrictions for in-person activities. For the first time, course directors invited
international facilitators and students to participate in the course virtually as
a pilot initiative. Planning for a hybrid, multinational course reopened discus-
sion about how to collaborate with partners in LMICs and the value in updat-
ing course material for international audiences. Course directors used the 2021
course as an opportunity to update out-of-date information and prepare for a
larger course revision to refocus the course back to its original aims (see Box 1).
This report describes our preparation processes for the novel 2021 PEDS
hybrid course while conducting needed course updates based on nominal
group technique and analysis of previous years’ course feedback. We aim to
provide suggestions for future iterations of the course and to share lessons
learned with global health educators seeking to transition from in-person to vir-
tual/hybrid learning or to attract global participation in existing courses.

METHODS
In early 2021, our group conducted discussions with key stakeholders (current
and previous facilitators, course directors, and CU faculty) regarding earlier
course successes and challenges, as well as ideas for how to improve and revise
the course. Involved parties participated in standard nominal group technique
for structured brainstorming to identify ways to update and improve the
course. Directors then organized feedback into ‘‘short-term updates’’ (for the
2021 course iteration) and ‘‘longer term updates’’ (to improve international
applicability of the course moving forward).
Course directors recruited international colleagues from CGH networks
with prior experience or interest in the PEDS course to participate in the pre-
course content revision. CU and international faculty grouped into teams
based on their module assignments or areas of expertise and communicated
via email, WhatsApp messaging, and zoom to review course module content

and feedback. Teams completed short-term or ‘‘low hanging fruit’’ updates for
the 2021 hybrid course. Course administrative teams created materials and
adapted course structure and start times to fit international audience and facil-
itator needs.
Course directors also invited the international colleagues to virtually cofaci-
litate the 2021 hybrid course. The hybrid structure included lectures and inter-
disciplinary small group discussions available synchronously (livestreaming
concurrent with in-person sessions) and asynchronously (daily recorded ses-
sions available online).
To assess overall participant and facilitator hybrid course satisfaction
following the 2021 course, we conducted an online, anonymous postcourse
satisfaction survey consisting of a Likert scale and free response questions
stored via REDCap online cloud platform (Vanderbilt University, http://proj-
ect-redcap.org) [24]. All course participants completed the postcourse satisfac-
tion survey as a course requirement, while facilitators completed surveys on
an optional basis. We obtained institutional review board approval from the
Colorado Multiple Institution Review Board (University of Colorado, Aurora,
CO, USA; #21–4090). We summarized descriptive statistics for participant de-
mographics and satisfaction responses. We implemented thematic induction to
draw conclusions about free-text responses to survey data querying the stron-
gest and weakest aspects of the course as well as suggestions for improvement.
In November 2021, course directors met and debriefed virtually with all in-
ternational facilitators, whose feedback informed our longer term plan for
course organization and revisions. Course directors also compared routine stu-
dent postcourse feedback and daily knowledge assessments from the 2019 (in-
person), 2020 (virtual), and 2021 (hybrid virtual and in-person) PEDS courses
to identify common themes and describe performance trends.

RESULTS
Course facilitation
Course directors recruited 28 Colorado-based facilitators and 10 international fa-
cilitators (from Uganda, Kenya, United States, Ethiopia, Zambia, Peru, and
South Africa), all of whom were involved with both module content updates
and 2021 course facilitation. Six course modules had one international facilitator
assigned to the team, whereas 4 modules had 2 international facilitators per mod-
ule. Course directors conducted 2 facilitator orientation sessions before the 2021
course, organized and disseminated course content via Dropbox cloud storage
(https://www.dropbox.com/home) accessible to multinational teams with
different institutional access and established communication channels between
local and international facilitators (primarily email and WhatsApp Messenger).

Short-term revision planning

Nineteen key stakeholders participated in the nominal group technique to pro-
vide overall course feedback and guide future course revisions. Before the 2021
course, module facilitator teams reviewed this information and successfully

identified and integrated ‘‘short-term’’ content revisions for all 10 modules. In

addition, each facilitator team identified module-specific revisions that were
more appropriate for the bigger planned course revision to expand interna-
tional applicability.
Course organization, participation, and completion
Regarding the 2021 course organization, there were 3 to 4 small group sessions
per module, one of which was a small group exclusively for virtual participants.
The international facilitator co-led the virtual small group session with an in-
person CU facilitator to ensure smooth coordination should international
facilitators have connectivity challenges. Before the course, administrators per-
formed technological trial runs with the module teams. During the course,
administrators recorded lectures and virtual small groups daily and posted
them online (via Canvas Instructure, https://canvas.instructure.com/login/
canvas) for any asynchronous international participants.
Regarding course participation, among 32 total participants, 21 attended in-
person, 4 attended virtually, and 7 attended both in-person and virtually. Par-
ticipants represented health professionals and trainees both locally (United
States; 30/32, 94%) and internationally (Uganda, and Kenya; 2/32, 6%). There
were a further 2 local asynchronous participants who engaged with the online-
only course due to unavailability during the course week.
Regarding course completion, 100% (30/30) of US-based participants
completed the full course. Neither of the 2 virtual international participants
did so, despite having all course content available asynchronously, noting on
postcourse evaluations that they participated in approximately 25% to 50%
of course activities. These participants reported they were unable to fully com-
plete the course due to Internet connectivity issues, time zone differences, and
lack of protected free time necessary to participate in synchronous sessions and
access asynchronous content. All participants who completed the full course
successfully passed daily student quizzes, with an average composite score of
86%.
Postcourse satisfaction survey
Thirty-seven students and faculty completed the postcourse satisfaction survey
(31 students [response rate 98%], 6 faculty [response rate 16%]) (Table 1).
Course satisfaction was similar among all participants and facilitators, with
81% (n ¼ 30/37) of respondents agreeing or strongly agreeing that the course
materials were helpful and 89% (n ¼ 33/37) agreeing or strongly agreeing that
their overall course goals were met and that they received information that
could be applied to their current or future professional activities. Regarding
previous disaster response experience, 16.7% (n ¼ 6/36) respondents indicated
prior involvement with disaster planning before the 2021 course.
Table 2 describes results from the satisfaction survey on perceived strengths
and weaknesses of in-person and hybrid course elements, including suggested
improvements to the course. Positive themes included international faculty and
participant presence and strong course organization with pertinent topics.

Table 1
Characteristics of 2021 pediatrics in disasters course satisfaction survey respondents

N (%)
Profession (n ¼ 37) Student, health professional 18 (48.6)
Resident or fellow 7 (18.9)
Clinician 5 (13.5)
Professor, lecturer, researcher 4 (10.8)
Public health professional 2 (5.4)
Nurse 1 (2.7)
Clinical specialty (n ¼ 26) Pediatrics 12 (46.2)
Emergency medicine 3 (11.5)
Family medicine/general practice 3 (11.5)
Internal medicine 1 (3.8)
Nursing 1 (3.8)
Pediatric subspecialist 1 (3.8)
Other 5 (19.2)
Practice/work setting Hospital 11 (29.7)
(n ¼ 37) Academic setting 7 (18.9)
Outpatient clinic/health center 5 (13.5)
Public health department 2 (5.4)
Other 12 (32.4)
Involvement in disaster Yes 6 (16.7)
planning (n ¼ 36) No 30 (83.3)

Notably, participants appreciated the flexibility and broader audience captured

by allowing a virtual option in the hybrid version of the course. Negative
themes focused on technological limitations (such as lack of reliable Internet
or not hearing speakers well on Zoom), not enough small-group discussion
time to share international experiences, limited applicability of course to
LMIC audiences (which was a previous complaint about the course) [2], and
logistical coordination for virtual participants. One international facilitator
commented, ‘‘We had to discuss with the videos off [due to poor Internet],
so I did not see the participants. As a virtual facilitator, I found it a bit difficult
to throw in comments between participants, as I could not tell how the flow
was from one candidate to another.’’

2019 to 2021 student course feedback

Table 3 describes a summary of 2019 to 2021 student course feedback, reflect-
ing 30 participants in 2019 (in-person), 31 participants in 2020 (virtual), and 26
participants in 2021 (hybrid). We included common themes in the table if 2 or
more participants mentioned the topic in their student feedback. Overall, there
were similar trends in general course satisfaction year to year despite the in-
person versus virtual versus hybrid formats.

Course debriefing
Finally, course directors conducted Zoom debriefs with most international facil-
itators (n ¼ 9/10, 90%). Open and frequent communication with course directors

8
October 06, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Table 2
Pediatrics in disasters course hybrid strengths, weaknesses, and suggested improvements
Hybrid course strengths Hybrid course weaknesses Suggested hybrid course improvements
General course 1. Course interactivity 1. Too much lecture time 1. Complete needed module content revisions
elements (discussion-based, hands-on 2. Too little hands-on and discussion time 2. Increase public health content
practice) 3. Challenges with small group sessions (ie, too 3. Tighten course time management (eg,
2. Course participants from many cases, too little time, lack of focused sessions sometimes ran over)
multidisciplinary backgrounds objectives) 4. Shorten small group content/time
3. Strong content (important, 4. Specific module content out of date, 5. Increase free discussion time to facilitate
international topics; good irrelevant, or missing exchanging experiences
breadth, good mix of global 5. Lack of balance addressing different 6. Include more personal stories/experiences,
health and pediatrics) resource contexts (HIC vs LMIC) especially related to lived experiences with
4. Strong course organization 6. Lack of balance between public health and global health work and career development
(coordination, administrative medical focus, specifically too little focus on
organization) public health
7. Administrative challenges (eg, online file

UMPHREY, WATHEN, CHAMBLISS, ET AL

organization, precourse preparation, and so
forth)
Virtual course 1. Expands audience (for 1. Difficult engagement of virtual learners for 1. Improve sound/audio to maximize virtual
elements international and distance hands-on components engagement (microphones, repeating
participants) 2. Communication challenges to balance in- questions, closed captioning, and so forth)
2. Presence of international person vs virtual discussions on zoom 2. Separate virtual and in-person facilitators
facilitators 3. Organization challenges (ie, too few and participants to maximize course
3. Increased flexibility for both participants assigned to virtual group) efficiency and conversation potential
participants and facilitators 4. Time zone challenges for international 3. Consider interactive videos for hands-on
4. Enriched, interactive small students and facilitators course elements
group discussions due to blend 5. Technological challenges (ie, cutting video, 4. Include international facilitators in module
of in-person and virtual students poor sound/video quality, difficult to hear lectures (via prerecorded sessions or better
and facilitators of various zoom conversations) course scheduling)
backgrounds 5. Improve virtual mass casualty simulation
option for virtual participants
Abbreviations: LMIC, low- to middle-income country; HIC, high-income country.
Downloaded for mohamed ahmed (dr.mms2020@gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on
October 06, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Table 3
Summary of 2019 to 2021 pediatrics in disasters course student feedback

PEDIATRICS IN DISASTERS
A: PEDS course strengths 2019–2021 2019 2020 2021
Interactive course with strong group discussions X X X
Hands-on sessions X X
Content (good breadth, relevant topics) X X
Facilitator expertise X X Xa
Course organization/presentation (balance of didactics and small groups) X Xb
Practical/applicable skills X X
MPH students incorporated well into course X
B: PEDS course weaknesses 2019–2021 2019 2020 2021
Long course/long days X X
Some duplicate information from other medical school courses X X
Too much information in case discussions X X
Heavy clinical focus lacking public health content X X X
Challenges with file formatting/management (hard to access after course) X
Logistically challenging to switch between small groups (in-person) X
Hard to interact/focus on zoom X
Quiz questions hard to interpret/difficult to reference X X
C: Suggested PEDS course improvements 2019–2021 2019 2020 2021
Increase hands-on components X
More practical/field experience shared by facilitators X
Increase nursing perspective in course content X
Increase public health content X
Improve quizzes X
Better course time management X
Attention to different contexts (LMIC/HIC, rural/urban, local/international) X X
More international speakers X
Increased personal experiences shared by facilitators X
Abbreviations: HIC, high-income country; LMIC, low- to middle-income country; PEDS, pediatrics in disasters course.
a
In 2021, students specifically mentioned the benefit of having international facilitators bring their experience/expertise to the course.

9
b
In 2021, students specifically mentioned that material built on itself logically as the week progressed.
10 UMPHREY, WATHEN, CHAMBLISS, ET AL

and administrators was a positive theme that emerged, as was consideration of

their time zone constraints. However, international facilitators would have appre-
ciated being incorporated more in module presentations and moved around to
different small groups, instead of always clustering with the virtual participants.
One facilitator mentioned that the ‘‘virtual facilitator needs to be pushy—it is easy
to not be heard or to speak when the rest of the group is in-person.’’ International
facilitators also mentioned that the hybrid course could have benefited from
‘‘dress rehearsals’’ of shared module activities between cofacilitators and stan-
dard evaluation practices to guide regular quality improvement cycles.

DISCUSSION
Our results describe the 2021 implementation of a novel hybrid PEDS course
during the COVID-19 pandemic and suggestions for general and virtual course
improvements. Feedback themes were consistent between facilitators, students,
and key stakeholders over several years’ worth of course feedback data. Over-
all feedback supported the importance of and interest in a pediatric disaster
course for the global health community, and the consistency in feedback will
guide course directors in prioritizing future revisions and iterations.
Although virtual approaches to GHE are spreading rapidly and have been
used worldwide in health care [22,25–33], there are limited current literature
documenting enablers and barriers when pivoting from in-person to virtual for-
mats, particularly from the perspective of LMIC partners [34,35]. A further
challenge is how to prioritize the needs of LMIC learners and colleagues
[20,22,36] while reinforcing general global health learner competencies
[29,30,32,33,37]. Descriptions of virtual GHE activities, such as our novel
hybrid PEDS course, will inform future discussions and help establish best
practice recommendations on virtual GHE.
International facilitators
The inclusion of international facilitators in the pilot hybrid course was deemed
as a positive contribution to student and faculty experiences, successful 2021
completion of minor content revisions, and collaboration for future course up-
dates. However, while grouping participants and facilitators into virtual and in-
person teams improved our 2021 day-of course logistics and coordination, a
near total separation of virtual participants and facilitators—who predominately
came from LMIC settings—diminished cross-national and cultural communica-
tion, exchanges, and engagement opportunities per student and facilitator feed-
back. Allocating dedicated time during future courses for international
facilitators to interact with all participants may address this challenge.
International participants
We found that a hybrid course with an international audience requires
thoughtful considerations for virtual engagement and course planning. First,
some of the challenges reported by international participants included a lack
of stable Internet connections, different time zones, and lack of protected
time. Course directors’ attempts to mitigate these challenges, such as recording

and posting sessions online daily, did not overcome the challenges to participa-
tion. Future courses may consider offering virtual-only or in-person-only op-
tions for participants with mixed in-person/virtual facilitators, customizing
online content for access in lower bandwidth regions, or dividing course mod-
ules during a several-week block to better accommodate those in LMIC settings
with more limited protected educational time.
Second, students consistently reported that hands-on sessions were a major
strength of the course. These practical sessions must continue to be a focus of
the course, and reasonable alternatives for virtual or low-bandwidth participation
must be found, such as high-quality virtual disaster simulations or tabletop drills.
Finally, courses conducted within the framework of global health partnerships
should discuss how to support needed technology upgrades for LMIC partners
to ensure effective participation despite technological limitations [38]. Our team
hopes to further mitigate challenges to international participants by following
new guidance on standardized virtual GHE communication and logistic practices
[39], continuing to provide regular and multimodal communication from a dedi-
cated administrator, and including adequate technological planning, trial-runs,
and support to ensure positive experiences for everyone involved in the course.
Incorporating multidisciplinary audiences
Another theme identified from discussions with key stakeholders and from
2019 to 2021 participant feedback is how best to incorporate public health stu-
dents and professionals, a growing audience for the course. Per student feed-
back, there was a notable positive incorporation of public health students in
the virtual 2020 course, which may reflect the fact that facilitators actively
sought public health student participation in the virtual small groups. There
is a need to balance the course aims and heavy medical content load with iden-
tified educational needs for public health personnel [40] and the benefit of hav-
ing multidisciplinary learner groups, which mimics real-life field experiences.
Potential solutions could be creating different small group sessions for public
health versus clinical learners, alternative case studies aimed at one specialty
versus the other, division of small group participants for case discussions
with later presentations to the larger group, or the inclusion of a finite number
of case scenarios per module, each discussing a different public health or med-
ical issue. In addition, although we will continue open enrollment in the course
for any CU health professional or student, moving forward we plan to more
clearly iterate our course aims and expectations for nonmedical participants.
Course evaluation and improvement
Regarding course evaluations, several stakeholders and facilitators mentioned a
need for standard evaluation practices to maintain course quality, effectiveness,
and applicability. Future PEDS course evaluations should permanently add stu-
dent and facilitator satisfaction surveys, using this feedback to regularly
(perhaps on a 2–3-year basis) guide standard quality improvement cycles
[41] for course updates and changes. Further, directors should reincorporate
a 6-month postcourse survey [2] to assess new or ongoing involvement in

disaster-related activities. Our course data indicated relatively few participants

engaged in disaster planning activities before the 2021 course, and we do not
yet know how many will seek out or be asked to participate in such activities
in the future; knowing how this rate evolves over time (and what, if any, effect
the course had on the participants’ decision to engage in disaster planning)
would be helpful to assess real-world course impact. Finally, analyzing
differences on course surveys and feedback between facilitators and partici-
pants from HIC versus LMIC settings may help improve course quality and
sustainability, advocate for securing course funding, or help integrate the
course into institutions or ministries of health responsible for disaster response
[2,16,42].

Limitations
Our program evaluation had several limitations. First, although we were able
to examine student and facilitator feedback over several years, the 2 major
changes between the 2020 and 2021 courses (virtual to hybrid format plus
content revisions) versus 1 major change between the 2019 and 2020 courses
(in-person to virtual format) may have changed participant and facilitator ex-
periences in a way that makes them incomparable. Despite this, we think that
the consistency in feedback themes provides clear areas for improvement and
ideas for future courses. Second, in 2021, there was a paucity of data from
faculty (only students were required to complete the postcourse satisfaction
survey) and international students (due to their inability to fully participate).
Third, we did not include a precourse knowledge assessment in the 2020
virtual or 2021 hybrid courses, which limited our ability to show measurable
knowledge gains; we do plan to reincorporate these moving forward.
Finally, we did not measure the impact of the PEDS course on real-world
disaster planning and response, a limitation we share with previous articles
[2,42].

SUMMARY
Due to the COVID pandemic, our group developed a hybrid PEDS course,
which successfully incorporated international facilitators and participants
from LMIC settings. An evaluation of previous and current course feedback
highlighted challenges and areas for improvement to future in-person and vir-
tual course iterations. Lessons learned from our novel hybrid PEDS course
may inform future approaches for virtual adaptation of GHE activities suitable
for global dissemination, particularly within multinational global health groups
and partnerships.

FUNDING/SUPPORT
Funding for salary support was made possible by the CGH (Aurora, CO). This
funding source had no role in the design of this study, during its execution, an-
alyses, or interpretation of the data.

AUTHOR CONTRIBUTIONS
L. Umphrey conceived the article idea. L. Umphrey, J. Wathen, and S. Berman
created original postcourse survey. A. Chambliss, M. Moua, L. Umphrey, J.
Wathen, and S. Berman contributed to overall course data collection. A.
Chambliss, L. Morgan, and L. Umphrey performed literature review. K. Ka-
lata performed analysis on student feedback and survey data. All authors
contributed to data analysis and synthesis. L. Umphrey created first manu-
script draft. All authors contributed to article editing and finalization.

Acknowledgments
The authors wish to thank Molly Lamb and Daniel Olson for their input on
the 2021 hybrid course survey and the 2021 hybrid PEDS course participants
and facilitators.

Disclosure
The authors have nothing to disclose.

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disaster" course: the Chinese experience. Am J Disaster Med 2012;7(3):231–41.

ADVANCES IN PEDIATRICS

The Effects of the COVID-19

Pandemic on Violent Injuries in
Children: A Literature Review
Christina Georgeades, MD*,
Katherine T. Flynn-O’Brien, MD, MPH
Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 999 North
92nd Street, Milwaukee, WI 53226, USA

Keywords
Pediatric trauma Violent injury Firearm injury Intentional injury
COVID-19 pandemic
Key points
The COVID-19 pandemic and implementation of stay-at-home orders led to
changes in the daily lives of children.
There have been reports of increases in pediatric violent injuries after the start of
stay-at-home orders.
Firearm injuries, both fatal and nonfatal, increased after the start of stay-at-home
orders, particularly in minority and socioeconomically disadvantaged children.

INTRODUCTION
The SARS-CoV-2 (COVID-19) pandemic impacted children and families
worldwide and led to changes in their daily lifestyle due to implementation
of stay-at-home orders (SHOs). As a result, children no longer had access to
school and extracurricular activities, and many families experienced unemploy-
ment and financial strain [1]. For many, this led to increased stress and social
isolation and had a negative impact on mental health [2,3]. In addition, social
determinants of health and socioeconomic hardship are associated with risk of
violent injury and adverse health outcomes in children, and there was concern
the COVID-19 pandemic exacerbated these risks [4–6]. Indeed, in the months
and years following the start of the COVID-19 pandemic in March 2020, there
were reports of an increase in pediatric violent traumatic injuries [3,7,8].

*Corresponding author, E-mail address: cgeorgeades@mcw.edu

https://doi.org/10.1016/j.yapd.2023.03.002
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

Specifically, the period of time when SHOs were initiated has been viewed as
the figurative starting point for the shift in traumatic injuries. The literature thus
far regarding pediatric violent injuries relevant to the pandemic has largely
compared periods of time after SHO implementation to historical controls dur-
ing the same time periods in prior years. A comprehensive review and synthesis
of the existing data has not been done. A broad understanding of the change in
quantity and character of pediatric violent injuries during the COVID-19
pandemic may help identify areas for targeted intervention and ascertain gaps
in the literature to guide future research, including reasons behind the trends.
The primary aim of this review is to summarize the existing literature
regarding pediatric violent injury during the COVID-19 pandemic. The sec-
ondary aim was to further explore the various aspects of violent injuries
such as demographic, injury, and hospital characteristics. Brief commentary
on firearm purchasing, laws, and safety is provided in addition to discussion
about structural inequalities and data source considerations.

CLASSIFICATIONS OF VIOLENT INJURY

Violent injury can be classified into different categories depending on the type,
mechanism, and intent of injury. The classification of injuries and additional
details are often obtained from International Classification of Disease 10th revi-
sion diagnosis codes. The literature regarding pediatric violent injuries after
SHO initiation (which is synonymous with the start of the COVID-19
pandemic in this review) often presented combinations of injury type, mecha-
nism, and intent. Box 1 outlines the definitions that are most often used to
describe violent injury in the literature; however, it is important to note that
the terminology is indistinct and variable.
Nonaccidental trauma (NAT), which is included in the category of child
abuse, is a distinct entity within the topic of violent injury due to the unique
physical, mental, emotional, and social impact on what is usually a younger
subset of children. In addition, child abuse also encompasses nonphysical
trauma such as emotional abuse, sexual abuse, and neglect. Concerns over
the impact of the COVID-19 pandemic on child abuse have been extensively
and specifically explored in the literature, including in systematic reviews [9–
14]. Therefore, a review of the literature pertaining to NAT was included in
this assessment only if it was specifically mentioned in studies pertaining to
all traumatic injuries.

INSTITUTION-SPECIFIC DATA
Initial studies that evaluated COVID-19 and violent injuries in children were
institution-specific, with data obtained from institutional trauma registries,
emergency department (ED) encounters, or trauma activations/consults.
Institution-specific studies were either single-institution studies or included sites
that were regionally related. To assist in data synthesis, studies that assessed
the relationship between SHOs and pediatric violent injuries were defined as
Early Studies (<6 months after SHOs) or Later Studies (6 months after

Box 1: Definitions used to describe violent injury in the literaturea

Types of violent injury:
Penetrating (eg, firearm, cut/pierce)
Blunt (eg, assault)
Other (eg, burn injuries)
Mechanisms of violent injury:
Firearm (including or not including airsoft or pellet guns or paintball guns)b
Cut/pierce (eg, stab wounds or lacerations)
Struck by/against
Nonaccidental trauma
Violent injury intents:
Unintentional (eg, accidental self-harm or against another individual)
Intentional, assault (eg, homicide)
Intentional, suicide or self harm
a
All classifications potentially included other, unknown, or undetermined categories, as well.
b
There is a lack of consistency regarding the use of the term firearm versus gunshot wound versus
bullet-related injury in the literature. In addition, the majority of studies describe firearm injuries
without specifying whether those included/excluded airgun (eg, BB gun) or paintball gun-
related injuries, which are considered blunt injury types by ICD-10 categorization.

SHOs). Key findings from institution-specific studies are described here, with
additional data provided in Table 1.

Early studies
Interestingly, there were few significant differences in volume of violent injuries
reported by authors in the first few months of the COVID-19 pandemic
compared with historical controls [15–20]. Sanford and colleagues noted that
intentional blunt injuries (defined by assaults, NAT, and self-harm injuries in
the study) decreased at the start of the COVID-19 era (prepandemic mean 20.6 chil-
dren [95% confidence interval (CI) 16.1–25.1] vs postpandemic mean 17 chil-
dren, P ¼ .04) [21]. Similarly, Haddadin and colleagues noted that intentional
injuries, which they defined by NAT, suicide, assault, or homicide, also decreased
after SHO initiation (70 children (1.9%) in 2018, 52 children (1.3%) in 2019, and
24 children (1.0%) in 2020, P ¼ .009) [22]. Sanford and colleagues found that
penetrating injuries increased (43 children vs 34 children, 95% CI 28–40,
P ¼ .002); however, animal bites were included in their definition of penetrating
injury along with stab/laceration and gunshot wound (GSW)/pellet gun injuries
[21]. Lastly, Bessoff and colleagues noted an increase in pediatric GSW injuries
after SHO initiation compared to a matched time period averaged across 3 years
before SHO initiation (3.3% vs 1.8%, P ¼ .038), though did not find a difference in
assaults, NAT, or stab wounds/lacerations [20].

Summary of institution-specific articles regarding pediatric violent injuries and the COVID-19 pandemic
Study period
(length of time
[months] for Patient
Data source Type of postpandemic population Pediatric violent
Author, year Journal (source population) study cohort) (ages) Type of injury injury data
Prepandemic Post-SHO Statistical
initiation significance
Early studies (<6 mo)
Qasim et al Journal of Four Philadelphia RC, MI chart Prepandemic: Adult and Penetrating, Penetrating, 8 (3.7) 10 (8.4) P ¼ .113
[19], 2020 Trauma and adult Level 1 Trauma review March 9-April pediatric NAT N (%)b
Acute Care Centers and two 19, 2019 (all ages)a NAT, N (%)b 29 (13.4) 21 (17.6) P ¼ .371
Surgery pediatric Level 1 Post-SHO initiation:
Trauma Centers March 9-April 19,
(all trauma patients) 2020 (1.5 mo)
Williams ANZ Journal One Australian major RC, SI chart Prepandemic: March Pediatric All traumatic Inflicted 2018: 2 4 —
[17], 2020 of Surgery pediatric trauma review 23-May 10, (<16 y) injuries (assault or 2019: 0
center (all patients 2018 & 2019 NAT), N
meeting criteria Post-SHO initiation: Self-harm, N 2018: 1 2 —
for Level 1 or 2 March 23-May 10, 2019: 1
trauma call) 2020 (1.5 mo)
Shi et al Pediatric Surgery One New York Level 1 RC, SI chart Prepandemic: March Pediatric () All traumatic Assault, N (%)b 2018: 3 3 (5.8) —
[15], 2021 International Pediatric Trauma review 27-May 14, injuries (2.7)
Center (trauma 2018 & 2019 2019: 1
registry of all trauma Post-SHO initiation: (1.0)
activations) March 27-May 14, Self-injury, N (%)b 2018: 1 0 (0.0) —
2020 (1.5 mo) (0.9)
2019: 1
(1.0)
SW, N (%)b 2018: 2 1 (1.9) —
(1.8)
2019: 3
(3.0)
Laceration, N (%)b 2018: 0 1 (1.9) —
(0.0)
2019: 3
(3.0)
GSW, N (%)b 2018: 2 1 (1.9) —
(1.8)
2019: 0
GEORGEADES & FLYNN-O’BRIEN

(0.0)

(continued on next page)

COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

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Table 1
22
(continued )

Study period
(length of time
[months] for Patient
Data source Type of postpandemic population Pediatric violent
Author, year Journal (source population) study cohort) (ages) Type of injury injury data
Ruhi-Williams The American 11 Southern California RC, MI Prepandemic: control: Pediatric All traumatic Assault, N (%)b,d Control: 21 12 (5.0) Control:
et al [16], Surgeon Level 1 & 2 Trauma chart March 19-June (13–17 y) injuries (7.4) P ¼ .247
2022 Centers (trauma review 30, 2019 Pre-SHO: 8 Pre-SHO:
patients) Pre-SHO: January (3.9) P ¼ .599
1-March 18, 2020 Penetrating, Control: 41 38 (15.8) Control:
Post-SHO initiation: N (%)b,d (14.5) P ¼ .696
March 19-June 30, Pre-SHO: 28 Pre-SHO:
2020 (3.5 mo) (13.8) P ¼ .560
GSW, N (%)b,d Control: 22 20 (8.3) Control:
(7.8) P ¼ .835
Pre-SHO: Pre-SHO:
18 (8.9) P ¼ .831
SW, N (%)b,d Control: 13 13 (5.4) Control:
(4.6) P ¼ .681
Pre-SHO: 7 Pre-SHO:
(3.4) P ¼ .325
Suicide attempt, Control: 6 3 (1.2) Control:
N (%)b,d (2.1) P ¼ .439
Pre-SHO: 3 Pre-SHO:
(1.5) P ¼ .832
Yeates et al Pediatric Surgery 11 Southern California RC, MI chart Prepandemic: control: Pediatric All traumatic Assault, N (%)b,d Control: 30 (5.3) Control:
[18], International Level 1 & 2 Trauma review March 19-June (<18 y) injuries 48 (7.6) P ¼ .105
2022 Centers (all 30, 2019 Pre-SHO: Pre-SHO:
trauma activations Pre-SHO: January 21 (4.4) P ¼ .497
or consults) 1-March 18, 2020 Penetrating, Control: 64 (11.3) Control:
Post-SHO initiation: N (%)b,d 52 (8.2) P ¼ .075
March 19-June 30, Pre-SHO: Pre-SHO:
2020 (3.5 mo) 43 (9.0) P ¼ .219
GSW, N (%)b,d Control: 25 (4.4) Control:
27 (4.3) P ¼ .912
Pre-SHO: Pre-SHO:
22 (4.6) P ¼ .886
SW, N (%)b,d Control: 13 (2.3) Control:
13 (2.1) P ¼ .783
GEORGEADES & FLYNN-O’BRIEN

Pre-SHO: Pre-SHO:
8 (1.7) P ¼ .474

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Later Studies (6 mo)
Collings et al Journal of Nine Midwestern RC, MI chart Prepandemic:c Pediatric Firearm injuries All firearm, 108 (1.8) 215 (3.0) P < .001
[23], 2022 Pediatric United States review March-September (<18 y) (prepandemic N (%)b
Surgery Level 1 30, 2016–2019 N is average Firearm, 29 (26.9) 52 (24.2) P ¼ .299
Pediatric Trauma Post-SHO initiation: of 2016–2019) unintentional,
Centers (trauma March-September N (%)
registry) 30, 2020 (6 mo) Firearm, assault, 64 (59.3) 136 (63.3)
N (%)
Firearm, suicide, 5 (4.6) 3 (1.4)
N (%)
Other intent 10 (9.3) 24 (11.2)
Flynn-O’Brien Journal of Nine Midwestern RC, MI chart Prepandemic:c Pediatric All traumatic injuries Struck by/against, 534 (9.1) 494 (7.0) P < .001e
et al [6], Trauma and United States Level 1 review March-September (<18 y) (prepandemic N N (%)b
2022 Acute Care Pediatric Trauma 30, 2016–2019 is average of Firearm, N (%)b 108 (1.8) 215 (3.1)
Surgery Centers (trauma registry) Post-SHO initiation: 2016–2019) Cut/pierce, N (%)b 182 (3.1) 251 (3.6)
March-September NAT, N (%)b 228 (3.9) 264 (3.8)
30, 2020 (6 mo)
Flynn-O’Brien Journal of Nine Midwestern United RC, MI chart Prepandemic:c Pediatric All traumatic injuries Struck by/against, 316 (9.6) 358 (7.8) P < .001e
et al [24], Surgical States Level 1 Pediatric review March-September (<18 y) (prepandemic N N (%)b
2022 Research Trauma Centers 30, 2016–2019 is average of Firearm, N (%)b 36 (1.1) 76 (1.7)
(trauma registry Post-SHO initiation: 2016–2019) Cut/Pierce, N (%)b 101 (3.1) 168 (3.6)
and interfacility March-September NAT, N (%)b 125 (3.8) 144 (3.1)
transferred patients) 30, 2020 (6 mo)
Crichton Journal of One Midwestern United RC, SI chart Prepandemic: February Pediatric Firearm injuries Violent firearm, 17 (60.7) 54 (67.5) P ¼ .51
et al [25], Applied States Level 1 Pediatric review 1, 2019-March 9, 2020 (<18 y) N (%) (Fisher’s
2022 Research Trauma Center Post-SHO initiation: Unintentional 8 (28.6) 22 (27.5) exact test)
on Children (patients assessed by March 10, firearm, N (%)
trauma surgery team) 2020-March 31, Unknown 3 (10.7) 4 (5.0)
2021 (12.5 mo) firearm, N (%)
Abbreviations: ED, emergency department; GSW, gunshot wound, MI; multi-institutional, NAT; nonaccidental trauma, RC; retrospective cohort, SHO; stay-at-home order, SI; single-institutional, SW; stab wound, y; years.
a
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

Only pediatric data presented in table.

b
Percents calculated from total population.
c
No specific date given for March for multi-institutional studies indicates varying SHO dates were used across different states.
d
Statistical significance label of ‘‘Control’’ is the comparison of control versus post-SHO initiation periods and ‘‘Pre-SHO’’ is the comparison of pre-SHO versus post-SHO initiation periods.
e
Statistical significance is for the entire mechanism of injury category within the manuscripts, which includes nonviolent injuries.

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24 GEORGEADES & FLYNN-O’BRIEN

Later studies
In studies that extended 6 months or beyond the SHOs, an increase in firearm in-
juries was more frequently described. Collings and colleagues found an increase in
pediatric firearm injuries in the first 6 months after SHOs compared with a prepan-
demic cohort (3.0% vs 1.8%, P < .001) [23]. Although these proportions may seem
low, the relative change is notable. An interrupted time series by Collings and col-
leagues comparing the expected rate of pediatric firearm injury based on data from
prior years to the observed rate after SHOs identified an 87% higher odds of
firearm injury in the first 6 months of the COVID-19 pandemic (odds ratio 1.87
[95% CI 1.54–2.28], P < .001) (Fig. 1) [23]. Collings and colleagues did not identify
a significant change in the number of assaults, stab wounds, or NAT, nor the intent
of firearm injury (unintentional, assault, suicide, or other) between pre- and post-
SHO implementation [9,10]. Flynn-O’Brien and colleagues found an increase in
admissions and transfers for firearm, cut/pierce, and overall penetrating injuries
in addition to a decrease in struck by/against and NAT injuries [6,24]. The study
by Crichton and colleagues is the only study that did not find a significant increase
in firearm injuries [25].

GUN VIOLENCE ARCHIVE DATA

The Gun Violence Archive (GVA), which is an independent collection of gun
violence incidents from multiple law enforcement, media, government, and com-
mercial sources [26], was retrospectively used in multiple studies to evaluate the

Fig. 1. An interrupted time series analysis with the interruption period representing stay-at-
home order initiation (March 13, 2020) in the United States. (Amelia T. Collings et al. The
COVID-19 pandemic and associated rise in pediatric firearm injuries: A multi-institutional
study, Journal of Pediatric Surgery, 57 (7), 2022, 1370-1376, https://doi.org/10.1016/
j.jpedsurg.2022.03.034.)

impact of the COVID-19 pandemic on the rate of firearm injuries. Studies ranged
from just over 4 months to nearly 2 years after SHO implementation (Table 2).
Based on data from the GVA, Donnelly and colleagues found that firearm-
related deaths in the United States increased during the SHO period compared
with 2018 historical controls while firearm-related injuries increased during the
reopening period (after SHOs were lifted) compared with 2018 historical con-
trols, 2019 historical controls, and the SHO period (all P < .05) [27]. The same
group also documented that overall child-involved firearm incidents increased
in 2020 compared to 2018 and 2019 controls (2018: 0.095 vs 0.124 incidents
per month per 100,000 children, P ¼ .003; 2019: 0.097 vs 0.124 incidents
per month per 100,000 children, P ¼ .010) [28]. Cohen and colleagues identi-
fied an increase in nonfatal firearm injuries in children under 12 years of age at a
point 6 months after the start of SHOs compared with the prepandemic cohorts
from 2016 to 2019 (relative risk [RR] 1.90 [95% CI 1.45–2.51]). Fatal firearm
injuries also significantly increased. The same study also identified an increase
in firearm injuries inflicted by children (RR 1.43 [95% CI 1.14–1.80]).
Other studies limited their analysis of the GVA to pediatric fatalities. While
Martin and colleagues did not report a difference during prepandemic and
postpandemic time periods when looking at 12 months after initiation of
SHOs, Peña & Jena reported that over the year and a half following SHOs,
and overall, an additional 1.12 children were killed every day [29]. Hence,
overall, nonfatal and fatal firearm injuries increased after the pandemic and
were potentiated as follow-up time periods lengthened. Fig. 2 depicts the daily
number of children killed by shootings in the United States, showing a distinct
rise in the 28-day moving average after the start of SHOs [29].

DATABASES AND INFORMATION SYSTEMS

There were a variety of other data sources that investigated the association of
the COVID-19 pandemic and/or SHOs on violent injuries in children. These
sources consisted of local or national information systems (eg, Pediatric Health
Information System [PHIS]), public-use databases, or police department regis-
tries and largely corroborated prior studies, especially regarding the rise in
firearm injuries after the start of SHOs (Table 3). One study that utilized the
PHIS database, a clinical and resource utilization database of 49 children’s hos-
pitals, found that firearm injuries increased by 38.8%, from a median of 575
encounters in 2017 to 2019 to 798 encounters in 2020 [30]. Overall, more
than an additional 9.0 encounters occurred per week after SHO initiation
(P < .01) [30]. Another PHIS study assessing traumatic injuries showed a
gradual post-SHO implementation percent increase as time progressed in sui-
cides and both cut/pierce and firearm injuries compared with pre-SHO time pe-
riods while homicides and both neglect/abuse and struck by/against injuries
decreased or remained similar [31].
Afif and colleagues, in their study evaluating Philadelphia Police department
registry shooting victims, noted that overall firearm injury occurrences in chil-
dren increased in the year following SHOs, compared to prior years (RR 1.17

Summary of Gun Violence Archive articles regarding pediatric violent injuries and the COVID-19 pandemic
Study period (length
of time [months] for
Source population post-SHO initiation Patient Type
Author, year Journal from GVA Type of study cohort) population of injury Pediatric violent injury data
Prepandemic Post-SHO Statistical
initiation significance
Donnelly Journal of United States Retrospective Prepandemic: Adult and Child-involved SHO 2018 vs SHO 0.02 (0.00, 0.17) 0.04 (0.00, P ¼ .054
et al [27], Surgical with database SHO: March 19- pediatric nonfatal firearm 2020 injuries, 0.17)
b
2021 Research a subanalysis review (all ages) injuries per day median (min, max)
May 24, 2018
on California (per 100,000 SHO 2019 vs SHO 0.02 (0.00, 0.15) 0.04 (0.00, P ¼ .241
& 2019
and Ohioa licensed firearm 2020 injuries, 0.17)
Reopening: May owners) median (min, max)
25-July 31, Reopening 2018 vs 0.04 (0.00, 0.28) 0.08 (0.00, P < .001
2018 & 2019 reopening 2020 0.34)
Post-SHO initiation: injuries, median
SHO: March 19- (min, max)
May 24, 2020 Reopening 2019 vs 0.02 (0.00, 0.38) 0.08 (0.00, P < .001
reopening 2020 0.34)
Reopening: May
injuries, median
25-July 31,
(min, max)
2020 (4.5 mo)
Cohen Pediatrics United States Cross-sectional Prepandemic: March- Pediatric Firearm injuries Total (fatal and 0.001 (0.005 to 0.128 RR ¼ 1.90 (95% CI
et al, 2021 database August, 2016– (<12 y) per month nonfatal), rate of 0.007) (0.092 1.58–2.29)
[53] review (per 1,000,000 change (95% CI) –0.164)
2019
children) Nonfatal, rate of 0.002 (0.003 to 0.093 (0.596 RR ¼ 1.90 (95% CI
Post-SHO initiation:
change (95% CI) 0.007) –0.127) 1.45–2.51)
March-August Fatal, rate of change 0.001 (0.006 to 0.35 (0.015 RR ¼ 1.89 (95% CI
2020 (6 mo) (95% CI) 0.003) to 0.085) 1.41–2.55)
GEORGEADES & FLYNN-O’BRIEN

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Donnelly Journal of United States Retrospective Prepandemic: Pediatric Child-involved All incidents, median 2018: 0.095 0.124 2018 vs 2020:
et al [28], Trauma and database January- (<18 y) firearm 2019: 0.097 P ¼ .003
2021 Acute Care review incidents 2019 vs 2020:
December, 2018
Surgery per month P ¼ .010
& 2019
(per 100,000 Nonfatal incidents, 2018: 0.060 0.073 2018 vs 2020:
‘‘Post-SHO children) median 2019: 0.066 P ¼ .007
c
Initiation:’’ 2019 vs 2020:
January-December P ¼ .128
2020 (9 mo) Fatal incidents, 2018: 0.031 0.039 2018 vs 2020:
median 2019: 0.288 P ¼ .068
2019 vs 2020:
P ¼ .068
Martin American United States Retrospective Prepandemic: March Pediatric Firearm incidents Firearm violence 9063 (0.21) 11,121 (0.28) —
et al [36], Journal of database 15-March 14, (5–17 y) (prepandemic incidents including
2022 Preventive review N is mean of at least 1 fatality in
2015–2020
Medicine 2015–2019) thousands, N
Post-SHO initiation:
(exposures per
March 15, 2020- year)
March 14, 2021
(12 mo)
Peña and JAMA United States Cross-sectional Prepandemic: January Pediatric Firearm fatalities Additional daily — — 1.12 (95% CI 0.70–
Jena [29], Network database 1, 2014-March (<18 y) number of children 1.53) additional
2022 Open review killed in shootings children killed per
15, 2020
after March 16, day
Post-SHO initiation:
2020 (95% CI) 733 (95% CI
March 16, 2020- 462–1003)
December 31, additional children
2021 (21.5 mo) killed over study
period
Abbreviations: CI, confidence interval; GVA, gun violence archive; max, maximum; min, minimum; RR, relative risk; SHO, stay-at-home order.
a
Subanalysis performed on California and Ohio due to variation in gun laws between the two states; data presented is overall United States data; North Dakota, South Dakota, Nebraska, Iowa, Arkansas, Wyoming, Utah,
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

and Oklahoma were excluded from analysis since they had partial or no stay-at-home orders implemented.
b
Only pediatric data presented in table.
c
The full year of 2020 was evaluated in the analysis; there was no distinction of a period after SHO implementation.

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28 GEORGEADES & FLYNN-O’BRIEN

Fig. 2. Presentation of 28-day moving averages for daily number of children killed by shoot-
ings, which includes less than 28 but 14 days at the start and end of the covered period. The
vertical line represents stay-at-home order initiation (March 16, 2020). (Peña PA, Jena A. Child
Deaths by Gun Violence in the US During the COVID-19 Pandemic. JAMA Netw Open.
2022;5(8):e2225339. https://doi.org/10.1001/jamanetworkopen.2022.25339.)

[95% CI 1.00–1.35], P ¼ .046) [32]. In addition, the mean number of children

shot per quarter significantly increased after SHO initiation (49 children [stan-
dard error (SE) 6.8] vs 26 children [SE 1.8], P ¼ .026) [32]. Another study of
police department registry information in Indianapolis also noted a significant
increase in the rate of pediatric firearm injuries between pre- and post-SHO im-
plementation [33].
Although a study by Chaudhari and colleagues evaluating multiple Los An-
geles County trauma centers through the Los Angeles County Trauma and
Emergency Medicine Information System found that GSW injuries increased
after SHO initiation (10.5% vs 7.5%, P ¼ .001), they interestingly identified
that assault injuries decreased (2.5% vs 3.9%, P ¼ .01) [34]. Evaluations of spe-
cific violent injury intents, such as unintentional, self-harm, or assault, and of
other specific violent injury mechanisms, such as stab wounds, did not show
any significant differences, although the studies which focused on these aspects
were limited [30,34,35].

DEMOGRAPHIC CHARACTERISTICS
There were a few studies that evaluated demographic characteristics of children
that were violently injured although all of them were regarding firearm injuries
(Table 4). Most studies did not find a difference in the proportion of males or

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Table 3
Summary of database articles regarding pediatric violent injuries and the COVID-19 pandemic
Study period
(length of time
Data source [months] for Patient
(source post-SHO population Pediatric violent
Author, year Journal population) Type of study initiation cohort) (ages) Type of injury injury data
Prepandemic Post-SHO Statistical
initiation significance
Gastineau Pediatrics Pediatric Health Retrospective Prepandemic: Pediatric Firearm injuries All firearm, N 575 798 —
et al, Information database March-August (<19 y) (prepandemic N for Unintentional 988 (57.7) 502 (62.9) P ¼ .053
2021 [30] System database review ‘all firearm’ is firearm, N (%) (Pearson v2)
2017–2019
(44 United median of Intentional or 46 (2.7) 17 (2.1)
Post-SHO initiation:
States children’s 2017–2019) self-harm
hospitals) March to August firearm, N (%)
2020 (6 mo) Assault firearm, 593 (34.6) 243 (30.5)
N (%)
Undetermined, 58 (3.4) 25 (3.1)
N (%)
Legal intervention, 5 (0.3) 6 (0.8)
N (%)
Multiple, N (%) 22 (1.3) 5 (0.6)
Chaudhari Journal of 15 Los Angeles RC, MI Prepandemic: Pediatric All traumatic Assault, N (%)a 105 (3.9) 42 (2.5) P ¼ .01
et al, 2022 Pediatric County ACS- cross-sectional January 1, (<18 y) injuries GSW, N (%)a 202 (7.5) 178 (10.5) P ¼ .001
[34] Surgery verified database study SW, N (%)a 92 (3.4) 54 (3.2) P ¼ .667
2019-March
trauma centers Self-inflicted, 19 (0.7) 19 (1.1) P ¼ .151
18, 2020
(Los Angeles accidental,
County Trauma Post-SHO initiation: N (%)a
and Emergency March 19, Self-inflicted, 5 (0.2) 8 (0.5) P ¼ .09
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

Medicine 2020-December intentional,

Information 31, 2020 (9.5 mo) N (%)a
System trauma
registry)

(continued on next page)

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29

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Table 3
30

(continued )
Study period
(length of time
Data source [months] for Patient
(source post-SHO population Pediatric violent
Author, year Journal population) Type of study initiation cohort) (ages) Type of injury injury data
Wells et al, Pediatrics Pediatric Health Retrospective Prepandemic: March Pediatric All traumatic injuries Suicide, prepandemic E: 1499 (0.6) E: 16.2% —
2022 [31] Information System database 15-March 14, (<18 y) (prepandemic is is mean volume M: 1580 (0.6) M: 19.9%
database (41 United review mean volume of (%)a and post-SHO L: 2012 (0.8) L: 21.8%
2017–2020
States children’s 2017–2020 for initiation is %
Post-SHO initiation:
hospitals; ED visits) each time period) change
Early: March Homicide, E: 3493 (1.5) E: 47.4% —
15-June 30, 2020 prepandemic M: 3770 (1.3) M: 34.2%
Middle: July is mean volume L: 4084 (1.7) L: 39.5%
1-October 31, 2020 (%)a and post-SHO
Late: November 1, initiation is %
2020-March 14, change
Cut/pierce, E: 7336 (3.1) E: 10.1% —
2021 (12 mo)
prepandemic is M: 8623 (3.1) M: 1.2%
mean volume (%)a L: 7367 (3.0) L: 7.2%
and post-SHO
initiation is %
change
Firearm, prepandemic E: 467 (0.2) E: 22.9% —
is mean volume M: 541 (0.2) M: 42.8%
(%)a L: 566 (0.2) L: 37.0%
and post-SHO
initiation
is % change
Neglect/abuse, E: 4712 (2.0) E: 20.6% —
prepandemic M: 5462 (1.9) M: 1.0%
is mean volume L: 5755 (2.3) L: 1.6%
(%)a
and post-SHO
initiation
is % change
Struck by/against, E: 36,939 (15.7) E: 51.4% —
prepandemic M: 43,489 (15.5) M: 38.9%
is mean L: 39,137 (16.0) L: 36.2%
volume (%)a and
GEORGEADES & FLYNN-O’BRIEN

post-SHO initiation
is % change

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Frost et al, Preventive Maryland Health Retrospective Prepandemic: July 1, Adult and Penetrating and Penetrating, <15 0.7 0.5 P ¼ .931c
2022 [35] Medicine Services Cost database 2017-March 31, 2020 pediatric firearm injuries year old, %a
Review Commission review (all ages)b Penetrating, 15–19 11.8 11.3
Post-SHO initiation:
public-use year old, %a
April 1, 2020-March
patient-level database Firearm, <15 year 1.4 1.3 P ¼ .942c
(all patients with 31, 2021 (12 mo) old, %a
Maryland ZIP Firearm, 15–19 14.6 13.9
code or ICD-10 year old, %a
external cause
code at a Maryland
acute care hospital)
Afif et al, Preventive Philadelphia Police Retrospective Prepandemic: Adult and Firearm All shootings, N (%)a 535 (7.8) 222 (9.0) RR ¼ 1.17
[32] 2022 Medicine Department database January 1, pediatric injuries (95% CI
(registry of review (all ages)b 1.00–1.35)
2015-March
shooting victims) P ¼ .046
15, 2020
Non-mass shootings, 480 (7.2) 198 (8.5) RR ¼ 1.18
Post-SHO initiation: N (%)a (95% CI
March 16, 2020- 1.01–1.38)
March 31, 2021 P ¼ .040
(12.5 mo) Mass shootings, 55 (10.3) 24 (10.8) RR ¼ 1.05
N (% of (95% CI
all shootings)a 0.67–1.65)
P ¼ .828
Mean number of 26 (1.8) 49 (6.8) P ¼ .026
children
shot per
quarter (SE)
Magee et al, BMJ Open IMPD, Indianapolis Retrospective Prepandemic: January Adult and Intentional, <15 year old, 5.76 6.14 P ¼ .001
2022 [33] Open Data Portal, database 2017-February 2020 pediatric nonfatal Incident Absolute/percent
and the United review (all ages)b firearm rate per 100,000 rate change:
Post-SHO initiation:
States Census injuries person-years 0.38/6.60%
March 2020-June
Bureau (all 15–17 year old, 72.9 77.7 P ¼ .001
2021 (16 mo)
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

records from Incident Absolute/percent

IMPD) rate per 100,000 rate change:
person-years 4.85/6.58%
Abbreviations: ACS, American College of Surgeons; CI, confidence interval; E, early; ED, emergency department; GSW, gunshot wound; ICD-10, International Classification of Disease 10th revision; IMPD, Indianapolis Metropolitan Police
Department; L, late; M, middle; MI, multi-institutional; RC, retrospective cohort; RR, rate ratio; SE, standard error; SHO, stay-at-home order; SW, stab wound.
a
Percents calculated from total population.
b
Only pediatric data presented in table.
c
Statistical significance is for the entire age category within the manuscript, which includes adults.

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Table 4
32

Demographic characteristics of pediatric violent injuries after initiation of stay-at-home orders during the COVID-19 pandemic

Author,
year Sex Age, years Race/ethnicity Insurance status Socioeconomic status
Collings Prepandemic, Male: 82 P value <1: 2 (1.9) P value White: Race Private: 19 (17.8) P value Social Vulnerability P value
et al [23], N (%) (76.6) 0.696 1–4: 12 0.948 23 (21.3) Public: 77 (72.0) 0.289 Index 0.277
2022 (11.1) Black: 76 (70.4) P value No insurance: 1st quartile: 8 (7.5)
5–9: 13 Other: 9 (8.3) 0.464 9 (8.4) 2nd quartile:
(12.0) — Unknown/ 19 (17.8)
10–14: 31 Hispanic: 4 (3.7) Ethnicity missing: 3rd quartile:
(28.7) Non-Hispanic: P value 38 (35.5)
15–17: 50 79 (73.8) 2 (1.9) 4th quartile:
<.001
(46.3) Unknown: 42 (39.3)
24 (22.4)

Post-SHO Male: 164 <1: 3 (1.4) White: 39 (18.1) Private: 26 (12.1) Social Vulnerability
initiation, (76.3) 1–4: 26 Black: 149 (69.3) Public: 156 (72.6) Index
N (%) (12.1) Other: 27 (12.6) No insurance: 1st quartile: 7 (3.3)
5–9: 20 — 22 (10.2) 2nd quartile:
(9.3) Hispanic: 17 (7.9) Unknown/ 48 (22.3)
10–14: 64 Non-Hispanic: missing: 3rd quartile:
(29.8) 187 (87.0) 69 (32.1)
15–17: Unknown: 11 (5.1) 11 (5.1) 4th quartile:
102 91 (42.3)
(47.4)
GEORGEADES & FLYNN-O’BRIEN

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Crichton Prepandemic, Male: 22 P value <10: 5 P value Black: 16 (57.1) P value — — — —
et al [25], N (%) (78.5) 0.81 (17.9) 0.70 White: 8 (28.6) 0.36 (Fisher’s
2022 Female: 6 (v2 ¼ 0.06) 10–17: 23 (v2 ¼ 0.15) Multiracial: exact test)
(21.5) (82.1) 4 (14.3)
Hispanic: 0 (0.0)
Unknown: 0 (0.0)
Post-SHO Male: 59 <10: 17 Black: 56 (70.0)
initiation, (74.0) (21.2) White: 15 (20.0)
N (%) Female: 21 10–17: 63 Multiracial: 6 (7.5)
(26.0) (78.8) Hispanic: 2 (2.5)
Unknown: 1 (1.3)
Martin Prepandemic, — — — — Black: 4.55 — — — —
et al [36], rate ratioa Hispanic: 2.18 Percent change
2022 Asian/Pacific
Islander:
1.18 Black: 11.6
Native American:
1.73 Hispanic: 8.0
2 races: 1.64
Other: 2.45 Asian/Pacific
Post-SHO — — Black: 5.07 Islander: 2.8 — —
initiation, Hispanic: 2.36
rate ratioa Asian/Pacific
Islander: Native
1.21 American:
Native American: 3.4
1.79
2 races: 1.79 2 races: 9.1
Other: 2.64
Other: 7.7
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

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34
Table 4
(continued )

Author,
year Sex Age, years Race/ethnicity Insurance status Socioeconomic status
Peña and Prepandemic, N — — — — — — —
Jena Post-SHO — 0–11: 1888b Mortality Low-minority Mortality — Low-income Mortality change
[29], initiation, 12–17: 6589b change areas: 3556b change (95% CI)c areas: (95% CI)c
2022 N (95% CI)c High-minority 6557b
areas: 4914b High-income
Low-minority: 0.39 areas: Low income:
0–11: (0.13–0.66) 1905b 1.14
(0.77–1.51)
0.38 (0.18–0.57) High-minority: 0.72
(0.41–1.04) High income:
12–17: 0.02
(0.21
to 0.16)
0.74 (0.39–1.10)
GEORGEADES & FLYNN-O’BRIEN

Post-SHO Male: 622 0–4: 94 Non-Hispanic Government: Child Opportunity

initiation, (78.8) (11.8) White: 621 Index
N (%) Female: 167 5–9: 105 138 (77.8) Very low:
(21.2) (13.2) (17.3) Private: 108 390 (48.9)
10–14: 235 Non-Hispanic (13.5) Low: 178
(29.4) Black: Other: 69 (22.3)
15–18: 364 492 (8.6) Moderate:
(45.6) (61.7) 121 (15.2)
Hispanic: 103 High: 64
(12.9) (8.0)
Asian: 8 (1.0) Very high: 39 (4.9)
Other: 57 (7.1)
COVID-19 PANDEMIC ON VIOLENT INJURIES IN CHILDREN

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36
Table 4
(continued )

Author,
year Sex Age, years Race/ethnicity Insurance status Socioeconomic status
Afif et al Prepandemic, Female: RR (95% CI): Mean (SE): — Black: 454 (84.9) RR (95% CI) — —
[32], N (%) 62 (11.6) 1.40 15.0 (0.2) Latinx: 58 (10.8) Black: 1.08
2022 (0.96–2.05) White: 17 (3.2) (1.03–1.14),
P value Other: 6 (1.1) P ¼ .009
Post-SHO Female: 36 Mean (SE): Black: 204 (91.9) Latinx: 0.66 —
0.084
initiation, (16.2) 15.3 (0.2) Latinx: 16 (7.2) (0.39–1.13),
N (%) White: 2 (0.9) P ¼ .126
Other: 0 (0.0) White: 0.28
(0.07–1.22),
P ¼ .068

Other: —
Abbreviations: CI, confidence interval; RR, rate ratio; SE, standard error; SHO, stay-at-home order.
a
Rate ratio is for minority disparity versus white.
b
Number of children killed in shootings.
c
Change in mortality measured by additional daily number (cubic time trend) of children killed in shootings after SHO initiation.
GEORGEADES & FLYNN-O’BRIEN

females and age groups violently injured after the start of SHOs [23,25,30,32].
However, another study that estimated the change in daily firearm fatalities af-
ter SHOs reported that, while deaths increased for all ages, the increase was
greater for children aged 12 to 17 years than for children younger than 12 years
[29]. Other aspects, such as insurance type, rurality, and regional differences of
firearm injuries in the United States did not differ pre- and post-SHO initiation
[23,25,30].
Although some studies found no significant differences in the proportion of
injuries for race/ethnicity between the pre- and postpandemic periods
[23,25,30], others found that minority race/ethnicities did experience a dispropor-
tionate amount of the increase in violence. Afif and colleagues identified that
Black children experienced an increase in firearm injury (RR 1.08 [95% CI
1.03–1.14], P ¼ .009) after SHO implementation while white and Latinx children
did not [32]. Another study showed that minority children, especially Black chil-
dren, had the highest increase in exposure risk of firearm violence incidents after
the start of SHOs compared with white children [36]. Fig. 3 represents the
disproportionate mean increases in firearm homicides by race/ethnicity [36]. In
addition, Peña and colleagues found that high-minority areas, where the census
tracts had a population in which more than 50% was Black or Hispanic, had a
higher increase in gun-related deaths than low-minority areas [29].

Fig. 3. Mean annual firearm homicide incidents (involving at least 1 homicide) in home
census tract, by child’s race/ethnicity. Racial/ethnic categories are mutually exclusive. Time
periods represent pandemic years, starting on March 15 of the listed year and ending on
March 14 of the following year. (Adapted from the ‘‘American Journal of Preventive Medicine,
63 (2), Martin et al., Racial Disparities in Child Exposure to Firearm Violence Before and Dur-
ing COVID-19, 204-212, Figure 1, Copyright (2022),’’ with permission from Elsevier.)

Regarding socioeconomic status (SES), a few studies showed no differences

between proportions of firearm-injured children before and after SHO imple-
mentation based on various SES measures, such as median household income,
the Social Vulnerability Index (SVI), and Childhood Opportunity Index (COI)
[23,30]. SVI ranks census tracts on 16 social factors comprising domains of
SES, household composition and disability, minority status and language,
and housing and transportation [37]. COI measures neighborhood-level condi-
tions using 29 indicators within domains of education, health and environment,
and social and economic factors [38]. However, another study that evaluated
gun-related deaths found that children in low-income areas, where the census
tracts had a median annual household income below $60,000, had a higher in-
crease in gun-related deaths than high-income areas [29].

RELEVANT FACTORS FOR CONSIDERATION

Early versus late trends after stay-at-home order initiation
Speculation existed regarding the decrease in injuries such as assault, NAT, and
self-harm initially seen after the start of SHOs. Because there was also a corre-
sponding overall decline in health care utilization, including ED visits [39], these
findings may be more reflective of a decrease in presentation rather than a true
decrease in incidence [22]. Particularly for NAT, underreporting may have
increased since children were isolated at home, preventing professionals such
as teachers and health care providers, who account for 30% of child abuse re-
porting, from noticing and reporting such concerns [15,40]. Regarding inten-
tional violent injuries such as firearm injuries, stab wounds, and assaults, there
had been an increase noted in the adult population during the first few months
after the COVID-19 pandemic started [18], but this same finding was only iden-
tified in one study in the pediatric population regarding firearm injuries [20].
This may be related to increased parental supervision due to the increase in adult
unemployment or remote-working [41]. In addition, since schooling became vir-
tual and children were less frequently able to gather with their friends, the pres-
sure to engage in violent behavior may have decreased [16]. For the study that
reported an initial increase in penetrating injuries in children, mechanisms such
as animal bites were also included in the analysis and comprised a significant pro-
portion (42%) of penetrating injuries [21], limiting its generalizability. In contrast
to earlier studies, institutional studies that examined longer periods of time after
SHO initiation showed an increase in violent injuries, particularly with firearms.
The eventual increase in firearm injuries could be related to reopening period
after months spent indoors in high-stress situations with limited access to extra-
curricular activities, increased firearm access, and/or other societal, economic,
and political stressors simultaneously occurring during that time.

Firearm violence
Prior studies have found a connection between firearm purchases/access and
firearm violence [42,43]. The Federal Bureau of Investigation reported a significant
increase in firearm purchasing at the start of the COVID-19 pandemic based on

records of background checks, of which a large proportion of individuals were first-

time buyers [44–46]. Reported reasons for obtaining a firearm included protection,
concern about crime, supply chain disruptions, health, and the economy [45]. In
addition, some families reported increasing the access of their firearms by changing
their storage practices during this time due to civil unrest, fear of home invasion and
crime, fear of the unknown, and provision of greater protection from an external
threat [47]. Unsafe firearm storage practices may have heightened risk of injury
as well. Sokol and colleagues reported that households that kept at least one firearm
both loaded and unlocked were more likely to purchase an additional firearm dur-
ing SHOs than those that kept firearms unloaded and/or locked [48]. First-time
buyers also may be less familiar with safe storage practices [46].
In addition, gun laws in particular likely played a role in rates of firearm
violence during COVID-19. Donnelly and colleagues showed that states in
the United States with the strongest gun laws correlated with decreased
child-involved shootings during the pandemic compared with states with
weaker gun laws, which is consistent with prior studies showing similar find-
ings before the pandemic [27,28,49,50].
Firearm-violence-prevention strategies are needed to further mitigate the
drastic rise in firearm injuries that started during the pandemic. Proper firearm
storage, gun-waiting periods, stricter gun laws, and mental health services are
evidence-based methods for decreasing firearm injuries and deaths in children
[28,51,52]. Furthermore, ensuring that gun owners, especially first-time owners,
receive adequate safety training is important, especially since such training may
have not been as available during the pandemic [53]. And lastly, health care
providers should screen for and provide education on firearm access and
safe storage techniques [54].

Structural inequalities
The increase in violent injuries during the COVID-19 pandemic disproportion-
ately occurred among minority children, who also historically experienced
higher rates of exposure to violence than white children [30,35,36,55,56].
These children continue to remain the most vulnerable and often have
increased mental health needs [57]. These children are also often impacted
by community violence and structural disadvantages, including poverty,
poor housing opportunities, low-quality education, and socioeconomic inequal-
ities [30,58]. The effect of structural racism at an individual, community, and
policy level also persists in these communities [35,59]. School closures during
the pandemic, which offer support services such as childcare, health and mental
health services, provision of meals, peer support, and internet access, may have
further contributed to the rise in violence [60,61].
The link between firearm violence and structural inequalities in disadvan-
taged neighborhoods and among pediatric minorities is well described in the
literature [62–66]. Therefore, firearm violence within a community must be
treated as a public health crisis, and regional and geographic variations must
be taken into account [33,36]. Provision of resources, such as mentoring

programs, through schools has been shown to be promising [67,68]. Working

to improve mental health services is important [69,70], and violence interven-
tion and family support programs that work with specific neighborhoods may
help mitigate violence [70].
Data source considerations
The literature regarding pediatric violent injuries and how trends have been
affected by SHO implementation and the COVID-19 pandemic comes from
a variety of different data sources on an institutional, local, and national level.
Although they each provide valuable information on an individual basis, they
are narrow in scope, focus on a limited sample, lack long-term outcomes, or are
missing data [71,72]. For example, the GVA can miss a significant number of
shootings, police department registries may not have all data publicly available,
and institution-specific data, often obtained from trauma registries, only include
children admitted and/or transferred to the hospital [71,73]. In addition, most
of the published literature focuses on firearm injury rather than all violent in-
juries. Other sources, such as the National Vital Statistics System through the
Centers for Disease Control, the Healthcare Cost and Utilization Project
through the Agency for Healthcare Research and Quality, and insurance
claims data, are other examples of data sources that have not been yet utilized
to evaluate the effect of the pandemic on violent injuries in children.

SUMMARY
The start of the COVID-19 pandemic and simultaneous initiation of SHOs had
an inevitable impact on children. As reopening started after a period of school
closures and social isolation, an increase in violent injury occurred, primarily
driven by firearms. Most published data evaluated changes in traumatic in-
juries within a 1-year period after SHO implementation.
More comprehensive data that include longer periods of time and focus spe-
cifically on violent injury in pediatric populations are needed. In addition, studies
further evaluating the disproportionate impact of the COVID-19 pandemic on
minority and socioeconomically disadvantaged children in relation to violent
trauma and exposure are also warranted. A deeper understanding of long-
term trends in violent injuries and the specific pediatric populations affected is
important for development and implementation of targeted intervention.

CLINICS CARE POINTS

Although institution-specific studies identified few significant differences in the vol-

ume of violent injuries in the first few of months of the COVID-19 pandemic, some
did note an increase in firearm and intentional injuries.
Institution-specific studies that evaluated the differences in the volume of violent in-
juries six months or later after the start of the COVID-19 pandemic noted an in-
crease in firearm injuries.

Gun Violence Archive data, which is an independent collection of gun violence

incidents from multiple law enforcement, media, government, and commercial
sources, identified an increase in fatal and nonfatal firearm injuries after Stay-at-
Home orders were implemented.
Database studies that utilized sources such as the Pediatric Health Information Sys-
tem public-use database and police department registries also found an increase
in firearm injuries after Stay-at-Home orders were initiated.
A few studies found that minority race/ethnicities and those at a socioeconomic
disadvantage experienced a disproportionate increase in firearm injuries and
fatalities.

DISCLOSURE
The authors have nothing to disclose.

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ADVANCES IN PEDIATRICS

Burns in Children
Accidental or Inflicted?

Katherine W. Canty, MDa,*, Catherine A. DeRidder, MDb

a
Child Protection Program, Division of General Pediatrics, Boston Children’s Hospital, 300
Longwood Avenue, Boston, MA 02115, USA; bViolence Intervention Program, Keck School of
Medicine of USC, LACþUSC Medical Center, 2010 Zonal Avenue, OPD 3P-61, Los Angeles, CA
90033, USA

Keywords
Burns Scalds Contact burns Child abuse Accidental burns Inflicted burns
Key points
Abusive burns are associated with increased morbidity and mortality compared
with accidental burns.
A comprehensive history is essential to distinguishing between accidental and
abusive burns and should always include questions regarding the child’s devel-
opmental capabilities.
Determination of the mechanism of injury requires a multidisciplinary investiga-
tion such as a scene investigation by a social worker and/or law enforcement.
When abusive burns are suspected, consideration of concurrent injury is
important, and depending on the child’s age, it may require evaluation for occult
fractures, intracranial injury, and intraabdominal injury.

INTRODUCTION
Burns comprise between 6% and 20% of child abuse cases [1]. The incidence of
abusive burns in children presenting to medical care varies but has been estimated
to be between 11% and 25% in children hospitalized for abusive injuries [2].
Abusive burns are most common in children between 2 and 4 years of age [2]
and compared with accidental burns are associated with an increased length of hos-
pitalization and morbidity. A burn can also be a sentinel injury. Sentinel injuries are
visible minor injuries that are suspicious for abuse and may portend future severe
abuse [3]. Recognition of abusive burns is critical so that intervention to mitigate an
unsafe environment and prevention of future injuries can occur.

*Corresponding author. E-mail address: katherine.canty@childrens.harvard.edu

https://doi.org/10.1016/j.yapd.2023.03.004
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

Risk factors for abusive burns are shared with those of other forms of phys-
ical abuse and include unrealistic expectations of a child’s behavior and/or
development, inconsolable crying in infants, history of child protective services
involvement, caretaker history of drug or alcohol abuse, having a single parent
household, being an adolescent parent, and social isolation [1,4]. Toilet training
and toileting accidents in toddler and preschool-aged children are unique risk
factors for inflicted burns [1,5,6].
As with any medical condition, obtaining a comprehensive history is essen-
tial to making the diagnosis and differentiating between inflicted and accidental
burn injury. In addition to the explanation for the injury, pointed questions
about the source of the injury (ie, tap water vs other liquid), duration of con-
tact, presence or absence of clothing, and the developmental level of the child
are crucial. A developmental history is essential to determining whether a pro-
vided injury mechanism is plausible. For example, by the age of 18 months,
close to 80% of toddlers in one study were able to climb into a 1499 tall bathtub
[7]. The same investigators also measured how far a group of 54 toddlers
ranging in age from 12 to 23 months could reach onto a standard kitchen coun-
tertop. Interestingly, 41/54 (76%) were able to reach the 3699 countertop, with a
few reaching 5 or more inches onto the counter [8,9]. A single 12-month-old
child was able to reach more than 199 onto the counter [8,9].

DESCRIBING BURNS
Burns are characterized as being either superficial, partial thickness, or full thick-
ness. Superficial burns involve the epidermis and are not associated with bullae
formation. In addition to the epidermis, partial thickness burns also affect a
portion of the dermis and may be classified as either superficial partial thickness
or deep partial thickness. Full-thickness burns involve the epidermis and dermis
and due to destruction of nerve innervation, the affected area is insensate. Full-
thickness burns seem waxy and are devoid of bleeding [10].
In addition to the depth, a measure of the total body surface area (TBSA)
affected is also important, as TBSA is used to calculate fluid resuscitation
and can be a predictor of morbidity and mortality. The Palmer method is an
easy way to roughly estimate the TBSA. The Palmer surface of the patient is
equal to 1% TBSA; this is especially relevant in pediatric patients, as different
areas of the body change size in their relation to TBSA throughout develop-
ment. For example, the head is a greater percentage of surface area in young
infants compared with adolescents. Importantly, areas of superficial burn depth
should not be included in the calculation of TBSA [10].

THERMAL BURNS
Scald
Scald burns occur from contact between the skin and a hot liquid or steam.
They can result from immersion in a liquid, contact with a flowing liquid, or
from a liquid splash or splatter. In children younger than 5 years living in
developed countries, scalds are the predominant mechanism of burn injury

[11]. Nonabusive scald burns most commonly occur via 3 mechanisms: (1) the
child reaches for or pulls on a container of hot liquid resting on an elevated sur-
face, knocking it over and spilling it on themselves; (2) the child spills/pours the
liquid directly on themselves after it has been heated (ie, microwaveable noo-
dles); and (3) the child falls into hot cooking liquid. With the first mechanism,
the burn typically localizes to the anterior surface of the upper body.
It often has a triangular appearance with nonuniform burn depth and irreg-
ular borders (Fig. 1). That said, one important consideration is the presence or
absence of clothing, which is why it is valuable to elicit this when obtaining a
history. As an example, a child who spills a hot liquid onto their thigh while
wearing shorts may have a well-circumscribed burn in an area where the shorts
absorbed the hot liquid and adhered to the child’s skin (Fig. 2). In this setting,
the fabric lengthens the contact time between the hot liquid and the skin sur-
face, resulting in a deeper burn depth in the clothed area.
In contrast, with abusive scalds, specifically forced immersion into a sink or
bathtub, the burn more often has a uniform depth. Additional features that are
concerning for forced immersion include bilateral burn symmetry and the
absence of splash marks. A sharp line of demarcation may give a ‘‘stocking-
glove’’ appearance (Fig. 3). Further, sparing in lines of flexion (‘‘zebra stripes’’)
or ‘‘donut-shaped’’ sparing of the buttocks are other features that suggest
forced immersion (Fig. 4). The palms and soles, which are thicker than other
skin surfaces, may also be relatively spared, especially if the exposure time is
brief [12].

Fig. 1. A 17-month-old child sustained a 15% TBSA superficial partial-thickness burn to his
upper chest, right shoulder, right side of his face, and upper back. Mother had made a cup
of tea with boiling water and left it in the center of a table while making food for his sibling.
Mother heard a scream and turned to find child on the floor with the mug broken next to him.
The distribution, irregular margins, and nonuniform burn depth are consistent with the history
provided of an accidental scald burn.

Fig. 2. A 4-year-old child with a well-circumscribed burn from an accidental scald after he
spilled a glass containing a hot liquid onto himself.

In a multicenter study of 215 children younger than 10 years who were

referred for evaluation of burn injuries attributed to potential physical abuse,
researchers examined the relationship between the burn type, agent, mecha-
nism, location, pattern, TBSA, thickness, and presence of additional injuries
and the likelihood of abuse [13]. Characteristics associated with a greater likeli-
hood of abuse included burns by hot water, immersion burns, bilateral/sym-
metric burn distribution, a TBSA greater than or equal to 10%, full-thickness
burns, and burns associated with additional injuries [13].

Case presentations
1. A 22-month-old previously healthy woman presented with burns to her left lower
face, left upper anterior chest, left shoulder, and left medial upper arm (Fig. 5).
Per history obtained from the child’s mother, the child’s sister had prepared
herself microwaveable noodles with boiling water, which she left unattended on
the kitchen counter for 3 to 4 minutes. During that time, the patient had gone into
the kitchen alone. Soon after, she came to her mother crying with her clothing
wet. Although there were no chairs or stools near the counter, the child had been

Fig. 3. Stocking distribution of a forced immersion burn in a 21-month-old that occurred while
being cared for by a babysitter. (Courtesy of Veena Ramaiah, MD; with permission.)

holding a toy when she entered the kitchen and her family suspected that she had
knocked over the cup with the toy. The appearance of the burn, in conjunction
with the history provided, was thought to be consistent with accidental injury.
2. A 30-month-old woman presented to medical care with symmetric superficial
partial-thickness burns to her bilateral lower legs, ankles, and feet (Fig. 6) with
sparing of the soles and distal toes. The child was accompanied by a nonrelative
who had assumed care of the child after mother had dropped her off ‘‘in the
middle of the night’’ the evening prior. The following morning, the caregiver
noted the burns, after removing the child’s socks, and brought her for evaluation.
On admission to the hospital, a provider asked the child, ‘‘What happened?’’
when pointing to her feet and the child responded, ‘‘Momma did it.’’ When in-
terviewed by law enforcement and the department of child and family services,
the mother provided differing histories for how the child sustained her injuries.

Fig. 4. Same child as depicted in Fig. 3 with sparing of the buttocks in a donut-shaped config-
uration. (Courtesy of Veena Ramaiah, MD; with permission.)

Fig. 5. Partial-thickness burns to the face, chest, and left arm of a 22-month-old following an
accidental scald burn.

Ultimately, the burns were determined to be consistent with an abusive immersion

burn.
Relationship of liquid type, time, and temperature to burn severity
Liquids such as grease and oil, among others, can reach temperatures greater
than the boiling point of water and have a greater viscosity [2]. As such,
they can cause a deeper burn.
Research into the minimum times and temperatures causing scald burns is
scarce due to Human Subjects Protections. However, experimental data from
Moritz and Henriques in 1947 and described by Feldman in 1983 offer esti-
mates of time-to-burn in seconds at varying temperatures [14,15]. More
recently, Abraham and colleagues used a computational model to predict the
time required to produce deep partial-thickness burns at varying exposure tem-
peratures [16]. Table 1 depicts the minimum time (in seconds) and temperature
required to reach the thresholds for superficial and partial-thickness burns in
children based on the aforementioned studies [14–16].

Fig. 6. Child with symmetric, healing burns to her feet. Note the sparing of the soles of her
feet and distal aspects of her toes.

Table 1
Calculated burn times in children that result in superficial, superficial partial-thickness, and
deep partial-thickness burns at varying temperatures

Time (s) to deep

Time to Time (s) to partial thickness
superficial superficial partial (2nd degree)
burn thickness Without postburn
Temperature ( F) (1st degree) (2nd degree) cooling
129 6.0 10.0 —
135 2.0 4.0 —
140 0.5 1.0 —
149 0.3 0.5 —
151 — — 15.0
154 — — 12.0
160 — — 9.2
171 — — 6.0
Adapted from Feldman and Metz 2019 [12] based on research from Moritz and Henriques 1947, Feldman
1983, and Abraham et al. 2015 [14–16].

Hot water splash burns compared with scald burns require higher tempera-
tures (at least 140 F) to cause cutaneous injury [2,12].

Contact
Abusive contact burns compared with accidental contact burns tend to be more
clearly demarcated, localize to the posterior aspect of the body (ie, back/neck)
or regions covered by clothing, and may be characterized by grouped lesions
(Fig. 7). In contrast, accidental contact burns typically have a smeared edge
appearance and most commonly involve the palmar or plantar surfaces while
children are exploring their environment, as well as areas of the body that are
commonly unclothed [12]. During Summer months, sun-heated surfaces such
as pavement and asphalt can become extremely hot and result in bilateral
plantar foot burns (Fig. 8) [12].
Similarly, reports of accidental burns from car seats exposed to radiant heat
have been documented [2]. An additional cause of unintentional burns that
warrants consideration are accidental contact burns from space/wall heaters,
which can result in burns to posterior or typically clothed regions such as
the buttocks. A common scenario might be that of a child who has showered
and huddles in front of the heater for warmth and backs up too far burning
their buttocks.
Examples of implements of inflicted contact burns include irons, cigarettes,
hair tools, and heaters/radiators, among others. Intentional cigarette burns
can be identified by their well-circumscribed, circular (5–10 mm diameter)
appearance, and rolled edges. In contrast, unintentional cigarette burns are
more commonly wedge or comet shaped because of brush-by contact or reflex-
ive movement away from the source once pain is sensed.

Fig. 7. A 6-month-old infant was referred to a clinic for an outpatient evaluation of suspected
physical abuse. On her back, the examining provider noted multiple patterned markings
consistent with a contact burn from a lighter. (Courtesy of Supriya Sharma, MD; with permis-
sion.)

Case presentation
A 2-year-old male patient was referred for evaluation after he presented to
school with 2 lesions that school staff suspected were burns. Because of the
child’s age, he was unable to provide a history. Per history obtained from
the child’s mother, his maternal grandmother was outside on the porch rolling
cigarettes when the child ran toward her at the very moment that she was
lowering her arm while holding a lit cigarette. The appearance of the lesion

Fig. 8. Child with partial-thickness burns to the soles of bilateral feet after standing outside
barefoot during peak sun in August.

(‘‘comet shaped’’) was thought to be consistent with an accidental burn (Fig. 9).
The small circular lesion beneath was hypothesized to be the result of an ember
from the cigarette falling into the fossa above his clavicle.

Radiant
Rare cases of microwave burns have been reported. A case report of 2 children
placed in microwave ovens was published by Alexander and colleagues [17].
The injuries sustained included well-demarcated full-thickness burns to areas
of skin in closest proximity to the radiation-emitting source [17]. Skin, subcu-
taneous fat, and muscle are differentially affected with less damage to subcu-
taneous fat because of its lower water content compared with skin and
muscle [2,17].

CHEMICAL BURNS
Household cleaning products and cosmetics are common causes of chemical
burns. Chemicals may be acidic or alkali, with alkali burns being more severe
due to deeper tissue penetration through liquefactive necrosis. With certain
chemicals (ie, concentrated bleach or low concentration hydrofluoric acid),
symptom onset may be delayed. Interestingly, cases of unintentional chemical
burns to the perineum from senna laxative, which can look similar to a choc-
olate bar, have been reported in young children [12].

Electrical burns
In children, electrical burns are frequently the result of the child biting an elec-
trical cord or inserting an object into an electrical outlet. The area of tissue

Fig. 9. Contact cigarette burn to the base of the neck in a comet-shaped configuration. The
smaller circular burn was felt to be the result of an ember falling into the fossa above the left
clavicle.

destruction is often larger than what is visible externally. Sequelae of electrical

burns include cardiac arrhythmias, compartment syndrome, and contractures.
A few case reports exist that describe the appearance of stun-gun injuries
from abusive acts by caregivers [2,19]. In one report, an 8-year-old child pre-
sented with multiple circular lesions (w0.5 cm) that included a mix of hypopig-
mented macules and erythematous lesions, some of which were grouped in
pairs separated by 4 to 5 cm [19]. The child disclosed that his mother’s
boyfriend had used a ‘‘shock gun’’ on him [19].
Case presentation
A caregiver woke to the sound of popping and saw fire around a 5-year-old
child’s neck. The child was known to wear a long necklace of his fathers
around his neck. The caregiver found a piece of the necklace had broken off
by the extension cord outlets and phone charger. It was thought that the child
went to charge the phone, and the necklace became caught between the prongs
of the phone charger plug and then when he went to plug it into the extension
cord, the fire started. Child sustained 1% TBSA superficial and deep partial-
thickness burns nearly circumferentially around his neck (Fig. 10).
Medical mimickers
Although much of this review has focused on differentiating between abusive
and accidental burns, there are specific medical conditions that can present
similarly to burns.
Bullous impetigo is a toxin-mediated skin infection caused by Staphylococcus
aureus. It presents with flaccid bullae that rupture and form crusted erosions.
Ecthyma is an ulcerative bacterial skin infection most often due to group A
beta-hemolytic streptococcus that is characterized by punched-out lesions that
may leave scarring and can be misattributed to cigarette burns.
Phytophotodermatitis is a phototoxic reaction that results when a chemical con-
taining psoralen, which is found in several plants, contacts skin and is exposed

Fig. 10. A 5-year-old child with nearly circumferential 1% TBSA mixed partial-thickness burns
to his neck.

to sunlight. The affected skin subsequently becomes hyperpigmented and may

even develop vesicles or bullae (Fig. 11). Citrus fruits, celery, and figs are a few
examples of causative agents. In addition to being a mimicker of abusive burns,
phytophotodermatitis may also be confused for bruising. Lesions are usually
noted several days after exposure so careful questioning of the recent environ-
ments of the child is necessary.
Postinflammatory hyperpigmentation is the darkening of skin that may occur in
areas of prior trauma or inflammation (Fig. 12).

EVALUATION
When abuse is suspected, a thorough physical examination looking for other
cutaneous injuries is necessary. For children younger than 2 years, a skeletal
survey is recommended. This recommendation is supported by a multicenter
study of children younger than 5 years who underwent evaluation due to con-
cerns for physical abuse. In the group of 97 children younger than 24 months
with burns, 18.6% were found to have fractures through skeletal survey [18].
Laboratory evaluation should include aspartate transaminase and alanine
transaminase to assess for occult intraabdominal trauma. For infants, particu-
larly those younger than 6 months, a computed tomography of the head
without contrast should be considered.
Role of a scene investigation
A scene investigation is particularly important in the evaluation of hot water
scald burns. Key parts of the investigation include documenting the water heat-
er temperature, the type of water heater (ie, gas vs electric), and the running hot
water temperature at varying time intervals. If the burn was reported to have
occurred while bathing, measurements of the sink or tub and the type of ma-
terial should be documented. Evidence worksheets have been developed to
aid documentation when conducting a scene investigation of hot water scald
burns [2,12].

Fig. 11. This child was sent for an evaluation after these markings were noted at day care.
On history, the child had recently gone to the beach. He was diagnosed with phytophotoder-
matitis.

Fig. 12. Child referred by the Department of Child and Family Services for evaluation of cir-
cular hyperpigmented lesions. On examination, the lesions were primarily on exposed areas
with relative sparing of the trunk. Although similar in their configuration, the lesions differed in
size. The child endorsed having been bitten by bugs, and she was diagnosed with postinflam-
matory hyperpigmentation.

Neglect
Neglect in childhood burns is very common and accounts for 9:1 of cases
compared with burns due to physical abuse [5,6,20]. Anticipatory guidance is
necessary to discuss setting water heaters at 120℉, safe storage of chemicals
and flammable materials, and education regarding close supervision of young
children, especially when bathing.

SUMMARY
Burns in children necessitate a thorough assessment, including a detailed his-
tory of the injury, physical examination, and home investigation. Burns due
to accidents and neglect are more common than abusive burns. The child
should be evaluated for additional injuries, including fractures as well as
head and abdominal trauma.

CLINICS CARE POINTS

A burn in a young child may be a sentinel injury and necessitates a careful his-
tory and examination as well as consideration of child abuse and neglect.
Accidental scald burns in ambulatory infants/toddlers typically present with
injury to the anterior, upper torso.
In young children in whom abuse is suspected, an evaluation for clinically
occult injuries should be considered.

DISCLOSURE
The authors have nothing to disclose.
References
[1] Peck MD, Priolo-Kapel D. Child abuse by burning: a review of the literature and an algorithm
for medical investigations. J Trauma 2002;53(5):1013–22.
[2] Knox BL, Starling SP. Abusive Burns. In: Jenny C, editor. Child abuse and neglect: diagnosis,
Treatment, and Evidence. WB Saunders; 2011. p. 222–38.
[3] Sheets LK, Leach ME, Koszewski IJ, et al. Sentinel injuries in infants evaluated for child phys-
ical abuse. Pediatrics 2013;131(4):701–7.
[4] Ferguson DM, Parker TD, Marino VE, et al. Risk factors for nonaccidental burns in children.
Surg Open Sci 2020;2(3):117–21.
[5] Maguire S, Moynihan S, Mann M, et al. A systematic review of the features that indicate
intentional scalds in children. Burns 2008;34(8):1072–81.
[6] Maguire S, Okolie C, Kemp AM. Burns as a consequence of child maltreatment. Paediatr
Child Health 2014;24(12):557–61.
[7] Allasio D, Fischer H. Immersion scald burns and the ability of young children to climb into a
bathtub. Pediatrics 2005;115(5):1419–21.
[8] Allasio D, Fischer H. How Far Can Toddlers Reach Onto a Standard Kitchen Countertop?
Clin Pediatr 2011;50(3):262–3.
[9] American Academy of Pediatrics. "Children as young as 12 months can reach a countertop;
Puts them at risk for severe burns." ScienceDaily. ScienceDaily, 4 October 2010. Available
at: www.sciencedaily.com/releases/2010/10/101003081456.htm.
[10] Toon MH, Maybauer DM, Arceneaux LL, et al. Children with burn injuries–assessment of
trauma, neglect, violence and abuse. J Inj Violence Res 2011;3(2):98–110.
[11] Sheridan RL. Burn Care for Children. Pediatr Rev 2018;39(6):273–86.
[12] Feldman K, Metz J, Burns. In: Laskey A, Sirotnak A, editors. Child abuse: medical diagnosis
and Management. American Academy of Pediatrics; 2019. p. 47–101.
[13] Pawlik MC, Kemp A, Maguire S, et al. Children with burns referred for child abuse evalua-
tion: Burn characteristics and co-existent injuries. Child Abuse Negl 2016;55:52–61.
[14] Moritz AR, Henriques FC. Studies of Thermal Injury: II. The Relative Importance of Time and
Surface Temperature in the Causation of Cutaneous Burns. Am J Pathol 1947;23(5):
695–720.
[15] Feldman KW. Help needed on hot water burns. Pediatrics 1983;71(1):145–6.
[16] Abraham JP, Plourde B, Vallez L, et al. Estimating the time and temperature relationship for
causation of deep-partial thickness skin burns. Burns 2015;41(8):1741–7.
[17] Alexander RC, Surrell JA, Cohle SD. Microwave oven burns to children: an unusual mani-
festation of child abuse. Pediatrics 1987;79(2):255–60.
[18] Frechette A, Rimsza ME. Stun gun injury: a new presentation of the battered child syndrome.
Pediatrics 1992;89(5 Pt 1):898–901.
[19] Degraw M, Hicks RA, Lindberg D, et al. Incidence of fractures among children with burns
with concern regarding abuse. Pediatrics 2010;125(2):e295–9.
[20] Chester DL, Jose RM, Aldlyami E, et al. Non-accidental burns in children-are we neglecting
neglect? Burns 2006;32:222–8.

ADVANCES IN PEDIATRICS

Medical Child Abuse

A Review by Subspecialty

Melissa K. Egge, MD
Pediatrics, Stanford Medicine Children’s Health – Lucile Packard, 700 Welch Road, Suite 300G,
MC 6583, Palo Alto, CA 94304, USA

Keywords
Medical child abuse MCA Munchausen syndrome by proxy MSP
Factitious disorder by proxy Child abuse in a medical setting
Key points
Consider MCA when unusual diseases do not fit expected patterns.
Objectively verify reported symptoms.
Communicate with all medical team members, the child directly, and both
parents.

BACKGROUND
Medical child abuse, via falsification by the caretaker, ‘‘occurs when a child re-
ceives unnecessary and harmful or potentially harmful medical care’’ [1]. Since
1977, various terms for the condition have been used. However, Munchausen
syndrome by proxy (MSBP), the initial term used, continues to be the most
recognizable term, although it emphasizes the caregiver’s pathologic condition
and motivation [2]. This article will use the term medical child abuse (MCA),
coined by Jenny and Roesler, and generally used by Child Abuse Pediatricians
because it focuses on the harm to the child. The hallmark of MCA is a child
evaluated for and diagnosed with conditions based largely on a caregiver’s
report of symptoms, leading to unnecessary and harmful tests, treatments,
and procedures. The most common subspecialties consulted in MCA cases
include gastroenterology (GI), psychiatry, neurology, pulmonology, and al-
lergy [1]. Common features of MCA include reported symptoms only observed
by mother; unusual disease presentations; unusual responses to treatment(s);

No disclosures.

E-mail address: Megge@stanford.edu

https://doi.org/10.1016/j.yapd.2023.03.005
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

repeated caregiver solicitation of more medical opinions; and withdrawal from

normal daily activities, peers, and family. The symptoms cease when the child
is no longer in care of the instigator. The most frequent symptoms reported in
MCA cases are apnea, feeding problems, diarrhea, seizures, cyanosis, behavior
problems, and asthma/allergy concerns. MCA may coexist with actual under-
lying medical conditions, physical or sexual abuse [3,4].

BARRIERS TO IDENTIFICATION AND REPORTING

Physicians do not recognize or address MCA for numerous reasons. Physicians
are trained to obtain detailed history from parents expected to be a trusted
source. Parental concerns may be pursued to avoid missing a treatable condi-
tion or to avoid confrontation. Primary care physicians may have a low
threshold for referring to a subspecialist when symptoms do not respond to
typical treatments, thinking they may be dealing with a rare or variant form
of a disease. Even when suspicion for MCA originates, physicians may prior-
itize maintaining good rapport with caretakers.
The task of reviewing a patient chart for possible MCA is extremely time-
consuming, particularly when falsifications and visits have been long-
standing. Reviewing documentation of concerning findings and reaching out
to other clinicians to verify information can take many hours. Although pedi-
atricians are usually familiar with the condition, they often lack any experience
with MCA cases and do not feel confident in filing reports. Physicians may
avoid confronting a parent as a possible perpetrator, or another colleague as
having ordered inappropriate studies or procedures. Physicians who openly
discuss suspicion of MCA may be met with resistance from colleagues that
are part of the child’s medical team. Finally, significant barriers to reporting
child abuse include a lack of confidence that responding agencies will offer
effective intervention and the sentiment that the primary provider can handle
the situation better themselves [5].

EPIDEMIOLOGY
Due to a broad spectrum in severity at the time of recognition of an MCA case,
ongoing changes in terminology, and lack of billable coding options, it is likely
that the often-reported incidence of 0.5 to 2 MCA cases per 100,000 children is
an underestimate [3]. The estimate of 1% incidence in an asthma clinic, re-
ported by Godding and Kruth, may more closely represent the true prevalence
in subspecialty practice [6]. MCA cases are concentrated in tertiary care chil-
dren’s hospital systems. Cases published in medical literature are the more
extreme in severity, and based on recall. In practice, there are far more low-
level cases, which are either abated by scrupulous clinicians, are less clear, or
never come to attention. Men and women are equally affected with the average
age at diagnosis around 4 years typically taking almost 2 years to diagnose.
Morbidity occurs in 100% of cases, and an estimate of long-term or permanent
injury associated with MCA is around 7%. In 25.2% of MCA cases, siblings
were deceased, and more than half of siblings shared similar problems [3].

Time from symptoms to diagnosis varies widely but is estimated at 14.9 months
[5] to 53.4 months [7]. Mortality rates vary according to definitions of MCA
from 6% to 9% [3,4].

REPORTING TO CHILD PROTECTIVE SERVICES

This MCA is not well understood by medical professionals, much less by child
protection service workers. Investigators may have the perspective of a ‘‘well
cared for,’’ medically complex child whose parent is adhering to prescribed
care or pursuing answers regarding her child’s continuing symptoms. Child
protection workers usually know the term MSBP, so explaining the medical
harm, being specific and using lay terms whenever possible is helpful.

PERPETRATOR PROFILE
Multiple studies confirm that the usual perpetrator of MCA is the mother, most
often the biological mother [3,8]. She tends to falsify her own medical history,
often reporting a history of obstetric problems. She may have comorbid mental
health issues such as personality disorder or depression [8,9]. A progression
from an anxious and emphatic parent to a medical child abuser has been
described. Dr Hoffman [10] described 2 types of abusers in MCA cases
(Table 1):
One type actively falsifies by deeds to offer objective data that convinces the
medical team of an ailment or symptom by showing them an induced or simu-
lated finding. This type is rarer and less likely to respond to therapeutic inter-
ventions. The second type falsifies in words, and their falsifications take the form
of exaggerations, coaching, and inventing symptoms to press for further inves-
tigations [10]. Early descriptions of MCA minimized secondary gain from the
motivation of perpetrators of MCA [3] but recent case descriptions highlight
social media solicitations for money or online empathy for caring for chroni-
cally ill children [10].

Table 1
Falsifications
Words Deeds
Exaggeration Induction of symptoms
(cutting, smothering, starving, poisoning)
Coaching Simulation (falsifying a test result by
contamination with blood)
Withholding important history Failure to provide treatment that would
improve condition (asthma or seizure
meds). Consider neglect
Providing false history (h/o cystic
fibrosis, seizure disorder or
anaphylaxis to drug)
Data from Hoffman A. Pulling the Wool Off Our Eyes: Medical Child Abuse. Pediatr Ann. 2020 Aug
1;49(8):e354-e358.

SCREENING AND DETECTION: ROLES OF ALL MEDICAL

PROVIDERS
Physicians can reduce medical harm to a child by directly observing unusual
symptoms a parent reports and communicating with other members of the
health-care team (Box 1: Core Concepts). Whenever possible, the child should
be asked privately about their physical and behavioral symptoms. When symp-
toms seem out of proportion to the child’s clinical appearance, ask to speak to
other caregivers (ie, father, daycare provider, and teacher). A study of perpetra-
tors found that 75% are married [8]. Greiner and colleagues published a
screening tool for MCA based on classic MCA case characteristics. Additional
signs may be used for screening in patients: injury to face/neck, history of
cyanosis, a request for apnea monitors and chronic unexplained vomiting and
diarrhea. History of leaving hospital against medical advice or demanding trans-
fer to other health-care facilities is additional red flags [9]. In addition, school
staff, occupational and physical therapists, and early interventionists, some of
whom see the family at home, have valuable information. Family members
may raise suspicion of MCA but often their reports to child protective services
are not taken seriously and cause further alienation from the child’s caregiver.
During hospitalization, providers can reduce medical harm by
Creating a plan for evaluation and treatment with a multidisciplinary team to
include or exclude diagnoses while minimizing procedures.
Requesting outside medical records.
Having a nurse/observer present to confidentially document verbal and phys-
ical interactions between the caretaker and the child, such as tampering with
equipment.
Giving all medications and foods by nursing staff while in hospital rather than
by caregivers.

Box 1: Core concepts

Is there concern for overmedicalization and harm of child?
Multidisciplinary conference, include primary care in open discussion with
goal to prevent further harm.
Questions to answer in case review
Have symptoms been observed by medical staff or outside observer?
Are there multiple/multisystem diagnoses/problems that have no unifying
theme or objective support?
Has the response to appropriate treatment been poor or variable?
Was there a third or fourth opinion obtained when consensus was estab-
lished? (ie, doctor shopping)
Does the caregiver insist on invasive tests or procedures?
Would observation in the hospital be useful?
Objective chart review by child abuse specialist?

Covert video surveillance (CVS) has documented proof of dramatic acts of

MCA [1,10]. CVS is a labor-intensive endeavor that is not put into practice
often. Risk management (legal), nursing, security, and hospitalist team mem-
bers need to coordinate who will watch the video feed. In some hospitals,
the general consent may legally cover the procedure of recording, and in other
jurisdictions, a court order may be required. CVS can also confirm a care-
giver’s report and detect organic disease processes or reveal symptoms previ-
ously unwitnessed. As a caregiver is often enmeshed with the medical team,
deciding who should be aware of the covert video plan is also an issue, given
cases of hospital team members ‘‘tipping off’’ the suspected perpetrator.
If the threshold for suspicion of MCA has been met and the case is reported,
child protective services may order temporary removal of the parent from the
child’s bedside to allow further observations and document improvement in
the child’s clinical status.

Primary care provider’s role

Ideally, the prevention of MCA centers on the primary care provider. All refer-
rals for subspecialist care should come from the child’s medical home. The pro-
vider should edit the problem list to accurately reflect only confirmed diagnoses.
Hamilton and colleagues offered insight to how the relationship between the
parent and physician escalates from concerns expressed to overmedicalization
to MCA. Tips are offered to halt the progression: detailed documentation about
who observes and reports symptoms, encouraging the doctor to stay within the
standard of care, and to confirm reported symptoms in person [11].

Subspecialist’s role
It is difficult for the subspecialist to entertain MCA in a differential diagnosis when
meeting a new patient with a dense medical record, if full records are available [10].
Given the subspecialist’s focus on a particular organ system, the greater context of
other strange multisystem diseases may be overlooked. When a caretaker is not
reassured by negative testing, and/or demands testing or procedures that are
beyond what is customary, more vigilance toward reviewing the totality of findings
and issues may alert the subspecialist to the possibility of MCA. A child abuse
specialist/program can provide a supportive role in assisting with communication,
chart review, and guidance. A sample letter (Box 2) may be distributed to alert the
medical team of concerns for MCA in order to prevent further harm.

Tips for records review

The electronic medical record (EMR) makes chart review an easier process
than looking through hard copies (Box 3). An overview of the problem lists
and encounters will direct the reviewer to the affiliated subspecialty clinics. It
can be insightful to tally the number of encounters, allergies listed, laboratory,
and radiology studies. Look for any special alerts, such as a social work alert or
earlier reports to child protective services. Chart reviews can demonstrate con-
cerns other than MCA, such as medical neglect. Search each subspecialty to re-
view the number of visits and providers. For each visit, note what the caregiver

Box 2: Sample note to medical team

This is a confidential note.
This note is to advise you that the Suspected Child Abuse and Neglect Team has
been consulted for concerns regarding overmedicalization and emotional abuse
of this child, instigated by the mother. The concerns were brought to our attention
by the subspecialty or primary care team who reports that histories provided may
be false or misleading. There seems to be evidence of seeking many opinions
from outside medical providers. Use confidential documentation encounters to re-
cord objective discrepancies in what is reported and what is observed on
examination.
Our aim in this communication is to inform you that MCA (formerly known as
MSBP) is being considered. The main goal at this point is to be sure that all refer-
rals stem from the primary care physician (not from specialists, ideally) and that
harmful or potentially harmful procedures or studies are carefully considered
based on objective data before ordering. When appropriate, the child’s father
should be included in care plans.
Feel free to reach out to discuss further

reported, objective observations, plan, and response to treatment. Some EMRs

allow outside medical records to be reviewed. Review photos and documents
uploaded into the Media tab by the parent.
Below is a list of diagnoses by specialty that commonly seem in suspected
MCA cases with guidelines for diagnosis, for reference. The purpose of refer-
encing diagnostic criteria is to facilitate chart review (Table 2). Testing and pro-
cedures are ordered at the discretion of the clinician.

Allergy and immunology

Allergies
Allergic symptoms and triggers are largely based on parent reports. By the time
a child gets to see a specialist, symptoms may have resolved, and without objec-
tive data, it may be difficult to decipher whether a parent’s report is untrue,
exaggerated, or real. Several food and nonfood allergies are a warning sign
of MCA [1,12]. In some cases, parents, unilaterally, restrict the child’s diet to
a degree that may cause significant malnutrition. The medical provider should
confirm whether the allergies are valid. Asthma or allergies were a significant
part of the complaints for 50% of children diagnosed with MCA in a Pacific
Northwest study. Of 104 MCA cases, 29% reported drug reactions or sensitiv-
ities. Eleven of the parents reported completely falsified immunodeficiencies
[13]. Warner and Hathaway reported 17 children with exaggerated food al-
lergies on restricted diets, none of whom had objective findings of food intol-
erance or allergy [14]. Of concern is a caregiver who refuses to accept the
removal of food allergen from the list of restricted food even after challenge
and testing are negative and insists on ongoing diet restriction is concerning
for MCA.

MEDICAL CHILD ABUSE

Box 3: Sample chart review grouped by specialty
Specialty Objective observations/ Tests Treatment
+ location Date Complaints examination Assessment/diagnosis ordered response Discrepant information
Pulm - X hospital 1/1/23 Wheezing, Clear lung exam, normal PFTs, No clinical evidene of PFTs N/A Subjective history
respiratory 100% oxygen saturation asthma at this time not verified on exam
distress on room air, normal
respiratory rate

Adapted from APSAC Taskforce (2017). APSAC practice guidelines: Munchausen by Proxy: Clinical and case management guidance. The APSAC Advisor, 30, 8-
31.

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Table 2
Medical child abuse diseases and symptoms by subspecialty
Test to evaluate
Subspecialty Symptom/date Diagnosis Questions to consider Relevant literature Questions
Allergy and Rashes Food allergies What was documented in the 14—food allergies Did child go to emergency
Immunology Lip swelling Anaphylaxis medical record? 15 dept? Was 911 called?
Breathing Mast cell Skin prick test food-specific 16 Are there multiple food and
problems activation immunoglobulin E (IgE) nonfood allergies listed
disorder testing without verified reactions?
Note: Immunoglobulin G (IgG) Has the child’s diet been
tests are not validated (overly) restricted without
Both an SPT wheal <3 mm and obvious benefit or with
a food-specific IgE resultant weight loss?
(sIgE) < 0.35 kUA/L have a Atypical allergic reactions?
high specificity and negative
predictive value
Consider double-blind placebo-
controlled food challenge
with specialist
Tryptase level >20 ng/mL
Second-tier test: Skin or bone
marrow biopsy

EGGE
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MEDICAL CHILD ABUSE

Cardiology Fainting/syncope POTS Criteria for POTS: the presence 17 Has anyone else witnessed a
Chest pain Hypertension of chronic symptoms of fainting episode?
orthostatic intolerance Are recommended electrolytes
(6 mo) accompanied by an and fluids not helping? Is
increased heart rate (HR) caregiver asking for IVF?
40 bpm within 10 min of
assuming an upright posture
and in the absence of
orthostatic hypotension
(blood pressure [BP]
fall >20/10 mm Hg) Be sure
child is not dehydrated
Tilt table test
Dermatology Rash hives Are there photos to review?
Is this a condition that should be
verified by biopsy?
ENT Snoring Sleep apnea Polysomnographic study: 18- indications Sleep study results?
Sleep disturbance Recurrent otitis clinically relevant symptoms for PE tubes Do the records document
Ear pain media and an apnea hypopnea examination findings
Hearing problem Recurrent index > 1 or hypoventilation consistent with AOM or is
sinusitis (carbon dioxide >50 mm Hg treatment given based on
for >25% total sleep time) parent report?
Examination findings
Duration of symptoms
Otoacoustic emissions
Pure tone screening or
tympanometry
(continued on next page)

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Table 2
(continued )

Test to evaluate
Subspecialty Symptom/date Diagnosis Questions to consider Relevant literature Questions
Endocrinology Altered mental Hypoglycemia Analysis of insulin type 19 Is there insulin or other glucose
status Hyperglycemia detection of hypoglycemic lowering medication in the
Seizure agents in the bloods low C home?
peptide and high insulin
levels in a first critical blood
sample of a child with
hypoglycemia
Inpatient observation
GI Abdominal pain, Intestinal pseudo- Inpatient hospitalization for 20—pseudo-obstruction Are there objective signs of
difficulty feeding obstruction direct observation with sitter 21—G-tube pain?
Vomiting Delayed gastric Antroduodenal manometry by 22—FTT Has feeding been directly
Diarrhea or emptying experienced observed?
constipation Celiac/nonceliac gastroenterologist who can In a child victim with slowed
Blood in vomit gluten sensitivity interpret accurately motility, assess for food
or stool Inability to feed Screen: Tissue restriction, meds or dietary
orally Transglutaminase-IgA, total influences
FTT IgA
IBS Diagnosis: Endoscopic biopsy
small intestine
Oral intake challenge under
direct observation. Have
nurse give food if possible
Analyze formula or gastric
contents
Analyze stool

Genetics Mitochondrial Markedly elevated plasma 23 Consider inpatient admission to

disorder lactate (>3 mmol/L), in a 24 observe symptoms
Ehlers Danlos- properly collected sample,

MEDICAL CHILD ABUSE

hypermobile suggests the presence of
type mitochondrial dysfunction
Gynecology Vaginal bleeding Menorrhagia Rule out pregnancy 25 https://www-nice-
Pelvic pain Objective org-uk.laneproxy.
Concern sexual evidence: stanford.edu/
abuse Hemoglobin guidance/ng88
Examination
findings
Hematology Anemia Are the bruises concerning for 27—iron infusion Is the parent requesting iron
Bruising physical abuse? infusion without evidence of
bleeding Blood type; DNA analysis failed oral iron?
Toxicology for blood thinning
agents
Infectious Fevers Central line Culture and sensitivity to 28—central venous Is culture growth
Disease infections determine likelihood of catheter polymicrobial/unusual?
fevers (intentional) contamination 29—Lyme Has the child traveled to an
Chronic Lyme Has a fever been documented endemic northeast state?
disease on examination?
Two-tiered testing algorithm. If
first step is negative, no
further testing recommended
Nephrology/ Blood in urine Recurrent UTIs Urine culture and sensitivity 26 Are urine samples submitted by
Urology Stones in urine Hematuria Check serum antibiotic levels patient alone?
Glucose or protein Hypertension or Collect urine under staff Meds or supplements causing
in urine urine retention supervision elevated blood pressure or
UTI Enuresis Test blood in urine abnormal laboratories
Hypernatremia or Ultrasound bladder Does the child really need a
hyponatremia diaper?
Polydipsia
Anuria
Renal failure

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Table 2
(continued )

Test to evaluate
Subspecialty Symptom/date Diagnosis Questions to consider Relevant literature Questions
Neurology/ Seizure apnea Seizure Witnessed by someone other 32—BRUE Any unexplained deaths in
Neurosurgery Headaches BRUE/ALTE than mother? 33—Chiari siblings?
weakness Headache EEG Prior ALTE/BRUEs? Was there
Weakness/ Ask parent to video record; facial blood/bruising
ataxia consider overt or CVS present?
CM-I Comprehensive drug Is parent seeking surgery when
toxicology and levels not indicated?
Objective evidence of pain,
weakness
Ophthalmology Redness Recurrent Is caregiver inducing injury or
Change in vision conjunctivitis irritation?
Unequal pupils or keratitis Coaching
Are eye drops being given
inappropriately?
Orthopedic Joint pain or Fracture How does the child do in 24—hEDS Is child in wheelchair/walker
Surgery popping Hip dysplasia physical therapy? unnecessarily?
Limp Hypermobility Is the parent requesting ankle- Is the reported level of disability
Gait abnormality foot orthoses or congruent with exam
handicapped placard for car observations?
when not indicated?

MEDICAL CHILD ABUSE

Psychiatry/DBP Developmental Behavioral/ Ask to review formal testing diagnostic and Sstatistical Does the caretaker report
delay personality documents manual of mental disorders, personal history of mental
hyperactivity disorders Review school documents 5th edition (DSM-V) health issues?
learning/attention Autism attention Are there multisystem
disability Tourette deficit hyperactivity complaints that do not seem
syndrome disorder (ADHD) to fit together?
Irritability Learning
Psychotic symptoms disability
Sleep disturbances Depression
Anxiety
Pulmonology Chronic cough Asthma Has wheezing beien observed
Wheezing Cystic fibrosis by medical professional?
Hemoptysis Demonstration of expiratory
airflow limitation, by
spirometry. Documentation of
reversible obstruction
Sweat chloride test (could be
falsified) or genetic
confirmation?
Rheumatology OCD/tic PANDAS (PANS) Group A strep test, 5 working 35 Are OCD symptoms or tics
Joint pain Fibromyalgia criteria 36 observed in clinic?
Chronic pain No antistreptococcal 38 Does pain respond to therapy?
antibodies, criteria Is family engaged in
Psychological assessment prescribed therapies?

71
72 EGGE

Anaphylaxis
Due to the high stakes in failure to treat anaphylactic reaction in children, most
err toward prescribing injectable epinephrine and supporting avoidance of the
reported trigger. In infants, symptoms can be vague and include cutaneous, res-
piratory, cardiovascular, and/or gastrointestinal systems, as well as behavioral
changes. Anaphylaxis can also be overdiagnosed. Most anaphylactic reactions
in infancy present with skin findings. However, it is important to note that
some urticaria, respiratory distress, and skin changes can be associated with viral
illnesses. Contact reactions with food can also be mistaken for serious allergic
reactions. Coughing or gagging on food may be unrelated to allergic response
rather than age-appropriate difficulties with chewing and swallowing in an infant.
Gastrointestinal symptoms may be due to nonallergic causes [15].
Mast cell activation syndrome
Systemic mast cell activation syndrome (MCAS) has become more prevalent in
MCA cases in recent years and may present with vague symptoms that do not
meet criteria for diagnosis. Basic laboratories and serum tryptase are part of the
algorithm for first-line screening when characteristic skin lesions are observed.
Both cutaneous and systemic MCAS have published criteria that suggest bi-
opsies of skin lesions or bone marrow for definitive diagnosis [16].

Cardiology
Postural orthostatic tachycardia syndrome and syncope
Postural orthostatic tachycardia syndrome (POTS) and vasovagal syncope are
clinical diagnoses that should not be made based solely on the results of head-
up tilt table test testing or orthostatic vital signs.
POTS is a clinical syndrome usually characterized by frequent symptoms
that occur with standing, increase in heart rate 40 bpm or greater, and the
absence of orthostatic hypotension. [17] Red flags may include multiple events
of syncope only witnessed by the primary caretaker and insistence on intrave-
nous fluids as treatment.

Ear, nose, throat

Allergy and sinopulmonary symptoms are common in MCA cases but were
only listed as ‘‘chief complaints’’ in 15% of 104 patients in one review. It is
thought that because these diagnoses are so commonplace in early childhood,
they have not been worth noting in the MCA literature [12]. Forty-three
percent of MCA cases had ear, nose, throat (ENT) surgeries including myrin-
gotomies, pressure equalizer (PE) tube placement, tonsillectomies, and adenoi-
dectomies. The PE tubes were often placed multiple times within the first year
of life [12]. Placement of PE tubes requires anesthesia and carries risk of persis-
tent tympanic membrane perforation. When a parent alleges ear infections are
refractory to standard treatments, they may report hearing loss and welcome
surgical intervention. A record check is recommended before surgical proced-
ures to confirm a parent’s reported history.

Guidelines for tympanostomy tubes recommend tubes should not be placed

in otherwise healthy children who have had middle ear effusion for less than
3 months or those without effusion at the time of surgical evaluation [18].
Endocrinology
Endocrinologists may encounter MCA patients with hypoglycemia or hyper-
glycemia. Several poisoning cases involving hypoglycemic agents have been re-
ported leading to seizures, pancreatectomy, or death [19]. C-peptide testing at
the time of presentation helps identify exogenous insulin administration.
Gastroenterology
GI symptoms are frequent primary problems of MCA cases with feeding is-
sues, food reactions, vomiting, and diarrhea being prevalent. Additional symp-
toms reported are abdominal pain, motility problems, and failure to thrive
(FTT). A variety of GI complaints are interwoven and can lead to nonoral
feeding via surgically placed feeding tubes followed by intravenous catheteriza-
tion. In Sheridan’s review, 25% of MCA patients reported anorexia or feeding
problems and 20% reported diarrhea [3,20]. Several chronic GI complaints
such as vomiting, diarrhea, and feeding intolerance may benefit from inpatient
observation with direct supervision.
Dysmotility
Patients present to GI subspecialty clinic with concerns of motility issues. Hy-
man and colleagues compared young children who presented with symptoms
of chronic intestinal pseudo-obstruction with kids who presented similarly but
were eventually diagnosed with MCA. Important differences were noted that
may alert the clinician to concern for MCA: daily abdominal pain, several
other multisystem problems, atypical rapid progression of GI symptoms, re-
ported history of prematurity, no radiographic evidence of intestinal dilatation,
and lack of urinary neuromuscular disease. Using research-based interpretation
of antroduodenal manometry, none of the children in the MCA group had
abnormal migrating motor complexes, indicating they all had the ‘‘ability to
eat.’’ With therapeutic interventions including nursing supervision during hos-
pitalization and separation from mother, all MCA children were able to orally
feed [20].
Feeding issues
When a child reportedly has difficulty feeding by mouth, before tube (G-tube)
placement, Seattle Children’s Hospital hospitalizes the child for direct obser-
vation of feeding abilities. Feldman and colleagues reviewed 143 children with
suspected MCA and compared them with other children admitted for G-tube
placement. Of the 143 suspected to have MCA, the minority of confirmed
MCA patients had been feeding by nonoral methods, indicating their prob-
lems with oral feeding had not been lifelong like in the control group. The
children with MCA had more GI complaints (40% compared with 15% in
comparison group), more multisystem complaints, and more complications
(68%) with nonoral feeding methods. Not surprisingly, complications in the

MCA group included significantly higher likelihood of dislodgment of feeding

tubes, G-tube site infection/bleeding, and displaced/infected central lines.
MCA victims had more earlier GI studies, nonoral feeding types, and unusual
diagnoses [21].
Failure to thrive
FTT is a common feature of children with chronic or complex medical condi-
tions frequently observed in those with GI complaints and MCA. It is impor-
tant to review growth charts to recognize patterns of underfeeding.
Malnutrition in young children causes a drop in weight first, followed by a
drop in height growth, with head circumference last, sparing the brain. If a
caregiver reports that a child cannot or will not eat, consider offering a snack
in clinic, or if weight has dropped significantly, admit and observe. In a com-
parison of 68 children with FTT with 17 referred for FTT and suspected
MCA, increased likelihood of MCA was associated with having 5 or more
multisystem diseases and allergies reported, no confirmed genetic diagnosis,
and parental refusal of services from a multidisciplinary team. Multiple unusual
food allergies led to extremely restrictive diets in MCA patients. Similar to
other studies, mothers of MCA patients endorsed abnormal obstetrics histories
and prematurity in their children. Seventy-six percent of MCA cases in this
study underwent evaluation for mitochondrial disorders [22].

Genetics
Puzzling cases are often referred to Genetics clinic after extensive outpatient
evaluations for nonspecific constellations of symptoms. The features of multi-
system disease: fatigue, pain, weakness, and feeding problems can be observed
in a variety of clinically based diagnoses. In some MCA cases, children have
been diagnosed with disorders only to have complete resolution of symptoms
once the parent is removed from providing care [21].
Mitochondrial disorders
Mitochondrial disorders (as prevalent as 1:5000) [23] are quite variable in their clin-
ical presentations. They can affect nervous and muscular systems with nonspe-
cific symptoms such as pain and weakness. The initial evaluation in blood for
mitochondrial disease may include several laboratory studies as a first step [24].
These studies should be performed under the guidance of a Genetics specialist
with consideration for inpatient admission and multidisciplinary assessment to
directly confirm symptoms that have not been observed in clinic.
Ehlers danlos syndrome-hypermobile type
There are currently 13 subtypes of EDS, the Ehlers danlos syndrome-
hypermobile type (hEDS) subtype is the only one that cannot be confirmed
by genetic testing and remains a clinical diagnosis [24]. Generalized joint hyper-
mobility can be subjective in children. It is important to note that children are
naturally flexible; the Beighton scoring system is not intended as a diagnostic
tool in young children. Not considerations of the diagnosis of hEDS are sleep

disturbance, fatigue, POTS, functional gastrointestinal disorders, dysautono-

mia, anxiety, and depression.
Gynecology
Pediatric patients present to gynecology with abnormal vaginal bleeding or pel-
vic pain.
When caregivers exaggerate the amount of pain or bleeding, excessive, and
potentially harmful tests, studies, and procedures may be performed. Often the
examination, vital signs, and laboratory studies refute the exaggerated history
[25].
Recurrent evaluations for falsely alleged sexual abuse are also considered a
form of MCA.
Hematology
Bleeding was a relatively common presentation in 83 out of 451 (18.4%) MCA
patients [3]. To exclude simulation, if available, test the blood type of the sam-
ple presented by parent and compare it to the patient’s, or send it for DNA
analysis if suspicion is high, and parent shares a common blood type with
the child [7].
Parenteral iron transfusion to treat anemia is second-line therapy, and when
this modality is requested early, this may raise concern for overmedicalization
related to MCA. To prevent unnecessary harm, indications for parenteral iron
therapy should be part of established protocols after an oral iron challenge to
test tolerance has been trialed [26].
Infectious disease
Blood and urine samples can be exogenously contaminated to simulate infec-
tion. Central venous catheters can be directly inoculated. Those scenarios bring
attention to possible MCA when infections are numerous in the same child or
cultures reveal abnormal polymicrobial growth, often from mouth or stool
flora [1,7,27]. Recurrent fevers are difficult to assess, may be falsified in elabo-
rate diaries, and lead to extensive investigations if never verified.
Chronic Lyme disease is a rare condition, without defined criteria, assigned
to patients with prolonged fatigue, chronic pain and otherwise unexplained
symptoms. The diagnosis is not accepted by most scientists. Long-term treat-
ment with antibiotics is strongly discouraged and carries significant risk [28].
Nephrology/urology
The earliest recognized cases of MCA involved children whose mothers simu-
lated hematuria and induced hypernatremia [2]. Almost any abnormality of the
urine or electrolytes can be simulated or induced to feign kidney disease. In one
large review of MCA victims evaluated for renal and urologic manifestations,
25% of MCA victims had urinary symptoms. Almost half reported urinary
tract infections (UTIs). Eight children reported symptoms of falsified hematu-
ria. The majority of falsifications were by untrue histories, and less commonly
by induction or simulation. Eleven children underwent urologic surgery. The
authors provide strategies to investigate potential unique false claims of a

variety of urological and renal problems [7]. Urine samples may be exoge-
nously contaminated with blood, bacteria, egg, or sand. Cultures and sensitiv-
ities may reveal unusual or resistant bacteria, concerning for MCA.
Neurologist/neurosurgery referrals
Neurological manifestations, particularly seizures and apparent life-threatening
events (ALTEs) are common falsifications in MCA cases. Studies estimate that
40% to 50% of MCA cases include some neurologic issues [1,4]. Seizures, ap-
nea, and altered mental status can be the result of historical fiction or induced
through poisoning or asphyxiation [29,30]. Overt video surveillance with video
electroencephalography (EEG) may record induced apnea or seizures. Seizures
more concerning for MCA are those that are atypical or prolonged, have not
been observed by anyone other than the caregiver, are recalcitrant to multiple
antiepileptic drugs, and are also reported in a sibling. Ask the caregiver to share
video recordings of seizures for review. Meadow suggested that it is judicious
for a neurologist to await prescribing long-term antiepileptic drugs until the
seizure has been witnessed by more than one person [29].
ALTEs are thought to be related to child abuse in a small percentage of in-
fants. Brief resolved unexpected events (BRUEs) is new terminology that de-
fines a low-risk ALTE [31]. High risk for intentional suffocation are previous
ALTEs, only the historian witnessed the event, facial blood or bruising present,
or a sibling with ALTEs or sudden infant death syndrome, unexplained death,
often during sleep, of a seemingly healthy baby (SIDS). Among children who
died with MCA, apnea was the most common presenting symptom [4]. Other
neurologic presentations of MCA include ataxia, weakness, chronic headaches,
and vision disturbance. Consider comprehensive drug toxicology panels to
include over-the-counter medications such as diphenhydramine and antiepi-
leptic prescriptions.
Parental requests for brain imaging are common and may uncover an inci-
dental finding such as a small intracranial cyst or Chiari malformation. A
parent eager for surgery to address an incidental finding without an objective
clinical indication is concerning for MCA.
Chiari malformation-I (CM-I) is often an incidental finding on brain or spine
imaging that usually requires no surgical intervention. The classic symptom of
CM-I is a severe transient occipital headache, which is aggravated by certain
positions or maneuvers [32].
Pain clinic
Ideally, a psychological assessment is a requirement for the initiation of man-
agement of chronic pain. Part of the psychological assessment should be a
one-on-one assessment of the child. When the parent impedes or refuses this
individual psychological assessment, red flags for abuse develop. Some pain
conditions reported in MCA cases include amplified musculoskeletal pain,
arthritis, hEDS, fibromyalgia. Red flags include failure of the pain to respond
to typical occupational, physical, and cognitive behavioral therapies or the care-
giver does not adhere to prescribed therapy despite significant dysfunction.

MCA patients seen in pain clinic tend to be younger and have a myriad of addi-
tional unrelated diagnoses [33].
Pulmonary
Asthma is a common childhood illness that relies on clinical history to catego-
rize as mild, moderate, or severe. Consider exaggeration of asthma symptoms
when the child has not been observed on examination or spirometry testing to
have signs congruent with the severity of asthma reported. Failure to give
necessary asthma treatment is another form of MCA intended to make the
asthmatic child’s symptoms worse [6].
Rheumatology
Cases of MCA do not often involve rheumatological diseases but they may pre-
sent with chronic pain syndromes or autoimmune syndromes that are primarily
endorsed by the parent. Pediatric autoimmune neuropsychiatric disorders asso-
ciated with streptococcal infection (PANDAS) may be exaggerated, coached, or
falsified if supporting symptoms only manifest at home. PANDAS have diag-
nostic criteria that include abrupt onset of obsessive-compulsive disorder and
or tic and movement disorder that develops between age 3 and adolescence after
a Group A Streptococcus infection [34]. Pediatric acute-onset neuropsychiatric
syndrome is similar to PANDAS without the requirement for a documented
infection [35]. Fibromyalgia, a form of central sensitization that involves chronic
pain, headaches, and fatigue with psychiatric comorbidities, shares characteristics
that MCA patients exhibit [36]. A study comparing MCA patients with central
sensitization patients noted the former maintained a ‘‘sick identity,’’ tended to be
homeschooled, had a parent with mental health disorder and caregiver with
classic behaviors of MCA [37].

TREATMENT OF MEDICAL CHILD ABUSE

As with other forms of child abuse, if the caretaker cannot acknowledge wrong-
doing, recidivism is high [38]. The parents and the child need therapy. Success-
ful treatment of the parent requires that the abuser acknowledges the abuse,
exhibits empathetic response to the harm caused to her child, and develops
and demonstrates strategies and coping skills for their own mental health is-
sues. Monitoring over a significant period of time is crucial. The partners of
the suspected abusers should also be included in the therapy because they
either actively participated in the abuse or failed to protect their child [39].

TESTIFYING IN COURT
MCA cases may go to family or dependency court and rarely criminal court. An
attorney may try to get the physician witness to say the doctors or hospital sys-
tem abused the child. The parent may endorse that they were following doctor’s
recommendations. The testimony must focus on the harm that came to the child
by way of falsification to the medical team, noting specific discrepancies in what
was reported verbally by the caretaker and what was documented as observed
on examination, imaging, or other findings. In dependency court, where the

decision of whether the child needs to be placed in protective custody is decided,

preponderance of evidence (more likely than not), rather than ‘‘beyond a reason-
able doubt’’ is what is needed to substantiate abuse.

FUTURE DIRECTIONS
Due to numerous encounters by MCA patients at various hospital systems, a
shared database of patients who are at risk for harm from overmedicalization,
similar to the controlled substance utilization review and evaluation system
(CURES) database, to prevent further harm would be useful. Moreover,
specialized training of child protection workers in MCA will improve
investigations.
Consistent nomenclature and billing codes for the purposes of tracking and
studying cases is needed to better understand the magnitude of the issue.
Currently, for billing in the United States, there is no specific international clas-
sification of diseases (ICD)-10 code for suspected or confirmed MCA. There
are billable codes for child abuse but their specifications include physical, sex-
ual, neglect, or psychological. The lack of current clear diagnostic codes, under-
reporting, and changing terminology make MCA difficult to track and study.

CLINICS CARE POINTS

Medical Child Abuse is an underrecognized and underreported form of child

maltreatment.
Multidisciplinary conference and chart alerts may prevent further harm to the child.
Document inconsistencies and concerns in confidential notes.
When a report for suspected MCA is filed with Child Protective Services, descrip-
tion of actual and potential harm is important.

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ADVANCES IN PEDIATRICS

Challenges in Diagnosing and

Treating Myasthenia Gravis in
Infants and Children with Presentation
of Cases
Ornella Bricoune, MDa,b, Bailey Hamner, BSb,
Maria Gieron-Korthals, MDc,*
a
Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL,
USA; bUniversity of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Boule-
vard, Tampa, FL 33612, USA; cPediatric Neurology, University of South Florida Morsani College
of Medicine, Tampa, FL, USA

Keywords
Myasthenia gravis Congenital syndromes Atypical presentation
Genetic testing for congenital myasthenic syndromes
Key points
Myasthenia gravis (MG) in infants and children is a rare neuromuscular disorder
(NMD).
Congenital myasthenic syndromes (CMS) are heterogeneous groups of disorders
and should be included in the differential diagnosis of early-onset NMD.
Genetic testing for CMS is highly recommended to provide treatment, prognosis,
and counseling.
Misdiagnosis or delay in diagnosing MG can occur in young patients who have
atypical features of disease or who have the rare CMS.
Treatment of MG is aimed at controlling symptoms with the acetylcholinesterase
inhibitor, pyridostigmine.

INTRODUCTION
Myasthenia gravis (MG) is a rare neuromuscular disorder (NMD) that is not
commonly seen in children. It impairs synaptic transmission at the neuromuscular

*Corresponding author. 1301 Bruce B. Downs Boulevard, Tampa, FL 33612. E-mail

address: mgieron@usf.edu

https://doi.org/10.1016/j.yapd.2023.03.007
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

junction of skeletal muscles, typically by acquired antibodies directed against the

postsynaptic acetylcholine receptors (AChRs; Fig. 1).
In addition to the more common autoimmune form, there are congenital
myasthenic syndromes (CMS), caused by a genetic defect in some component
of the junction, and transient neonatal myasthenia gravis (TNMG), seen in in-
fants of mothers with MG. MG disorders are often not included in the initial
differential diagnosis of infants and young children presenting with weakness
and hypotonia. We describe 5 cases of MG. Two cases involve teenage girls
with autoimmune MG with atypical clinical features, one of which had gastro-
intestinal symptoms leading to malnutrition. The other 3 are CMS cases with
onset during the neonatal period and early childhood that illustrate clinical and
genetic challenges in establishing diagnosis.
TNMG is acquired when a mother with MG passively transfers AChR anti-
bodies to her fetus across her placenta. Infants with TNMG typically present in
the immediate postnatal period (hours to 3 days of life) with weakness, poor
suck, and hypotonia [1]. Ophthalmoplegia and ptosis are rare manifestations.
The incidence of this condition ranges from 9 to 21 cases per million and affects
10% to 15% of infants born to mothers with MG [1]. The risk and severity of
TNMG are especially high when there is a high ratio of maternal antibodies
directed against the fetal AChR. There have also been case reports of
TNMG caused by anti-muscle-specific kinase (anti-MuSK) antibodies. This

Fig. 1. Stimulation of the nerve terminal triggers the release of acetylcholine (ACh) from pre-
synaptic vesicles into the synaptic cleft. Binding of ACh to its receptor (AChR) at the motor end-
plate depolarizes the cell and causes muscle contraction. In autoimmune MG, AChR
antibodies block acetylcholine from binding, impairing signal transduction, and causing skel-
etal muscle weakness.

condition occurs in about 15% of mothers with MG with a 75% rate of recur-
rence in subsequent pregnancies [2].
Diagnosis of TNMG is typically made based on the history of maternal MG.
If the mother does not have known disease, the diagnosis can be made based
on infant response to an anticholinesterase inhibitor. In this population,
neostigmine methylsulfate (0.15 mg/kg intramuscular or subcutaneous) is
used most commonly.
The management of TNMG is largely supportive. In addition to small
frequent feedings, neostigmine methylsulfate can be given before each feeding
(0.05–0.1 mg/kg intramuscularly or subcutaneously, or 0.5–1 mg/kg orally if
tolerated). This dose can eventually be tapered with clinical improvement.
Most infants recover fully before reaching 2 months of age [2].
The CMS are rare causes of neuromuscular junction failure in infants and
children, with an incidence of about 0.2 per million and a prevalence ranging
from 1 to 9 cases per million. This group of disorders can be caused by genetic
defects in presynaptic, synaptic, basal lamina, and postsynaptic components of
the neuromuscular junction [3].
Children with CMS typically present within the first few years of childhood
with fatigable weakness, affecting mainly their ocular and bulbar muscles but
they may go undiagnosed until much later, with some cases occasionally diag-
nosed in adulthood. When presenting in infancy and early childhood, symp-
toms typically include hypotonia and delay in motor development [4]. Some
phenotypes are more commonly associated with ophthalmoplegia and bulbar
and respiratory muscle weakness, causing life-threatening episodes of apnea.
Infants may also have arthrogryposis multiplex or ptosis at birth. Some pheno-
types can also present later in childhood or adolescence, typically with limb-
girdle weakness and ocular sparing [4–7].
Common types of CMS are listed in Table 1.
Diagnosis is supported by clinical response to acetylcholinesterase inhibitors
and decremental response to repetitive nerve stimulation at low frequency
(2 Hz). Certain mutations require prolonged stimulation with a higher fre-
quency (10 Hz) to induce a response. Genetic testing, either targeted or with

Table 1
Genetic types of congenital myasthenic syndromes
Mutation Effect
AChR subunit genes: CHRNA, CHRNB, Primary AChR deficiency—reduced amount of
CHRND, CHRNE AChR expressed at endplate (most common)
‘‘Slow’’ channel syndrome—abnormally slow
closure of AChR ion channels
‘‘Fast’’ channel syndrome—impaired opening
of AChR ion channels
RASPN Impaired clustering of AChR
COLQ Endplate acetylcholinesterase deficiency
DOK7 Aberrant synaptic mutations and maintenance

whole-exome sequencing, can also help establish the diagnosis, as well as

inform treatment and prognosis [3,7]. Treatment of CMS is largely based on
the suspected syndrome. Usually, the treatment with acetylcholinesterase in-
hibitor alone is not very efficacious and benefits from the addition of 3,4-diami-
nopyridine (3,4-DAP). Other potentially beneficial treatments for weakness
include albuterol and ephedrine [3,7–9]. Slow channel syndromes may respond
to fluoxetine, quinidine, or quinine [3].
Autoimmune MG is an acquired condition characterized by bouts of fatigable
weakness involving variable combinations of ocular, bulbar, respiratory, and
limb muscles with an incidence of 9 to 30 per million and a prevalence ranging
from 100 to 140 per million. It is caused by autoantibodies to the postsynaptic
AChR at the neuromuscular junction [10]. More than 80% of those antibodies
are thought to originate in hyperplastic germinal centers in the thymus. The
antibodies attack the AChR by initially binding and eventually decreasing
the number of receptors expressed over time [11,12]. Some individuals have
antibodies directed against MuSK or lipoprotein-related protein 4 (LRP4),
the agrin-binding receptor of the MuSK complex [13,14]. There is an additional
subset of individuals with seronegative MG who share the electrophysiologic
and clinical findings of patients with seropositive MG but who do not have an-
tibodies against AChR, MuSK, or LRP4. These patients are thought to have
antibodies directed toward other components of the neuromuscular junction
or toward intracellular proteins [15,16].
The age of onset of MG follows a bimodal distribution, with first peak inci-
dence in young adults, especially women aged 20 to 30 years, and second peak
incidence in older adults, especially men aged 60 to 80 years. There are 2 clin-
ical syndromes of MG. The ocular type affects mainly ocular muscles, and the
generalized type is characterized by more extensive weakness affecting not only
ocular but also bulbar, respiratory, and proximal limb muscles [17]. More than
50% of those with the ocular form will develop generalized disease within 2
years. Symptoms can range and fluctuate from transient mild weakness to se-
vere disease requiring hospitalization, ventilator support, and/or tube feedings,
in what is described as a myasthenic crisis. Symptoms are characteristically fati-
gable, and severity tends to worsen as the day progresses. MG symptomatic
progression typically peaks within 2 to 3 years of onset [17]. There are 3 recog-
nized stages of the disease. The first is the active phase, which occurs during the
first 5 to 7 years after onset and is characterized by marked fluctuations with
more severe symptoms. The second is a more stable phase, at which point
symptoms persist and may worsen in the context of toxic-metabolic derange-
ments, infections, and MG medication changes. The third phase is character-
ized by remission, at which time immunotherapy can be slowly tapered [17].
Diagnosis can be established by clinical and laboratory testing, including
serologic (antibody testing) and electrophysiologic studies (eg, repetitive nerve
stimulation and single-fiber electromyography) [10,12]. A bedside ice pack test
is a screening method that is sensitive for screening for MG in patients with
observable ptosis. It is performed by applying a bag of ice on a closed eyelid

for 2 minutes and is considered positive if there is subsequent improvement in

ptosis [18]. All patients should also have imaging of their chest to determine if
there is an underlying thymoma [19]. MG is managed supportively, with die-
tary consistency modifications or tube feeds if dysphagia is present, and venti-
lator support in cases of respiratory failure. Symptomatically, it is managed
with an acetylcholinesterase inhibitor, typically pyridostigmine, with initial
dose for children being 0.5 to 1 mg/kg every 4 to 6 hours. Other therapies
include immunomodulatory therapies for myasthenic crisis (eg, plasma ex-
change and intravenous immune globulin [IVIG]), chronic immunosuppressive
therapies to prevent exacerbations, and thymectomy if abnormal thymic tissue
is identified on imaging [20].

CASE DESCRIPTION
We describe 5 cases of MG. Two cases involve teenage girls with autoimmune
MG with atypical clinical features, one of which had gastrointestinal symptoms
leading to malnutrition. The other 3 are cases of CMS with onset during the
neonatal period and early childhood that illustrate clinical and genetic chal-
lenges in establishing diagnosis.
Patient 1 is a 5-year-old girl who presented at birth with hypotonia and res-
piratory difficulties. Examination was abnormal for micrognathia, flexion con-
tractures at elbows and knees, and hypotonia. Due to dysphagia, she required
gastrostomy tube placement.
Patient 2, who is the younger sister of patient 1, also presented at birth with
hypotonia and respiratory distress. On examination, she was found to have a
weak cry, poor head control, a decreased gag reflex, and dysphagia requiring
nasogastric tube feedings. She was hypotonic with decreased movements of
arms and legs and mild joint contractures.
An extensive workup in both patients, including brain imaging, metabolic
testing for Pompe and Krabbe leukodystrophy, and genetic testing for
muscular dystrophy and spinal muscular atrophy, were all negative. A muscle
biopsy in patient 1 showed nonspecific myopathic changes.
Initial whole exome sequencing (WES) of both patients showed homozygous
variants of uncertain significance (VUS) in the VAMP1 gene, associated with
autosomal dominant VAMP1-related hereditary spastic ataxia. WES of the
mother and father showed they were both silent carriers of the variant. Repeat
WES analysis at a later time, including samples from both patients and their
parents, revealed that both patients were homozygous for a newly classified
pathogenic variant in the VAMP 1 gene, causing autosomal recessive CMS,
while both parents were heterozygous (Table 2). This variant is characterized
by a presynaptic defect that results in impaired acetylcholine release [21]. Both
patients improved on treatment with pyridostigmine, and later, the addition of
3,4-DAP resulted in further clinical benefits and less fluctuation in strength be-
tween pyridostigmine doses.
Patient 3, a 10-year-old boy, presented with slowly progressive limb-girdle
muscle weakness. He had been experiencing fatigue with physical exertion

Table 2
Whole exome sequencing analysis of patient #1, patient #2, and their parents
Gene Variant Zygosity Variant classification
Patient #1 VAMP1 c.340delA Homozygous PATHOGENIC
Patient #2 VAMP1 c.340delA Homozygous PATHOGENIC
Mother VAMP1 c.340delA Heterozygous Carrier
Father VAMP1 c.340delA Heterozygous Carrier

relieved by rest. Examination showed mild weakness in the limb-girdle distri-

bution and fatigue of proximal muscles with repeated muscle contractions. Cra-
nial nerve function was clinically intact. Repetitive nerve stimulation of the
spinal accessory nerve at 3Hz evoked a decremental response, with the ampli-
tude of the fourth evoked compound muscle action potential about 30%
smaller than that of the first. A broad gene panel for NMDs, including a select
number of CMS, was performed on the patient and both parents. The patient
was found to have compound heterozygous mutations in the GFPT1 gene asso-
ciated with CMS [3]. The maternal variant c.331 C > T (p.Arg.111 Cys) was
classified as pathogenic. The paternal variant c.362 T > C (p.ile121Thr) was of
uncertain significance (Table 3). Pyridostigmine was initiated with marked
improvement in his weakness.
Patient 4, a 12-year-old girl with a 4-year history of unexplained progressive
weakness, myalgias, and arthralgias of unclear cause, presented at our acute
care facility with acute respiratory failure 2 days after the onset of a febrile up-
per respiratory illness. Earlier medical records confirmed chronic weakness
prompting her withdrawal from dancing classes, cessation of strenuous phys-
ical activity, and dysphagia resulting in unintentional weight loss. At the time
of her initial outpatient neurological evaluation, an NMD was suspected. Ge-
netic testing revealed a heterozygous pathogenic variant in the PYGM gene
linked to McArdle disease. As no second variant was identified, the diagnosis
of McArdle disease could not be made. MG was not suspected and, therefore,
not included in the workup.
On arrival to the emergency department, she was intubated and placed on
mechanical ventilation due to acute respiratory failure; a nasogastric tube
was also placed. A respiratory viral panel was positive for human rhino/

Table 3
Whole exome sequencing analysis of patient #3 and their parents
Variant
Gene Variant Zygosity classification
Patient #3 GFPT1 c.331C > T (P.Arg111Cys) Heterozygous PATHOGENIC
GFPT1 c.362T > C (P.Ile121Thr) Heterozygous VUS
Mother GFPT1 c.331C > T (P.Arg111Cys) Heterozygous PATHOGENIC
Father GFPT1 c.362T > C (P.Ile121Thr) Heterozygous VUS

enterovirus. Neurologically, she was lethargic but answered questions and fol-
lowed commands appropriately. She was unable to abduct her eyes completely
in either direction and had bilateral ptosis, more prominent on the right. She
had weakness of bilateral eye closure and neck flexion/extension, as well as
proximal muscle weakness in her arms and evident muscle fatigability. An
ice pack test was inconclusive. MG was highly suspected and pyridostigmine
was started with rapid improvement in her strength testing. The AChR binding
antibody test was elevated at greater than 1500 nmol/L. IVIG was started at
2 g/kg during a 5-day course. She showed dramatic improvement with treat-
ment and thus was extubated and started on oral feeds. She was discharged
home soon after.
Patient 5, a 12-year-old girl, presented with malnutrition and dysarthria
with nearly unintelligible speech to our acute care facility. A review of her
medical records revealed a 2-year history of failure to thrive and weight
loss, including 3 hospitalizations and a diagnosis of anorexia by a psychia-
trist. She was admitted for the management of malnutrition and a nasogas-
tric tube was placed. On day 2 of admission, the patient was noted to have
significant hypercapnia and poor inspiratory effort. A neurological examina-
tion revealed bilateral fatigable ptosis and diplopia, moderate-to-severe
dysarthria, dysphagia to both solids and liquids, and proximal muscle
weakness.
A repetitive nerve stimulation study was consistent with a neuromuscular
junction disorder. She was started on pyridostigmine and subsequently
completed a 5-day course of 2g/kg of IVIG and high-dose methylprednisolone,
with significant clinical improvement in all deficits. Serum testing was positive
for anti-MuSK antibodies and a diagnosis of MG was made. At 3 weeks, the
patient had improved respiratory function, skeletal muscle strength, and could
tolerate meals by mouth throughout the day. She was discharged home on pyr-
idostigmine with regular pediatric neurology follow-up visits. Subsequently,
she had 2 more admissions for exacerbation of respiratory symptoms and
dysphagia. She was treated with plasma exchange on both occasions and given
5 treatments with rituximab. Eight months later, she reported increased appe-
tite and energy levels. Her dysarthria had resolved, and she reported feeling the
best that she had in a long time.

DISCUSSION
All 5 cases demonstrate diagnostic challenges as MG was not considered in the
initial differential diagnosis.
Cases 1 to 3 demonstrate that molecular genetic analysis for CMS should
be performed in children with bulbar weakness, skeletal muscle weakness,
hypotonia, and contractures. VUS can complicate the interpretation of ge-
netic analysis, and clinicians should assess the results in the context of famil-
ial or reported phenotypes. Repeating genetic testing at different points in
time is also important because VUS can be reclassified. Patients 1 and 2
had a VAMP1 mutation causing a presynaptic defect at the neuromuscular

junction. These 2 cases highlight the importance of familial phenotypic traits

in identifying CMS. Patient 3 had a GFPT1 mutation causing a protein glyco-
sylation defect of the AChR at the neuromuscular junction [3]. We highly
suspect that the compound mutations are pathogenic in this patient given
phenotype, electrodiagnostic findings, and positive response to pyridostig-
mine treatment.
Patients 4 and 5 illustrate the long journey that may ensue from the initial
presentation to final diagnosis of MG. These cases highlight that child neurol-
ogists must consider MG in the differential diagnosis of progressive muscle
weakness or failure to thrive in infants and children, even in the presence of
atypical features. With patient 4, the mother reported that the child had muscle
and joint pains in the evenings, which skewed the earlier outpatient evaluation
to diagnoses of progressive muscle weakness known to be associated with my-
algias, such as McArdle disease. Another potential confounder in this case was
the lack of clear signs of ocular weakness or fatigability on the initial presenta-
tion. This case highlights that the absence of clear signs of ocular/bulbar
involvement or fatigability in a patient’s history should not exclude MG as a
potential diagnosis. Patient 5 illustrates the importance of considering a neuro-
muscular diagnosis in patients with poor oral intake and weight loss because
these can occur secondary to dysphagia, especially in the context of co-
occurring dysarthria.
Several factors caused challenges in the identification and management of
myasthenic syndromes in these 5 pediatric patients. Consideration of these fac-
tors may enable clinicians to diagnose and treat MG earlier in its course. An
early diagnosis of MG can prevent the disease from reaching the severity of
a myasthenic crisis requiring critical care hospitalization. Furthermore, estab-
lishing a speedy diagnosis can help to prevent physical, psychosocial, and eco-
nomic implications for patients and their families that can be devastating,
especially in the pediatric population. Pediatricians can also make a difference
by referring infants and children with progressive muscle weakness or failure to
thrive to a child neurologist without delay.

SUMMARY
Misdiagnosis or delay in diagnosis of MG can occur in patients with atypical
features of disease or with rare forms of MG such as CMS. This can lead to
the progression of MG and complications including myasthenic crises, multiple
hospitalizations in intensive care units, malnutrition, emotional distress to pa-
tients and their families, and astronomical costs. CMS, in particular, encom-
passes a heterogeneous group of disorders. Thus, genetic testing for CMS is
highly recommended in suspected cases, although often complicated due to
VUS. In such cases, clinicians should assess the results in the context of familial
or reported phenotypes and consider repeating genetic testing at different
points in time because VUS can be reclassified with continuing genetic ad-
vances. Overall, MG disorders should be included in the differential diagnosis
of early-onset NMDs.

CLINICS CARE POINTS

In newborns and young infants with hypotonia, consider congenital myopathies

and neuromuscular junction disorders such as MG.
In older children and adolescents with autoimmune MG, involvement of other sys-
tems may initially overshadow frank neuromuscular symptoms, such as gastroin-
testinal upset ultimately caused by dysphagia, which leads to prolonged
duration of symptoms and worsening outcomes. It is thus crucial to evaluate
such patients for presence of more typical neuromuscular signs/symptoms,
including muscle fatigability.
Consider a genetic NMD panel if in doubt about type of NMD, as congenital
myasthenic syndromes have varying phenotypes and initial testing may be compli-
cated by VUS.
If initial testing reveals VUS, consider repeating genetic testing in the future as ad-
vances continue to be made in diagnosing and treating rare neurological disor-
ders. Additionally, it is our responsibility as physicians to counsel patients and
families on their significance.
In cases of VUS, if the clinical diagnosis of MG is highly suspected based on
phenotype, treatment should still be considered, and the family should be coun-
seled accordingly.

Acknowledgments
The authors would like to acknowledge Jane Carver, Professor at the Univer-
sity of South Florida, Department of Pediatrics, who assisted in editing this
article. The authors would also like to thank doctors Raymond Fernandez
and Racha Khalaf for referring patients to us. Illustration was created by Bailey
Hamner. No conflicts of interest were identified in publishing these case
reports.
Disclosure
The authors have nothing to disclose.
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ADVANCES IN PEDIATRICS

Guillain–Barre Syndrome in
Children and Adolescents
Megan M. Langille, MD
Pediatrics UCLA, 1000 West Carson Street, Box 468, Torrance, CA 90509, USA

Keywords
Pediatric GBS Pediatric AIDP Weakness
Key points
Keep Guillain–Barre syndrome (GBS) diagnosis in mind in a child who is not
bearing weight, especially with other hallmarks of GBS: decreased or absent
deep tendon reflexes, ascending paralysis, and history of a preceding infection.
Symptom onset is progressive over hours to days, most reach maximal symptoms
by 2 weeks, and almost everyone reaches it by 4 weeks.
Small children may have vague symptoms of pain accompanying weakness.
A subset of patients with GBS will suffer respiratory failure, important to assess
respiratory status and treat like a neurologic emergency. If symptoms are rapid in
onset consider intensive care unit admission.
If diagnosis is unclear nerve conduction study testing is often abnormal as early
as 4 days from symptom onset and can help support diagnosis of GBS.

OVERVIEW
Guillain–Barre syndrome (GBS) is the most common cause of acute flaccid pa-
ralysis around the world for people of all ages. It is an immune-mediated dis-
ease of the peripheral nervous system and affects infants and children as well
as adults. The classic presentation of GBS is weakness that is symmetric, pro-
gressive, and ascending. Although commonly starting in the lower extremities,
over time weakness can involve arms and cranial nerves. Deep tendon reflexes
(DTRs) are diminished or absent on presentation. Pain can be a prominent
symptom especially in young children. There are distinct subtypes with vari-
able presentations which can make the diagnosis more difficult, especially in
young children who do not cooperate with a detailed neurologic examination.
Patients with GBS should be monitored closely for evolving weakness which
E-mail address: mlangille@dhs.lacounty.gov

https://doi.org/10.1016/j.yapd.2023.04.001
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

could include bulbar symptoms, respiratory failure, and autonomic dysfunc-

tion. GBS represents a neurologic emergency in a subset of patients.

EPIDEMIOLOGY
GBS affects children and adults of all ages. It is rare in very young children un-
der 2 years of age. Reported incidence ranges in North American studies vary
from 0.81 to 1.91 cases per 100,000. In children (0–15 years), incidence has
been reported at 0.34 to 1.34 cases per 100,000. Unlike most autoimmune con-
ditions, it is more common in men [1]. GBS occurs year-round, but there are
regional variations, and studies suggest in Western countries a peak in winter
versus in China, India, and Latin America where disease peaks in summer [2].

DIAGNOSIS
Diagnosis of GBS is based on clinical examination and history, but laboratory
tests and electrophysiologic examination findings add supporting evidence and
can help rule out other conditions. If a patient presents with typical signs and
symptoms of GBS then treatment should commence without delay. Specialized
testing is particularly helpful with unusual presentations or in different sub-
types of GBS where presentations can vary from the classic clinical scenario.
The National Institute of Neurological Disorders and Stroke (NINDS) devel-
oped diagnostic criteria for GBS. The features required for diagnosis are pro-
gressive bilateral weakness of legs and sometimes arms (which may not be
involved initially), and absent or decreased DTR (Table 1) [3].
Increased protein levels in cerebrospinal fluid (CSF), and electrodiagnostic
features of motor or sensorimotor neuropathy on nerve conduction testing sup-
port GBS diagnosis. Timing of the testing affects interpretation. For example,
CSF protein is most likely to rise 7 days after onset of GBS symptoms, so
normal protein, especially early in someone’s course does not rule out the diag-
nosis. MRI of the lumbar spine can show enhancement of nerve roots which is
not specific for GBS but also can support diagnosis. MRI of the spine helps rule
out other causes of weakness such as compressive or inflammatory lesions [4].

PRESENTATION AND DISEASE COURSE

Classically, GBS presents with acute to subacute symmetric, ascending weak-
ness of the legs. Weakness can progress to involve the arms and/or cranial
nerves. A person may experience paresthesia or sensory loss, also starting in
the legs. Pain can be a prominent symptom, particularly in children, and
may be described as neuropathic, radicular or musculoskeletal. DTRs are ab-
sent in most patients at presentation and almost all by nadir of illness. Motor
symptoms evolve over hours to days with most people reaching maximal
symptoms by 2 weeks [5]. Patients should be monitored carefully for respira-
tory failure. Fifteen percent of children with GBS and 30% of adults will expe-
rience respiratory compromise and require intervention including mechanical
ventilation [6]. The risk of intubation has been associated with decreased
time between symptom onset and hospitalization, facial/oropharyngeal

GBS IN CHILDREN AND ADOLESCENTS

Table 1
Guillain–Barre syndrome diagnostic criteria and considerations

Required for diagnosis Strongly support diagnosis Red flags to consider other diagnosis
Bilateral progressive weakness of legs and Progression to nadir of symptoms over 14 d Marked asymmetry of weakness
arms (may not involve arms initially (days to 4 wk) Bowel/bladder dysfunction
Absent or diminished deep tendon reflexes Symmetric symptoms Sensory level
No other more plausible alternative diagnosis Mild sensory symptoms (relative to motor Ptosis
symptoms) Significant bulbar symptoms
Autonomic dysfunction Descending weakness
Back/limb pain
Increased protein with normal white blood
count (WBC) in cerebrospinal fluid (CSF)
Features of motor/sensorimotor neuropathy
From NINDS criteria.

93
94 LANGILLE

weakness, and greater severity of limb weakness [7]. Also, extremes of age,
those who are youngest, and the elderly are most at risk for complications.
Those with flaccid quadriparesis, rapid progression of weakness, bulbar
involvement, and autonomic dysfunction should be monitored in an intensive
care unit (ICU) [8].
Dysautonomia
Dysautonomia occurs in children with GBS, although it may be underrecog-
nized. In some series, as many as 25% of children have dysautonomia [9].
Symptoms can include instability in blood pressure or heart rate, pupillary
dysfunction, and bowel/bladder dysfunction. Exaggerated drug responses,
gastrointestinal tract dysfunction, cardiac arrhythmias, and hypersecretion
can also occur. Demyelination of the vagus nerve is one hypothesis for dysau-
tonomia symptoms. Also, sympathetic nerves have less myelin, and this could
produce sympathetic overdrive [7].
Atypical presentation
It is important to be aware of atypical GBS presentations. In some instances,
severe or diffuse pain can precede motor symptoms. A common first presenta-
tion in young children less than 6 year of age is nonspecific features such as
irritability, refusal to bear weight, or non-localizable pain. In a child with vague
pain and refusal to walk combined with inability to cooperate with neurologic
examination, a diagnosis of GBS may be delayed [10]. Other rare presentations
are weakness or sensory disturbance that starts proximal or involves the arms
first or all limbs together, these occur in a minority of patients, instead of the
classic distal ascending pattern [4]. Table 2 outlines some differences in GBS
presentation and course in children versus adults.
Disease course and recovery
There are three phases to the illness: (1) progressive, (2) plateau, and (3) recov-
ery. The progressive phase lasts anywhere from days to 4 weeks with most
people reaching the nadir of neurologic function by 2 weeks and 98% by 4
weeks [5]. The plateau phase, where little clinical change occurs, can last
days to months. Recovery phase lasts weeks to months and 80% will recover
completely. Children generally recover well and if there are residual symp-
toms/disability, it is generally mild (Fig. 1).
Triggering events
Many GBS patients have an infection or other potential triggering event before
motor symptoms. In the International GBS Outcome Study, 76% of patients had
a prior infection. In the United States and Europe, the most common infection
was a upper respiratory infection (URI) (35%), whereas gastroenteritis was
more common in Bangladesh (27%) [5]. Infectious causes vary including associ-
ation with Campylobacter jejuni, cytomegalovirus, Epstein–Barr virus, influenza A,
Mycoplasma pneumonia, Haemophilus influenzae, hepatitis A, B, E, Zika virus, and
most recently case reports/case series of COVID 19 (SARS-CoV-2). Most of
the reports involve adults with COVID and GBS. There have been a handful

Table 2
Guillain–Barre syndrome in pediatric versus adult
Pediatric GBS Adult
Examination can be complicated by Pain is less common feature
young age/inability to cooperate Respiratory compromise in up to 30%
Pain can be prominent feature
Outlook improved compared with
adults
Respiratory compromise 15%
Refusal to walk is common
presentation in children under 6 y

of reports of pediatric patients with GBS and COVID [11,12]. In adult case series
of COVID-19 associated GBS, the most common type is Acute Inflammatory
Demyelinating Polyradiculopathy (AIDP) followed by Acute Motor Axonal Neu-
ropathy (AMAN) then Acute Motor Sensory Axonal Neuropathy (AMSAN) [13].
Other potential triggers are rare vaccine complications and treatment with
immune checkpoint inhibitors. Immune checkpoint inhibitors are used to treat
cancer. A GBS-like condition develops rarely, seen in 0.1% of patients with me-
dian onset after three treatment cycles. Management involves stopping the
medication and initiation of steroids. GBS after influenza vaccine varies from
three cases per million to 0 cases. There have also been reports of GBS after
COVID vaccines and some evidence of increased risk over background rate
following administration of Johnson and Johnson adenovirus vector COVID-
19 vaccine. Hanson and colleagues’ reports on GBS cases reported to Vaccine
Adverse Events Reporting System, and all individuals with GBS associated
with COVID-19 were over 12 years of age, the majority being over 18 years

Fig. 1. Phases of GBS. (Courtesy of Alex Truberg.)

of age. Analysis showed no increased risk associated with messenger ribonu-

cleic acid (mRNA) COVID vaccines [14].

VARIANTS
GBS was long considered a single disease caused by immune-mediated attack
of the myelin sheath leading to demyelination and secondary axonal damage of
peripheral nerves. Now three phenotypes are the most common: (1) demyelin-
ating, (2) axonal, and (3) demyelination with axonal involvement. AIDP, the
most common variant in North America and Europe, is demyelinating.
AMAN and AMSAN are axonal. The immune target in both AMAN and AM-
SAN is the axon rather than myelin (Fig. 2). The prevalence of variant varies
greatly by region. See Table 3 for list of more common variants and typical
weakness and sensory involvement [2,4,7].
Miller Fisher syndrome (MFS) is a variant of GBS that presents with paral-
ysis starting in the eyes. MFS is also associated with unsteady gait/ataxia. It is a
sensory ataxia due to the loss of proprioception from damage to sensory
nerves. Although MFS is rare in the United States, it is common in Asia [3].
Technically, patients with MFS do not meet diagnostic criteria for GBS but
are included as a GBS variant because of shared pathophysiologic features.
This is the case with other variants such as pure sensory variant.

PATHOPHYSIOLOGY
Immune targets
GBS can be broken down into two major classifications: demyelinating and
axonal. The pathophysiology of GBS is still not completely understood; how-
ever, the discovery of axonal versus demyelinating types and glycolipid anti-
bodies has enhanced understanding. Immunopathogenesis, response to
treatment and outcome, is different in demyelinating and axonal forms of
the disease. AIDP is a demyelinating form, whereas AMSAN and AMAN
are axonal forms of GBS first recognized in the 1980s.
Animal and postmortem studies in AIDP showed deposition of activated
complement, macrophages, and activated T cells on Schwann cells (these are

Fig. 2. Immune target in both AMAN and AMSAN. (Courtesy of Alex Truberg.)

GBS IN CHILDREN AND ADOLESCENTS

Table 3
Guillain–Barre syndrome variants and associated characteristics
Estimated proportion of
GBS variants GBS cases Region where most common Sensory affects Cranial nerves involved Clinical features
Classic, AIDP 30%–85% Europe/USA Yes Yes
(demyelinating)
AMSAN (axonal) 20% China/South America Yes Yes Clinically like GBS may
have more protracted
recovery
Pure motor AMAN 5%–70% Bangladesh North China No Yes Motor weakness with no
(axonal) sensory signs/symptoms
Pure Sensory <1% Yes No Sensory neuropathy without
other features
Miller Fisher, classic 4%–25% Asia Ataxia Ocular motor nerves Restricted eye movements,
ataxia, areflexia
Abbreviations: AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor and sensory axonal neuropathy.

97
98 LANGILLE

cells that make myelin). These inflammatory cell depositions provide evidence
of an antibody-mediated immune attack. In AMAN, axonal damage is seen
with activated complement deposits on nodal and internodal axolemma.
Antibodies
Gangliosides are glycolipids found in the nervous system, especially at nodes of
Ranvier and motor nerve terminals. Patients with AMAN can have antibodies
to specific gangliosides, namely gangliosidemonosialic acid 1 (GM1) and
GD1a. Molecular mimicry is a theory for the mechanism of inducing autoim-
munity. As an example, C jejuni infection is linked to AMAN. The C jejuni lip-
ooligosaccharide has similarities to the structure of GM1/GD1a gangliosides.
Human immune cells become activated against the C jejuni infection but even
when the infection clears, activated immune cells attack the GM1/GD1a gangli-
osides at the node of Ranvier because of the structural similarity between the
bacterial components and human glycolipids. This attack produces axonal
injury [2].
MFS patients often have antibodies to anti-gangliosides (GQ1b), which can
be found near nodal regions of extraocular motor nerves. Currently, there is
no antibody association with AIDP.
Outcomes
Recovery is different for AMAN/AMSAN versus AIDP. In AIDP, remyelina-
tion is necessary for restoration of function. In AMAN/AMSAN, the severity of
damage from antibody deposition to the axon influences timing and degree of
recovery. Axonal forms of GBS tend to show longer time to recovery and less
recovery than demyelinating forms.

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of GBS can be broad, but when tailored to a patient’s
specific symptoms and clinical history then a narrowed differential and targeted
workup can take place. An overview of the more common disorders on the dif-
ferential can be found in Box 1, and conditions seen in children are highlighted.
Patients with classic GBS symptoms and onset may be easily diagnosed, but it
is important to distinguish GBS from other conditions that are treatable and
have high morbidity, such as spinal cord compression or transverse myelitis.
See Table 4 which outlines typical GBS symptoms versus red flag/concerning
symptoms which should prompt further workup. As abuse of nitrous oxide
(NOS) is on the rise in teens, more cases of subacute combined degeneration
(SACD) and peripheral neuropathy from B12 deficiency are seen in young peo-
ple which can mimic GBS [15]. Acute flaccid myelitis (AFM) due to infection
presents with weakness and areflexia and can be confused with GBS. It is
seen in mainly young children in a biennial pattern [16].
Compression of the spinal cord or transverse myelitis caused by inflamma-
tion or infection can present with increased reflexes and tone; however, early
in the course, reflexes can be diminished. Persistent back pain, asymmetric
weakness or sensory symptoms, a sensory spinal cord level, or sphincter

Box 1: Differential of Guillain–Barre syndrome

Central nervous system (CNS)
Demyelination
ADEM
anti-MOG
NMO
Malignancy
Inflammation
Sjogren’s
Sarcoidosis
Spinal compression
Vitamin Deficiency
Subacute combined degeneration (B12)
Wernicke’s encephalopathy (B1)
Anterior Horn Cell
Acute flaccid myelitis (polio, enterovirus D68)
Peripheral Nerves
CIDP
Tick paralysis
Toxic neuropathy
Vitamin deficiency (B12, B1, E)
Neuromuscular Junction
Myasthenia gravis
Botulism
Muscle
Viral myositis
Inflammatory myositis
Metabolic myopathy
Drug-induced myopathy
Other
Conversion or functional disorder
Abbreviations: ADEM, acute disseminated encephalomyelitis; CIDP, chronic inflammatory demy-
elinating polyneuropathy; MOG, myelin oligodendrocyte glycoprotein antibody-associated disor-
ders; NMO, neuromyelitis optica.

dysfunction should raise concern for spinal cord lesions and, if suspected,
prompt emergency imaging.
SACD of the spinal cord is a finding of B12 deficiency seen more often in the
elderly or those with abnormal gastrointestinal absorption (bariatric surgery).

100
October 06, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Table 4
Guillain–Barre syndrome symptoms versus red flags that should prompt further workup
Raise concern for GBS diagnosis: Red flags that should prompt further workup:
Subacute, progressive, ascending symmetric weakness þ/ Marked asymmetry of weakness
sensory deficits, paresthesia Bowel/bladder dysfunction
Unsteady walking/difficulty with climbing stairs Sensory level
Hyporeflexia or areflexia Ptosis
Autonomic dysfunction: Descending weakness
Rapid heart rate Significant bulbar symptoms
Low/high blood pressure CSF pleocytosis .50 cells/mm3
Leg and back pain that may feel achy, shooting, or cramp-like and may be worse at night
Bulbar symptoms including difficulty with facial movement, speaking, chewing, swallowing,
double vision, or inability to move eyes.
Difficulty breathing

LANGILLE
GBS IN CHILDREN AND ADOLESCENTS 101

Teens and young adults who abuse NOS can have SACD and present with
symptoms of difficulty walking and numbness. The posterior columns of the
spinal cord are especially sensitive to B12 depletion and present with symptoms
of paresthesia of the lower extremities and sensory ataxia evolving over days to
weeks. Imaging of the cervical and thoracic spine will show evidence of damage
restricted to the posterior columns without contrast enhancement. Proper his-
tory, examination, and imaging in combination with a history of NOS abuse
and low or borderline levels of B12 and elevated methylmalonic acid
(MMA) helps distinguish from GBS. AFM with effects to the anterior horn cells
causes a polio-like illness. In recent years, an association of AFM with entero-
virus D68 infection has been described in young children. Although this can
cause bilateral lower extremity weakness and absent reflexes, it is more likely
asymmetric at presentation and more sudden in onset, usually developing over
hours. It is important to distinguish as these patients can have further progres-
sion of weakness and lack treatment options.
Botulism causes weakness in infants from disordered neuromuscular trans-
mission. The bowel becomes colonized by botulinum spores found in food
or soil. Usually, seen in infants less than 1 year of age, GBS is rare in this
group. After infancy, botulism from contamination of food or wounds can
rarely occur. Botulism causes a descending paralysis starting with cranial
nerves. Constipation, dry mouth, and urinary retention can occur in the weeks
before onset of weakness. Quadriparesis and respiratory failure can occur
without prompt treatment.

MANAGEMENT
Monitoring and preventative care
All children with GBS require evaluation of swallowing, respiratory function,
and vital signs to monitor for instability. Bedside swallow testing helps deter-
mine a patient’s aspiration risk. Serial vital capacity testing monitors for im-
pending respiratory compromise. Those with GBS are also at risk of deep
vein thrombosis from prolonged immobility. Patients may experience pain in
the back or legs requiring treatment with non steroidal anti inflammatory
drug (NSAID), gabapentin, pregabalin, or other treatment for neuropathic
pain. Pain may be quite severe. Patients should begin physical therapy as
soon as possible to counteract immobility and improve recovery.

Immunotherapy
The mainstay of treatment is intravenous immunoglobulin (IVIG) and plasma
exchange (PE). In both treatments, the goal is to hasten recovery and reduce
likelihood of mechanical ventilation (or shorten use if patient is already venti-
lated). PE removes antibodies and other inflammatory components. IVIG treat-
ment mechanism is not fully understood, but it may bind pathologic antibodies.
Both treatments seem equally effective. Combining treatments does not have
additive benefits and can lead to increased side effects and higher cost, thus
is discouraged. PE may not be advisable in those with autonomic instability

as the large fluid shifts lead to hypotensive events. IVIG is rarely associated
with liver dysfunction and thromboembolic events; more common side effects
are headache, nausea, myalgia, fever, and hypersensitivity reaction. Steroids
are not effective on their own but combined with IVIG could be beneficial
in the short term, but literature shows no long-term differences in outcome [2].
In children, IVIG is more practical due to ease of administration over PE.
Typical dose of IVIG is 2 g/kg divided over 2 to 5 days. Higher rates of tran-
sient relapses/clinical fluctuations occur with 2-day administration compared
with 5 days [17]. For children already in the plateau phase of illness, treatment
may not be indicated, but many child neurologists still favor treatment, partic-
ularly if the child has significant disability.

PROGNOSIS
Children generally have good long-term outcomes and a better prognosis than
adults. Eighty percent of patients of all ages with GBS regain ability to walk
within 6 months. Death is rare when access to ICU management is available.
Mortality is associated with advanced age, usually caused by cardiovascular or
respiratory complications. These complications occur in both acute and recovery
phases of illness. Long-term residual symptoms can affect quality of life. This in-
cludes neuropathic pain, fatigue, and residual weakness. Roodbol and colleagues
report on long-term complications of childhood GBS with 65% of patients in their
study suffering residual symptoms, namely severe fatigue, pain, or paresthesia of
hands/feet. Thirty-six percent had neurologic deficits on examination [18].
Fatigue is one of the most common residual symptoms after GBS recovery,
reported by 40% to 86% of people [19]. Fatigue is defined as a continual sense
of tiredness not overcome by sleep which affects daily activities and productiv-
ity. Fatigue can have an enormous impact on quality of life and persist years
after GBS recovery of motor function.
During the acute phase of illness, anxiety and delirium symptoms can be
common and associated with increased severity of illness. In a study by Co-
chen and colleagues reporting on a cohort of 139 adult GBS patients with
ICU admission, 70% experienced delusions. In another study looking at
severely affected GBS patients, 82% had anxiety during the initial phase of
illness. Also reported were depression, psychosis, emotional disturbance, and
hopelessness [20].
In GBS patients (including those recovered from motor symptoms), depres-
sion has also been reported at an increased rate compared with control groups.
The presence of depression correlates with anxiety, which is increased in those
with more severe GBS symptoms.
One hundred percent of the children in Roodbol’s study regained ability to
walk within 1 year, even those with high severity during acute illness (vent-
dependent, wheelchair bound). Although children recover well and without se-
vere disability, it is important to monitor for depression and other psycholog-
ical ramifications of GBS. Treatment for residual symptoms such as pain and
fatigue is vital to maximize quality of life and patient well-being.

CLINICS CARE POINTS

Imaging and ancillary testing to rule out differential diagnoses with high morbitity
like spinal cord compression.
Dysautonomia can occur and is an underrecognized feature of GBS.
Recognize and treat long term complication after GBS like fatigue and pain.

DISCLOSURE
The author has nothing to disclose.
References
[1] Sejvar JJ, Baughman AL, Wise M, et al. Population incidence of Guillain-Barre syndrome: a
systematic review and meta-analysis. Neuroepidemiology 2011;36:123–33.
[2] Shahrizaila N, Lehmann H, Kuwabara S. Gillain-barre syndrome. Lancet 2021;397:
1214–28.
[3] Willison HJ, Jacobs BC, van Doorn PA. GBS. Lancet 2019;388:717–27.
[4] Leonhard S, Mandarakas M, Gondim F, et al. Diagnosis and management of GBS in ten
steps. Natl Rev 2019;15:671–83.
[5] Doets AY, Verboon C, va den Berg B, et al. Regional variation of GBS. Brain 2018;141:
2866–77.
[6] Rosser T. Pediatric neurology: a case-based review. Philadelphia: Lippincott Williams & Wil-
kins; 2007. p. p53–8.
[7] Wijdicks E, Klein C. GBS. Mayo Clin Proc 2017;92(3):467–79.
[8] Agrawal S, Peake D, Whitehouse WP. Management of children with GBS. Arch Dis Child
Edu Pract Ed 2007;92(6):161–8.
[9] Karalok Z, Taskin B, Yanginlar Z, et al. GBS in children: subtypes and outcomes. Child’s
Nerv Syst 2018;34:2291–7.
[10] Roodbol J, de Wit M, Walgaard C, et al. Recognizing GBS in preschool children.
Neurology 2011;76:807–10.
[11] Kanou S, Wardeh L, Govindarajan S, et al. GBS associated with COVID infection resolved
without treatment in a child. BMJ Case Rep 2022;15:45–55.
[12] Curtis M, Bhumbra S, Felker M, et al. GBS in a child with COVID 19. Pediatrics
2021;147(4):1–5.
[13] Khan F, Sharma P, Pandey S, et al. COVID-19 associated GBS: postinfectious or neuroinva-
sive too? J Med Virol 2021;93:6045–9.
[14] Hanson K, Goddard K, Lewis N. Incidence of GBS after Covid 19 vaccination. JAMA
2022;5(4):879–92.
[15] Al-Sadawi M, et al. Inhaled Nitrous Oxide ‘Whip-Its!’ Causing Subacute Combined Degen-
eration of Spinal Cord. Am J Med Case Rep 2018;6(12):237–40.
[16] Murphy OC, Pardo CA. Acute flaccid myelitis: a clinical review. Semin Neurol 2020;40(2):
211–8.
[17] Korinthenberg R, Schessl J, Kirschner J, et al. Intravenously administered IG in the treatment
of childhood GBS: a randomized trial. Pediatrics 2005;116:8–14.
[18] Roodbol de, Wit M, Aarsen F, et al. Long-term outcome of GBS in Children. J of peripheral
Nerve Nervous Sys 2014;19:121–6.
[19] Hillyar C, Nibber A. Psychiatric Sequalae of GBS: towards a multidisciplinary team
approach. Cureus 2020;19(12):e7051.
[20] Cochen V, Arnulf I, Demeret S, et al. Vivid dreams, hallucinations, psychosis and REM sleep
in GBS. Brain 2005;128:2535–45.

ADVANCES IN PEDIATRICS

Appendicitis in Children
Lindsay A. Gil, MD, MPHa,
Katherine J. Deans, MD, MHScb,
Peter C. Minneci, MD, MHScc,*
a
Pediatric Surgery Research Fellow, Nationwide Children’s Hospital, The Ohio State University
Wexner Medical Center, 700 Children’s Drive, Columbus, OH 43206, USA; bDepartment of
Surgery, Nemours Children’s Health, Delaware Valley, 1600 Rockland Road, Wilmington, DE
19803, USA; cDivision of Pediatric Surgery, Nationwide Children’s Hospital, The Ohio State
University Wexner Medical Center, 611 East Livingston Avenue, Columbus, OH 43206, USA

Keywords
Pediatric appendicitis Non-operative management Shared decision-making
Key points
Patient history, physical exam, laboratory results, and ultrasound as first-line
diagnostic imaging modality should be considered together to improve diag-
nostic accuracy of pediatric appendicitis.
Treatment options primarily depend on whether the patient has uncomplicated or
complicated appendicitis.
Patient/family shared decision-making should be utilized in the treatment choice
between non-operative and operative management for uncomplicated
appendicitis.

INTRODUCTION
Pediatric appendicitis constitutes a considerable burden of disease in children
and is associated with substantial health care cost and resource utilization.
Research surrounding the diagnosis and management of pediatric appendicitis
has led to continued advancement in practices, development of standardized
evidence-based treatment algorithms, and promotion of patient-centered ap-
proaches to management. This review summarizes the current evidence and
controversies surrounding contemporary approaches to the management of
acute appendicitis in children.

*Corresponding author. E-mail address: Peter.Minneci@nationwidechildrens.org

https://doi.org/10.1016/j.yapd.2023.03.003
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

EPIDEMIOLOGY OF PEDIATRIC APPENDICITIS

Appendicitis is one of the most common surgical conditions in children with an
estimated annual incidence of 83 per 100,000 [1]. In the United States, it is the
fifth most common reason for hospitalization in children. Appendectomy is one
of the most common surgical procedures performed accounting for approxi-
mately 40,000 hospital stays with aggregate costs, totaling $492 million in
2018 [2,3]. Globally, peak incidence occurs in the 15 to 19-year-old age group,
and there has been an overall steady increase in incidence and concurrent
decrease in mortality rate over the last two decades [4].

PATHOPHYSIOLOGY OF PEDIATRIC APPENDICITIS

Although the exact pathogenesis of acute appendicitis remains uncertain, the
most frequently cited etiology entails a pathophysiologic process originating
with luminal obstruction due to stool, lymphoid hyperplasia, or in rare cases,
an appendiceal neoplasm. Luminal obstruction then results in an increase in in-
traluminal pressure, vascular compromise with mucosal ischemia, and bacterial
invasion of the appendiceal wall [5,6]. A number of bacterial, viral, fungal, and
parasitic organisms have been shown to infect the appendix, resulting in a wide
range of specific and non-specific histologic pathologic findings [7]. However,
the exact pathogenesis of inflammation and mechanism of bacterial invasion
into the appendiceal wall remain unknown. Prior studies have also demon-
strated a wide variety of environmental and genetic risk factors associated
with appendicitis including a three-fold greater relative risk in those with a pos-
itive family history [5,6,8].

DIAGNOSIS OF PEDIATRIC APPENDICITIS

Clinical presentation
Children with acute appendicitis commonly present with periumbilical abdom-
inal pain with migration to the right lower quadrant typically within 24 hours
of the onset of symptoms. They also may present with fever, anorexia, nausea,
and vomiting. Signs of localized or generalized peritonitis include involuntary
guarding, rebound tenderness, Rovsing sign (palpation of the left lower quad-
rant elicits right lower quadrant pain), obturator sign (flexion and internal rota-
tion of the right hip elicits pain), and iliopsoas sign (right hip extension elicits
pain) [9–13]. Previous studies have evaluated the accuracy of these signs and
symptoms and have found that the Rovsing, obturator, and iliopsoas signs
have low sensitivity (16%–44%) and high specificity (86–98%) in diagnosing
appendicitis [9–11]. Symptoms also have varying accuracy depending on the
age group. The likelihood of appendicitis in those with a history of focal right
lower quadrant pain, history of migration of pain, and diarrhea is greater for
younger patients (3–6-year-old age group) [11]. A systematic review of 21
studies including 8605 pediatric patients found that migration of pain to the
right lower quadrant and presence of pain with coughing or hopping were
most strongly associated with appendicitis with a positive likelihood ratio of
4.81 and 7.64, respectively [14].

Laboratory tests
There is no known biomarker that is specific for appendicitis. Commonly used
laboratory tests such as white blood cell count (WBC), absolute neutrophil
count (ANC), and c-reactive protein (CRP), are limited in their ability to
discriminate between appendicitis and other inflammatory conditions and
cannot be used in isolation to diagnose appendicitis. Although reported values
for sensitivity and specificity for these tests vary widely [14–17], they have been
shown to be useful in improving diagnostic accuracy when used in combination
with radiographic imaging [18]. A recent retrospective study investigating chil-
dren with suspected appendicitis demonstrated that among children with a non-
diagnostic ultrasound, the combination of having >72 hours of symptoms and
a normal WBC had an NPV of 100% [19]. Lab tests also have been shown to
have time-dependent accuracy with a prospective cohort study demonstrating
that WBC peaked at <24 hours and CRP peaked at 24 to 48 hours of pain for
non-perforated appendicitis, and WBC peaked at 24 to 48 hours and CRP
peaked at >48 hours of pain for perforated appendicitis [20].

Radiographic imaging studies

Ultrasound is the diagnostic imaging modality of choice in children due to its
low cost, lack of need for sedation, and avoidance of radiation [21,22]. Re-
ported sensitivity ranges from 72.5% to 94.8%, and specificity ranges from
95% to 99% [21,23–25]. In a systematic review and meta-analysis, pooled sensi-
tivity and specificity were 89% and 97%, respectively, when performed by
Emergency Medicine physicians and 96% and 97%, respectively, when per-
formed by non-Emergency Medicine physicians [26]. Diagnostic accuracy of ul-
trasound is operator-dependent with previous studies demonstrating lower
accuracy in children with obesity and improved accuracy with specialized pe-
diatric sonographers [23,25,27]. Standardized reporting systems and templates
for radiologists have also been associated with improvement in diagnostic accu-
racy with one study reporting an increase in sensitivity from 66.7% to 92.2%
[28]. Fallon and colleagues developed the Appy-Score where 1 is a normal
completely visualized appendix, 2 is a normal partially visualized appendix, 3
is a non-visualized appendix, 4 is equivocal, 5a is non-perforated appendicitis,
and 5b is perforated appendicitis. In their initial experience with the implemen-
tation of this scoring system, there was no significant improvement in diag-
nostic accuracy, but the rate of computed tomography (CT) imaging after
implementation decreased by 31% [29]. Another study evaluating the imple-
mentation of a standardized reporting system for ultrasound findings similarly
found a decrease in the rate of CT imaging from 44.3% to 9.6% and an annual
cost reduction of $300,527 [30]. Additionally, previous studies have demon-
strated that the implementation of diagnostic algorithms for appendicitis is asso-
ciated with decreased rates of CT imaging [31,32].
Although ultrasound is the first-line diagnostic imaging modality of choice
for appendicitis, CT is still performed in >50% of children with a majority
of CT scans being performed at non-pediatric hospitals [33]. A meta-analysis

comparing ultrasound and CT demonstrated a pooled sensitivity and speci-

ficity of ultrasound of 88% and 94%, respectively, and 94% and 95% for CT
[34]. Despite CT having greater diagnostic accuracy and previous studies
demonstrating that CT imaging can be performed with reduced doses of radi-
ation [35,36], there is no evidence that CT is associated with lower rates of
negative appendectomy [37], and overall sensitivity and specificity for detecting
appendiceal perforation in the absence of a well-formed abscess is reported to
be only 62% and 81%, respectively [38]. CT can be a useful adjunct in the
setting of indeterminate findings or non-visualized appendix on ultrasound
[22,39]. MRI similarly can be a useful adjunct in the setting of a non-
visualized appendix on ultrasound with similar sensitivity and specificity to
CT imaging [40–42]. However, it is not utilized as frequently due to higher
costs, slower acquisition time, the potential need for sedation, and limited avail-
ability [22]. Furthermore, in most children’s hospitals with MRI availability, ul-
trasound is utilized as the first-line diagnostic imaging modality of choice and
MRI is used when results are indeterminate.

Pediatric appendicitis risk scores

Given the limitations of the aforementioned diagnostic testing modalities and
the potential consequences of missed or delayed diagnosis, several composite
risk scores have been developed to help improve the diagnostic accuracy of pe-
diatric appendicitis. The most commonly studied scores include the Alvarado
score, Pediatric Appendicitis Score (PAS), Appendicitis Inflammatory Response
(AIR) score, and the pediatric Appendicitis Risk Calculator (pARC).
The Alvarado score, also known as MANTRELS (Migration, Anorexia-
acetone, Nausea-vomiting, Tenderness in right lower quadrant, Rebound
pain, Elevation of temperature, Leukocytosis, Shift to the left), is a 10-point
clinical scoring system for the diagnosis of acute appendicitis based on clinical
signs and symptoms in patients presenting with abdominal pain. The scoring
system is coupled with recommendations regarding patient disposition
including discharge (score 1–4), observation (score 5–6), or surgical interven-
tion (score 7–10) [43]. It has been validated in a number of different popula-
tions including adults and children [44]. In a systematic review and
meta-analysis, at the cutoff point of 5 for differentiating between discharge
and admission for observation, the Alvarado score had a sensitivity of 0.99
and a specificity of 0.57 in children [45]. A subsequent meta-analysis demon-
strated that in children with pretest probabilities 60%, a score < 4 is associ-
ated with a 3% probability of appendicitis, and thus, can be used to rule out
appendicitis [46].
The PAS is a scoring system ranging from 0 to 10 based on patient history,
physical exam, and laboratory testing including migration of pain, anorexia,
nausea/vomiting, fever >38 C, cough/percussion/hopping tenderness, right
lower quadrant tenderness, leukocytosis >10,000 cells/mm3, and polymorpho-
nuclear neutrophilia >7,500 cells/mm3. In his initial experience with the scoring
system, Samuel found that a score 6 was highly associated with appendicitis

[47]. The PAS was externally validated and found to be useful in ruling out
appendicitis with a score 2 and ruling in appendicitis with a score 7 [48].
The AIR score is an 8-point scoring system developed via weighted ordered
logistic regression analysis involving characteristics of the patient history, phys-
ical exam, and laboratory testing, including vomiting, right lower quadrant
tenderness, rebound tenderness, fever 38.5 C, the proportion of polymorpho-
nuclear leukocytes, WBC, and CRP [49]. The score was recently validated by the
authors in a large prospective study involving 3878 children and adult patients
presenting with <5 days of abdominal pain. The authors found that the AIR
scoring system was more accurate in detecting appendicitis in patients <15 years
of age with a receiver operating curve (ROC) area of 0.87. It performed even
better when detecting complicated appendicitis with an ROC area of 0.93 [50].
The most recently developed scoring system for pediatric appendicitis is the
pediatric Appendicitis Risk Calculator (pARC) which includes age, sex, tem-
perature, nausea/vomiting, pain duration, pain location, pain with walking,
pain migration, guarding, WBC, and ANC. The score ranges from 0% to
100% and stratifies patients across seven clinically actionable risk categories
(<5%, 5%–14%, 15%–24%, 25%–49%, 50%–74%, 75%–84%, and 85%),
each corresponding to a negative appendectomy rate of 8.8%, 7.7%, 6.8%,
5.2%, 5.5%, 2.6%, and 1.2%, respectively. In the authors’ validation sample,
the pARC had an AUC of 0.85, outperforming the PAS which had an AUC
of 0.77 [51]. The pARC was externally validated across 11 community emer-
gency departments in patients 5 to 20.9 years of age who presented with
abdominal pain. In this patient population, the pARC similarly outperformed
the PAS with a ROC curve of 0.89 versus 0.80 [52].
Several comparative studies have investigated differences in diagnostic accu-
racy of the various pediatric appendicitis risk scores [53–55]. Based on these
studies, pediatric appendicitis risk scores do not appear to be sufficient alone
to determine the diagnosis of appendicitis without imaging. The scores can
be valuable tools in clinical algorithms for triaging patients with a higher likeli-
hood of appendicitis to undergo additional workup including imaging to deter-
mine if appendicitis is the cause of the patient’s symptoms.

MANAGEMENT OF PEDIATRIC APPENDICITIS

Management strategies for uncomplicated appendicitis
Uncomplicated acute appendicitis in children can be managed non-operatively
with antibiotics alone or operatively with appendectomy, with laparoscopy be-
ing the preferred approach (Fig. 1). Laparoscopic appendectomy is now the
current standard of care with an average length of stay of 1 day [56,57].
Same-day discharge is possible in many patients with a recent study demon-
strating no differences in rates of readmission or complications between those
undergoing same-day discharge and those discharged on post-operative day 1
or 2 in pediatric patients with uncomplicated appendicitis [58].
Over the last decade, there has been mounting evidence demonstrating that
non-operative management with antibiotics is safe and effective for uncomplicated

Fig. 1. Clinical treatment algorithm for acute appendicitis in children.

acute appendicitis in children (Table 1) [59–75]. Several meta-analyses have re-

ported overall pooled treatment success rates ranging from 60 to 90% and no in-
crease in treatment-associated complications with an initial non-operative
management strategy compared to surgery [76–81]. The most recent meta-
analysis involving 5727 children across 21 studies demonstrated that 8% of pa-
tients had early failure and underwent appendectomy during their initial hospital
stay, and 16% of patients underwent appendectomy after discharge. There was no
statistically significant difference in length of stay between non-operative and oper-
ative management groups across seven studies. Two studies reported total hospi-
tal stay, which included the initial hospital admission and hospital readmission,
and there were still no differences between groups [79]. Huang and colleagues per-
formed a meta-analysis of randomized clinical trials and prospective clinical
controlled trials investigating non-operative management of pediatric appendi-
citis. 404 patients were included across five studies; 168 patients underwent
non-operative management, and pooled analysis demonstrated that 11 (6.5%) pa-
tients had early failure of non-operative management. Of the 157 patients with
early success, 5 (3.2%) patients had late failure, resulting in an overall treatment

APPENDICITIS IN CHILDREN
Table 1
Cohort studies and trials investigating the effectiveness of non-operative management of acute uncomplicated appendicitis in children
Overall
treatment Early treatment Early failure Late failure
Author, year Study design Study population Antibiotics success success NOM NOM
Armstrong Retrospective 12 children <18 years Ciprofloxacin 5/12 10/12 2/12 (16.7%) 5/10
et al [59], review undergoing NOM of þ metronidazole or (41.7%) (83.3%) (50%)
2014 early uncomplicated Ampicillin
acute appendicitis þ gentamycin
þ metronidazole
Caruso Prospective 362 children with Cefotaxime 103/197 115/197 82/197 12/115
et al, case series appendicitis, 197 (52.4%) (58.4%) (41.6%) (10.4%)
2016 undergoing NOM of
uncomplicated
appendicitis
Gorter Multi-institutional 25 patients 7–17 years Amoxicillin/clavulanic 23/25 25/25 0/25 (0.0%) 2/25
et al, prospective of age undergoing acid þ gentamycin (92.0%) (100.0%) (8.0%)
2014 cohort study NOM of uncomplicated
appendicitis
Hartwich Prospective 75 patients 5–18 years of Piperacillin-tazobactam 19/24 21/24 3/24 (12.5%) 2/21
et al [63], nonrandomized age with uncomplicated (79.2%) (87.5%) (9.5%)
2016 controlled trial appendicitis (24 NOM)
Koike Retrospective 130 children 1–15 years Cefoperazone 101/130 125/130 5/130 (3.8%) 24/125
et al [64], review of age undergoing NOM (77.7%) (96.2%) (19.2%)
2014 of uncomplicated
appendicitis
Lee et al [65], Prospective 83 children 3–17 years of Ceftriaxone 26/51 35/51 16/51 9/35
2017 age with uncomplicated þ metronidazole (51.0%) (68.6%) (31.4%) (25.7%)
appendicitis (51 NOM)

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Table 1
(continued )

Overall
treatment Early treatment Early failure Late failure
Author, year Study design Study population Antibiotics success success NOM NOM
Mahida Prospective 14 children 7–17 years of Piperacillin-tazobactam 2/5 (40%) 3/5 (60%) 2/5 (40%) 1/3
et al [67], nonrandomized age with uncomplicated or ciprofloxacin (33.3%)
2016 controlled trial appendicitis (5 NOM) þ metronidazole
Minneci Prospective 102 children 7–17 years Piperacillin-tazobactam 28/37 35/37 2/37 (5.5%) 7/35
et al [68], nonrandomized of age with uncomplicated or ciprofloxacin (75.7%) (94.6%) (20.0%)
2016 controlled trial appendicitis (37 NOM) þ metronidazole
Minneci Prospective 1068 children 7–17 years Piperacillin-tazobactam 245/370 317/370 53/370 72/317
et al [69], nonrandomized of age with uncomplicated or ciprofloxacin (66.2%) (85.7%) (14.3%) (22.7%)
2020 controlled trial appendicitis (370 NOM) þ metronidazole
Mudri Retrospective 52 children 6–17 years of Ceftriaxone 17/26 26/26 0/26 (0.0%) 9/26
et al [70], review age with uncomplicated þ metronidazole (65.4%) (100.0%) (34.6%)
2017 appendicitis (26 NOM)
Perez Otero Randomized 39 children 6–17 years of Piperacillin-tazobactam 14/20 17/20 3/20 3/17
et al [71], controlled trial age with uncomplicated (70.0%) (85.0%) (15.0%) (17.6%)
2022 appendicitis (20 NOM)
Sajjad Randomized 180 children 5–15 years of Meropenem 75/90 85/90 5/90 (5.6%) 10/85
et al., controlled trial age with uncomplicated þ metronidazole (83.3%) (94.4%) (11.8%)

GIL, DEANS, & MINNECI

2021 appendicitis (90 NOM)
Steiner Prospective 45 children 4–15 years of Ceftriaxone 40/45 42/45 3/45 (6.7%) 2/42
et al [72], cohort study age undergoing NOM for þ metronidazole (88.9%) (93.3%) (4.8%)
2015 uncomplicated appendicitis
Steiner Prospective 197 children 4–15 years Ceftriaxone 157/197 187/197 10/197 20/187
et al [73], cohort study of age undergoing NOM þ metronidazole (79.7%) (94.9%) (5.1%) (10.7%)
2017 of uncomplicated
appendicitis
Downloaded for mohamed ahmed (dr.mms2020@gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on
October 06, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

APPENDICITIS IN CHILDREN
Svensson Randomized 55 children 5–15 years of Meropenem 15/24 23/24 1/24 (4.2%) 8/23
et al [74], controlled trial age with uncomplicated þ metronidazole (62%) (95.8%) (34.8%)
2015 appendicitis (24 NOM)
Tanaka Prospective 164 children 6–15 years of Cefmetazole 55/78 77/78 1/78 (1.2%) 22/77
et al [75], nonrandomized age with uncomplicated þ ampicillin (70.5%) (98.7%) (28.6%)
2015 controlled trial appendicitis (78 NOM)

113
114 GIL, DEANS, & MINNECI

success rate of 90.5%. The authors also demonstrated that appendicolith was asso-
ciated with increased risk of treatment failure with a risk ratio of 10.43 (95% CI
1.36–74.26) [78]. Other studies have demonstrated that factors such as rebound
tenderness, muscle guarding, appendiceal diameter >9 mm, intraluminal appen-
diceal fluid, higher pain scores, and longer duration of pain are significantly asso-
ciated with recurrence [64,73,82].
The largest prospective clinical trial investigating non-operative management of
pediatric appendicitis to date includes 1068 children 7 to 17 years of age across 10
tertiary children’s hospitals. Non-operative management consisted of hospital
admission with a minimum of 24 hours of intravenous antibiotics and observation
with subsequent discharge home with oral antibiotics for a total course of 7 days of
therapy. Of the 370 patients who underwent initial non-operative management, 53
(14.3%) patients had early treatment failure and required appendectomy during
their initial hospitalization. Of the 317 patients with early treatment success, 72
(22.7%) had late treatment failure requiring appendectomy. After adjusting for
baseline patient sociodemographic and clinical characteristics, the overall success
rate of non-operative management at 1 year was 67.1%. The authors also
compared disability days between groups and found that non-operative manage-
ment was associated with significantly fewer patient and caregiver disability days
compared to surgery at 30 days and 1 year and higher quality-of-life scores at
30 days [69]. Given the results of this study and the previous evidence demon-
strating the safety and efficacy of non-operative management of pediatric appendi-
citis, many have advocated that the decision surrounding treatment approach
should be the patient/family’s choice and shared decision-making should be the
standard of care [83–90]. Through this approach, patients and their families are em-
powered to make a treatment decision that is aligned with their unique priorities
and values based on the different risks and benefits associated with surgery (ie,
higher disability days, post-operative pain, risk of post-operative complications)
as compared to non-operative management (ie, risk of early treatment failure or
subsequent recurrence) with antibiotics alone.
Operative management of uncomplicated appendicitis is associated with
complication rates ranging from 5% to 15%, including intra-abdominal abscess,
superficial and organ space surgical site infections, small bowel obstruction, and
ileus [91,92]. Given the time-dependent pathophysiology of acute appendicitis
with increasing risk of appendiceal perforation as time passes without interven-
tion, several studies have investigated the association of operative timing and
risk of post-operative complications. One study including 2429 children who
underwent appendectomy within 24 hours of presentation across 29 hospitals
in the National Surgical Quality Improvement Program-Pediatric (NSQIP-Pedi-
atric) database demonstrated that there was no evidence of a significant associ-
ation between timing of operative intervention and post-operative
complications [93]. However, a subsequent study including 18,927 children
who underwent appendectomy within 24 hours of presentation found that pa-
tients who underwent appendectomy 16 to 24 hours after presentation were
more likely to have operative findings of complicated appendicitis, higher rates

of post-operative percutaneous drain placement, increased use of post-operative

total parenteral nutrition (TPN), and increased length of stay compared to
those who underwent appendectomy within 16 hours of presentation. There
were no significant differences in the rates of organ space surgical site infections
or readmissions between groups [94]. An additional study across 16 NSQIP-
Pediatric hospitals demonstrated that institutions in the longest quartile of
time to appendectomy had significantly longer lengths of stay and higher
average total costs compared to institutions in the shortest quartile of time to
appendectomy [95]. Given the results of the aforementioned studies, when pa-
tients/families decide to pursue operative management, while immediate appen-
dectomy confers no benefit, appendectomy should be performed within
16 hours of presentation to minimize complications associated with appendiceal
perforation and its associated increase in health care resource utilization.

Management strategies for complicated appendicitis

Complicated appendicitis can be defined as appendicitis with either a grossly
identifiable hole in the appendix, a fecalith in the abdomen, or the presence
of a well-formed abscess or frank pus in the abdomen. [96]. Complicated
appendicitis is observed in about 30% of hospital admissions for appendicitis
[97], and is associated with overall worse outcomes and an increase in resource
utilization with a three-fold increase in length of stay and 50% increase in total
cost [98–100]. Complicated appendicitis can be managed in one of three ways:
antibiotics alone, antibiotics and subsequent interval appendectomy, and early
appendectomy at the time of initial presentation (see Fig. 1). Management with
antibiotics alone remains controversial as the risk of incidental significant path-
ologic findings and risk of recurrence remain uncertain. With regard to the risk
of pathologic findings, a recent study investigating histopathologic findings in
149 children who underwent interval appendectomy 6 to 8 weeks after initial
presentation found no neoplasms were identified, however, all children had ev-
idence of persistent inflammation on histopathology [101]. Pooled results from
a systematic review and meta-analysis demonstrated the incidence of carcinoid
tumor was low at 0.9% [102]. With regard to the risk of recurrence, if interval
appendectomy is not performed, the same meta-analysis revealed that the inci-
dence of recurrence ranged from 0% to 42% with an overall pooled risk of
20.5%. However, there was an overall lack of rigorous studies comparing an-
tibiotics alone and antibiotics with interval appendectomy [102]. Based on
the available data, a shared decision-making process with the patient and their
caregiver about interval appendectomy should be performed that allows them
to evaluate the risks and benefits of interval appendectomy versus the approx-
imately 20% risk of developing recurrent appendicitis.
There is also a paucity of rigorous prospective data comparing the effectiveness
of antibiotics with subsequent interval appendectomy and early appendectomy
at the time of initial presentation. Previous studies report heterogeneous results
[103–107], likely due to the wide variety of characteristics and range of disease
severity in the presentation of complicated appendicitis. Overall, complicated

appendicitis can be categorized into two groups: perforation without abscess/

phlegmon and perforation with abscess/phlegmon. A recent systematic review
and meta-analysis investigated the non-operative management of complicated
pediatric appendicitis and specifically stratified the results by disease category
(presence of abscess/phlegmon vs no abscess or phlegmon [‘‘free perforated’’])
[108]. A total of 1288 patients across 14 studies were included in the analysis.
The authors found that the relative risk (RR) of complications in those with ab-
scess/phlegmon undergoing initial non-operative management (NOM) versus
early appendectomy was 0.7. Conversely, the RR of complications in those
with free perforated appendicitis undergoing initial NOM versus early appendec-
tomy was 1.56. Similarly, readmission rates were favorable to initial NOM in the
abscess/phlegmon group (RR 0.35) and favorable to surgery in the free perfo-
rated appendicitis group (RR 1.49). The overall pooled success rate of the initial
NOM was 90%. With regard to cost, there were no significant differences be-
tween initial NOM versus surgery. The authors concluded that children present-
ing with complicated appendicitis with abscess/phlegmon have better outcomes
with initial NOM and interval appendectomy whereas those presenting with
free perforation without abscess/phlegmon have better outcomes with early ap-
pendectomy during initial hospitalization [108].

SUMMARY
The management of pediatric appendicitis continues to advance with the devel-
opment of evidence-based treatment algorithms and a recent shift toward
patient-centered treatment approaches. The available evidence can be used to
develop standardized institution-specific diagnostic and treatment algorithms
based on available resources (eg, use of scoring system to triage to imaging;
choice of secondary imaging modality after ultrasound) to decrease rates of
missed diagnosis and appendiceal perforation, and to promote patient-
centered care that can minimize disability, complications, and health care
resource utilization.

CLINICS CARE POINTS

Ultrasound is the diagnostic imaging modality of choice in children and should be

performed to diagnosis and differentiate between uncomplicated and complicated
appendicitis.
Non-operative management of uncomplicated pediatric appendicitis is safe and
effective with reported overall treatment success rates ranging from 40% to 92%.
Complicated appendicitis with abscess or phlegmon should be managed with an-
tibiotics with or without interval appendectomy, while early appendectomy is indi-
cated in the absence of abscess or phlegmon.
For complicated appendicitis, early appendectomy is indicated in the absence of
abscess/phlegmon, while non-operative management is more appropriate if
phlegmon or abscess is present.

DISCLOSURE
The authors have nothing to disclose.

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ADVANCES IN PEDIATRICS

Surgery for Thyroid Disease in

Children
Steven W. Bruch, MD, MSc
University of Michigan, C.S. Mott Children’s Hospital, 1540 East Hospital Drive, Ann Arbor, MI
48109, USA

Keywords
Thyroid Multiple endocrine neoplasia Graves’ disease Thyroid cancer
Key points
Multiple Endocrine Neoplasia type 2 patients require a prophylactic thyroidec-
tomy early in life.
Graves’ disease in childhood may be treated with radioactive iodine ablation or
a total thyroidectomy after proper medical preparation.
Thyroid nodules require evaluation with ultrasound and fine needle aspiration.
The Bethesda classification results of the fine needle aspiration drive the extent of
the thyroidectomy.

C
hildren with thyroid disease require surgery in three situations: prophy-
lactic thyroidectomy for Multiple Endocrine Neoplasia (MEN) type 2,
total thyroidectomy for Graves’ Disease, and thyroid lobectomy or to-
tal thyroidectomy for nodular thyroid disease.

MEN 2
Children with MEN 2 develop abnormalities of the thyroid, parathyroid, and
adrenal glands based on the specific mutations of the RET protooncogene. All
these children will develop medullary thyroid cancer (MTC) and therefore
require an elective prophylactic total thyroidectomy. The timing of this proced-
ure depends on the abnormal codons in the RET protooncogene which in turn
determine the specific phenotype of the MEN 2 syndrome: MEN 2A (medul-
lary thyroid cancer pheochromocytoma and hyperparathyroidism) and MEN
2B (medullary thyroid cancer pheochromocytoma and ganglioneuromas of the

E-mail address: sbruch@umich.edu

https://doi.org/10.1016/j.yapd.2023.04.005
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

aerodigestive tract.) Tables 1 and 2 depicts the distribution of abnormalities based

on the codons involved.
Most children with MEN 2 syndrome are part of an affected family and,
therefore, are diagnosed by genetic screening that should be done prenatally
or shortly after birth. Occasionally, a child will be unexpectedly diagnosed
with MTC after a nodule undergoes an FNA. If this occurs the child should
have genetic screening, and if a RET mutation is identified, the first-degree rel-
atives should also be screened for MEN 2. These children are usually old
enough to require screening for a pheochromocytoma prior to any thyroid
operation. If a pheochromocytoma is identified, it should be removed prior
to the thyroid surgical procedure.
Children with known MEN 2 syndrome will all develop MTC and should
undergo thyroidectomy. The timing of the thyroidectomy is based on the age
of onset of MTC which differs according to the specific RET mutation. The
American Thyroid Association (ATA) has classified children with MEN 2
into three risk categories for developing medullary thyroid cancer depending
on the RET mutation [1]:
Highest risk (MTC may present prior to a year of age)– codon 918–should have a
total thyroidectomy in the first year of life. The ATA recommendation includes
a central neck dissection if there are suspicious nodes. If there are no suspicious
nodes a central neck dissection should be performed only if the parathyroid
glands can be identified and protected in situ or by autotransplantation.
High risk–codons 883 and 634–should have a total thyroidectomy at age 5 or
earlier based on calcitonin levels. These high-risk children should be screened

Table 1
Summary of RET mutations in the MEN 2 syndrome and their medullary thyroid cancer risk
category, and the chance of developing a pheochromocytoma or hyperparathyroidism
Medullary
thyroid MEN
RET mutation cancer risk syndrome Pheochromocytoma Hyperparathyroidism
G533 C Moderate 2A 10% -
C609 F/G/R/s/Y Moderate 2A 10%–30% 10%
C611 F/G/s/y/W Moderate 2A 10%–30% 10%
C618 F/R/s Moderate 2A 10%–30% 10%
C620 F/R/s Moderate 2A 10%–30% 10%
C630 R/y Moderate 2A 10%–30% 10%
D631Y Moderate 2A 50% -
C634 F/G/R/s/W/y High 2A 50% 20%–30%
K666 E Moderate 2A 10% -
E768D Moderate 2A - -
L790 F Moderate 2A 10% -
V804 L/M Moderate 2A 10% 10%
A883 F High 2B 50% -
S891 A Moderate 2A 10% 10%
R912P Moderate 2A - -
M918 T Highest 2B 50% -

Table 2
MEN2 syndrome phenotype distribution and associated codons
MEN2
95% MEN2A 5% MEN2B
95% codon mutation 609, 611, 618, 95% codon mutation 918
620, 634
5% codon mutation 533, 630, 631, 666, 5% codon mutation 804, 883
768, 790, 804, 891, 912
Codon 804 has been reported in both MEN2A and MEN2B.

with an annual physical examination, a neck ultrasound, and serum calcitonin

beginning at age 3. The total thyroidectomy should be accompanied by a cen-
tral neck dissection if the calcitonin level is above 40 pg/mL or if there is evi-
dence on pre-operative imaging of lymph node metastasis.
Moderate risk–all other codon mutations–screening should begin at age 5 and the
timing of the total thyroidectomy should be based on calcitonin levels. If the fam-
ily is not interested in long-term monitoring, the thyroid should be removed at
age 5.

GRAVE’S DISEASE
Graves’ disease, an autoimmune disease resulting in stimulation of TSH recep-
tors, causes hyperthyroidism. Treatment usually begins with anti-thyroid medi-
cation, methimazole in children, with the addition of a beta-blocker if
necessary. Due to frequent side-effects, the use of methimazole is limited. Defin-
itive therapy, which consists of radioactive iodine ablation or total thyroidec-
tomy, can be initiated at any time, but usually no later than 2 years after
diagnosis if remission has not occurred. Remission, defined as remaining euthy-
roid after stopping anti-thyroid medication for 1 year, occurs in 20%-30% of
children. These two modalities are equally effective with few side effects thus
leaving the choice to the family. Surgical treatment is favored in young children
(<5 years) and those with large gland size or Graves’ orbitopathy. In children
with moderate to severe Graves’ orbitopathy, the exophthalmos remains stable
in 60% and improves in 40% following total thyroidectomy [2].

NODULAR THYROID DISEASE

Nodular thyroid disease occurs less frequently in children compared to adults.
However, the risk of an individual nodule harboring a differentiated thyroid
cancer is greater in a child compared to an adult. Each thyroid nodule should
be evaluated with the goal of giving the family a reasonable estimate of the like-
lihood of thyroid cancer in the nodule. Factors that increase the risk of a nodule
being cancerous include a family history of a differentiated thyroid cancer in
first degree relatives and a history of ionizing radiation to the neck. This
ionizing radiation can originate from treatment of other cancers or from the
environment due to events such as radiation exposure.

Physical findings of lateral neck lymph nodes or a paralyzed vocal cord on

physical exam increase the risk of a nodule being malignant. The central
compartment neck lymph nodes (Level 6), where thyroid cancer often metas-
tasizes first, are difficult to palpate or visualize by ultrasound pre-operatively.
However, the lateral neck lymph nodes (Levels 1–5) are more easily palpated
and identified with ultrasound. If an abnormal lymph node is identified, it
should undergo a fine needle aspiration (FNA) with a thyroglobulin wash.
If the FNA reveals thyroid cancer, or the thyroglobulin is elevated, a modified
radical neck dissection should be added to the initial thyroid surgery. Chil-
dren who develop a voice change in the period during the discovery of a thy-
roid nodule should have their vocal cords evaluated to ensure proper motion.
This can be done with direct or indirect laryngoscopy, or by ultrasound ex-
amination of the vocal cords. Many thyroid surgeons will evaluate the vocal
cord motion of all children who require thyroid surgery, while others do so
selectively. In the event of a thyroid cancer invading or encasing the recur-
rent laryngeal nerve, it is helpful to know the function of the nerve preoper-
atively. This will assist in the intra-operative decision to sacrifice the nerve or
leave tumor in place to be addressed by post operative radioactive iodine
therapy.
The most important laboratory assessment includes the Thyroid Stimulating
Hormone (TSH) level. If the TSH is low, suggesting that the child is hyperthy-
roid, a diagnostic radioactive iodine scan should be performed to differentiate a
hyperfunctioning nodule from a diffuse hyperthyroid process. If the area of hy-
perfunction on the RAI scan correlates with the location of the nodule in ques-
tion, then the hyperfunctioning thyroid nodule should be removed with a
thyroid lobectomy.
Ultrasound is the imaging modality of choice to evaluate thyroid nodules.
Several risk stratification systems including the American College of Radiology
Thyroid Imaging Reporting and Data System (ACR-TIRADS) and the Amer-
ican Thyroid Association guidance exist and have been verified in the adult
population. However, their use in stratifying childhood thyroid nodules is
currently in evolution. Both systems incorporate the nodule’s echogenicity,
margins, shape, and echogenic foci to determine the radiologic risk of the
nodule and to help determine if an FNA should be performed. Nodules at
high risk for cancer are hypoechoic compared to the normal thyroid gland,
have irregular margins or extrathyroidal extension, are taller than wide, and
have punctate calcifications. FNA ultimately stratifies the risk of cancer in thy-
roid nodules. All thyroid nodules greater than 1 cm in largest diameter on ul-
trasound should have an FNA biopsy in children. Nodules smaller than 1 cm
may require biopsy if risk factors are noted on history or physical exam or the
nodule displays high-risk ultrasound features. The Bethesda Classification dis-
criminates the cytopathologic risk of cancer into one of 6 categories (Table 3).
Compared to adults, the risk of cancer in Bethesda classes III–V are higher
in children. The clinical approach is dictated by the classification as follows:
Bethesda Class I nondiagnostic result: repeat FNA after 3 months.

Table 3
Bethesda classification of fine needle aspiration results in children with the risk of developing
differentiated thyroid cancer in each group

Bethesda classification Nomencalture Risk of cancer in children

I Nondiagnostic
II Benign 3%–5%
III Atypia or Follicular lesion of Up to 28%
undetermined significance
IV Follicular neoplasm/Hurthle Up to 58%
Cell neoplasm
V Suggestive of Malignancy 70%–85%
VI Malignant 99%

Bethesda Class II benign result: continued follow up and re-biopsy with in-
crease in size of the nodule or development of worrisome ultrasound features.
Bethesday Class III-IV: thyroid lobectomy.
Bethesda Class V: lobectomy alone, a lobectomy with frozen section, or a
total thyroidectomy after discussion with the family.
Bethesday Class VI malignant: total thyroidectomy with a strong recommen-
dation for a central neck lymph node dissection depending on the surgeon’s
comfort level and experience with central neck dissections [3].

OPERATIVE APPROACH
Both thyroid lobectomy and total thyroidectomy patients arrive at the hospital on
the day of the operation. The children are anesthetized and, if recurrent laryngeal
nerve monitoring is utilized, a Neural Integrity Monitor-Electromyogram (NIM-
EMG) endotracheal tube is positioned between the vocal cords. Optimal patient
positioning requires neck extension provided by a bump under the scapula, proper
padding of the occiput, and the upper half of the operating table elevated to 45 to
decrease venous pressure. No perioperative antibiotics are required. A curved inci-
sion hidden in the lower neck skin lines provides adequate exposure. After dividing
the platysma muscle, flaps are created superiorly to the thyroid cartilage, laterally,
and inferiorly to the sternal notch. The strap muscles (sternohyoid and sternothy-
roid) are separated in the midline. The Vagus nerve is identified in the carotid
sheath and stimulated to ensure the nerve monitoring system is functioning prop-
erly. Lateral retraction of the strap muscles exposes the thyroid gland. Blood ves-
sels leading to the thyroid gland require division while avoiding injury to the
superior laryngeal nerve, the inferior and superior parathyroid glands, and the
recurrent laryngeal nerve (Fig. 1). Berry’s ligament attaches the medial portion
of the thyroid lobe to the trachea and must be divided to release the thyroid.
The isthmus is elevated over the trachea to the opposite lobe and removed to com-
plete the lobectomy, whereas a total thyroidectomy would involve dissection of the
opposite lobe as described above. If using nerve monitoring, the Vagus nerve
should be stimulated to ensure the recurrent laryngeal nerve is intact at the end
of a lobectomy and before moving on to the subsequent side if removing the entire

Fig. 1. Relationship of superior and inferior parathyroid glands to the recurrent laryngeal
nerve. (Source: Sabine Hombach-Klonisch, Thomas Klonisch and Jason Peeler. Sobotta Clin-
ical Atlas of Human Anatomy, 11, 517-551, Figure 11.62, Elsevier; 2019.)

thyroid. Following completion of the thyroidectomy meticulous hemostasis should

be obtained. The strap muscles are brought together in the midline leaving a
generous opening inferiorly for blood to escape into the superficial layers in case
a postoperative hematoma occurs. The platysma muscles, subcutaneous layer,
and skin are then closed. Most children spend the night in the hospital to monitor
for bleeding issues and symptoms of hypocalcemia in those requiring a total thyroi-
dectomy.Some may be discharged the day of surgery depending on the surgeon’s
comfort.

Postoperative complications
There are three major complications that are associated with thyroid operations:
post-operative hemorrhage, hypocalcemia, and recurrent laryngeal nerve injury.
1. Bleeding resulting in a post operative neck hematoma occurs in less than 1% of
cases and is avoided by obtaining meticulous hemostasis during the operation.
Postoperative bleeding may result in a neck hematoma with neck swelling, dif-
ficulty breathing, and a feeling of impending doom. This complication requires
immediate action to relieve the pressure on the airway. The wound should be
opened, including the strap muscles in the midline, to allow the hematoma to
extrude. An instrument tray is often sent with the patient from the operating room
to the floor so that no time is lost in opening the wound if it becomes necessary.
2. Hypocalcemia occurs due to devascularization or removal of parathyroid glands.
This rarely occurs with a thyroid lobectomy but is relatively common (up to 30%)
after a total thyroidectomy, especially if a central neck lymph node dissection is
included. Perioral and fingertip numbness and tingling along with a positive

Chvostek’s and/or Trousseau’s sign on physical exam suggest hypocalcemia.

There are three strategies employed to detect and correct hypocalcemia: routine
supplementation of all children after total thyroidectomy, supplementation after
symptoms arise, or 4-h parathyroid hormone levels and supplementation based
on these labs. Most of the hypocalcemic events can be controlled with oral cal-
cium with or without calcitriol supplementation, but on occasion very low calcium
levels require intravenous calcium supplementation. Permanent hypocalcemia is
a rare event occurring in 1% to 4% of children and will require lifetime calcium
and calcitriol replacement. Meticulous dissection and knowledge of the location
of parathyroid glands mostly prevents this complication. In 20% to 24% of total
thyroidectomies performed in children, an inadvertently removed parathyroid
gland is noted in the specimen. These are occasionally located inside the pa-
renchyma of the thyroid gland and removal is unavoidable. If a compromised
parathyroid gland is identified during the operation, the parathyroid gland
should be auto transplanted after biopsy confirmation by reimplanting the
parathyroid tissue into a pocket made in the muscle bed of the sternocleido-
mastoid or a forearm muscle [4].
3. Recurrent laryngeal nerve injury occurs rarely in about 1% to 2% of cases. Again,
meticulous dissection with or without the assistance of recurrent laryngeal nerve
monitoring avoids this complication. If the recurrent laryngeal nerve appears to be
damaged after the first side of a total thyroidectomy, strong consideration should
be made for stopping the operation, evaluating the vocal cord mobility post-
operatively, and waiting to remove the other side depending on pathology results
and the status of the vocal cords. If a nerve transection is recognized during the
dissection, repair with fine suture and the aid of an operative microscope can be
attempted. If this is not available, or not technically feasible, a delayed repair with
use of the Ansa Cervicalis as a nerve graft can be attempted.

POSTOPERATIVE CARE
All patients who have had a total thyroidectomy will require thyroid hormone
replacement with levothyroxine. The vast majority of children who undergo a
thyroid lobectomy will not require hormone supplementation as long as their
remaining lobe is normal.
Following total thyroidectomy for differentiated thyroid cancer, most children
will require radioactive iodine ablation depending on the size and pathologic fea-
tures of the thyroid cancer. For example, RAI may not be required in a small, uni-
focal thyroid cancer with no capsular invasion, lympho-vascular invasion,
extrathyroidal extension, and no positive lymph nodes. RAI is usually performed
6 to 8 weeks after the thyroidectomy after children are placed on a low iodine diet
and taken off their thyroid replacement to make them ‘‘iodine hungry.’’ Ideally,
radioactive iodine ablation selectively removes the remainder of the thyroid tissue
present after surgery. Children are then followed to look for cancer recurrence at 6-
month intervals with physical exam, ultrasound exam of the neck, TSH levels, and
a measure of thyroglobulin. The levothyroxine dose is kept artificially high to
lower the TSH to the 0.01 to 0.05 mIU/L range (normal being 0.1 mIU/L) to sup-
press any residual thyroid tissue. If the physical exam or ultrasound notes a

suspicious mass a fine needle aspiration with a thyroglobulin wash is performed. If

the thyroglobulin level is elevated with no other findings, a radioactive iodine scan
can be used to localize the source of the thyroglobulin. Recurrent or residual dis-
ease is treated with surgery if possible, including excision of any residual thyroid
bed disease and central compartment or modified radical neck dissection for lymph
node involvement. If disease is not amenable to surgical removal, or if there is
distant metastatic disease, radioactive iodine ablation should be considered.
Although thyroid nodules occur uncommonly in children, there is a higher
risk of malignancy in a nodule found in a child compared to an adult. While
only 5% to 10% of adult nodules develop into thyroid cancer, up to 22% to
26% of nodules in children harbor thyroid malignancy. Children often have
more disease extension outside the thyroid gland at diagnosis with more
regional lymph node involvement and more pulmonary metastasis compared
to adults after controlling for tumor size and pathologic classification. Despite
presenting with more extensive disease, mortality from thyroid cancer in chil-
dren is < 2% which is much lower compared to adults [3].

CLINICS CARE POINTS

MEN 2 patients develop medullary thyriod cancer at different ages depending on the
abnormal codon. The specific codon thus drives the timing of total thyroidectomy.
Total thyroidectomy or radioactive iodine ablation treats childhood Grave’s Dis-
ease difinitively depending on patient characteristices and patient and parent pref-
erences. Proper medical preparation allows for safe thyroidectomy surgery.
Use of the Bethesda classification of fine needle aspiration samples of thyroid nod-
ules completes the work up of thyroid nodules in children. The Bethesda classifica-
tion then determines the extent of thyroid surgery which is requires with any
outcome other than a benign Bethesda classification.

DISCLOSURE
The author has no commercial or financial conflicts of interest. The author has
no funding sources.
References
[1] Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the
Management of Medullary Thyroid Carcinoma. The American Thyroid Association Guide-
lines Task Force on Medullary Thyroid Carcinoma. Thyroid 2015;25:567–610.
[2] Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association. Guidelines for
Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thy-
roid 2016;26:1343–421.
[3] Francis GL, Waguespack SG, Bauer AJ, et al. Management Guidelines for Children with Thy-
roid Nodules and Differentiated Thyroid Cancer. The American Thyroid Association. Guide-
lines Task Force on Pediatric Thyroid Cancer. Thyroid 2015;25:716–59.
[4] Bruch SW. Thyroidectomy in Children. In: Davenport M, Geiger JD, editors. Operative pedi-
atric surgery. 8th edition. Boca Ratan, FL: CRC Press; 2020. p. 583–7.

ADVANCES IN PEDIATRICS

Lower Urinary Tract Obstruction

in Newborns
Jaime Flores-Torres, MDa,*, Amarilis Sanchez-Valle, MDb,
Jose R. Duncan, MDc, Valerie Panzarino, MDd,
Jessica Marie Rodriguez, MDe,f, Russell S. Kirby, PhD, MSg
a
Division of Neonatology, Department of Pediatrics, Morsani College of Medicine, University of
South Florida, Tampa General Hospital, 5 Tampa General Circle HMT 4th Floor, Suite 450,
Tampa, FL 33606, USA; bDivision of Genetics and Metabolism, Department of Pediatrics, Morsani
College of Medicine, University of South Florida, Tampa General Hospital, 2 Tampa General
Circle, Tampa, FL 33606, USA; cDivision of Maternal-Fetal Medicine, Department of Obstetrics
and Gynecology, Morsani College of Medicine, University of South Florida, Tampa General
Hospital, 2 Tampa General Circle, Tampa, FL 33606, USA; dDivision of Pediatric Nephrology,
Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa
General Hospital, 2 Tampa General Circle, Tampa, FL 33606, USA; eDivision of Pediatric
Nephrology, Department of Pediatrics, Morsani College of Medicine, University of South Florida,
Tampa General Hospital, Tampa, FL, USA; fJohns Hopkins All Children’s Hospital, St. Joseph’s
Hospital, 601 5th Street South, Suite 304,Street, Petersburg, FL 33701, USA; gChiles Center,
College of Public Health, University of South Florida, 13201 Bruce B Downs Boulevard, MDC56,
Tampa, FL 33612, USA

Keywords
Lower urinary tract obstruction Posterior urethral valves Urethral atresia
Prune belly syndrome Pulmonary hypoplasia End-stage renal disease
Key points
Lower urinary tract obstruction is one of the most common causes of congenital
abnormalities of the renal tract with a prevalence of one in 5,000 and one in
25,000 pregnancies.
Lower urinary tract obstruction is a significant cause of morbidity and mortality in
newborns, causing significant end-stage renal disease and pulmonary hypo-
plasia, both of which can lead to devastating long-term health effects in affected
infants.
Continued

*Corresponding author. E-mail address: jflorest@usf.edu

https://doi.org/10.1016/j.yapd.2023.03.001
0065-3101/23/ª 2023 Elsevier Inc. All rights reserved.

Continued
Urethral atresia and posterior ureteral valves cause 50% of lower urinary tract
obstruction cases.

INTRODUCTION
Congenital abnormalities of the kidney and urinary tract (CAKUT) are among
the most commonly diagnosed abnormalities identified by antenatal ultrasound
(US) with a rate of one in 250 to one in 1000 pregnancies [1]. Lower urinary
tract obstruction (LUTO) is one of the most common causes of congenital ab-
normalities of the renal tract. This review focuses mainly on LUTO.
LUTO prevalence is reportedly between one in 5,000 and one in 25,000 [2]
pregnancies, which might be underestimated secondary to increased rates of
fetal demise and termination of pregnancy. Most of the LUTO cases are diag-
nosed during the second trimester (18–20 weeks gestational age), but with
improved US technology and increasing first-trimester screening, severe cases
of LUTO can be diagnosed as early as 11 to 14 weeks gestational age [3].
LUTO is a significant cause of morbidity and mortality in newborns, causing
significant end-stage renal disease (ESRD) and pulmonary hypoplasia (PH),
both of which can lead to devastating long-term health effects in affected in-
fants. LUTO is a heterogenous condition caused by obstructive uropathy at
the level of the neck of the bladder. Urethral atresia [4] and PUVs [5] cause
50% of LUTO cases. Less common causes of LUTO are anterior urethral
valves, cloacal malformations and prolapsed urethrocele [6], prune belly syn-
drome (PBS), meatal stenosis, mid-urethral hypoplasia, obstructing urethrocele,
cloacal dystrophy, megacystis-microcolon-intestinal hypoperistalsis syndrome
(MMIHS), and chromosomal disorders such as trisomy 21 and trisomy 18.
LUTO can present both in utero and after birth with a spectrum of symp-
toms and characteristics. Typically, LUTO is accurately diagnosed by US,
with prenatal findings being dependent on the severity of the obstruction.
Usual prenatal US findings associated with LUTO are unilateral or bilateral
hydronephrosis, enlarged bladder with keyhole sign, dilated ureters, and oligo-
hydramnios or anhydramnios (Fig. 1). These US findings can also be associ-
ated with cystic changes of the renal parenchyma. The prenatal US findings
of renal echogenicity and oligohydramnios with megacystis are predictive of
LUTO in up to 87% of cases [7]. Prenatal detection of LUTO gives the option
of prenatal assessment and presents opportunities to discuss with parents
possible prenatal and postnatal treatments and potential outcomes and
prognoses.

PATHOPHYSIOLOGY OF LOWER URINARY TRACT

OBSTRUCTION
The pathogenesis of LUTO is secondary to outflow obstruction of the bladder
during fetal urinary tract development, leading to progressive bladder dilation

Fig. 1. Pregnancy at 22 weeks with lower urinary tract obstruction. (A) Note the enlarged
bladder with dilation of proximal urethra showing the ‘‘Keyhole sign’’ (yellow arrow). (B)
Enlarged echogenic kidneys with dysplastic cystic changes (white arrows) and anhydramnios.
(Courtesy of Dr Jose Duncan.)

and bladder wall thickening. These changes in the urinary tract cause hydro-
ureteronephrosis, kidney parenchymal compression, and oligohydramnios or
anhydramnios [6]. Abnormal renal parenchymal development and function
are the main etiologies for prenatal anhydramnios/oligohydramnios, which
can lead to fetal PH that causes severe respiratory distress, respiratory failure,
and death.
In anhydramnios, fluid around the airspaces is reduced, decreasing the abil-
ity of the lungs to distend and adequately develop [8]. Oligohydramnios com-
promises the size of lung cells and interferes with epithelial–endothelial cell
development. Oligohydramnios also affects the differentiation of type I cells
in the lungs, which cover most of the alveolar surface area and are essential
in gas exchange within the lungs.
In patients with LUTO, for example, posterior urethral valves (PUVs) or ure-
thral atresia, there is a structural barrier to the normal flow of urine, which leads to
distinctive changes in the genitourinary tract upstream, starting with proximal
urethral dilation. Bladder dilation, bladder wall thickening, and hypertrophy of
the detrusor muscle are characteristic and result in decreased compliance and
increased intravesical pressure, which is then conducted to the ureters and
kidneys; this condition is identified radiographically as hydroureteronephrosis.

Depending on the severity of the obstruction and how readily the diagnosis is
made, clinical manifestations may vary. In severe cases, diminished or absent
fetal urine output cause PH, as described above. Bladder dysfunction, including
incontinence, vesicoureteral reflux, urinary tract infections and renal impairment
up to ESRD and dialysis dependence, can be seen [9,10].

Genetics of lower urinary tract obstruction

Genetic factors are known to play a role in CAKUT, and multiple genes have
been associated with its development. However, here, the authors focus only
on the genetic aspects of LUTO (Table 1). LUTO can be due to a functional
or anatomical obstruction. LUTO due to functional obstruction has been
described in syndromes such as PBS, urofacial syndrome (UFS), and MMIHS.
PBS is characterized by a lack of abdominal wall musculature, cryptorchi-
dism in males, and urinary tract abnormalities [11]. Although most cases are
sporadic with unknown etiology, several genes have been found to be involved
in familial cases. In 2011, a few patients with PBS were found to be homozy-
gous for a loss of function mutation in the CHRM3 gene. The CHRM3 gene
encodes the muscarinic acetylcholine receptor M3 subtype (MIM: 118494)
which is the main receptor responsible for mediating urinary bladder contrac-
tion [12]. The mode of inheritance for PBS due to mutations in this gene is
autosomal recessive. Filamin A with an X-linked inheritance pattern has also
been reported to play a role in PBS.
UFS is a rare autosomal recessive disorder characterized by congenital uri-
nary bladder dysfunction associated with an abnormal facial expression on
smiling, laughing, and crying (MIM: 100100). More than 80% of UFS patients
reported to date have mutations in the HPSE2 (inactive heparanase-2; MIM:
613469) or LRIG2 (leucine-rich repeats and immunoglobulin-like domains pro-
tein 2; MIM: 608869) genes [13].
MMIHS is characterized by bladder distention in the absence of mechanical
obstruction, microcolon, and intestinal hypoperistalsis (dysmotility) [14]. Muta-
tions in ACTG2 (actin gamma-2 smooth muscle), LMOD1 (leiomodin1), MYH11
(myosin smooth muscle heavy chain 11), MYL9 (myosin light chain 9 regulato-
ry), and MYLK (myosin light chain kinase) have been described in patients with
MMIHS. Although most observed inheritance patterns are autosomal recessive,
ACTG2 is dominant and the most commonly affected gene. Owing to genetic
heterogeneity, many patients lack a molecular confirmation of disease.
Until very recently, there were no known genetic causes of LUTO due to
anatomical obstruction. The most common cause of anatomical LUTO is
PUVs [15]. In 2015, Boghossian and colleagues published the first genome-
wide population-based study of copy number variants in isolated PUVs, iden-
tifying several novel candidate gene regions not previously reported, including
microdeletions and duplications.
Vivante and colleagues identified a truncating mutation of T-box transcrip-
tion factor 18 in a family with an autosomal-dominant form of CAKUT with
predominant ureteropelvic junction obstruction [16].

LUTO IN NEWBORNS
Table 1
Several genes associated with lower urinary tract obstruction and the inheritance patterns observed
Gene name Syndrome (s) Inheritance pattern
Cholinergic receptor, muscarinic subtype 3 (CHRM3) Prune belly syndrome Autosomal recessive
Filamin A (FLNA) Prune belly syndrome X-linked
Heparanase 2 (HPSE2) Urofacial syndrome Autosomal recessive
Leucine-rich repeats and immunoglobulin-like domains-containing Urofacial syndrome Autosomal recessive
protein 2 (LRIG2)
Smooth muscle gamma-2 actin (ACTG2) Megacystis-microcolon-intestinal hypoperistalsis Autosomal dominant
Smooth muscle myosin heavy chain 11 (MYH11) Megacystis-microcolon-intestinal hypoperistalsis Autosomal recessive
Smooth muscle myosin regulatory light chain 9 (MYL9) Megacystis-microcolon-intestinal hypoperistalsis Autosomal recessive
Leiomodin 1 (LMOD1) Megacystis-microcolon-intestinal hypoperistalsis Autosomal recessive
Myosin light chain kinase (MYLK) Megacystis-microcolon-intestinal hypoperistalsis Autosomal recessive
T-box transcription factor 18 (TBX 18) CAKUT with ureteropelvic junction obstruction Autosomal dominant
Basonuclin 2 (BNC2) Congenital LUTO Autosomal recessive
Abbreviations: CAKUT, congenital abnormalities of the kidney and urinary tract; LUTO, lower urinary tract obstruction.
Table provided courtesy of Dr. Amarilis Sanchez-Valle.

135
136 FLORES-TORRES, SANCHEZ-VALLE, DUNCAN, ET AL

In 2019, the first gene implicated in congenital anatomical LUTO was re-
ported in a family affected by LUTO with variants in the BNC2 gene [17].
The inheritance pattern observed was autosomal dominant. BNC2 is involved
in urethral development [18].
As technology continues to advance, more genes and their interactions will
be identified in the pathophysiology of LUTO. Identification of a genetic basis,
if possible, can assist in developing a more individualized plan of care, coun-
seling on recurrence risk, and identifying possible areas for treatment. Clini-
cians should consider genetic testing in all patients with LUTO.

PRENATAL DIAGNOSIS AND MANAGEMENT OF LOWER

URINARY TRACT OBSTRUCTION
Fetal LUTO can be diagnosed as early as in the first trimester of pregnancy,
using prenatal US [19,20]. During the first trimester, an enlarged bladder (meg-
acystis) is seen in about 1 of 1500 pregnancies [21]. The longitudinal measure-
ment of the bladder is important for the prognosis, as almost 80% of the
megacystis measuring 7 to 15 mm will resolve, whereas a longitudinal measure-
ment greater than 15 mm is almost always associated with LUTO [21].
In the second trimester, diagnosis of LUTO is based on US identification of a
dilated bladder, thick-walled bladder, bilateral hydronephrosis, dilated ureters,
and a visible posterior urethra (keyhole sign) [22] (see Fig. 1). The amniotic fluid
volume (AFV) can be normal, decreased (oligohydramnios), or completely absent
(anhydramnios). As fetal renal damage worsens, the renal parenchyma US appear-
ance changes from normal to echogenic enlarged kidneys to dysplastic cystic
changes. The presence of oligohydramnios/anhydramnios and dysplastic cystic
changes of the renal parenchyma are considered signs of poor prognosis [20,23].

PRENATAL MANAGEMENT
Once the diagnosis is made, the case should be managed by a multidisciplinary
team led by a maternal-fetal medicine specialist with experience in this pathol-
ogy. The aim of this team is to identify and manage pregnancies that could
benefit from a potential intervention that can improve outcomes. Other special-
ists, such as genetic counselors, pediatric urologists, pediatric nephrologists,
neonatal intensivists, and pediatric cardiologists, are usually part of the caring
team. Parents whose fetus is diagnosed with advanced disease or poor prog-
nosis should be informed of all available options including termination of preg-
nancy or the provision of comfort care after delivery.

ANEUPLOIDY TESTING
A common approach begins with genetic testing to evaluate for aneuploidy, us-
ing chorionic villus sampling when testing is done in the first trimester or
amniocentesis after 15 to 16 weeks of gestation. If anhydramnios is present,
fetal karyotype or a microarray can be performed by a placental biopsy, peri-
umbilical blood sampling, or from the fetal urine if vesicocentesis is performed.
Another option is to perform sampling of the amniotic cavity if an

amnioinfusion is used to prepare the patient for a vesicoamniotic shunt (VAS)

if no previous results are available. Cell-free DNA is a screening test for aneu-
ploidy with acceptable negative predictive values.

DETAILED ANATOMY ULTRASOUND

Because LUTO often occurs in association with other birth defects [24], most
centers recommend a detailed anatomy survey with special evaluation of the
renal tract and AFV. In addition, a fetal echocardiogram is usually performed.
The assessment of the renal tract and AFV should be done every week once
the diagnosis is made after 15 to 16 weeks [23].

VESICOCENTESIS AND BIOCHEMICAL MARKERS

The next step is to identify patients who will benefit from therapeutic options
based on gestation at presentation, association with aneuploidy, etiology, and
prognostic factors (AFV, urine biochemical markers, renal tract US findings).
Although of debatable utility, fetal urine biochemical markers have been stud-
ied to predict renal function by serial fetal vesicocentesis [25]; these are usually
performed soon after diagnosis is suspected and almost always after AFV ab-
normalities are seen. When used, most experts recommend obtaining three
samples and using the last one to assess fetal renal function preservation. Favor-
able fetal urine biochemistry results are sodium less than 100 mEq/L, chloride
less than 90 mEq/L, calcium less than 8 mg/d, osmolarity less than 200 mOsm/
L, and beta-2 microglobulin less than 6 mg/L.

PRENATAL INTERVENTIONS AND STAGING SYSTEMS

Patients with favorable urine biochemistry, oligohydramnios, or anhydramnios
without renal changes may be candidates for fetal interventions that may
improve outcomes such as a VAS [26]. The objective of this procedure is to
decrease the chance of severe PH and slow the deterioration of the renal func-
tion [27]. Although usually performed after 18 weeks, some investigators have
reported favorable outcomes with this procedure before 16 weeks of gestation
in cases with severe LUTO [28].
Ruano and colleagues developed a staging system for LUTO to guide the
management of these patients, using fetal biochemical markers, AFV, bladder
size, and the presence of renal dysplastic cysts (Table 2) [29]. Those with low
AFV, favorable urine chemistry, and no renal dysplastic changes or stage II are
candidates for a fetal cystoscopy procedure or VAS. Fetal cystoscopy, first re-
ported in 1995 [5], can be used to diagnose and treat PUV both VAS, but it is
not effective for urethral atresia. This procedure has also been shown to
improve survival [20,26]. Fetal interventions are less likely to be effective in
cases with evidence of renal dysplastic changes on US, non-favorable biochem-
istry, or inadequate refilling of the bladder after vesicocentesis [29].
Although serial amnioinfusion has been proposed by some investigators as
an option for patients with early onset anhydramnios due to fetal renal anom-
alies, this is considered investigational [30].

Table 2
Ruano staging system for lower urinary tract obstruction
Stage I Stage II Stage III Stage IV

FLORES-TORRES, SANCHEZ-VALLE, DUNCAN, ET AL

Ultrasound Normal amniotic fluid Oligohydramnios, bilateral Oligohydramnios or Anhydramnios with
volume, no kidney hydronephrosis, no anhydramnios with echogenic and dysplastic
dysplastic changes kidney dysplastic echogenic and dysplastic kidneys, anuria after
changes kidneys monitoring for bladder
refilling
Biochemistry results Favorable Favorable Unfavorable Unfavorable
Therapeutic options None Vesicoamniotic shunt or Vesicoamniotic shunt or Amnioinfusion
cystoscopy cystoscopy
Adapted from ‘‘Ruano R et al. Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity. Ultrasound Obstet
Gynecol. 2016 Oct;48(4):476-482’’.
LUTO IN NEWBORNS 139

PROGNOSIS AND OUTCOMES AFTER PRENATAL DIAGNOSIS

OF LOWER URINARY TRACT OBSTRUCTION
Prenatal diagnosis can assist in identifying patients who may benefit from fetal
intervention, which may decrease the rate of PH and possibly the progression
to ESRD. In the only randomized controlled trial of intervention versus conser-
vative management, the prenatal diagnosis of LUTO without treatment was
associated with higher perinatal mortality with survivals of less than 30% at
28 of days of life with a conservative approach while survival improved almost
twofold by placing a VAS [31]. However, the results were not significant due to
low recruitment. A systematic review that included this trial demonstrated
decreased perinatal mortality in both fetal interventions (VAS or fetal cystos-
copy) compared with conservative management, but neither intervention
improved survival with good renal function [26].
US parameters are not reliable predictors of neonatal outcomes. Up to 28%
of fetuses with normal AFV in the second trimester at initial evaluation will still
develop ESRD [32]. A multivariate model that included low AFV and echo-
genic kidneys had a low predictive value for ESRD [33].
Inadequate bladder refilling may be a promising marker of permanent renal
damage. In one small series, inadequate bladder filling after serial vesicocentesis
was associated with perinatal death or need for dialysis [19]. A recent study re-
ported poor correlation between renal echogenicity, cortical cysts, severe oligo-
hydramnios, and fetal urinary concentration of sodium, chloride, calcium,
osmolality, and beta-2 microglobulin [34].
Researchers from the Netherlands have developed a staging system for
LUTO with the goal of predicting severe renal impairment or perinatal death.
Patients with mild LUTO (normal AFV at 26 weeks) have an 11% risk for se-
vere renal impairment and 14% risk for perinatal mortality. Patients with mod-
erate LUTO (bladder volume <5.4 cm3 and normal AFV at 20 weeks) have a
31% for severe renal impairment and 26% perinatal mortality. Patients with se-
vere LUTO (bladder volume >5.4 cm3 with low AFV at 20 weeks) have a 44%
risk for severe renal impairment and 54% risk for perinatal death [35].
Despite advances in this field, fetal interventions do not reduce the risk for
ESRD [26]. Despite prenatal interventions for LUTO, ESRD occurs in at least
18% of cases with stage II LUTO and in 100% of cases with stage III [23] at
2 years of life. The limited predictive value of US assessments of fetal renal
function and urine chemical markers make it unlikely that antenatal interven-
tions will prevent advanced renal disease.

FETAL INTERVENTION RISKS AND COMPLICATIONS

Prenatal interventions are not without risk. In a single-center study, VAS was
associated with preterm premature rupture of membranes, perinatal loss, and
shunt dislodgement [36]. Although fetal cystoscopy is only successful in cases
with PUV, the procedure is not therapeutic in cases with urethral atresia. In
addition to increased risk for premature rupture of membranes, VAS is associ-
ated with perineal fistulas [36].

Postnatal management
LUTO should be managed in a tertiary center using a multidisciplinary
approach. The initial management focuses on providing needed respiratory
support, and once LUTO is symptomatic, treating the kidney disease. PH in
the neonatal period can present with mild to severe respiratory compromise,
leading to high rates of neonatal morbidity and mortality. Radiological findings
of PH are a small bell-shaped chest with well-aerated lung fields and elevated
diaphragm; in some cases, air leaks (pneumothoraxes) can be seen. Clinical
findings are usually a small chest circumference and severe pulmonary compro-
mise requiring high ventilatory settings. Echocardiogram findings associated
with PH are mainly pulmonary hypertension. Pathological findings associated
with PH postmortem are abnormally low lung-to-body weight [37] and radial
alveolar counts [38]. Even neonates who survive the initial period of respira-
tory compromise will have significantly compromised renal function, with as
many as less than 50% having ESRD requiring dialysis [29].
Treatment for PH is mostly supportive care, oxygen supplementation, treat-
ment for pneumothoraxes, and monitoring of pulmonary hypertension. Oxy-
gen supplementation can be delivered by different ventilatory modalities
such as continuous positive airway pressure, mechanical ventilation, high-
frequency oscillator, and so forth. Pneumothoraxes are common in infants
born with PH, and they are a common cause of increased morbidity and mor-
tality during the initial period of treatment. In the presence of tension pneumo-
thorax, the treatment is placement of a chest tube to evacuate the free air.
Infants with PH have an increased risk of pulmonary hypertension, which is
a secondary finding that is usually diagnosed clinically and by echocardiogram.
Pulmonary hypertension in the presence of PH is secondary to underdevelop-
ment of the pulmonary vasculature resulting in increased pulmonary vascular
resistance. Clinically, infants with pulmonary hypertension might present with
respiratory distress, pulse oximetry differences of greater than 10% between
pre- and post-ductal oxygen saturation, and low arterial partial pressure of ox-
ygen (<100 mm Hg in infants who require oxygen concentrations of 100%).
Echocardiogram is essential in the diagnosis of pulmonary hypertension, which
usually shows elevated right ventricular pressures with flattening of the ventric-
ular septum and right-to-left shunting through the patent ductus arteriosus.
Management of pulmonary hypertension is based on severity, but the goal is
to maintain 90% to 95% oxygen saturation, normal ventilation (pCO2 between
45 and 55 mm Hg), and pre- and post-ductal saturation differences less than
10%. The goal of initial management is to maintain normal blood pressure
with the use of vasoactive medications and maintain oxygenation with the
use of adequate ventilatory support and a pulmonary vasodilator such as
inhaled nitric oxide.
After stabilization of the infant, postnatal management should include tempo-
rary drainage of the urinary tract. In most centers, this is achieved by place-
ment of a urethral catheter into the bladder. Soft feeding tubes are preferred
rather than Foley catheters with balloons. The feeding tubes have larger

internal diameters allowing for better drainage, and inflation of the balloon on a
Foley catheter can cause irritation to the bladder with spasms and secondary
obstruction of the ureteral orifices [39]. In addition, it is important that the
tube is fastened securely to prevent urethral trauma associated with multiple
catheterizations. It is beneficial to document correct placement of the bladder
catheter with US as the catheters can coil in the dilated posterior urethra rather
than be within the bladder. In addition, US is used to monitor for improvement
in the hydroureteronephrosis with adequate bladder drainage.
After the placement of bladder catheter and drainage is established, it is impor-
tant to observe for a post-obstructive diuresis and electrolyte disturbances related
to tubular dysfunction. Accurate intake and output measurement and serial
monitoring of serum electrolytes, blood urea nitrogen, and creatinine levels
with appropriate fluid and electrolyte replacement are essential.
Voiding cystourethrography (VCUG) is an essential component of postnatal
imaging in infants with PUVs. The VCUG will provide important information
including the presence or absence of vesicoureteral reflux; bladder size, shape,
and capacity; and appearance of the urethra including degree of dilation. The
diagnosis of PUV is confirmed by direct visualization with cystoscopy. Primary
valve ablation during cystoscopy is the preferred initial surgical treatment of
PUV [40]. In preterm infants, the urethra may be too small to safely accommo-
date the smallest available cystoscope for primary valve ablation. In that case,
the main two options include the surgical placement of a vesicostomy with sub-
sequent valve ablation after the infant has grown and his urethra can accommo-
date the cystoscope [41] versus management with progressive dilation of the
urethra over time with serial catheter placements [42]. There are pros and
cons to both approaches; the treatment decision should be made by the uro-
logic team in conjunction with the family with consideration given to the num-
ber of surgical procedures required, associated risks, and optimization of future
bladder and kidney function. In rare cases where there is a secondary func-
tional upper tract obstruction affecting kidney function, upper urinary tract di-
versions, such as pyelostomies or ureterostomies, may be indicated.
Abnormal renal function in infants with PUV is multifactorial. There is an
obstructive component that is addressed immediately after birth with appro-
priate urinary tract drainage. In addition, infants with PUV have varying de-
grees of renal dysplasia. A major risk factor for ESRD is persistently
elevated serum creatinine after relief of the obstruction [43]. Other manifesta-
tions of renal dysfunction include tubular dysfunction with acidosis and
inability to concentrate the urine [44]; these conditions are treated with alkali
supplementation and adequate hydration, respectively. Renal protective mea-
sures should be instituted in all infants with PUV, including avoiding potential
nephrotoxic agents. Males with PUV are at risk for ongoing bladder dysfunc-
tion ranging from mild to severe [45]. Nonsurgical interventions include an
effective bowel regimen to avoid constipation, timed double-voiding schedules,
medications to ‘‘relax’’ the bladder, and clean intermittent catheterizations.
Males with PUV have been shown to have a delay in achieving day time

and night time dryness compared with age-matched controls [46]. Also, mild
lower urinary tract symptoms have been shown to persist into adulthood,
including hesitancy, weak stream, incomplete emptying, urgency, and stress in-
continence [47].

SUMMARY
LUTO is a significant cause of morbidity and mortality in newborns with
possible long-term health effects such as PH and ESRD. Fetal and postnatal in-
terventions are available. LUTO should be managed in a tertiary center using a
multidisciplinary approach where maternofetal, neonatology, pediatric cardiol-
ogy, nephrology, and urology services are available.

CLINICS CARE POINTS

Lower urinary tract obstruction (LUTO) is one of the most common causes of
congenital abnormalities of the renal tract.
LUTO can present both in utero and after birth with a spectrum of symptoms.
The pathogenesis of LUTO is secondary to outflow obstruction of the bladder dur-
ing fetal urinary tract development.

DISCLOSURE
The authors have nothing to disclose.

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ADVANCES IN PEDIATRICS

Chronic Myeloid Leukemia in

Children and Adolescents
Moran Gotesman, MDa,b,*, Sahar Raheel, MDa,
Eduard H. Panosyan, MDa,b
a
Department of Pediatrics, Harbor UCLA Medical Center, 1000 West Carson Street Box 468,
Torrance, CA 90509, USA; bThe Lundquist Institute of Biomedical Innovation, 1124 West Carson
Street, Torrance, CA 90502, USA

Keywords
Chronic myeloid leukemia (CML) BCR–ABL1 fusion t(9:22)
Tyrosine kinase inhibitor (TKI) Leukocytosis Splenomegaly Compliance
Monitoring

Key points
Chronic myeloid leukemia (CML) is rare, accounting for only 2% to 3% of all
leukemia in childhood and 9% in adolescents.
Pediatric treatment and management guidelines are typically based on data from
adult recommendations.
Tyrosine kinase inhibitors (TKIs) are the approved treatment of CML in pediatric
populations, but compliance can be a major contributing factor for a nonoptimal
response.
Pediatric patients are at risk for the long-term side effects of TKI, particularly
related to growth and development.

INTRODUCTION
Acute leukemia is the most common malignancy in childhood, while chronic
myeloid leukemia (CML) is rare, accounting for only 2% to 3% of all leukemia
in childhood and 9% in adolescents, with an annual incidence of 1 and 2.2 cases
per million in the two groups [1–3]. With the majority of patients presenting in
the fifth and sixth decades, the pediatric treatment and management guidelines
are typically based on extrapolation from adult recommendations and expert

*Corresponding author. 1000 West Carson Street Box 468, Torrance, CA 90509. E-mail
address: mgotesman@dhs.lacounty.gov

opinions [2–4]. The goal in pediatrics is to cure with newer tyrosine kinase in-
hibitors (TKIs) available and approved for patients under 18 years of age—this
is often achieved [5]. Care needs to be taken to monitor for sequela of long-
term use of TKIs [6].

History
Virchow first coined the term leukemia when describing CMLin 1844/5, but it
was not until 82 years later that the Philadelphia chromosome was discovered
and t(9:22) became the hallmark of the disease [7]. Before the understanding of
the molecular signature of CML, treatments included arsenic and splenic irra-
diation, followed by busulfan in 1953 [7]. In 1963, hydroxyurea became the
treatment of choice and in the late 1970s, the first patient was cured by bone
marrow transplant [8]. Just as the understanding of the molecular backbone
was better understood, interferon alpha started to show efficacy in the treat-
ment of patients with CML [7,9,10].
In the early 1960s, a team in Philadelphia first made the association between
a chromosomal change on chromosome 22 in seven patients with leukemia
[11]. The detection of the ABL-oncogene was a byproduct of the search for
a human leukemia virus and was isolated from the acutely transforming mu-
rine Abelson leukemia virus in 1980 [12]. Eventually, it was discovered that
ABL was found on chromosome 9 and translocated to BCR on chromosome
22 [13]. Finally, the genetic fusion of BCR-ABL1 or translocation 9:22 became
the defining signature of CML. See Fig. 1A for an example karyotype with 9:22
translocation and Fig. 1B for a detailed graphic of BCR–ABL1 product.

PATHOGENESIS
CML is a myeloproliferative neoplasm that results from translocation t(9:22)
and the resultant BCR–ABL1 fusion. The translated oncoprotein, in most
cases, is 210 kd and called p210 BCR–ABL1. Alternative splicing results in

Fig. 1. (A) Karyotype of patient with chromosome 9 and 22 translocation. (B) Detailed
description of 9:22 translocation and production of BCR–ABL1 oncogene.

p190 and p230 BCR–ABL1 and are more typically seen in Philadelphia
chromosome-positive acute lymphoblastic leukemia. This translocation gener-
ates messenger ribonucleic acid (RNA) and results in constitutive kinase activ-
ity, which leads to a growth advantage for leukemia cells [14]. See Fig. 2 for
BCR–ABL kinase cascade which ultimately causes increased cell growth and
proliferation.

CLINICAL MANIFESTATIONS
There are data suggesting that CML is often more aggressive in pediatric pa-
tients for many different reasons, likely related to biology and genetics [2,3].
More often pediatric patients present with more aggressive and advanced dis-
ease in the accelerated phase (AP) or blast phase (BP) [2]. Patients typically pre-
sent with leukocytosis and impressive splenomegaly [15]. Patients may also
present with malaise, fatigue, fever, night sweats, and weakness. They can
have symptoms of abdominal pain or distension as related to splenomegaly
and bleeding from platelet dysfunction. Occasionally, a patient may present
with headache, visual disturbances, or priapism secondary to significant leuko-
cytosis. Children who present with the CML BP have typical symptoms seen in
acute leukemia—such as fever, bleeding/bruising, hepatosplenomegaly, lymph-
adenopathy, and bone pain [16].

LABORATORY INVESTIGATIONS
At diagnosis, the National Comprehensive Cancer Network (NCCN) guide-
lines recommend obtaining a history and physical examination, including
spleen size, complete blood count with differential, chemistry profile, bone
marrow aspirate and biopsy, and quantitative reverse transcription - polymer-
ase chain reaction (RT-PCR) of BCR–ABL1 (international scale) from the

Fig. 2. BCR–ABL-activating intracellular kinase pathways which ultimately lead to prolifera-

tion and cell survival.

peripheral blood [17]. Cerebral spinal fluid is not needed if in the chronic
phase. Other guidelines also recommend a baseline endocrine evaluation
including lipase, glucose, cholesterol, hemoglobin A1C, lipid profile, and thy-
roid function. Some also suggest bone mineral density and human leukocyte
antigen (HLA) typing at diagnosis [6].

DEFINITIONS
Chronic phase
In the chronic phase (CP), the peripheral blood smear will show leukocytosis
with granulocytes in various stages of maturation, mostly mature segmented
neutrophils and myelocytes, while blast cells will account for less than 2%.
Increased basophils and eosinophils are common and monocytosis may be pre-
sent, but is usually less than 3% of the white blood cells. Platelets usually range
from normal to increased and thrombocytopenia is not commonly seen. The
bone marrow will have similar findings and should not have any evidence of
dysplasia, but may have myelofibrosis [18].
Accelerated phase
Previously, the AP was defined as a peripheral smear or bone marrow with
increased blasts (10% to 19%), however, in the current World Health Organi-
zation (WHO) classification, the AP is omitted and emphasis is made on fea-
tures associated with CP progression and resistance to TKI [19].
Blast phase
A small percentage (5%–7%) of patients will evolve into the BP. The WHO de-
fines BP as peripheral or bone marrow aspirate with greater than 20% blasts, or
with extramedullary proliferation of blasts [19]. In adults, most BP is myeloid
lineage with only 20% to 30% being lymphoblastic, but in Pediatrics, BP is pre-
dominantly lymphoblastic [20]. Extramedullary proliferation is most commonly
seen in the skin, lymph nodes, bone, and the central nervous system.
Scoring system
Multiple scoring systems (Sokal, Hasford, and european treatment and
outcome study [EUTOS]), using age, spleen size, platelet count, and peripheral
blasts are used in the adult population to help assess the prognosis in a newly
diagnosed patients. None of these scoring systems have been validated in the
pediatric population [21].

MANAGEMENT
Hyperleukocytosis
Leukapheresis in CML is not generally indicated due to the increased amount
of mature/maturing white blood cells (WBC) circulating in the bloodstream. By
contrast, leukapheresis is indicated in acute leukemia, where a high number of
immature blasts account for hyperleukocytosis [22]. Early initiation of hy-
droxyurea has been shown to decrease the WBC without the need for apher-
esis in patients with CML. Leukapheresis may be considered emergently if

there are signs of leukostasis or end-organ damage such as respiratory distress,

priapism, and stroke [22].

Tyrosine kinase inhibitors

TKIs were revolutionary for the treatment of CML. Fig. 3 shows the specific
blockage of the BCR–ABL-activated tyrosine kinase pathway. In adults, the
life expectancy is almost identical to age-matched healthy population [23,24].
Imatinib has been approved for use in children for CML since 2003 and
also has improved outcomes in pediatrics [25]. More recently second-
generation TKIs, Dasatinib and Nilotinib, have been approved as upfront treat-
ment of children and adolescents with CML [26]. Bosutinib and Ponatinib are
now being evaluated as other potential treatment options in pediatrics [6,27]. In
adults, the second-generation TKIs have been shown to have a faster and
deeper molecular remission but there was no difference in overall survival
[28]. In children, there are no randomized trials to compare first- and
second-generation TKIs but the second-generation TKIs are showing similar
molecular responses as in adults [26]. Imatinib, Dasatinib, and Nilotinib are
all potential upfront treatments for pediatric patients with CML. Table 1 shows
differences in dosing frequency and some unique side effects, typically seen in
adults, per TKI [5].
Allogenic stem cell transplant
Allogenic stem cell transplant (SCT) is the only known curative therapy for
CML at this time, however, given the risks of SCT versus the few associated
toxicities with TKI therapy. TKI treatment is the overall preferred method of
treatment in both adult and pediatric patients with CML. Currently, SCT is
indicated if patients present or progress to AP or BP and should be done within
3 to 6 months [29]. SCT may also be considered if patients fail two TKIs or
experience intolerable toxicities [30]. In addition, patients who harbor the

Fig. 3. TKIs specifically block BCR–ABL kinase-induced activity.

Table 1
Tyrosine kinase inhibitors
Generation Dosing Side effects
Imatinib First Once daily Muscle cramps, edema, diarrhea
Dasatinib Second Once daily Pleural/pericardial effusions,
pulmonary hypertension, GI
bleed, prolonged QTc
Nilotinib Second Twice daily. No Prolonged QTc, arterial occlusion,
food 2 h prior glucose instability
and 1 h after
Bosutinib Second Once daily with Diarrhea, transaminitis
food
Ponatinib Third Once daily Arterial and venous thrombosis,
pancreatitis

T315I mutation may benefit from SCT as Ponatinib (the only TKI used in this
scenario) is not approved in pediatrics and has shown decreased efficacy when
compared to SCT in adults in the BP [31,32]. In general, children have fewer
complications and have better outcomes with SCT when compared to adults,
therefore, SCT may be an option for those who do not tolerate or do not want
to continue with TKI treatment [16].

RESPONSE
TKI therapy response is determined by measuring hematologic, cytogenic, and
molecular responses. The hematologic response is the normalization of periph-
eral blood counts and regression of hepatosplenomegaly. The cytogenic
response is a decrease in Ph-positive chromosomes in the bone marrow. The mo-
lecular response is a decrease in BCR–ABL1 analyzed by PCR [17]. See Fig. 4 for
disease monitoring frequency and expected response per the NCCN guidelines.

Fig. 4. Expected TKI response based on PCR BCR–ABL1 (IS) at different time intervals.

In adults with CML, response to TKI is the most important prognostic fac-
tor, but currently in pediatrics, there are no comparable data to correlate cyto-
genic or molecular response, therefore, the recommendation is to follow the
criteria based on adult recommendations such as the NCCN or the European
Leukemia Net (ELN) [17,33].

Resistance
If an optimal response is not achieved and compliance is confirmed, testing for
BCR–ABL1 tyrosine kinase domain mutation analysis should be done. Tak-
ing into consideration multiple adult guideline recommendations, mutational
analysis should be done with inadequate initial response, loss of response, 1-
log increase in BCR–ABL1, or if there is disease progression to AP or BP
[6,17].
If mutations are detected, patients should be switched to a different TKI that
has efficacy for the known alterations. For example, Ponatinib is the only
known TKI used for a T315I mutation in BCR–ABL1, though it is not
approved in pediatrics and has only anecdotal experience [34].

Compliance
One known major contributing factor to nonoptimal response and treatment
failure in patients with CML, particularly adolescents, is noncompliance
[35]. Young adults with CML have impaired quality-of-life issues related
to TKI therapy, which are reported to be significantly worse than in the
older adult population [36]. It is essential to educate patients and their fam-
ilies on the importance of compliance at every visit. There is no evidence to
support routine monitoring of TKI levels, but if there is a concern for
compliance, a plasma imatinib (only TKI level available) trough level may
be obtained with the target trough level being >1000 ng/mL in adults [37].
There are no data currently to support trough levels in the pediatric CML
population. The importance of compliance should be addressed during
every clinic visit and this should include a discussion of ways to improve
adherence if needed.
Patients should also be asked about concomitant medications as well as sup-
plements, over-the-counter medications, and dietary habits that may interact
with TKIs.

LONG-TERM CARE
The goals of management in children and adolescents are typically for pro-
longed remission and cure. This may be different from the typical older patient
with CML whose goal often is to remain stable in the CP. Younger patients will
need to remain on TKI for a prolonged period and have the risk of developing
TKI resistance or going into AP or BP. They are also at risk for the long-term
side effects of TKI, particularly related to growth and development. Table 2
demonstrates the potential toxicities with TKIs in general and the needed
long-term monitoring [6,16].

Table 2
Tyrosine kinase inhibitors toxicity and long-term monitoring
Toxicity Exam/laboratory frequency and management
Decreased bone density Monitor vitamin D, calcium and phosphorus, and
parathyroid hormone 6 weeks after the start of TKI
and every 6 months. Supplement as needed.
DEXA scan at baseline and yearly or if evidence of
decreased bone density on plain film or
unprovoked fracture
Growth delay Height, weight, BMI, and tanner staging at every
visit
Consider bone age if growth velocity decreased
Puberty delay Consider sex steroid evaluation and endocrinology
referral
Fertility and reproduction TKIs are teratogens and should be held during
pregnancy
No known effects on male fertility or male partner’s
pregnancy
Thyroid dysfunction TSH and free T4 4–6 weeks after initiation of TKI,
followed yearly or if symptomatic
Glucose instability HbA1C at baseline and yearly
Cardiac toxicity Echocardiogram yearly electrocardiogram (QT
Prolonged QT interval) yearly
Impaired immunity Killed vaccines given per schedule; live vaccines are
not recommended
Low blood cell count Monitor blood count with every visit

Stopping tyrosine kinase inhibitors

Several studies have been published regarding stopping TKIs in adults after at
least 3 years of therapy and with a sustained molecular remission for greater
than 2 years. The NCCN recently came out with new guidelines for stopping
TKIs in a select patient population who are over the age of 18, but so far there
are no data to show the feasibility of stopping TKIs in the pediatric CML pop-
ulation [17]. TKI therapy should only be stopped in pediatric patients in the
context of a clinical trial at this time. In adult patients who stopped TKI,
50% to 60% have disease recurrence after 6 months but can re-achieve molec-
ular remission after reinitiating TKI.

Transition of care
Typical transition to adult care happens between the ages of 18 and 21 years
old depending on the center. Like other chronic conditions, care should be
taken to identify a proper adult oncology center and educate the patient on
the disease, medication, and the needed follow-up [38].

SUMMARY
CML, a myeloproliferative neoplasm that results from translocation t(9:22) and
the resultant BCR–ABL1 fusion, is a rare malignancy in the pediatric population

with treatment and management currently guided by adult patient recommen-

dations. Pediatric patients can present with more aggressive forms of the dis-
ease compared to adult patients and that is why frequent physical exams,
laboratory monitoring, and discussion of medication compliance are important.
Treatment with TKIs is the preferred method for prolonged remission and
cure in pediatric patients, but long-term use can lead to adverse sequelae that
particularly affect the pediatric population including decreased bone density,
growth and puberty delay, and cardiac toxicities among others. TKI therapy
should only be stopped in the context of a clinical trial at this time given the
limited data. Other options for CML therapy include allogenic stem cell trans-
plant, which is curative, but less commonly used given the risks associated with
SCT. Transition to adult care when appropriate is key to optimizing prolonged
remission and cure of the disease.

CLINICS CARE POINTS

CML is often more aggressive in the pediatric population than in the adult pop-
ulation and patients may present in the AP or BP with splenomegaly and
leukocytosis.
TKIs are the preferred treatment approach in all patients with CML, however,
allogenic SCT is the only known curative treatment.
Patients with chronic TKI use should be frequently monitored for growth and
developmental delays.
Educating patients and families on the disease, medication compliance, and
long-term follow-up is key at every visit.

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ADVANCES IN PEDIATRICS

Update on Atopic Dermatitis

Caitlyn Kellogg, MDa, Jan Smogorzewski, MDb,*
a
Department of Internal Medicine, Harbor-UCLA, 1000 West Carson Street, Box 458, Torrance,
CA 90509, USA; bDepartment of Internal Medicine, Division of Dermatology, Harbor-UCLA,
1000 West Carson Street, Box 458, Torrance, CA 90502, USA

Keywords
Atopic dermatitis Pediatric Topicals Biologics Phototherapy
Key points
There is a high prevalence of atopic dermatitis (AD) among the pediatric
population.
The pathogenesis of AD involves genetic, immunologic, and environmental
factors.
There recently has been an expansion of treatment modalities including therapies
targeting immune modulators known to be upregulated in AD.

INTRODUCTION
Atopic dermatitis (AD) is a chronic inflammatory skin disorder with a lifetime
prevalence of up to 20% which can occur at any age but is most common among
children. In many cases, AD is part of the ‘‘atopic march,’’ in which children with
AD are at higher risk for developing allergic conditions including asthma and
allergic rhinitis as they age. Approximately 50% of patients are treated by pri-
mary care providers [1], and there is a significant burden of pediatric AD in
the primary care setting [2]; thus, the ability to recognize and manage AD is of
utmost importance to pediatricians. In prior years, management of AD has con-
sisted mainly of nonspecific pharmacotherapies targeting the immune system,
including topical and oral corticosteroids. As research continues to elucidate
the pathophysiology of AD, there has been an expansion of treatment modalities
including therapies targeting immune modulators known to be upregulated in
AD. Here, the authors provide the most current information on pediatric AD
epidemiology, pathogenesis, clinical presentation, and treatment.

*Corresponding author. E-mail address: JSmogorzewski@dhs.lacounty.gov

EPIDEMIOLOGY
The worldwide prevalence of AD has been estimated as 15% to 20% among chil-
dren and 1% to 3% among adults [3]. Prevalence varies widely among different
geographic regions. Overall, higher rates of AD have been observed in Africa
and Oceania versus Northern and Eastern Europe [4]. A recent study based on
reports published between 2009 and 2019 found that the highest prevalence of
AD was 35% among Swedish children and the lowest was 0.65% among Tunisian
children. Within the United States, the prevalence of AD is estimated to be 24%
among children aged 0 to 5 years, 14.8% among children aged 5% to 15%, and
7.2% to 10.2% among adults [5], with increased prevalence among African Amer-
ican (19.3%) compared with European American (16.1%) children [4]. The prev-
alence of AD has increased two- to threefold in the past decade in industrialized
countries and is especially increasing among young children (aged 6–7 years) [3].
Disease onset occurs within the first year of life for approximately 60% of
patients and within the first 5 years of life for 90% of patients [6,7]. Sponta-
neous resolution by adolescence will occur in approximately 75% of children
with AD. [8]. Risk factors associated with the persistence of AD into adoles-
cence and adulthood include female gender, AD onset after 2 years of life,
already persistent AD, and more severe disease [9]. The severity distributions
of AD within the United States has been found to be mild in 67% of cases, mod-
erate in 26% of cases, and severe in 7% of cases with highest prevalence of se-
vere cases in Northeastern and Midwestern states [10]. AD severity has been
found to be associated with factors including older age, African American
and Hispanic race/ethnicity, lower household income, dilapidated housing,
and garbage on the streets, highlighting the impact of environmental factors
on AD severity, more of which are described below [10].

PATHOPHYSIOLOGY
Overview
The pathogenesis of AD involves genetic, immunologic (T helper [Th] cells),
and environmental factors. The cause of AD is multifactorial and includes
skin barrier dysfunction, a Th2-skewed response, and increased susceptibility
to microbes. For decades, the two hypotheses for the development of AD
included the ‘‘inside-out’’ and ‘‘outside-in’’ hypotheses. The ‘‘inside-out’’ hy-
pothesis involves the concept of existing inflammation in non-lesional AD skin
contributing to breakdown of the skin barrier, allowing for penetration of aller-
gens which stimulate activation of Th2 and Th22 in the acute phase, and Th2,
Th22, and Th1 in the chronic phase. In the ‘‘outside-in’’ hypothesis, an impaired
skin barrier leads to allergens and microbes infiltrating the epidermis and
creating an inflammatory environment; currently, the prevailing idea is that
the pathogenesis of AD likely involves a combination of both hypotheses [11].
Impaired skin barrier
The stratum corneum is crucial for a healthy skin barrier, which helps to prevent
both trans-epidermal water loss and environmental compounds, including

microbes such as Staphylococcus Aureus, from infiltrating the dermal and epidermal
layers and provoking an immune response. Lipids are important in maintaining
the skin barrier—specifically, cholesterol, free fatty acids, and ceramides—and
changes in lipid composition, as seen in AD, can cause skin barrier dysfunction
[12]. Studies have found increased levels of cholesterol-3-sulfate in AD, which
has been postulated to be a barrier disruptor and has shown to positively corre-
late to levels of S aureus [13]. A reduced average length of ceramides, which
constitute 50% of the epidermis, has also been linked to AD. [14].
Genetics plays an important role in the loss of skin barrier function seen in
AD. Loss-of-function mutations in filaggrin (FLG), a protein which binds to
keratin fibers in the epithelial cells of the stratum corneum and helps to main-
tain the integrity of the skin barrier, have been associated with the risk of AD.
Two independent loss of function mutations, R510X and 2282del4, are very
strong risk factors for AD. [15]. FLG mutations are associated with palmar hy-
perlinearity in addition to early onset, severe, persistent AD associated with
allergic conditions and risk of infection [16] including eczema herpeticum.
Other gene variants associated with AD include filaggrin-2, hornerin, loricrin
(LOR) [17], and SRP-3, all of which encode epidermal proteins affecting the
skin barrier’s epidermal differentiation complex [16]. Defects in FLG are less
common among African American than in European American and Asian pa-
tients and thus seems to have a lesser role in AD pathogenesis among these pa-
tients [4]. Impaired function of LOR is seen in European American and African
American populations but not in Asian populations [17].
Susceptibility to microbes
The skin microbiome has a key role in the pathogenesis of AD. S aureus coloni-
zation has been found to be more prevalent in the skin of AD patients (20% in
healthy patients vs 30%–100% in AD patients) [18] due to factors including
increased receptors for S aureus and decreased levels of antimicrobial peptides
(AMPs) that control growth of microorganisms on the skin surface [19],
including LL-37, B-defensins, and dermcidin [18]. In addition, a healthy skin sur-
face contains coagulase negative Staphylococcus species which can produce anti-S
aureus peptides. In AD, these strains are deficient on lesional and non-lesional
skin [16,18], thus resulting in an overabundance of S aureus. There is evidence
that S aureus influences AD flares and disease phenotype and studies have found
that the application of commensal organisms may decrease S aureus colonization
in AD, which has implications for future AD treatment approach [19,20].
Immune dysfunction
For decades, studies have demonstrated that AD patients’ skin contains high
immunoglobulin E (IgE), interleukin (IL)-4, and IL-13 levels. More recent
studies demonstrating an upregulated Th2 system in AD have further eluci-
dated the immune dysfunction present in AD. The inflammatory mediators
that have recently been identified in addition to IL-4 and IL-13 include Th2,
Th22, Th1, and Th17. It is hypothesized that pediatric AD is driven by the
Th2 pathway with a Th22 component and also involves Th17 signaling, which

has been found to be more pronounced in children than in adults with AD.
[21]. A recent study demonstrated that among AD biomarkers, chemokine
C-C motif ligand 17/thymus and activation-regulated chemokine, chemoattrac-
tants of Th2 cells, correlated with strongest with AD clinical severity [22]. The
key role that the Th2 system plays in AD is further supported by the efficacy of
biologics targeting Th2 cytokines including dupilumab, tralokinumab, lebriki-
zumab, and nemolizumab.
The Th2-skewed response observed in AD plays a role in skin barrier and mi-
crobiome dysfunction. Th2 response affects the epidermal barrier by suppressing
keratinocyte differentiation, inducing epidermal hyperplasia, and modulating
the production of AMPs [16]. Th2 cytokines in skin of AD patients have been
shown to be associated with S aureus colonization and eczema herpeticum [16].
Studies have demonstrated racial differences in immune pathway activation
with European descendants demonstrating a dominance of the Th2/Th22
pathway, Asian individuals demonstrating additional activation of the Th1/
Th17 pathway, and African individuals demonstrating a lack of activation of
the Th1/Th17 pathway and highest serum IgE levels [4]. Other inflammatory
mediators found to be of importance in recent years, some of which have led to
the development of targeted therapies described below, include phosphodies-
terase 4 (PDE4), the Janus Kinase (JAK) pathway, natural killer cells, natural
killer T cells, and fibroblasts [22].

RISK FACTORS
The two risk factors consistently shown to be associated with AD are family
history of atopy and loss of function in the FLG gene. However, there are
many other factors that may play a role in AD prevalence and severity. Studies
have suggested that male gender is a risk factor for AD in infancy, whereas fe-
male gender is a risk factor for AD in adolescence [23]. The role of diet in AD is
controversial and currently not well understood. Food allergy is known to be
associated with early-onset AD and plays a role in AD chronicity and severity.
However, studies have shown that maternal dietary restriction during preg-
nancy is not a protective factor against AD [24], and delaying introduction
of solid foods is a risk factor for AD. [3]. There is no definitive research on
optimal diet for patients with AD; however, in a cross-sectional study, AD pa-
tients reported improvement in symptoms when removing white flour prod-
ucts, gluten, and nightshades from their diet. Improvement was also noted
with the addition of vegetables, fish oil, and fruit to the diet [25].
Environmental exposures have been shown to affect AD. For example,
pollution epidemiologic studies have demonstrated a link between pollution,
exacerbation of AD symptoms, and increased AD prevalence [26]. Although
the direct effect of pollution on the skin is unknown, a recent study found
that among mice, particulate matter exposure led to skin inflammation through
differential expression of genes related to skin barrier integrity and immune
response [27]. A patient’s home environment also has the potential to affect
AD; an association was recently found between factors including using

composite wood floors, living in a villa/townhouse, presence of mold or damp

stains in the room, and rarely cleaning child’s room [28]. Three or more chil-
dren in household has been shown to be a risk factor for severe AD. [29].
Although dogs in the household has been found to be a protective factor
against AD, the results are inconclusive for cats [3]. In addition, studies have
found that living in urban environments versus rural is a risk factor for AD.
[3]. This is possibly related to the hygiene hypothesis, in which a decrease in
early childhood exposure to microbes from the environment leads to increased
susceptibility to atopy [3].
Studies have found higher socioeconomic status (SES) to be associated with
higher AD prevalence and lower SES to be associated with increased AD severity
[30], suggesting that access to AD care and treatment is lacking in low-income
populations. A recent study analyzing two large health care claims databases in
the United States between 2011 and 2016 demonstrated significant differences
in AD care between commercially and Medicaid-insured children; namely, the
Medicaid-insured children received fewer outpatient and specialist care visits
and had higher emergency department/urgent care utilization and high-
potency topical corticosteroids (TCSs) and calcineurin inhibitors were less often
prescribed to these patients [31]. Solutions are thus required to alleviate dispar-
ities in AD care, which have potential to have long-term health consequences.

PRESENTATION AND DIAGNOSIS (I) CLINICAL FEATURES AND

COMORBIDITIES
AD is a clinical diagnosis with features generally including erythema, edema,
xerosis, erosions/excoriations, oozing and crusting, and lichenification [32].
AD in African American children may have a more papular or follicular
appearance, and these patients often experience more post-inflammatory hyper-
pigmentation or hypopigmentation [33]. Pruritus is present in most cases and is
a very bothersome symptom to patients, leading to impairment in quality of life
in addition to an ‘‘itch-scratch cycle’’ in which eczema lesions are exacerbated
by physical trauma to the skin.
According to the most recent American Academy of Dermatology (AAD)
guidelines, features that must be present to diagnose a patient with AD include
pruritus and eczema with typical morphology and age-specific distribution pat-
terns and chronic or relapsing history [32]. Regarding distribution patterns, le-
sions typically spare the groin and axillary regions and are commonly seen in
the facial, neck, and extensor surfaces in infants and children and flexural areas
in all age groups [32]. Other important features commonly seen in AD include
early age of onset, atopy, and xerosis. Associated features that comprise the mi-
nor criteria may be seen in conjunction with AD and thus may be helpful in
diagnosis establishment include palmar hyper-linearity, keratosis pilaris, pityri-
asis alba, facial pallor or erythema, and orbital darkening [34].
Providers should maintain suspicion for other differential diagnoses to be
excluded, especially if AD is not responding to therapy [32]. For example,
scabies, a contagious skin condition caused by a burrowing mite and presenting

with linear, erythematous papules, can be distinguished by ability to isolate

scabies mites from skin scrapings and history of other household members
with a rash. Seborrheic dermatitis, which is caused by the yeast Malassezia furfur
and presents with greasy yellow plaques on the scalp and face, can be distin-
guished by lack of pruritis and involvement of the axillary and groin regions
[32]. Psoriasis, another skin condition caused by immune dysregulation,
presents with erythematous scaly plaques and can be differentiated by involve-
ment of diaper area and nails. In addition, hemophagocytic lymphohistiocyto-
sis (HLH), a potentially deadly [35] condition involving abnormal macrophage
activation, should be considered. HLH has a heterogeneous appearance overall
but may present similarly to AD [36].
Other diagnoses to consider include contact dermatitis, ichthyoses, cuta-
neous T-cell lymphoma, photosensitivity dermatoses, immune deficiency dis-
eases, and erythroderma of other causes [32].
There are a number of comorbidities among pediatric patients with AD which
can significantly impact their health and quality of life. A recent study among
86,969 pediatric AD patients in the United States found significant associations
between AD and multiple allergic conditions including asthma, allergic rhinitis,
eosinophilic esophagitis, and food allergy [37]. A significant association was also
demonstrated between AD and mood and behavior disorders including depres-
sion, attention deficit hyperactivity disorder (ADHD), anxiety, and behavioral/
personality disorders. Other studies have demonstrated sleep disturbance
among patients with AD in part attributed to itch [32], which may modulate
ADs effect on mood. Pediatric AD patients also had higher rates of multiple types
of infections, including methicillin resistant staph aureus (MRSA), varicella, and
herpes, autoimmune conditions including vitiligo and alopecia areata, lymphoid/
hematologic malignancies, and obesity/metabolic syndrome [37].

Atopic dermatitis severity

The most commonly used AD disease severity scales include the Severity Scoring
for Atopic Dermatitis (SCORAD) index, the Eczema Area and Severity Index
(EASI), Investigator’s Global Assessment, and the Six Area, Six Sign Atopic
Dermatitis severity score with the SCORAD being the most widely used instru-
ment [38]. However, for the general management of patients with AD, severity
and quality of life measurement scales are not recommended for routine use in
practice and providers should instead generally assess itch, sleep, impact on daily
activity, and persistence of disease [32]. In addition, patients with AD are often
found to have elevated IgE levels, and IgE levels are often used in clinical research;
however, it is not recommended to measure specific biomarkers or monitor IgE
levels as part of AD severity assessment, diagnosis, and management [32].

TREATMENT
Lifestyle modifications
Lifestyle modifications are the key in the management of AD. Skin moisturiza-
tion is an integral component of AD management due to skin barrier dysfunction

and trans-epidermal water loss, and patients should be advised to apply emol-
lients daily. AAD recommendations for nonpharmacologic interventions for
AD treatment include application of moisturizer soon after bathing [39]. There
is no consensus on optimal frequency of bathing. Although some studies have
suggested no relationships between bathing frequency and AD [40], others
have shown AD improvement with bathing twice daily versus twice weekly
[41] and some have suggested increase in trans-epidermal water loss and AD
severity with increased bathing frequency from once weekly to at least daily
[42]. Bleach baths, in which one-fourth to half cup of bleach is added to a bath
tub filled with water, have been shown to be effective in reducing colonization
with S aureus and thus improving AD. [43].
It is recommended that moisturizer be applied at least twice daily; moistur-
izer has been shown to significantly improve the skin barrier in children with
AD, reduce AD flares, and may delay AD development for infants at high
risk of developing AD. [44]. Specific moisturizers that have been proven to pro-
vide hydration and decrease trans-epidermal water loss include Cetaphil Re-
storaderm moisturizer and wash, Eucerin Eczema Body Cream, and Eucerin
Flare-Up Treatment [44]. Wet wrap therapy (WWT) is recommended for pa-
tients with moderate-to-severe AD to reduce AD severity and flares [39].
WWT involves administering topical emollients or pharmacologic agents
such as corticosteroids under a wet bandage, gauze, or cotton wrap dressing;
following this, a second layer of dry dressing is applied. The wrap may remain
in place for up to 24 hours [39].
Skin exposure to environmental and cosmetic irritants has the potential to
exacerbate AD and thus should be avoided if possible and appropriate. Prod-
ucts applied to the skin should be hypoallergenic and fragrance free and should
avoid harsh chemicals. Food allergies may worsen AD; however, the avoidance
of foods is not recommended until appropriate allergy testing has been
completed and relevance of food allergy to AD has been established [45].

Topicals
Corticosteroids
For decades, TSCs have been used in the treatment of AD, and there is exten-
sive evidence demonstrating their efficacy [39,46]. Topical steroids function by
binding to DNA, decreasing the production of inflammatory mediators and
stimulating the production of anti-inflammatory products [47]. Per AAD guide-
lines, topical steroids should be used in patients not responding to the nonphar-
macologic methods outlined above [39]. Twice daily application for up to
several weeks is recommended for flares, and TSC should be used in combina-
tion with emollients. More recently, maintenance therapy 1 to 2 times weekly
has been recommended for areas of the body that commonly flare. TCSs are
grouped into different classes, ranging from I to VII with class I TSC being
very high potency and class VII being low potency [39]. Patients should be
advised to use only low-potency steroids, such as hydrocortisone, on areas
more susceptible to adverse effects, such as face, axilla, and genital region.

Medium- to high-potency steroids may be used on thicker, eczematous plaques

elsewhere on the body in the setting of moderate-to-severe eczema.
Adverse effects of TCSs in the setting of long-term inappropriate steroid use
include atrophy, striae, rosacea, telangiectasias, acne, petechiae, and purpura
[47]. More serious, systemic adverse effects in children include suppression
of the hypothalamic-pituitary-adrenal axis and growth suppression [48]. In
recent years, there has been an expansion of social media discussions on nega-
tive effects of TSC, including skin disease that occurs on TSC cessation. A sys-
tematic review of 34 studies established TSC withdrawal as a clinical adverse
effect of TSC after TSC discontinuation [49]. For AD patients, TSC with-
drawal presents as erythroderma, scaling, and edema and can be distinguished
by underlying AD exacerbation by the presence of a burning sensation or his-
tory of long-term TSC use on the face or genital region [49]. Most cases of TSC
withdrawal occurred in patients with daily prolonged (>1 year) use of TSC. It
is thus of utmost importance to counsel patients on proper use of TSC [49].
Calcineurin inhibitors
Topical calcineurin inhibitors (TCIs) including pimecrolimus and tacrolimus
are immunosuppressing agents that, unlike TSC, are nonsteroidal and do
not cause the same adverse effects. Calcineurin is a protein phosphatase with
a role in T-cell activation [50]; TCI bind to intracellular proteins and inhibits
the activity of calcineurin, thereby suppressing T-cell activity and synthesis
of pro-inflammatory cytokines [51]. They are recommended for use in AD
cases that do not respond to conventional therapy with TSC, and additionally
can be used as a steroid-sparing agent for both active AD and as maintenance
therapy two to three times weekly on skin areas that commonly flare. Patients
should be counseled on adverse effects including skin burning, pruritis, and er-
ythema [52].
In 2005, 5 years after the Federal Drug Administration (FDA) approval of
tacrolimus and pimecrolimus, the FDA issued a black box warning due to
lack of long-term safety data and reports of cutaneous malignancies and lym-
phoma reported in patients treated with TCI [53]. Since then, many studies
have demonstrated no clear relationship between TCI use and cancer [54–
56]. However, other studies have found increased risk of lymphoma among
TCI users [57,58], including a recent systematic review and meta-analysis
including 408,366 patients which demonstrated no association between TCI
and cancer overall but found increased risk of lymphoma among patients
treated with TCI versus controls or those treated with TCS [59]. Overall, how-
ever, the AAD still supports the use of TCI for AD as a safe and effective
treatment.
Janus Kinase inhibitors
Topical JAK inhibitors including tofacitinib, ruxolitinib, and delgocitinib have
emerged as a promising therapy for AD, although they are not yet FDA
approved for treatment of AD in the United States. JAK proteins play a role
in a signaling pathway that mediates the effect of inflammatory Th2 cytokines

including IL-4, IL-13, and IL-31 [60]. Delgocitinib was the first topical JAK in-
hibitor ever to be approved for use in AD. It was approved for treatment of
adults and children in Japan in January 2020 and March 2021, respectively.
It inhibits all types of JAKs including JAK1, JAK2, JAK3, and tyrosine kinase
2 [60]. Most clinical trials demonstrating the efficacy of delgocitinib have been
among patients less than 16 years [60,61], though a recent randomized
controlled trial among patients in Japan aged 2 to 15 years demonstrated
improvement in AD signs and symptoms and was well tolerated over a treat-
ment period of 56 weeks. The most common adverse effects reported were na-
sopharyngitis, impetigo, and urticaria [62].
Topical ruxolitinib, which inhibits JAK 1 and 2, was approved by the FDA
for the treatment of mild-to-moderate AD in patients 12 years and older in
September 2021. The two major clinical trials, Topical Ruxolitinib Evaluation
in Atopic Dermatitis 1 and 2, involved patients at least 12 years of age and
demonstrated efficacy and tolerability throughout a 44-week treatment period
[63]. The most common adverse event was a burning sensation at the applica-
tion site [63]. Tofacitinib inhibits JAK 1 and 3 and has shown efficacy in trials
for adult AD [64], but has not been studied in pediatric populations.
Phosphodiesterase inhibitors
Crisaborole, a PDE4 inhibitor, was approved in May 2016 for mild-to-
moderate AD treatment in patients greater than 2 years; in March, it extended
to patients 3 months and older [60]. PDE4 is an enzyme that degrades cyclic
adenosine monophosphate and has a role in the production of pro- inflamma-
tory and anti-inflammatory cytokines; its inhibition leads to an increase in anti-
inflammatory cytokines and inhibition of reactive oxygen species production.
A 2019 systematic review and meta-analysis concluded that the use of topical
PDE4 inhibitors for 14 to 28 days significantly improves the severity of disease
and has mild adverse effects including application site pain, burning, and sting-
ing [65]. In phase 3 trials, 94.2% of treatment-related adverse events were mild-
to-moderate and most resolved within 1 day [66]. In addition, crisaborole has
low systemic absorption and has been shown to be safe long term with low fre-
quency of treatment-related events over 48 weeks [67,68].
Systemics
IL-4 and IL-13 inhibitors
In recent years, advances have been made in systemic treatments for AD,
including biologic pharmacotherapies that block IL-4 and IL-3. Dupilumab, a
monoclonal antibody that inhibits IL-4/IL-13, was the first biologic agent
approved by the FDA in 2017 for the treatment of moderate-to-severe AD
not responsive to topical therapy in adults AD patients; recently, in June
2022, it was approved for use in children 6 months and older. It is also
approved for use in asthma, chronic rhinosinusitis with nasal polyps, and eosin-
ophilic esophagitis.
A multitude of data has established the efficacy of dupilumab for AD. A
recent systematic review and meta-analysis among 24 publications found that

85.1% of patients had 50% improvement in EASI score, 75% of patients had
59.8% improvement, and 90% had 26.8% improvement with an average reduc-
tion in EASI of 69.6% across all groups [69]. Dupilumab has been shown to be
safe for long-term use [70]. It is known to cause ocular adverse effects, which
tend to appear in the first weeks to months after initiating dupilumab and
resolve over time, even in the absence of treatment cessation [71]. The most
common adverse effect reported is conjunctivitis (reported in 26% of patients);
other adverse effects include blepharitis, uveitis, injection site reactions, head-
ache, and HSV infections [69]. In addition, recent evidence suggests an associ-
ation between dupilumab and inflammatory arthritis, which has been found in
9% of patients and has been shown to resolve after dupilumab cessation [72].
Corticosteroids, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil
Nontargeted systemic immunosuppressive agents can be used in the treatment
of AD when disease burden is not adequately controlled by topical agents, bio-
logic agents, or phototherapy. These pharmacotherapies target inflammation in
a nonspecific manner and are often used for chronic autoimmune diseases. Of
these agents, for long-term treatment, cyclosporine is considered to be the first-
line agent, followed by methotrexate and azathioprine [73]. Systemic steroids
may also be used but should only be used as a short-term therapy in acute, se-
vere exacerbations due to adverse effects including potential to lead to meta-
bolic syndrome and decreased linear growth in children [74].
Phototherapy
Phototherapy may be used for patients with moderate-to-severe AD who are
nonresponsive to first-line treatments. Patients generally attend two to three
sessions weekly with progressive increase in dosing for weeks to months.
Dose is determined based on a patient’s minimal erythema dose and/or Fitzpa-
trick skin type [39]. Of the many subtypes of UVA and ultraviolet B (UVB)
radiation, narrow-band UVB is most commonly recommended by providers
due to its efficacy, availability, and favorable safety profile [39]. UV radiation
has been found to reduce the function of inflammatory cells, induce stratum
corneum thickening, and may limit skin colonization with S aureus [75]. Photo-
therapy has been shown to be efficacious and well tolerated in children [76,77]
with common adverse events including erythema, herpes simplex reactivation,
and polymorphous light eruption [78].

SUMMARY
AD is a common condition among pediatric patients that has the ability to
greatly affect patients’ quality of life. It is thus valuable for pediatricians to
be familiar with AD pathophysiology and treatment modalities. Recent ad-
vances in AD treatment that target known molecular pathways in AD patho-
physiology have greatly impacted the ability of physicians to manage AD,
especially in its severe form. Treatment of AD requires a multifaceted approach
based on a patient’s severity including behavioral modifications, topical and
systemic pharmacologic therapies, and phototherapy. Referral to a

dermatologist may also be considered when an AD diagnosis is uncertain, espe-

cially when considering more serious conditions such as HLH. In addition, pa-
tients should be referred to a dermatologist when AD is not responding to
topical treatments and systemic therapies are being considered.

CLINICS CARE POINTS

First line therapies for atopic dermatitis in the pediatric population may include
topical corticosteroids and topical calcineurin inhibitors.
Moderate to severe cases of atopic dermatitis would benefit from referral to
Dermatology for management with systemic immunosuppressants and new bio-
logic therapies.

DISCLOSURE
The authors report no conflicts of interest or funding sources.

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ADVANCES IN PEDIATRICS

Chest Pain, Palpitations, and

Syncope
Preventing Sudden Cardiac Death in Children

Saar Danon, MDa,b,*

a
Pediatric Cardiology and Congenital Cardiac Catheterization, Miller Children’s and Women’s
Hospital Long Beach, 2701 Atlantic Avenue, Long Beach, CA 90806, USA; bUniversity of Cali-
fornia, Irvine, CA, USA

Keywords
Chest pain Palpitations Syncope Cardiac arrest Sudden cardiac death
Key points
Most pediatric chest pain is noncardiac, but if it is exercise-related or associated
with syncope, cardiac etiology should be ruled out.
Palpitations that start and stop suddenly and are associated with heart rate
greater than 150 are more likely to represent an arrhythmia.
Syncope that is exercise-related, preceded by palpitations, or associated with
chest pain should increase suspicion for cardiac etiology.
Exertional symptoms are more likely to represent cardiac pathology and warrant
further evaluation.

INTRODUCTION
Sudden cardiac death is defined as an abrupt, unexpected death of cardiovas-
cular cause with loss of consciousness within 1 hour of onset of symptoms
[1,2]. Aborted sudden death occurs if spontaneous circulation is restored,
which may lead to long-term morbidity [2]. In either situation, there is a
tremendous impact on the patient, their family, and the community. In an
effort to prevent these events, clinicians need to recognize symptoms to identify
at risk patients. This responsibility falls predominantly on primary care and
emergency physicians. There is often an overlap in symptoms of chest pain,

*Corresponding author. Pediatric Cardiology, 2701 Atlantic Avenue, Long Beach, CA

90806. E-mail address: SDanon@MemorialCare.org

palpitations, and syncope [3,4]. The workup depends on the characteristics of

these symptoms.

GENERAL CONTENT
Patients may present with symptoms or as part of a routine check-up or sports
clearance. Box 1 is a screening tool which expands on previously published ta-
bles intended for screening of athletes [5,6]. This includes personal history,
family history, and physical examination. Any positive findings may warrant
further evaluation and possible referral to cardiology, particularly before
participating in sports.
The history includes questions related to cardiac symptoms, such as chest
pain, palpitations, dyspnea, and syncope/near-syncope. Symptoms that occur
primarily with exertion should raise concern [4,7]. In those situations, patients
should be restricted from playing sports and participating in other strenuous
activity until further evaluation. A prior history of Kawasaki disease, recent se-
vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, or

Box 1: Screening for pediatric cardiovascular disease[5,6]

Medical History
Personal History
1. Chest pain/discomfort related to exertion
2. Palpitations or excessive dyspnea related to exertion
3. Unexplained syncope/near-syncopea
4. History of moderate or severe SARS-CoV-2 infection (past 6 months)
5. History of Kawasaki disease or MIS-C
6. Previous heart murmur or cardiac testing
7. Elevated blood pressure/hypertension
8. Prior restriction from exercise by a physician
Family History
9. Congenital heart disease
10. Premature death or disability <50 y of age attributable to heart disease
11. Hypertrophic or dilated cardiomyopathy, long QT syndrome, other ion
channelopathies, Marfan syndrome or other connective tissue disorder,
arrhythmia, and other genetic cardiac conditions
Physical Examination
12. Heart murmurb
13. Absent or diminished femoral pulses
14. Physical stigmata of Marfan syndrome or other connective tissue disorder
15. Elevated blood pressure/hypertension
a
Judged not to be neurally mediated/vasovagal in origin; increased concern when occurring dur-
ing or after physical exertion.bNot consistent with innocent/physiologic murmur.

multisystem inflammatory syndrome in children (MIS-C) should raise partic-

ular concern in a symptomatic patient due to risk of coronary aneurysm,
myocarditis, and other abnormalities [7–9]. Concerning family history includes
congenital heart disease, premature cardiac death or disability before age 50
years, arrhythmia, or known genetic cardiac disease such as cardiomyopathy,
long QT syndrome and other channelopathies, and Marfan syndrome and
other connective tissue disorders [5].

SYMPTOMS
Table 1 summarizes the symptom characteristics that warrant further cardiac
evaluation.

Chest pain
Patients often equate chest pain with a heart abnormality, despite cardiac chest
pain being rare in pediatrics. The history and physical are instrumental in
deciding whether further evaluation is warranted. Exertional, pressure-like
chest pain is most concerning and warrants an electrocardiogram (EKG) and
echocardiogram. If the pain is sharp, mostly at rest, and self-resolves, it is
much less likely to be cardiac. Other etiologies of chest pain include musculo-
skeletal, respiratory, gastrointestinal, and psychological [7,10].
For musculoskeletal chest pain, precordial catch should be differentiated
from costochondritis and other forms of chest wall inflammation. Precordial
catch is sharp, stabbing, sudden onset, occurs at rest, self-resolves within a

Table 1
Symptom characteristics requiring further cardiac evaluation
Symptom Require further cardiac evaluation Less-concerning characteristics
Chest pain Exercise-related Mostly at rest
Pressure-like, dull Sharp, stabbing, or burning
Associated with palpitations Short duration (seconds)
and/or syncope Related to meals
Self-resolving
Emotionally induced
Palpitations Exercise-related Gradual onset and termination
Start and stop suddenly Occur with orthostatic changes
Associated with near-syncope Preceded by feeling
or syncope lightheaded/dizzy
Heart rate >150 bpm Heart rate <150 bpm
Emotionally induced
Syncope Exercise-related Preceded by feeling
Preceded by palpitations lightheaded/dizzy
Associated with chest pain Following orthostatic changes
Auditory triggers Full and quick recovery
Seizure-like activity Situationala
a
Situational syncope includes syncope associated with coughing, swallowing, micturition, hair grooming,
blood draws, and other situations associated with vasovagal syncope.

few minutes, and is sometimes worse with inspiration. There is no reproducible

chest pain on examination. Patients should be reassured, and no treatment is
needed. In costochondritis, there is inflammation of the chest wall leading to
reproducible chest pain with palpation [7,10]. These patients usually respond
to non-steroidal anti-inflammatory drugs (NSAIDs), typically a 5-day course.
It is important that it is given for this duration to decrease the inflammation
and not just as a response to pain.
Gastrointestinal chest pain is usually related to reflux and/or esophagitis.
The pain is substernal or upper abdominal, may involve a burning sensation,
and can be related to meals [7,10]. The pain often improves with dietary
changes to avoid spicy and fried foods and sometimes requires a trial of antacid
or referral to a gastroenterologist.
Respiratory chest pain may be related to asthma or exercise-induced bron-
choconstriction and may also be infectious in etiology [7,10]. If it is exercise
induced, asthma/bronchoconstriction is difficult to differentiate from cardiac
etiology. This may be achieved with an exercise treadmill study with pulmo-
nary function testing (PFT).
Psychological chest pain can typically be diagnosed based on the history and
normal cardiac examination. There may be a recent stressor, and the symp-
toms exacerbated by fear of a heart attack or other severe cardiac disease. Reas-
surance is helpful in alleviating anxiety related to the chest pain, and there
should be avoidance of unnecessary cardiac testing [7,10].

Palpitations
Palpitations are a common complaint in pediatrics. Some patients describe of a
skipped beat or funny feeling in their chest while at rest, lasting for a few sec-
onds which self-resolves. These symptoms are usually not associated with pa-
thology. If palpitations are longer in duration, an arrhythmia is more likely if
they start and terminate suddenly [4]. Young children may have difficulty
describing what they feel and complain of pain. Palpitations that precede
pre-syncope or syncope, as well as those brought on by exercise, are more
likely to be secondary to an arrhythmia. If the symptoms are related to an
emotional state, this is typically consistent with sinus tachycardia. Often it is
difficult to differentiate whether the anxiety preceded the symptoms or if it
was brought on as a result of feeling the palpitations.
It is helpful to know the heart rate during the symptoms. This used to be
dependent on capturing an episode with a cardiac monitor such as a Holter or
event recorder. With so many wearable devices, many patients have the ability
to check their heart rate during their symptoms. There are also free phone apps
which use the camera to monitor finger pulsations and measure a heart rate. If the
heart rate is less than 150 during the symptoms, an arrhythmia is much less likely
[4]. Parents and patients should download a heart rate app to check their heart
rate when experiencing symptoms. They should maintain a diary documenting
symptoms, approximate duration, associated activity, and heart rate. If there is
concern for an arrhythmia, a home cardiac monitoring study is indicated.

Syncope
There is an overlap in the etiology and terminology of syncope, including
neurally mediated, vasovagal, neurocardiogenic, postural orthostatic tachycardia
syndrome, situational syncope (eg, related to coughing, swallowing, micturition,
hair grooming, blood draws), and other potential causes. If syncope occurs dur-
ing or immediately following exercise, then cardiac etiology needs to be ruled out
and the patient should not participate in exercise until further workup. If the syn-
cope is related to positional changes and there is a prodrome such as dizziness,
pallor, or diaphoresis, then neurally mediated syncope is more likely. If the syn-
cope occurs following palpitations, then an arrhythmia should be considered.
This is often difficult to ascertain as positional changes may lead to palpitations
related to orthostatic sinus tachycardia. Other concerning syncope characteristics
are associated chest pain, auditory triggers, or seizure-like activity. Positive family
history of cardiac disease such as long QT syndrome, other channelopathies,
arrhythmia, and cardiomyopathy should raise concern. EKG is indicated as
part of the workup, and unless there is a clear benign cause for the syncope,
then an echocardiogram is warranted [3].
Most often the neurally mediated causes of syncope may improve with
increased hydration (64–100 ounces of water per day), increased salt intake,
adequate diet without skipping meals, sleep of at least 9 hours per night, and
daily exercises with a goal of 1 hour per day. In addition, if patients feel pre-
syncopal, they should squat down, which may prevent syncope by increasing
preload and cardiac output. If they do faint, they are much less likely to be
injured from a squatting position. If these measures do not improve the symp-
toms, there are medications that may be used to help alleviate the symptoms.

Dyspnea
The shortness of breath or dyspnea is a common symptom although difficult to
differentiate from normal fatigue. This may be concerning if related to activity
and out of proportion to normal dyspnea related to exercise [5,6]. This is sub-
jective and difficult to ascertain. When obtaining a history, it is important to
ask whether this is a new or worsening symptom. These symptoms may
also be related to deconditioning. This is one of the sequalae seen as a result
of the COVID-19 pandemic and shut down of schools, sports, and other
activities.

EVALUATION AND WORKUP

Physical examination
The physical examination, including vital signs, may yield a lot of useful infor-
mation. Box 1 includes physical examination findings, which warrant further
evaluation. Blood pressure should be checked in the right arm using an appro-
priately sized cuff. If the blood pressure is elevated, it should be rechecked after
allowing the patient to be seated and rest for 5 minutes. A blood pressure
95th percentile is classified as hypertension [11]. In patients with orthostatic
symptoms, near-syncope, or syncope, orthostatic vitals should be assessed.

The heart rate and blood pressure are measured following 5 minutes in the su-
pine position, and again 1 and 3 minutes after standing. Orthostatic tachycardia
is defined by an increase in heart rate of greater than 40 with standing, and
orthostatic hypotension is defined as a drop in systolic BP of 20 mm Hg
or diastolic BP of 10 mm Hg within 3 minutes of standing [3,12].
The cardiac examination includes inspection for scars and chest wall defor-
mities. Palpation may identify an increased right ventricular impulse, and
reproducible chest pain or tenderness. Auscultation is performed for rhythm
irregularity, murmurs, and other abnormal heart sounds. An innocent murmur
should be distinguished from a pathologic murmur when deciding whether to
refer to cardiology. A vibratory murmur which is louder in the supine position
is more likely to be physiologic. Auscultation should be performed in the su-
pine and standing positions or with a Valsalva maneuver. This may intensify
a murmur associated with dynamic left ventricular outflow tract (LVOT)
obstruction seen in hypertrophic cardiomyopathy. Both standing and perform-
ing a Valsalva maneuver acutely decrease preload, exacerbating the degree of
LVOT obstruction, which causes a more pronounced murmur. Pulses should
be felt in the right upper extremity and at least one lower extremity. Absent or
diminished femoral pulse or brachial–femoral delay warrants an echocardio-
gram to evaluate for coarctation of the aorta.
Physical signs of Marfan syndrome and other connective tissue disorders,
such as Louis–Dietz and Ehlers–Danlos, warrant further evaluation due to
their association with valvar abnormalities and aortic root dilation, which
carries a risk of aortic dissection [3,13,14]. Although significant valve abnormal-
ities will cause a murmur, patients with even severe aortic root dilation may
have a completely normal cardiac examination.
Electrocardiogram
EKG is usually the first test performed in evaluating patients with cardiac
symptoms. Although a normal EKG (Fig. 1) cannot rule out pathology, an
abnormal result can help guide further workup. It may identify the most com-
mon cause of sudden cardiac death in children, hypertrophic cardiomyopathy,
as well as long QT syndrome (Fig. 2), other ion channelopathies, and Wolff–

Fig. 1. EKG performed in a 12-year old boy with irregular rhythm noted on physical exam-
ination. The EKG demonstrates sinus arrhythmia. This is a normal finding of physiologic heart
rate variation with the respiratory cycle.

Fig. 2. EKG of an 8-year old boy with syncope demonstrating findings of long QT syndrome.
There is significant prolongation of the QT interval. There is also T-wave alternans (asterisk), a
beat-to-beat variability in T-wave morphology, which has been associated with an increased
risk of ventricular tachyarrhythmias and sudden cardiac death. (Image borrowed with permis-
sion from Anjan Batra, MD, MBA, Professor of Pediatrics, University of California, Irvine.)

Parkinson–White syndrome. The EKG is also useful in post-viral myocarditis.

It is important that the EKG is read by a cardiologist experienced in reading pe-
diatric EKGs [15]. The automated read by the machine is often incorrect, and
adult cardiologists may not recognize findings typically seen in children [16].

Echocardiogram
An echocardiogram is a cardiac ultrasound often performed as part of the eval-
uation by a pediatric cardiologist. This is a noninvasive study that provides
both anatomic definition and functional assessment of the heart and great ves-
sels. A complete echocardiogram includes the assessment of systolic and dia-
stolic myocardial function, valvar abnormalities, shunt lesions, chamber
enlargement or thickening, aortic and pulmonary artery abnormalities, and cor-
onary artery anomalies. It is also used in the following progression of disease
once identified. Imaging quality and portability continues to improve, making
it the primary imaging modality in the diagnosis and management of cardiac
disease. Fig. 3 demonstrates echocardiographic findings in a patient who pre-
sented with an aborted sudden death episode and subsequently diagnosed
with hypertrophic cardiomyopathy.

Advanced cardiac imaging

Computed tomography (CT) and MRI are used to obtain cross-sectional im-
ages of the heart, which can be reconstructed into several different planes
and 3-dimensions. This is instrumental in making a correct anatomic diagnosis

Fig. 3. Echocardiogram of a 13-year old boy who collapsed while running track. He was
noted to be in ventricular fibrillation when paramedics arrived and was defibrillated. Echocar-
diogram in two views, long axis (A) and short axis (B), demonstrating a concentrically thick-
ened myocardium consistent with hypertrophic cardiomyopathy. There is a small left
ventricular (LV) cavity and increased dimensions of the interventricular septum (IVS) and poste-
rior wall (PW). Ao, aorta; LA, left atrium.

Fig. 4. CT of anomalous aortic origin of the right coronary artery from the left coronary sinus
in a 14-year old boy who presented with chest pain while running. (A) 3D reconstruction
demonstrating the right coronary artery (RCA) originating from left coronary sinus and
coursing anterior to the aorta (Ao) toward the right. (B) In the cross-sectional image, the
RCA is seen coursing anterior and rightward between the Ao and the pulmonary artery
(PA), where it is at risk for compression during exercise. A, anterior; I, inferior; L, left; P, pos-
terior; R, right; S, superior. *NRCAO (normal right coronary artery origin) is the location
where the RCA normally originates. (Image borrowed with permission from Wilson King,
MD, Associate Professor of Pediatrics, Saint Louis University.)

and in planning surgical or transcatheter interventions. These studies can also

be used to obtain moving images to demonstrate cardiac function and flow.
Cardiac CT uses ionizing radiation to obtain high-resolution images of cardiac
and vascular structures, including the coronary arteries (Fig. 4). Cardiac MRI
uses magnetic fields and radio waves to obtain the images; therefore, there is no
exposure to ionizing radiation. The MRI can provide anatomical and func-
tional data, as well as characterizing myocardial tissue, such as assessing for
myocardial inflammation seen in post-viral myocarditis (Fig. 5).

Home cardiac monitor

Wearable devices and phones are beneficial in identifying the heart rate during
symptoms, and some can even obtain a single-lead EKG. If further cardiac
monitoring is warranted, there are multiple home monitoring devices. These
have become much smaller and are now a single patch with the entire device
embedded and do not require multiple leads and wires. Patients wear these de-
vices from 24 hours up to 30 days in attempt to capture the episodes and make
a definitive diagnosis. Some have the option to include real-time telemetry, so a
physician is notified within minutes of a critical abnormality. The monitors pro-
vide minimum, maximum, and average heart rates during the monitoring
period, quantification of premature atrial and ventricular contractions, and
identification of brady and tachyarrhythmias (Fig. 6). In patients with more
rare symptoms and high suspicion for a potentially life-threatening arrhythmia,
an implantable loop recorder can be placed for up to several years.

Fig. 5. MRI of a 16-year old girl who presented with intermittent chest pain and dyspnea
2 weeks following a viral illness. (A) Short axis view depicting the left ventricle (LV) in cross
section, with area of late gadolinium enhancement (LGE), consistent with myocarditis involving
the posterior/inferior LV myocardium. (B) Four-chamber view demonstrating a small pericardial
effusion (PCE) consistent with pericardial inflammation. A, anterior; I, inferior; L, left; P, poste-
rior; R, right; RV, right ventricle; S, superior. (Image borrowed with permission from Wilson
King, MD, Associate Professor of Pediatrics, Saint Louis University.)

Fig. 6. Holter monitor of a 16 year old female with palpitations, with sudden onset and termi-
nation, lasting from a few seconds up to a minute. The Holter captures a 5 beat run of ventric-
ular tachycardia (red arrows).

Exercise studies
In patients who have exertional symptoms, an exercise study can be done to
simulate a similar situation to what the patient was doing while experiencing
symptoms. An exercise treadmill study can be performed with EKG, blood
pressure, and pulse oximeter monitoring. This can detect exercise-induced
abnormal blood pressure response, ischemic changes, arterial desaturation,
and rhythm disturbances (Fig. 7). If there is concern for exercise-induced
asthma/bronchoconstriction, PFT can be performed before and after exercise
with the assessment of response to bronchodilator therapy. To obtain addi-
tional metabolic information, a cardiopulmonary exercise test is performed
with expiratory gas analysis through a mouthpiece analyzer. This is usually
reserved for patients with known underlying heart disease to differentiate car-
diac from noncardiac cause of symptoms or exercise limitations.

Fig. 7. Treadmill Exercise study in a 14 year old male with hypertrophic cardiomyopathy.
There are ischemic T-wave changes (red arrows) followed by an abrupt change in rhythm
(blue arrow) to Torsades de Pointes, a polymorphic ventricular tachycardia. (Image borrowed
with permission from Anjan Batra, MD, MBA, Professor of Pediatrics, University of California,
Irvine.)

Cardiac catheterization and electrophysiologic studies

Attributable to availability of multiple noninvasive imaging modalities and
other diagnostic studies, cardiac catheterization is most often reserved for pa-
tients once a diagnosis is made, and there is indication for an interventional
procedure. It is usually performed with general anesthesia, and catheters are
inserted via the vein and artery, typically the femoral vessels. Pressure mea-
surements and blood gases are obtained from the cardiac chambers and vascu-
lature, and imaging is performed by the direct injection of contrast. Various
interventions may be performed for structural abnormalities, including device
closure of defects and abnormal vasculature, balloon valvuloplasty and angio-
plasty, stent placement, and transcatheter valve replacement.
Electrophysiologic studies are performed in a similar manner, using catheters
and specialized software to map the electrical activity of the heart. An
arrhythmia can be induced for diagnostic purposes. If an abnormal electrical
focus or pathway is identified, it can be ablated with radiofrequency or cryoa-
blation. If indicated, a permanent pacemaker or automatic implantable
cardioverter-defibrillator (AICD) can be placed (Fig. 8).

Genetic testing
Cardiovascular genetic testing is becoming more prevalent but should be used
with caution. Although it may identify a known pathogenic chromosomal ab-
normality or gene mutation, often results include a variant of unknown clinical
significance. It is most useful if there is a known family history of inheritable
genetic cardiac disease. In these situations, if the affected gene is identified,
then genetic testing can be performed in blood-related family members to assess
whether they have the same gene mutation. Otherwise, screening with

Fig. 8. Chest X-ray demonstrating placement of an automatic implantable cardioverter-

defibrillator (AICD) in a patient with hypertrophic cardiomyopathy following an episode of
aborted sudden cardiac arrest.

diagnostic studies such as EKG and echocardiogram may need to be performed

at regular intervals. There are other scenarios where genetic testing may be use-
ful, but it should be reserved to situations with high likelihood of disease.
Appropriate pretesting and posttesting counseling should be performed in these
situations [17].

DISCUSSION
Symptoms that patients perceive to be cardiac in origin often cause significant
anxiety. This is exacerbated by the publicity following sudden cardiac death in
a child, despite these being very rare occurrences. Although chest pain, palpi-
tations, and syncope are usually benign, the challenge is to recognize and diag-
nose those associated with pathologic conditions that increase the risk for
sudden cardiac death. The two most common causes in the pediatric popula-
tion are hypertrophic cardiomyopathy and coronary artery abnormalities,
but there are multiple other causes that need to be ruled out when patients pre-
sent [1,2,18]. The history and physical examination often provide sufficient in-
formation, but additional testing is sometimes required to make a definitive
diagnosis or rule out pathology. Primary care and emergency physicians see
most of these patients and need to recognize the concerning characteristics of
these symptoms. If the symptoms are primarily exercise-related, patients
should discontinue physical activity until evaluation by a cardiologist. An
EKG helps in deciding whether to refer to a pediatric cardiologist, but a nega-
tive test does not rule out pathology.
Some patients may not present with specific complaints, but as part of an
annual physical or sports clearance. Although concern for cardiac disease is
sometimes focused on athletics, only 25% of cases of sudden cardiac death
are sports-related [2]. EKG is not part of the routine sports screening physical
examination. This is controversial in the United States but is mandated in some
countries such as Italy and Israel. Although there are some data that EKG
screening decreases the incidence of sudden death in athletes, there are also
data to the contrary [5,15,19,20]. Currently, the American Heart Association
and American Academy of Pediatrics (AAP) do not recommend including
EKG as routine sports screening for cardiovascular causes of sudden death.
In patients who have recent infection with SARS-CoV-2 with moderate or
severe symptoms, EKG should be performed before clearance to participate
in sports, and if abnormal, referred to cardiology before clearance [21]. In those
with asymptomatic or mild infection, EKG should be performed if they had
any cardiac-related symptoms. Patients should then follow a gradual return
to play protocol, and if they experience symptoms with exercise, discontinue
sports and have further evaluation. The reason for this is possible cardiac
inflammation or myocarditis related to SARS-CoV-2 infection. The AAP has
additional screening recommendations regarding previous SARS-CoV-2 infec-
tion, which may be found on their website [21].
Regardless of the cardiac diagnosis, the terminal rhythm resulting in sudden
cardiac arrest and death is pulseless ventricular tachycardia (VT) or ventricular

fibrillation (VF) [1,22]. The definitive treatment is defibrillation, and survival

depends on how soon after the onset of the VT/VF it is performed [23]. Until
the time of defibrillation, it is important to perform good quality cardiopulmo-
nary resuscitation (CPR). Automated external defibrillators (AED) have
become much more readily available. They do not require medical expertise
and are present in many school, athletic complexes, airports, and other public
places. It is critical that when someone suddenly collapses, immediate action is
taken. Education of school and athletic personnel on appropriate CPR and defi-
brillation with an AED is crucial. In patients determined to be high risk for sud-
den cardiac arrest, an AICD can be placed.

SUMMARY
Chest pain, palpitations, and syncope are common complaints in pediatrics.
Clinicians need to identify patients at risk for sudden cardiac death. The
history and physical examination often provide adequate information, but
additional testing and referral to pediatric cardiology are sometimes indicated.

CLINICS CARE POINTS

Sudden cardiac death is defined as an abrupt, unexpected death of cardiovascu-

lar cause with loss of consciousness within 1 hour of onset of symptoms.
The 2 most common causes of sudden cardiac death in the pediatric population
are hypertrophic cardiomyopathy and coronary artery abnormalities.
Exercise related symptoms including dyspnea, chest pain, palpitations, and syn-
cope warrant further diagnostic evaluation.
Most pediatric chest pain is non-cardiac and includes musculoskeletal, gastrointes-
tinal, respiratory, and psychological etiologies.
Wearable devices and phones are very helpful in documenting heart rate during
symptoms of palpitations.
Palpitations that start and stop suddenly with documented heart rate >150 are
more likely to represent an arrhythmia.
Neurally mediated causes of syncope often improve with increased hydration and
salt intake, adequate diet, improved sleeping habits, and daily exercise.
Sinus arrhythmia is a common cause of irregular rhythm and represents a normal
finding of heart rate variation with the respiratory cycle.
Genetic testing for cardiovascular diseases should be performed with caution and
appropriate counseling due to frequent results of unknown clinical significance.
When evaluating cardiac symptoms, the history and physical examination often
provide sufficient information, but additional testing and referral to pediatric cardi-
ology are sometimes indicated.

DISCLOSURES
The author does not have any commercial or financial conflicts of interest.

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ADVANCES IN PEDIATRICS

Care of Transgender and

Gender-Diverse Children and
Adolescents
Jennifer K. Yee, MDa,b,*, Catherine S. Mao, MDa,b
a
Division of Endocrinology, Department of Pediatrics, Harbor-UCLA Medical Center, David
Geffen School of Medicine at University of California, Los Angeles; bThe Lundquist Institute of
Biomedical Innovation at Harbor-UCLA Medical Center, 1000 West Carson Street, Harbor Box
446, Torrance, CA 90509, USA

Keywords
Transgender Gender diversity Gender identity Gender affirmation
Adolescents Children
Key points
Transgender and gender diverse (TGD) individuals comprise a patient population
that experiences societal discrimination and health care disparities.
All pediatric practices should create a safe and supportive clinic environment so
that TGD patients feel comfortable with establishing care and returning for follow-
up.
All pediatric health care workers should commit to gaining knowledge and skills
on gender development to provide gender-affirming care to children and
adolescents.
Social transition is the primary focus of TGD management in the prepubertal
child. The timing and degree of social transition depend on each individual’s
own pace.
Pediatricians and other pediatric health care professionals should encourage
families to accept the child/adolescent’s gender identity and use the chosen
name and pronouns to promote optimal health outcomes.

INTRODUCTION
Transgender and gender diverse (TGD) individuals comprise a patient popula-
tion that experiences societal discrimination and health care disparities. This

*Corresponding author. E-mail address: jyee@lundquist.org

article discusses the approach to medical care for children and adolescents who
identify as transgender or as gender-diverse individuals. The aim of the article is
to provide an overview of the concepts of care for this patient population, the
current challenges, and a general approach to providing gender-affirming care
by the primary care pediatrician.
The sex of an individual is usually assigned at birth based on external anat-
omy or chromosomes. An individual’s internal sense of gender, i.e., gender
identity, begins to develop around the age of 2 to 4 years and may continue
to evolve through adolescence. An individual is cis-gender if he or she identifies
with the sex assigned at birth. Gender incongruence refers to gender identity or
expression that differs from a person’s birth sex. Gender incongruence is not
always associated with distress and is no longer considered a mental disorder
[1]. However, when psychological distress or social discomfort occurs as a
result of gender incongruence, this situation is called gender dysphoria. Trans-
gender refers to gender identity that does not match the assigned sex, with feel-
ings that continue in a consistent, persistent, and insistent pattern. Nonbinary
refers to individuals who identify as neither male nor female, whereas gender
fluid is is the term used when a person identifies as either male or female at
various time points.
In a systematic review of published studies, the proportions of adults who
identified as transgender ranged from 0.3% to 0.5%. Among children and ad-
olescents, the proportions ranged from 1.2% to 2.7% [2]. In the 2017 of US
high school students, the percentage of youth identifying as transgender was
estimated to be 1.8% [3]. In studies that inquired more expansively about
gender identity, the proportions of individuals reporting gender diversity was
0.5% to 4.5% among adults and 2.5% to 8.4% among children and adolescents
[2].
The best practices for the health care approach to TGD individuals have
been evolving. Since 1979, the World Professional Association for Trans-
gender Health (WPATH) has published standards of care (SOC) guidelines,
and the most up-to-date version 8 is now available as of 2022 [1]. In 2017,
the Endocrine Society, in collaboration with international professional societies
including the Pediatric Endocrine Society, published their updated clinical prac-
tice guidelines [4]. This publication includes tables for dosing of hormonal treat-
ments and schedules for medical surveillance, including children and
adolescents. In 2018, the American Academy of Pediatrics (AAP) published
a policy statement that summarized essential concepts, endorsed the Endocrine
Society guidelines, and suggested an overall approach for pediatric health care
providers to provide gender-affirming care in the context of developmental
considerations [5]. While the AAP and Endocrine Society publications remain
valuable resources, perspectives of care continue to evolve. The 2022 WPATH
SOC version 8 encompasses the most updated perspectives by recognizing a
wider spectrum of gender diversity and the importance of individualized care
and presents revised criteria for treatment options for greater flexibility and
to reduce unnecessary barriers to care. More specifically, SOC version 8 has

expanded the sections relevant to pediatric care with new articles to address
prepubertal children separately from adolescents.
The AAP 2018 policy statement describes 4 categories of gender affirmation:
social affirmation, legal affirmation, medical affirmation, and surgical affirma-
tion. This article focuses on social and medical affirmation from the pediatri-
cian’s office.

MENTAL HEALTH OUTCOMES

Transgender individuals experience minority stress [6] and demonstrate dispar-
ities in health outcomes, including higher rates of suicidality than cis-gender peers
[7,8]. There is growing evidence to support positive outcomes for gender-
affirming medical interventions in TGD adolescents although the body of the liter-
ature is still relatively small with heterogenous outcomes involving various stages
of gender-affirming interventions. In a longitudinal follow-up study, de Vries and
colleagues [9] from a Dutch clinic reported that transgender individuals who had
received multidisciplinary care beginning in adolescence, along with hormonal
and eventual surgical interventions, had better psychological functioning after-
ward, with well-being comparable to that of the general population. In a cohort
of 315 TG and nonbinary youth in the United States, Chen and colleagues [10]
reported that after 2 years of gender-affirming hormone therapy (GAHT), youths
demonstrated improvement in survey scores for appearance congruence and psy-
chosocial functioning. In a cohort of 50 adolescents who completed quality-of-life
surveys, undergoing pubertal suppression or GAHT resulted in decreases in
depression scores and suicidal ideation over time, with improvement in quality-
of-life scores [11]. In a cohort of 104 transgender or nonbinary youths, those
who received hormonal interventions (pubertal suppression, GAHT, or both)
demonstrated lower odds of depression and suicidality at 12 months from baseline
than those who did not receive medical interventions [12].

PROMOTION OF A SAFE AND SUPPORTIVE CLINIC

ENVIRONMENT
TGD individuals may have previously experienced discrimination in the health
care setting. Creating a safe and supportive clinic environment is important for
TGD patients to feel comfortable with establishing care and returning for
follow-up. Pediatric clinics may implement the following procedures to provide
a gender-affirming environment.
At check-in, when confirming identity, clinic staff should routinely inquire
whether the child/adolescent uses names or pronouns different from sex at birth
or sex on legal identification documents (ID).
Clinic staff should use the patient’s preferred name and pronouns at each point
of contact during the clinic encounter.
Add fields in the electronic medical record system to accommodate chosen
names and pronouns that may be different from their identification documents.
Include a nonbinary option for sex at birth, now that some states include this as
a third option on birth certificates.

Designate at least one all-gender bathroom.

Include staff members’ preferred pronouns on workplace identification badges.
Staff members may verbally introduce themselves by name and pronouns.
Hold regular staff training or in-services to review practice implementation to
sustain the gender-affirming health care environment.

PREPUBERTAL CHILDREN
During childhood, gender exploration is part of normal development and
should not always be assumed to represent TGD identity. If a child reveals
possible gender incongruence or dysphoria, the pediatrician should focus on
establishing a collaborative relationship with the patient and family members
to promote the child’s overall wellbeing through an environment of acceptance.
Health care providers should stay open-minded and nonjudgemental and avoid
steering the child toward any gender. The SOC 8 recommends against conver-
sion therapy. It is important to understand and be respectful of each child in
his/her/their own cultural context to support gender development.
Any licensed and qualified medical provider with knowledge and skills per-
taining to gender identity in childhood can diagnose gender incongruence; the
person does not need to be a mental health provider. The general aim of the
assessment is to determine whether the patient expresses gender incongruence
in a consistent pattern, with persistence over time and repeated assertions (insis-
tence). The diagnostic criteria for gender incongruence of childhood are based
on the World Health Organization (WHO) International Classification of Ed-
itors, 11th revision, ICD-11 classification under ‘‘conditions related to sexual
health’’ (not mental or behavioral disorders). Diagnostic criteria for gender
dysphoria are described in the American Psychiatric Association Diagnostic
and Statistical Manual of Mental Disorders (DSM-5 TR) [13] and the Endo-
crine Society Guidelines [4].
From ICD-11: ‘‘Gender incongruence of childhood is characterized by a
marked incongruence between an individual’s experienced/expressed gender
and the assigned sex in prepubertal children. It includes a strong desire to be a
different gender than the assigned sex; a strong dislike on the child’s part of his
or her sexual anatomy or anticipated secondary sex characteristics and/or a
strong desire for the primary and/or anticipated secondary sex characteristics
that match the experienced gender; and make-believe or fantasy play, toys,
games, or activities and playmates that are typical of the experienced gender
rather than the assigned sex. The incongruence must have persisted for about
2 years. Gender variant behavior and preferences alone are not a basis for
assigning the diagnosis [14].’’

During the clinic encounter, the pediatrician can elicit the patient’s feelings
about gender identity, using open-ended questions based on the situations
described in the criteria. In follow-up assessments, the pediatrician can revisit
the criteria and evaluate for evolution in the patient’s desires and preferences.
During the physical examination of a child with gender incongruence, the
pediatrician may observe evidence of gender expression in grooming by

clothing, hairstyle, or other expressions. Pubertal staging should be performed

in anticipation of development of secondary sex characteristics that may poten-
tially cause distress in the child. Thelarche (breast development) is the first sign
of puberty in a child with female birth sex and may occur as early as 8 years of
age (or 7 years of age in African Americans of female birth sex). A sexual matu-
rity rating (SMR) stage 2 is represented by areolar enlargement with or without
breast buds limited to the areolae, while progression to stage 3 involves expan-
sion of breast glandular tissue beyond the areolae. Testicular enlargement is the
first sign of puberty in a child with male birth sex, occurs physiologically as
early as 9 years of age, and is usually represented by size exceeding 3 mL in
volume. An orchidometer may be a helpful examination tool to estimate testic-
ular volume. Pubic hair is a sign of adrenarche and does not signify the onset of
puberty.
Social transition is the primary focus in the management of TGD in the pre-
pubertal child. The pediatrician should provide guidance and support during
discussions about potential positives and negative aspects of social transition-
ing. The following are various aspects of social transition for the pediatrician
to address with the family during the process.
Timing and degree of social transition occur at each individual child’s own
pace.
Social transition may be situational (eg, at home, at school, out in public, and
so forth).
The patient may choose a new name and pronouns.
The patient might begin wearing different clothing, hair styles, or accessories.
Gender expression varies, ranging from minimal to significant changes.
TGD youth should not be expected to adopt stereotypical behaviors of the new
gender identity to any particular degree or extent.
The patient chooses when to come out to others: ie, immediate family members,
extended family, friends, classmates, acquaintances, people in public, and so
on.

Family acceptance of the child’s gender identity is important. Parents should

be informed that gender incongruence is likely to persist. In the Trans Youth
Project, out of 317 youth who initiated transgender social transitioning (at a
mean age of 8.1 years), 94% identified as transgender 5 years later. Of the
cohort population, 1.3% experienced retransition but identified as transgender
at 5 years, 3.5% identified as nonbinary, and only 2.5% had detransitioned to
being cis-gender [15]. Although parents often express concerns about who the
child ‘‘is going to be’’ in the context of future outcomes, they should also reas-
sure the child of being accepted in the present, now and today, during any
point in transition. Parents are recommended to use the patient’s chosen
name and pronouns, as this has been associated with lower depression and sui-
cidality in older youths [16]. (Using the prior ‘‘dead-name’’ and pronouns
might provoke feelings of denial or rejection.)
When approaching the age of puberty, the pediatrician should discuss ex-
pected pubertal changes of the birth-assigned gender and the affirmed gender

identity, along with potential interventions to stop pubertal progression when it

starts. Gonadotropin-releasing hormone (GnRH) agonist therapy becomes an
option after the onset of puberty, at SMR stage 2. The discussion of gender-
affirming medical therapy, fertility issues, fertility preservation, and future sur-
gical options can also be introduced if the pediatrician and family are comfort-
able with the discussion. Pediatric endocrinologists may be consulted for
anticipatory guidance about future GAHT. TGD children in the prepubertal
age group are not candidates for surgical interventions.
Behavioral health specialists are valuable collaborators in the clinical care of
the TGD patients in childhood. Mental health referrals should be made if there
are mental health concerns that might interfere with diagnosing gender incon-
gruence, ability to consent, or gender-affirming medical interventions. Licensed
clinical social workers may conduct social assessments to address social deter-
minants of health that might interfere with progress in medical care. Psycho-
therapy by a licensed family therapist or clinical psychologist may help
youths better navigate family and societal stressors and provide a safe place
for exploration of gender identity or other behavioral concerns. Family mem-
bers may also want psychotherapy to process their own emotions about the
child with gender diversity. Referrals to psychiatry may be indicated for sus-
pected mood disorders, suicidality, or other psychiatric comorbidities.

ADOLESCENTS
During adolescence, the pediatrician’s management of the TGD patient should
include the assessment for gender incongruence and provision of support for
social transition, but also should include evaluation for capacity to give
informed consent for gender-affirming medical interventions. Adolescence is
characterized by cognitive, emotional, and social development, with a growing
focus on peer relationships. Although adolescents often prioritize satisfying im-
mediate needs and exhibit risk-taking behaviors, their cognitive development
includes greater capacity for abstract thinking and an emerging ability to
consider potential outcomes from their actions. This development is important
for the adolescent to consent for hormonal and surgical interventions.
The diagnostic criteria for gender incongruence in adolescents are separate
from the criteria for children, but are the same as for adults, and are based
on the ICD-11 definition under sexual health. Diagnostic criteria for gender
dysphoria are described in the American Psychiatric Association Diagnostic
and Statistical Manual of Mental Disorders (DSM-5 TR) [13] and the Endo-
crine Society Guidelines [4].
From ICD-11: "Gender incongruence of adolescence and adulthood is char-
acterized by a marked and persistent incongruence between an individual’s
experienced gender and the assigned sex, which often leads to a desire to
‘transition’, to live and be accepted as a person of the experienced gender,
through hormonal treatment, surgery, or other health care services to make the
individual’s body align, as much as desired and to the extent possible, with the
experienced gender. The diagnosis cannot be assigned prior to the onset of

puberty. Gender variant behavior and preferences alone are not a basis for
assigning the diagnosis [14].’’

Social transition is an essential part of TGD management in adolescence and

should be supported by the pediatrician beginning with the same basic aspects
as for prepubertal children. However, adolescents may possess unwanted phys-
ical features of their assigned sex and may benefit from additional health edu-
cation on methods to address this, such as chest binding and genital tucking.
Education on these options before complaints of dysphoria may be helpful
so that adolescents can implement them safely as needed.
Chest binding is the practice of wearing a tight-fitting garment to flatten the
breasts by transgender boys/men. Binders are available through retailers or
nonprofit foundations. Patients should be advised that binders should fit snugly,
but not to wear them too tight. Risks include interference with breathing, skin
rashes, and rib fractures [17], while benefits include better life satisfaction
through reduction of misgendering [18].
Genital tucking is the practice of moving the testicles and/or penis closer to the
body to promote a smoother, flatter appearance in the genital area for trans-
gender girls/women. Tight-fitting underwear designed for this purpose may be
used. The literature about tucking is extremely sparse. Risks include skin irrita-
tion, discomfort/pain, and decreased spermatogenesis [19,20]. Patients
should receive education on the potential reduction of fertility and fertility
preservation options.

Menses cessation may be desired by postmenarcheal transgender adolescents

assigned female at birth to reduce psychological distress from the monthly
events. Pediatricians may offer individualized management, including the
following options: estrogen-progestin pills taken continuously; progestins
administered orally, as a depot injection, or subcutaneous implant; or intrauter-
ine devices. If a GnRH agonist is considered, the pediatrician should follow the
recommendations in the next section to evaluate the patient as a candidate.
Gender-affirming medical treatment may be desired by the adolescent,
including pubertal suppression and GAHT. A biopsychosocial assessment is
recommended to determine an adolescent’s readiness for GAHT. This assess-
ment may be done by any health care provider and is not required to be a
mental health provider. The SOC 8 recommends gender-affirming medical
treatment if the adolescent
Meets the ICD-11 diagnostic criteria,
Demonstrates persistence,
Has the capacity to provide informed consent,
Has addressed any mental health concerns that might impact the above,
Has received education on reproductive effects and potential fertility preser-
vation methods,
Is at least at SMR stage 2 for puberty.

For pubertal suppression, GnRH agonists are used and are considered a revers-
ible treatment. Several formulations are available in depot injection forms

(leuprolide, triptorelin) for varying intervals (1 month, 3 months, or 6 months), or

as a subcutaneous implant (histrelin, duration 1 year). The safety and efficacy of
this class of medications have been established through the data for central pre-
cocious puberty, the official indication approved by the Food and Drug Admin-
istration (FDA) since 1993. However, emerging evidence from off-label use in the
transgender patient population appears consistent in the suppression of luteiniz-
ing hormone (LH) and follicle-stimulating hormone (FSH) [21]. The prescribing
pediatrician should become familiar with the GnRH agonist(s) label content
including risks and benefits and obtain informed consent with the patient and
parent/guardian(s) with initiation of treatment. A referral to pediatric endocri-
nology may be considered for GnRH agonist therapy if desired.
GnRH agonist therapy initiated in early puberty limits the maturation of gam-
etes, and therefore, fertility may be impaired [22] for those who do not go
through puberty of their assigned sex at birth. Patients should be counseled on
reduced fertility potential and assisted reproductive technology options.
The use of GnRH agonists also leads to reversible hypogonadism during use,
and therefore, the impact on bone mineralization has been investigated
because adolescence is a time of bone mineral accrual. Several studies on
GnRH agonist use in adolescents suggest that bone mineral density (BMD) z-
scores might decrease during treatment but the addition of cross-sex hormone
therapy causes BMD to be restored or improve [23–25].
Common side effects include local reactions to the injection, and symptoms
associated with hormone withdrawal (eg, hot flashes in assigned female sex).
A rare serious side effect is pseudotumor cerebri [26].
Insurance coverage of GnRH agonists for transgender care will vary by health
plan. If a prior authorization is required, providing precise prescription infor-
mation will reduce delays in processing, i.e. name the exact brand of medi-
cation, specify the pediatric formulation (not adult formulation), and note the
duration of depot action.

GAHT in adolescents involves administration of hormones to induce the pu-

berty of the identified gender. The SOC 8 has removed the previous minimum
start age (previously 16 years) and acknowledges that care plans should be indi-
vidualized and that patients may be assessed to start earlier than this age if
appropriate. General pediatricians may consider referrals to specialists such
as pediatric endocrinologists as needed for GAHT. This section of the article
will provide a general overview of the approach to GAHT, but does not
include sufficient detail. We recommend that pediatricians who are providing
GAHT should consult the Endocrine Society Guidelines [4] for dosing and
monitoring schedules.
Pediatricians should conduct a thorough baseline physical examination and
laboratory evaluation to assess cardiovascular and metabolic risk factors that
may be impacted by GAHT.
The Endocrine Society guidelines include detailed tables for suggested
evaluations to be performed at baseline and in follow-up intervals during
GAHT dose escalation and for long-term monitoring [4].

Informed consent with the patient and parent should be obtained, specific to the
gender being affirmed (testosterone for transmen, estrogen for transwomen).
Informed consent should include effects of hormone therapy that are reversible
and those that are irreversible; the risks and benefits of GAHT; impact on
fertility; and fertility preservation options (and that it might not be covered by
insurance).
Informed consent forms through Fenway Health are available online for
public use (fenwayhealth.org).
For transgender boys/men, testosterone is most commonly administered in
formulations delivered by injection intramuscularly, subcutaneously, or deliv-
ered transdermally. Testosterone use is considered off-label in transgender
care.
For transgender girls/women, 17-beta estradiol is the estrogen of choice, and
may be delivered through oral tablets, transdermal patches, or injected as a
conjugated ester. Ethinyl estradiol has increased risk of venous thromboembo-
lism and is not recommended for GAHT.
Additional formulations of testosterone or estradiol may be available for con-
ditions such as hypogonadism, but the ability to achieve levels with sufficient
effect for transgender care might be unknown.
To initiate gender-affirming puberty, low doses of testosterone or estradiol
would be used in the beginning, with interval dose escalation to goal effect
over 2 years.
Suggested dose ranges are provided in the Endocrine Society Guidelines [4].

If a transgender patient has consultants from different specialties or disci-

plines, care should be coordinated among providers as a team. A multidisci-
plinary team would address gender identity, social development and support,
assessment for co-occurring mental health concerns, and capacity for consent
[1]. The team members are encouraged to communicate during the course of
evaluation and follow-up so that there is general consensus and consistent sup-
port as a patient proceeds in gender-affirming care. However, access to multi-
disciplinary care or specialists may be limited, and lack of specialized services
should not be a barrier to patient care.
The SOC 8 notes that gender-affirming surgical treatment in adolescents is not
recommended until the adolescent has at least 12 months of GAHT unless hor-
mone therapy is either not desired or is medically contraindicated. GAHT leads
to anatomical, physiological, and psychological changes with the peak effect ex-
pected at 1–2 years. To ensure sufficient time for psychological adaptations to
the physical changes for the adolescent, 12 months of GAHT is suggested, but
a longer period of time may be required for presurgical preparation or other rea-
sons. Surgical interventions are irreversible, and the ability of the young person
to consent with comprehension of the long-term effects on fertility and reproduc-
tion is essential. Discussion of the evaluation for surgery and of specific surgical
procedures is beyond the scope of this article. The SOC 8 discusses potential
benefits of surgery before the age of 18 years for chest contouring, breast
augmentation, and vaginoplasty but recommends against phalloplasty younger
than age 18 years because of complexity and high complication rates.

WORKING WITH PARENTS AND FAMILY MEMBERS

Parents and family members may experience a variety of reactions and
emotions to their child’s identity as TGD. The range of reactions may include
but are not limited to acceptance, denial, and grief. Sometimes parents or
family members have conflicting reactions that contribute to a more complex
family dynamic [27]. In the literature, better family functioning has been
associated with better mental health outcomes in TGD adolescents [28].
The role of the pediatrician in supporting the patient in the family context
is to first listen with an open mind, provide evidence-based information
(and correct misinformation) about gender identity, establish respect among
the family members, and promote acceptance of the child’s gender identity.
Providing knowledge about gender development and promoting gender liter-
acy may help family members to view the process of gender development
more positively. If the transgender youth and the parents(s)/guardian(s)
demonstrate conflict, it may be helpful to interview them separately. Referral
for psychotherapy and/or family therapy may be helpful in improving family
dynamics.

SUMMARY
The pediatrician’s office may be the first place where a child or adolescent re-
veals TGD identity. To promote a gender-affirming environment, pediatric
practices can educate staff members and implement workflows that will pro-
mote patient comfort and safety in the exploration of gender diversity.
Providing gender-affirming care will reduce gender minority stress in the health
care setting and encourage patients to return for follow-up visits, thereby opti-
mizing the emotional and physical health of TGD children and adolescents.

CLINICS CARE POINTS

Transgender individuals experience minority stress and demonstrate disparities in

health outcomes, including higher rates of suicidality compared to cis-gender
peers.
There is growing evidence in the medical literature that supports positive outcomes
for gender-affirming medical interventions in TGD adolescents.

References
[1] Coleman E, Radix AE, Bouman WP, et al. Standards of care for the health of transgender
and gender diverse people, version 8. International Journal of Transgender Health
2022;23(Suppl 1):S1–259.
[2] Zhang Q, Goodman M, Adams N, et al. Epidemiological considerations in transgender
health: a systematic review with focus on higher quality data. International Journal of Trans-
gender Health 2020;21(2):125–37.
[3] Johns MM, Lowry R, Andrzejewski J, et al. Transgender identity and experiences of violence
victimization, substance use, suicide risk, and sexual risk behaviors among high school stu-
dents - 19 states and large urban school districts, 2017. MMWR Morb Mortal Wkly Rep
2019;68(3):67–71.

[4] Hembree WC, Cohen-Kettenis PT, Gooren L, et al. endocrine treatment of gender-
dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline.
J Clin Endocrinol Metab 2017;102(11):3869–903.
[5] Rafferty J. Ensuring comprehensive care and support for transgender and gender-diverse
children and adolescents. Pediatrics 2018;142(4):e20182162.
[6] Johns MM, Zamantakis A, Andrzejewski J, et al. Minority stress, coping, and transgender
youth in schools-results from the resilience and transgender youth study. J Sch Health
2021;91(11):883–93.
[7] Thoma BC, Salk RH, Choukas-Bradley S, et al. Suicidality disparities between transgender
and cisgender adolescents. Pediatrics 2019;144(5):e20191183.
[8] Kingsbury M, Hammond NG, Johnstone F, et al. Suicidality among sexual minority and
transgender adolescents: a nationally representative population-based study of youth in
Canada. CMAJ (Can Med Assoc J) 2022;194(22):E767-e74.
[9] de Vries AL, McGuire JK, Steensma TD, et al. Young adult psychological outcome after pu-
berty suppression and gender reassignment. Pediatrics 2014;134(4):696–704.
[10] Chen D, Berona J, Chan YM, et al. Psychosocial functioning in transgender youth after 2
years of hormones. N Engl J Med 2023;388(3):240–50.
[11] Achille C, Taggart T, Eaton NR, et al. Longitudinal impact of gender-affirming endocrine
intervention on the mental health and well-being of transgender youths: preliminary results.
Int J Pediatr Endocrinol 2020;2020:8.
[12] Tordoff DM, Wanta JW, Collin A, et al. Mental health outcomes in transgender and nonbi-
nary youths receiving gender-affirming care. JAMA Netw Open 2022;5(2):e220978.
[13] American Psychiatric Association, Diagnostic and statistical manual of mental disorders, 5th
ed., 2013. https://doi.org/10.1176/appi.books.9780890425596.
[14] International Classification of Diseases, Eleventh Revision (ICD-11), World Health Organi-
zation (WHO) 2019/2021 https://icd.who.int/browse11. Licensed under Creative Com-
mons Attribution-NoDerivatives 3.0 IGO licence (CC BY-ND 3.0 IGO).Organization WH.
International statistical classification of diseases and related health problems, 11th edition,
2019.
[15] Olson KR, Durwood L, Horton R, et al. Gender identity 5 years after social transition. Pedi-
atrics 2022;150(2):e2021056082.
[16] Russell ST, Pollitt AM, Li G, et al. Chosen name use is linked to reduced depressive symptoms,
suicidal ideation, and suicidal behavior among transgender youth. J Adolesc Health
2018;63(4):503–5.
[17] Peitzmeier SM, Silberholz J, Gardner IH, et al. Time to first onset of chest binding-related
symptoms in transgender youth. Pediatrics 2021;147(3):e20200728.
[18] Julian JM, Salvetti B, Held JI, et al. The impact of chest binding in transgender and gender
diverse youth and young adults. J Adolesc Health 2021;68(6):1129–34.
[19] Trussler JT, Carrasquillo RJ. Cryptozoospermia associated with genital tucking behavior in a
transwoman. Rev Urol 2020;22(4):170–3.
[20] Turley R, Potdar N. A case of oligoasthenoteratozoospermia following genital tucking: trans-
gender fertility preservation. Reprod Sci 2023; https://doi.org/10.1007/s43032-023-
01168-1.
[21] Mejia-Otero JD, White P, Lopez X. Effectiveness of puberty suppression with gonadotropin-
releasing hormone agonists in transgender youth. Transgender Health 2021;6(1):31–5.
[22] Cheng PJ, Pastuszak AW, Myers JB, et al. Fertility concerns of the transgender patient. Transl
Androl Urol 2019;8(3):209–18.
[23] Vlot MC, Klink DT, den Heijer M, et al. Effect of pubertal suppression and cross-sex hormone
therapy on bone turnover markers and bone mineral apparent density (BMAD) in trans-
gender adolescents. Bone 2017;95:11–9.
[24] Schagen SEE, Wouters FM, Cohen-Kettenis PT, et al. Bone development in transgender ad-
olescents treated with GnRH analogues and subsequent gender-affirming hormones. J Clin
Endocrinol Metab 2020;105(12):e4252–63.

[25] Klink D, Caris M, Heijboer A, et al. Bone mass in young adulthood following gonadotropin-
releasing hormone analog treatment and cross-sex hormone treatment in adolescents with
gender dysphoria. J Clin Endocrinol Metab 2015;100(2):E270–5.
[26] Omar AA, Nyaga G, Mungai LNW. Pseudotumor cerebri in patient on leuprolide acetate
for central precocious puberty. Int J Pediatr Endocrinol 2020;2020(1):22.
[27] Fey B, Ahola J, Casoy F. Treating Family members of transgender and gender-
nonconforming people: an interview with eric yarbrough, M.D. Focus. Am Psychiatr Publ
2020;18(3):296–9.
[28] Katz-Wise SL, Ehrensaft D, Vetters R, et al. Family functioning and mental health of trans-
gender and gender-nonconforming youth in the trans teen and family narratives project.
J Sex Res 2018;55(4–5):582–90.

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Aap 2023 Revistas

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ADVANCES IN

PHILADELPHIA LONDON TORONTO MONTREAL SYDNEY TOKYO

RONALD BRUCE HIRSCHL, MD, Arnold G. Coran Collegiate Professor of Pediatric

CONTENTS VOLUME 70  2023

Preface: Is It Over Yet? Did I Miss Anything? xxi

Pediatrics in Disasters: Evolution of a Hybrid Global

The Effects of the COVID-19 Pandemic on Violent Injuries

Burns in Children: Accidental or Inflicted? 45

Medical Child Abuse: A Review by Subspecialty 59

Screening and detection: roles of all medical providers 62

Challenges in Diagnosing and Treating Myasthenia

Guillain–Barre Syndrome in Children and Adolescents 91

Appendicitis in Children 105

evidence-based clinical treatment pathways that reduce

Surgery for Thyroid Disease in Children 123

Lower Urinary Tract Obstruction in Newborns 131

urethral valves and urethral atresia. Despite available

Chronic Myeloid Leukemia in Children and Adolescents 145

Update on Atopic Dermatitis 157

Chest Pain, Palpitations, and Syncope: Preventing

often provide adequate information, but additional testing

Is It Over Yet? Did I Miss Anything?

atypical features. On the other hand, Guillain-Barre syndrome, though rare in

COVID-19 emergency over, which impacts on a multitude of things, personal,

E-mail address: cberkowitz52@gmail.com

Lisa Umphrey, MDa,b,*, Joseph Wathen, MDa,b,

Abbreviations: LMIC, low- to middle-income country; PEDS, pediatrics in disasters course.

Short-term revision planning

identified and integrated ‘‘short-term’’ content revisions for all 10 modules. In

Notably, participants appreciated the flexibility and broader audience captured

2019 to 2021 student course feedback

UMPHREY, WATHEN, CHAMBLISS, ET AL

and administrators was a positive theme that emerged, as was consideration of

disaster-related activities. Our course data indicated relatively few participants

The Effects of the COVID-19

*Corresponding author, E-mail address: cgeorgeades@mcw.edu

CLASSIFICATIONS OF VIOLENT INJURY

Box 1: Definitions used to describe violent injury in the literaturea

(continued on next page)

Only pediatric data presented in table.

GUN VIOLENCE ARCHIVE DATA

DATABASES AND INFORMATION SYSTEMS

[95% CI 1.00–1.35], P ¼ .046) [32]. In addition, the mean number of children

Medicine 2020-December intentional,

(continued on next page)

records from Incident Absolute/percent

(continued on next page)

Post-SHO Male: 622 0–4: 94 Non-Hispanic Government: Child Opportunity

(continued on next page)

Regarding socioeconomic status (SES), a few studies showed no differences

RELEVANT FACTORS FOR CONSIDERATION

records of background checks, of which a large proportion of individuals were first-

programs, through schools has been shown to be promising [67,68]. Working

CLINICS CARE POINTS

Although institution-specific studies identified few significant differences in the vol-

Gun Violence Archive data, which is an independent collection of gun violence

Katherine W. Canty, MDa,*, Catherine A. DeRidder, MDb

*Corresponding author. E-mail address: katherine.canty@childrens.harvard.edu

In a multicenter study of 215 children younger than 10 years who were

Ultimately, the burns were determined to be consistent with an abusive immersion

Time (s) to deep

destruction is often larger than what is visible externally. Sequelae of electrical

to sunlight. The affected skin subsequently becomes hyperpigmented and may

CLINICS CARE POINTS

Medical Child Abuse

E-mail address: Megge@stanford.edu

repeated caregiver solicitation of more medical opinions; and withdrawal from

BARRIERS TO IDENTIFICATION AND REPORTING

REPORTING TO CHILD PROTECTIVE SERVICES

SCREENING AND DETECTION: ROLES OF ALL MEDICAL

Box 1: Core concepts

Covert video surveillance (CVS) has documented proof of dramatic acts of

Primary care provider’s role

Tips for records review

Box 2: Sample note to medical team

reported, objective observations, plan, and response to treatment. Some EMRs

CONTENTS VOLUME 70 2023

Medical Child Abuse is an underrecognized and underreported form of child

In newborns and young infants with hypotonia, consider congenital myopathies