FEBRUARY

MARCH 2021
2023
Vol. 22
24 No. 2
3
www.neoreviews.org

ARTICLES
PERSPECTIVE
Collaboration between
Gastroesophageal Maternal-Fetal
Reflux Disease in
Medicine and Neonatology When
Neonates: Facts and Figures
Counseling at Extreme Prematurity
Fetal Heart Rate Tracing Category II:
ARTICLES
A �road Category in Need of Stra� fi ca�
Diabetes Mellitus in Pregnancyon
Small and Mighty: Micronutrients
Maternal
at Hematologic Condi�
the Intersection ons and
of Neonatal
Fetal/Neonatal Outcomes of Pregnancy
Immunity and Infection
CongenitalObesity
Cutaneous
andCandidiasis
Pregnancy
in Preterm Infants
COMPLEX
INDEX OF SUSPICION FETAL
IN THE CARE
NURSERY
Fetal Sacrococcygeal
Umbilical Teratoma
Cord Bleeding and the
in a Neonate
Development of Hydrops
Dry Gangrene of Feet in an
Apparently WellDIAGNOSIS
VISUAL Neonate
Sudden Onset of awith
An Infant Unilateral Erythematous
Intrauterine Growth
Preauricular
Restriction, aMass in Umbilical
Single a PretermArtery,
Infant
and Abdominal Wall Defect
VISUAL DIAGNOSIS
Unilateral Neck Swelling in a Newborn
VIDEO CORNER
A Neonate with Obstructed Nasal Breathing
EQUITY, DIVERSITY, AND INCLUSION CASE STUDIES
Defining Gender in Infant Care

NeoReviews® and NeoReviewsPlus™ are supported,

in part, throu�h an educa�onal �rant from A��o�
Nutri�on, a proud supporter of the American Academy
of Pediatrics.

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 NeoReviews
PERSPECTIVE
e137 Collaboration between Maternal-Fetal Medicine and
Neonatology When Counseling at Extreme Prematurity
Anne Sullivan, Bridget Donovan, Brett C. Young, Christy Cummings
ARTICLES
e144 Diabetes Mellitus in Pregnancy
Jean Ricci Goodman
e158 Small and Mighty: Micronutrients at the Intersection of
Neonatal Immunity and Infection
Laura G. Sherlock, Nancy F. Krebs
e175 Congenital Cutaneous Candidiasis in Preterm Infants
Chelsea Shope, Alexandra Ritter, Samantha Karlin, Lara Wine Lee,
Colleen H. Cotton
INDEX OF SUSPICION IN THE NURSERY
e181 Umbilical Cord Bleeding in a Neonate
Alina Ivashchuk, Wendy Sturtz
e184 Dry Gangrene of Feet in an Apparently Well Neonate
Kumar Ankur, Aparna Prasad, Gaurav Kharya, Sanjeev Chetry
e188 An Infant with Intrauterine Growth Restriction, a Single
Umbilical Artery, and Abdominal Wall Defect
Senthil Kumar Arumugam, Ramalingam Rangasamy, Raeshmi Ramalingam,
Maheshwari Doreraju
VISUAL DIAGNOSIS
e191 Unilateral Neck Swelling in a Newborn
Juliana da Silva Cardoso, Cristina Godinho, H
elder Morgado,
Jo~ao Pinheiro de Amorim, Sara Leite, Isabel Mendes
VIDEO CORNER
e195 A Neonate with Obstructed Nasal Breathing
Juniper Lyra Burch, Emily Whitesel, Brian Manzi, Eelam Adil
EQUITY, DIVERSITY, AND INCLUSION CASE STUDIES
e199 Defining Gender in Infant Care
Kathryn J. Paul, Daria Murosko, Vincent C. Smith, Diana Montoya-Williams,
Joanna Parga-Belinkie
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Answer Key appears on page e205.
 PERSPECTIVE

Collaboration between Maternal-Fetal

Medicine and Neonatology When
Counseling at Extreme Prematurity
Anne Sullivan, MD*‡ Bridget Donovan,†§ Brett C. Young, MD, FACOG,†§ Christy Cummings, MD*‡
*Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA
†
Department of Maternal-Fetal Medicine, Beth Israel Deaconess Medical Center, Boston, MA
‡
Department of Pediatrics, Harvard Medical School, Boston, MA
§
Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, MA

PRACTICE GAPS

Joint-specialty counseling between neonatology and maternal-fetal medicine

specialists with families anticipating the birth of an extremely premature infant
is vital to ensure effective communication between teams and facilitate
informed decision making. Furthermore, this collaboration helps to minimize
inconsistent messaging and bias. Clinicians should be aware of best practices
for specialty collaboration and ways to overcome barriers in practice.

OBJECTIVES After completing this article, readers should be able to:

1. Describe current evidence and practice guidelines regarding joint-

specialty counseling between maternal-fetal medicine/obstetrics and AUTHOR DISCLOSURES Drs Sullivan,
neonatology at extreme prematurity. Donovan, Young and Cummings have
disclosed no financial relationships
2. Summarize barriers to joint-specialty counseling and communication at relevant to this article. This commentary
extreme prematurity. does not contain a discussion of an
unapproved/investigative use of a
3. Describe joint-specialty counseling methods to enhance communication, commercial product/device. The authors
collaboration, and counseling at extreme prematurity. are grateful for support by the Eunice
Kennedy Shriver National Institute of
Child Health and Human Development
(NICHD) of the National Institutes of
ABSTRACT Health under award number
R01HD094794 (CC PI) for work related to
Enhanced communication between maternal-fetal medicine (MFM)/obstetrics this review, cited. The content is solely
and neonatology regarding counseling at extreme prematurity remains an the responsibility of the authors and
essential element of prenatal consultations. Together, the obstetrician and does not necessarily represent the official
views of the National Institutes of Health.
neonatologist can collaborate to provide timely and synergistic information to
affected couples during a dynamic period, combining their expertise to
elucidate values and formulate a plan that best supports the pregnant person ABBREVIATIONS

and partner’s goals. Such collaboration can help resolve differing perspectives AAP American Academy of
between specialties, minimize redundancy and inconsistencies, and mitigate Pediatrics
ACOG American College of
the impact of clinician bias. Best practices for joint-specialty collaboration Obstetricians and Gynecologists
include a precounseling clinician huddle, contemporaneous counseling by IAT Implicit Association Test
MFM specialists/obstetricians and neonatologists with the expectant parents MFM Maternal-Fetal Medicine
SMFM Society for Maternal-Fetal
or individualized sequential counseling if preferred by the couple, and a
Medicine

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 postcounseling clinician debrief. This approach can help establish a trusting relationship with families facing
possible extremely preterm delivery and optimize the overall counseling experience. Future efforts focused on
education and research, including a standardized approach to educational curricula among fellowship programs,
should be emphasized.
INTRODUCTION
Prenatal counseling at extreme prematurity remains challeng-
ing for maternal-fetal medicine (MFM) specialists/obstetricians
and neonatologists and emotionally difficult for pregnant per-
sons and their partners. Extremely preterm birth near the limit
of viability has been defined broadly as 20 0/7 to 25 6/7
weeks’ gestation in an executive summary provided by a joint
workshop that included the American Academy of Pediatrics
(AAP), Society for Maternal-Fetal Medicine (SMFM), and
American College of Obstetricians and Gynecologists (ACOG).
(1) The AAP further specifies that due to uncertain outcomes
in infants born between 22 and 24 weeks’ gestation, a shared
decision-making approach between expectant parents and clini-
cians, emphasizing parental values regarding the best interest
of the child, should be used regarding delivery room manage-
ment for these infants. (2) Both the AAP and ACOG recom-
mend multidisciplinary counseling of families with threatened
preterm delivery during the periviable period, specifying that
obstetricians and neonatologists should communicate be-
fore and jointly during prenatal counseling with families.
(2)(3) Practicing neonatologists and MFM specialists/obste-
tricians also prefer joint counseling, reporting that it im-
proves the counseling provided to patients. (4)(5)(6)
However, in practice, such joint-specialty counseling oc-
curs rarely, despite recommendations from both the AAP
and ACOG. One recent study found that 52% of 424 neona-
tologists and 35% of 115 MFM specialists reported ‘rarely or
never’ applying this approach, though they acknowledged its
importance. (4)
OBSTETRICAL ROLE IN COUNSELING
During the joint-specialty counseling, MFM specialists/obstetri-
cians can outline various obstetrical management options for
the current clinical situation to help facilitate decision making
by the pregnant patient. MFM specialists/obstetricians can use
their expertise to discuss maternal interventions such as pre-
ferred mode of delivery (cesarean or vaginal), administration of
betamethasone, and magnesium sulfate treatment, along with
the role of fetal monitoring. In addition, there needs to be on-
going discussion regarding potential maternal risks with certain
obstetrical management decisions including cesarean delivery
and expectant management with attempts at delaying delivery
for neonatal benefit; this second topic is particularly important
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in the setting of severe pregnancy complications such as pre-
eclampsia with severe features. Together, the MFM spe-
cialist/obstetrician and neonatologist can collaborate to
provide timely and synergistic information for this dy-
namic periviable period, combining their expertise to elu-
cidate a plan that best supports the pregnant patient’s
goals.
NEONATOLOGY ROLE IN COUNSELING
Although the neonatologist can provide a wide breadth of
information, the general goal of counseling is to comple-
ment obstetrical information and then transition the focus
to the plan for care of the infant after delivery. The goals
of counseling are to assess family understanding, elucidate
values and preferences, and share prognostic information
and its limitations to reach a decision regarding delivery
room management for the infant. Expectant parents need
information, including potential outcomes, both short-
and long-term, to make informed decisions about poten-
tial resuscitation and treatment of their premature infant.
This can include information surrounding complications
of prematurity, what to expect in the delivery room, and
procedures that the infant may need after birth. However,
despite efforts to refine our predictions of neonatal sur-
vival and long-term morbidities, there remains significant
uncertainty in our ability to prognosticate for families.
This is related to institutional and clinician differences,
and characteristics inherent to individual infants. (7) Neo-
natologists should be transparent with families about ex-
isting uncertainty, but use evidence-based frameworks
when able, to help guide parental decision making.
Some MFM specialists/obstetricians and neonatologists
may have extensive experience or advanced training in
complex decision making amidst uncertainty or palliative
care. Clinician experience and comfort level varies. In one
study, neonatologists reported feeling more comfortable
discussing comfort care compared with MFM respond-
ents. (4) In simulation studies of counseling expectant pa-
rents, most neonatologists (compared with obstetricians)
emphasized medical information surrounding short-term
neonatal complications, resuscitation decisions, and content
related to values, comfort/suffering, and uncertainty. (8) These
concerns are vital to address in light of previous studies,
 which found that parents tended to value religion, spirituality,
and hope in their decision making and place relatively little
weight on the clinician’s prognostication regarding morbidity
and mortality. (9)(10)(11)(12) A discussion of comfort-focused
end-of-life care should also include a discussion of palliative
care options in the delivery room and beyond. With joint-
specialty collaboration, these differences in experience and
comfort level may be balanced by including both teams in the
counseling.
IMPORTANCE OF MFM/NEONATOLOGY
COLLABORATION
Joint-specialty counseling has the potential benefit of bringing
all invested parties together, ensuring communication be-
tween teams and facilitating informed decision making, while
minimizing redundancy and inconsistent messaging. When
performed asynchronously, counseling can often result in de-
ferrals to the other specialty about specific treatments or out-
comes. In one study, both obstetricians and neonatologists
commonly deferred questions about steroid administration to
the other specialty, (8) leaving couples with potentially unan-
swered questions. Such deferments to the other specialty can
erode communication with expectant parents and may im-
pede decision making. However, when specialties collaborate,
the counseling provided can be complementary and allow
each specialty to supplement each other’s expertise. (8)
Collaboration between MFM specialists/obstetricians
and neonatologists can also help resolve differing perspec-
tives between the specialties. In one study, disagreement
between obstetricians and neonatologists about proactive
management of infants between 23 and 26 weeks’ gesta-
tion was associated with an inconsistent management
approach such as a lack of antenatal steroids and/or a vag-
inal delivery despite delivery room resuscitation, increas-
ing the odds of neonatal death in the first day after birth.
(13) These differing perspectives can stem from a delay in
translation of neonatal outcome data into practice and the
subsequent dissemination of this into a policy statement,
which can lead to significant differences within and across
institutions in the management of extremely premature
infants. (7)(14)
Such differences in perspectives and policies should be
discussed among specialties prior to meeting with a family to
ensure consistency in information and recommendations
presented. The provision of life-sustaining interventions for
infants born at 22 weeks’ gestation, and often the reticence
to do so, offers such an example. Despite policy statements
from the AAP, ACOG, and SMFM to use shared decision
making at this gestational age regarding resuscitation and
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provision of antenatal steroids, (1)(2)(15) institutional inertia
and beliefs surrounding neurodevelopmental outcomes can
lead to differential treatment of these infants. (14) Change re-
quires a deliberate team effort and collaboration between ob-
stetricians and neonatologists.
From the family’s perspective, inconsistencies may convey
a sense of disjointedness rather than a ‘team’ approach. One
recent qualitative study on parental perspectives about the ap-
proach to counseling at extreme prematurity found that any
disagreements or inconsistencies presented by the different
teams was distressing for families and affected parental trust
in the care team, highlighting the importance of joint-specialty
communication and consistent messaging. (16) In this same
study, participating expectant parents did not have strong pref-
erences about joint versus sequential counseling, though
some couples reported feeling overwhelmed by information
or number of clinicians present. (16) Rather, what mattered
most to families was consistent communication and team
synergy. (16) This is supported by a recent literature review of
parental experiences in receiving a prenatal diagnosis, which
showed that multidisciplinary counseling with synergism
among disciplines decreased parental distress and allowed pa-
rents to feel empowered and supported. (17)
Lastly, collaboration between obstetricians and neonatolo-
gists during perinatal counseling may help mitigate the impact
of clinician bias inherent in the counseling process. Message
framing and implicit biases can affect counseling and patient
decision making. (18)(19)(20)(21) In one study, an obstetrician’s
willingness to perform an induction, administer steroids, or
perform a cesarean delivery at 23 weeks’ gestation was signifi-
cantly associated with physicians’ personal characteristics, geo-
graphic region, and religious and political views. (21) When
counseling occurs in a silo, these biases have the potential to
cloud the counseling process and potentially affect decision
making. With joint-specialty counseling or a precounseling
huddle, differing perspectives (both personally and profession-
ally) and adherence to evidence-based recommendations may
help mitigate potential bias. This may be limited, however, by
pessimism from both the obstetricians and neonatologists
when describing long-term outcomes, (22) and additional bias
mitigation techniques (see “Bias Training” section later) may
be necessary.
BARRIERS TO JOINT-SPECIALTY COUNSELING
Several barriers exist to joint-specialty counseling. In a busy
perinatal unit, time constraints and clinical obligations can
make it difficult to coordinate a mutual time for antenatal
counseling. This may be exacerbated at night when staffing
may be reduced. In one study, most respondents found that
Vol. 24 No. 3 MARCH 2023 e139
 the greatest barrier was difficulty coordinating counseling
with another service due to clinical responsibilities, followed
by the longer time needed for adequate, high-quality counsel-
ing. (4)
In addition, the complexities of antenatal counseling
and resuscitation decisions may be taught differently to
neonatologists and MFM specialists during training, lead-
ing to differing perspectives and barriers to joint counsel-
ing. One study surveyed fellowship program directors in
both neonatology and MFM to compare trainee education
related to periviability. (23) Overall, educational curricula
(topics covered as well as learning methods used) varied
significantly between specialties, with MFM programs be-
ing less likely to provide education on ethics of extremely
premature infant resuscitation and more likely to provide
no training at all on periviable deliveries. (23) In this same
study, there was significant variation in practices related to
delivery room decision making and management at ex-
treme prematurity as well as how specialties communi-
cated with regard to counseling. (23) Fellows exposed to
conflicting and variable approaches during training may
then practice with similar inconsistencies and model this
behavior for future trainees, thus promulgating nonopti-
mal practices.
It is possible that differing opinions regarding care may
also act as a barrier to joint counseling. Obstetric and neo-
natal perspectives can be different, (13)(23) which may be
related to differences in practice patterns or education be-
tween MFM specialists/obstetricians and neonatologists
with regard to counseling at extreme prematurity. (23)(24)
There may also be differences in risk/benefit determina-
tions of a specific treatment decision for both the pregnant
person and fetus, which may cause divergences in willing-
ness to offer or recommend certain interventions. These
differing perspectives can lead to inconsistent and asyn-
chronous counseling and the potential of providing con-
flicting messages to expectant parents. (8)(13)(25)
RECOMMENDATIONS FOR APPROACH
Precounseling Huddle
Before counseling expectant parents who are anticipating
an extremely preterm delivery, it is important for all team
members (ideally, MFM/obstetrics, neonatology, social
work, and the bedside nurse) to meet (Fig 1). This huddle
offers the opportunity for all disciplines to review the clini-
cal scenario; share their perspectives, including maternal
and fetal risks and prognosis; discuss possible options;
share any initial insights into the family’s perspectives and
values, if known; align messaging; and determine who
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will communicate with the family. This is also an impor-
tant time for each team member to acknowledge their per-
sonal biases and put those aside before counseling the
family. (26)
Joint Counseling
When possible, joint counseling by MFM specialists/obste-
tricians and neonatologists is the recommended approach
for consultations for extremely premature gestational ages,
generally 22 to 24 6/7 weeks’ gestation. During such
counseling, it is important to tailor the approach and overall
decision making to the needs of the expectant parents and/
or support persons and include these important individuals
in the consultation, as able. This includes elucidation of pa-
rental values, preferred way to receive information (eg, big
picture or details), and preferred degree of involvement in
decision making. This can be achieved by learning about
the family through open-ended questioning and active
listening. Information should be presented to expectant
parents using simple, concise, and unbiased language and
possible options for interventions should be offered. Planned
follow-up should be discussed with the family, emphasizing
the need to provide time for couples to process the informa-
tion. The Table summarizes recommendations for counseling
with multidisciplinary colleagues.
In some circumstances, joint counseling may not be
possible or preferable due to time constraints and diffi-
culty coordinating specialties. If there will be a substantial
delay in speaking with the family due to these constraints,
it may be more practical to meet with the family separately.
In addition, some families may prefer separate counseling
due to the potential for information overload or being over-
whelmed by the number of clinicians present. (16) In these
Pre-counseling huddle
Joint specialty collaboraon/
communicaon
Joint-counseling
Post-counseling
1. Incorporate and
debrief understand parental
Share informaon learned
Confirm care plan decisions
values/priories
Recognize implicit bias
Confirm follow-up
Share informaon with
Document in maternal chart
family including
maternal and fetal risks
3. Develop joint understanding 2. Offer opons, including
of plan comfort care
Acknowledge dynamic Focus on shared-decision
decision-making process making re: obstetrical and
Plan follow-up delivery room plan of care
Figure 1. Recommendations for approach to joint-specialty counseling at
extreme prematurity.
 Table. Best Practices for Joint Counseling with Multidisciplinary Colleagues
Best Practice
Use similar phrasing to avoid confusion
Invite clarification if jargon is being used
Avoid biased language and terminology
Acknowledge emotional challenges of such conversations
Invite participation
Politely interrupt when needed
Redirect the conversation
Show respect and gratitude for team members to promote trust
Examples/Terminology
Use descriptors and terminology that the expectant parents
understand.
“What do you mean by comfort care?”
“Can you explain that in a different way?”
Give balanced examples (e.g. predicted functional abilities in
addition to potential disabilities, mortality/survival statistics).
“Many loving couples facing these decisions feel overwhelmed.”
“What is your perspective?
“What do you think the best-case outcome is?”
“Is it okay if I add/ask something?”
“I wonder if we should move to talking about … ”
“Thank you for your insights.”

situations, the precounseling huddle should still occur with Bias Training
both specialties reconvening after speaking with the family Although joint counseling may mitigate some elements of
to ensure a shared plan. Figure 2 illustrates differing situa- personal clinician bias, there are evidence-based strategies
tions when joint versus asynchronous counseling may be that can be implemented to educate health care professio-
preferred. nals on acknowledging, addressing, and decreasing biases.
To establish intention, clinicians should be encouraged to
Postcounseling Debrief complete the Implicit Association Test (IAT), (27) an on-
A postcounseling debrief among clinical team members line exercise to measure several types of unconscious
should occur to share information learned, confirm any biases (eg, race, disability, religion). Once biases are recog-
care plan decisions made, and discuss the follow-up that nized, lessening the effects involves bias mitigation inter-
is needed. Finally, a summary of the couple’s preferences ventions. One recent study found a reduction in the effect
and goals, key points of the counseling, and components of implicit bias and personal preferences in a hypothetical
of the shared care plan should be clearly documented in prenatal setting after completing the IAT and an educa-
the maternal chart. tional module on patient counseling. (28) Such bias-reduc-
tion interventions should be offered to faculty, in addition
Joint MFM/Neonatology
Individualized, sequenal to being incorporated into all MFM, OB, and neonatal-
counseling (but with pre-
contemporaneous perinatal medicine fellowship program curricula.
counseling specialty
counseling may be
collaboraon) may be
preferred:
preferred:
Standardized Checklists
A standardized protocol for prenatal counseling may hin-
Delivery may be imminent Difficult to coordinate a mutual
and decision-making is
me between family and der a personalized approach. However, a practice plan or
mulple clinicians, which
me-sensive would delay counseling checklist that includes collaboration between MFM spe-
To allow for real-me
communicaon surrounding Family prefers smaller cialists/obstetricians and neonatologists may help estab-
mutual plan, parcularly with group to avoid being
complex cases and decision- overwhelmed
lish joint huddle and counseling as a standard approach
making
Informaon received in and minimize the potential impact of clinician bias and
To migate individual smaller chunks may be variability (Fig 3). Such a practice plan should also include
clinician biases absorbed beer by certain
families national and local data to help decrease variability in man-
To avoid redundancy or
Time for processing agement strategies for pregnant persons and extremely
between counseling
inconsistent messaging
sessions desired by family premature infants. (2) Standardized guidelines and prac-
tice plans have been successfully implemented, accepted,
and used by neonatologists and obstetricians (29)(30) and
perceived as useful by families. (31)

CONCLUSIONS AND FUTURE DIRECTIONS

Figure 2. Comparison of situations when joint versus sequential counsel-
ing may be preferred. (Note: Some families may desire an initial joint con-
Joint obstetrical and neonatal counseling at extreme prematu-
sultation with subsequent visits/follow-up sequentially.) rity plays an important role in providing a consistent, team-

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 Prenatal Consultaon Joint-Specialty Communicaon Checklist:

Obstetrician/MFM Specialist:___________________ Neonatologist:_____________________

Joint consultaon:  yes  no (if no,  not feasible or  parental preference)

Preparaon:
 Review pernent medical records
 Hold pre-counseling huddle with MFM/OB, Neonatology, Social Work and Nurse
 Share clinical perspecves regarding maternal/fetal risks, permissible opons, and prognosis
 If known, share parental understanding, perspecves, values, preferences
 Create a safe space with privacy and limited interrupons
 Ensure support person(s) present, if able

Counseling:
 Use simple, concise, unbiased language
 Inquire about decision-making preferences
 Ask how couple is referring to their ancipated child and mirror parental preferred terms and language
 Clearly describe permissible opons, prognosis, risks/benefits
 Elucidate/help arculate parental preferences and values
 Ensure consistency between MFM/OB and Neonatology

Post-Counseling:
 Debrief/huddle between MFM/OB and Neonatology
 Discuss follow-up plan
 Complete documentaon including specifics about plan as well as parental preferences and values

Figure 3. Example prenatal joint-specialty communication checklist. (29)(32)

based approach to care for the maternal-fetal dyad. This ap-

proach can help establish and maintain a trusting relationship
with expectant parents and optimize the overall counseling ex-
perience. Despite recommendations from professional socie-
ties to perform such integrated counseling and the overall
perceived importance among clinicians, the practice still re-
mains infrequent. Future efforts focused on education and re-
search, including standardized approaches to educational
curricula among MFM/obstetrics and neonatology fellowship
programs, should be emphasized. Future research should ex-
amine the use of any developed curricula or institutional
guidelines, their application to subsequent cases, and resulting
patient-centered outcomes.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the risks of neurodevelopmental impairments in
term infants, late preterm infants, moderately preterm in-
fants, and extremely preterm infants, with and without
neurologic risk factors.
• Know the issues in the organization of perinatal care (e.g.,
regionalization, transport, practice guidelines, benchmark-
ing data, quality improvement).
• Know the components of bereavement counseling prior
to, during, and after the death of a newborn infant, in-
cluding palliative care.
References
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executive summary of a Joint Workshop by the Eunice Kennedy
Shriver National Institute of Child Health and Human
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Academy of Pediatrics, and American College of Obstetricians and
Gynecologists. J Perinatol. 2014;34(5):333–342
2. Cummings J; Committee on Fetus and Newborn. Antenatal
counseling regarding resuscitation and intensive care before 25
weeks of gestation. Pediatrics. 2015;136(3):588–595
3. Obstetric Care Consensus No. Obstetric care consensus no. 6
summary: periviable birth. Obstet Gynecol. 2017;130(4):
926–928
4. Reed R, Grossman T, Askin G, Gerber LM, Kasdorf E. Joint
periviability counseling between neonatology and obstetrics is a rare
occurrence. J Perinatol. 2020;40(12):1789–1796
5. Geurtzen MR, Van Heijst A, Hermens R, et al. Preferred
prenatal counselling at the limits of viability: A survey among
Dutch perinatal professionals. BMC Pregnancy Childbirth.
2018;18(1):7
6. Krick JA, Feltman DM. Neonatologists’ preferences regarding
guidelines for periviable deliveries: do we really know what we want?
J Perinatol. 2019;39(3):445–452

• Recognize the controversies associated with treating ex- 7. Rysavy MA, Li L, Bell EF, et al; Eunice Kennedy Shriver National
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Antenatal consultations at extreme prematurity: a systematic review of
parent communication needs. J Pediatr. 2018;196:109–115.e7
11. Tucker Edmonds B, Savage TA, Kimura RE, et al. Prospective
parents’ perspectives on antenatal decision making for the
anticipated birth of a periviable infant. J Matern Fetal Neonatal Med.
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12. Payot A, Gendron S, Lefebvre F, Doucet H. Deciding to resuscitate
extremely premature babies: how do parents and neonatologists
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13. Guinsburg R, Branco de Almeida MF, Dos Santos Rodrigues Sadeck
L, et al; Brazilian Network on Neonatal Research. Proactive
management of extreme prematurity: disagreement between
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14. Lantos JD. Ethical issues in treatment of babies born at 22 weeks of
gestation. Arch Dis Child. 2021;106(12):1155–1157
15. American College of Obstetricians and Gynecologists, Society for
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clinical-guidance/practice-advisory/articles/2021/09/
use-of-antenatal-corticosteroids-at-22-weeks-of-gestation.
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perspectives on prenatal counseling at extreme prematurity. J Pediatr.
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perinatal decisions. Pediatrics. 2008;122(1):109–118
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21. McKenzie F, Robinson BK, Tucker Edmonds B. Do maternal
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willingness to intervene when managing periviable deliveries?
J Perinatol. 2016;36(7):522–528
22. Saigal S, Stoskopf BL, Feeny D, et al. Differences in preferences for
neonatal outcomes among health care professionals, parents, and
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23. Arzuaga BH, Cummings CL. Practices and education surrounding
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Vol. 24 No. 3 MARCH 2023 e143
 ARTICLE

Diabetes Mellitus in Pregnancy

Jean Ricci Goodman, MD, MBA*
*Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, MO

EDUCATION GAPS

1. Preconceptual glucose control of diabetes mellitus (DM) is critical to

improve outcomes for the pregnant person, fetus, and infant.
2. Optimizing glycemic control in persons with DM throughout pregnancy
and during labor and delivery also improves outcomes.
3. Understanding risks for infants born to persons with DM is important for
postdelivery management.

OBJECTIVES After reviewing this article, readers should be able to:

1. List the complications to the pregnant patient, fetus, and neonate that may
be encountered in pregnancies complicated by diabetes mellitus (DM).
2. Review current approaches to screening and diagnosis of DM in pregnancy.
3. Explain the methods and goals of managing pregestational DM and
gestational DM.
4. Recognize the importance of peri/preconceptual care of pregnant patients
with DM.
AUTHOR DISCLOSURES Dr Goodman
has disclosed no financial relationships
relevant to this article. This commentary ABSTRACT
does not contain a discussion of an
Diabetes mellitus (DM) in pregnancy imposes increased risks for the pregnant
unapproved/investigative use of a
commercial product/device. person, fetus, and infant, which includes miscarriage, congenital anomalies,
accelerated fetal growth, iatrogenic prematurity, preeclampsia, delivery-related
ABBREVIATIONS
trauma, cesarean section, neonatal hypoglycemia, and respiratory distress
syndrome. Preconceptual counseling for people with type 1 or type 2 DM who
ACOG American College of
Obstetricians and Gynecologists
are contemplating pregnancy includes education about these risks, and
ADA American Diabetes Association optimization of glucose control. Fetal screening early in pregnancy in persons
BMI body mass index with type 1 or type 2 DM allows for early diagnosis and therapy optimization. In
BPA bisphenol A
addition, screening for gestational DM in the late second trimester is routine
DKA diabetic ketoacidosis
DM diabetes mellitus given that such pregnancies are also affected. The overall perinatal morbidity
FGR fetal growth restriction and mortality of pregnancies complicated by DM is substantially higher than in
GDM gestational diabetes mellitus
the general obstetric population, proportionate to the level of glucose control.
HbA1C hemoglobin A1C
IADPSG International Association of
Diabetes in Pregnancy Study
Groups
IUFD intrauterine fetal death INTRODUCTION
OGTT oral glucose tolerance test
RDS respiratory distress syndrome
The prevalence of diabetes mellitus (DM) complicating pregnancy continues to
WHO World Health Organization increase worldwide, currently affecting more than 21 million births annually. (1)

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 The prevalence varies according to the demographics of
the population assessed. For example, pregnant persons
from diverse racial and ethnic backgrounds are dispropor-
tionately at risk for gestational DM (GDM) as well as DM
before the pregnancy. (2)
The incidence of type 1 DM has increased to 3% to 4%
over the past 30 years, with environmental factors playing
a major role. (3) Rates are higher in areas with decreased
access to green space and less walkability. (4) Amongst
women who delivered a liveborn infant in the United
States between 2012 and 2016, 0.9% were diagnosed with
pregestational DM and 6% were diagnosed with GDM. (5)
For GDM, the incidence can vary from 5% to 16% depend-
ing on the diagnostic test used. (6) The overall body mass
index (BMI) of the population also significantly affects the
reported incidence; populations with a high BMI have a
much higher risk of GDM (15%) compared to those with a
normal BMI (4%). (7)(8)
CLASSIFICATION, PATHOPHYSIOLOGY, AND
DIAGNOSIS OF DM IN PREGNANT PERSONS
As part of the normal physiologic changes that accompany
any pregnancy, insulin sensitivity increases beginning
early in pregnancy to allow for an increase in maternal fat
storage. (9) This is mediated primarily by human placental
lactogen, but also by estrogen, progesterone, and cortisol.
As the pregnancy proceeds, there is a 2- to 3-fold increase
in peripheral insulin resistance, leading to a state of rela-
tive decline in insulin sensitivity, accompanied by a corre-
sponding increase in insulin production. All of these
physiologic changes are designed to provide energy sub-
strate in the form of glucose to cross the placenta to sup-
port the developing fetus. (9)(10)(11)
Gestational Diabetes
GDM, defined as DM diagnosed during pregnancy, was
not recognized as a unique condition until the 1960s. (12)
GDM essentially results from an inadequate insulin secre-
tory response in combination with peripheral insulin re-
sistance that occurs naturally in pregnancy. Approaches to
the diagnosis of GDM vary widely, though in routine preg-
nancies testing typically occurs between 24 and 28 weeks’
gestation. In 2013, the World Health Organization (WHO)
adopted the International Association of Diabetes in Preg-
nancy Study Group’s (IADPSG) 2010 criteria for GDM.
(13)(14) The IADPSG criteria use a single 2-hour 75-g oral
glucose tolerance test (OGTT). This contrasts with the tra-
ditional 2-step Carpenter and Coustan approach of using a
screening 1-hour 50-g glucola test, followed by a diagnostic
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3-hour 100-g OGTT, which the American College of Ob-
stetricians and Gynecologists (ACOG) recommends based
on a National Institutes of Health consensus summary.
(15)(16) Table 1 summarizes these 2 types of screening ap-
proaches and corresponding diagnostic criteria. (15)(16)(17)
The 2-step diagnostic approach has not been validated against
the IADPSG diagnostic approach. Although ACOG supports
using the 2-step approach, it does acknowledge that the 1-step
approach may be appropriate for certain populations. The
American Diabetes Association (ADA) supports the 1- and 2-
step approaches outlined in Table 1 to diagnose GDM. (17)
Regardless of which approach is used, GDM is separated
into 2 types: GDMA1, which is managed with diet and activ-
ity modifications, and GDMA2, which requires medication.
Whether GDM is solely a disease of late pregnancy is
controversial and needs to be researched further. (18)
Some experts advocate for testing before 24 weeks’ gesta-
tion for those with risk factors such as high BMI, or prior
history of GDM, though consensus about the diagnostic
criteria in early pregnancy has not been established. If
DM is diagnosed early in pregnancy based on the criteria
in Table 1, affected patients are designated as either hav-
ing overt DM (as per the IADPSG) or simply just labeled
as having DM in pregnancy (as per the WHO).
Pregestational DM (Type 1 and Type 2 DM)
The diagnosis of pregestational DM is based on the ADA
criteria as follows:
• Hemoglobin A1C (HbA1C) $6.5% or fasting blood glu-
cose $126 mg/dL (7 mmol/L) or
• 2-hour postmeal glucose $200 mg/dL (11.1 mmol/L) or
• Diabetic ketoacidosis (DKA) or symptoms of DKA with a
random glucose $200 mg/dL (11.1 mmol/L) (19)(20)
Patients with type 1 DM cannot increase their insulin
secretion, which is a needed response during pregnancy.
Patients with type 2 DM are challenged with insulin resis-
tance before pregnancy, which worsens during pregnancy.
Type 1 DM results from destruction of pancreatic islet B
cells via an immune-mediated response. Autoantibodies to
pancreatic islet B cells can be found up to 20 years before the
clinical onset of disease. (21) However, the etiology of type 1
DM is heterogenous. A genetic predisposition and response
to inflammatory mediators, as well as environmental factors
such as infection, poor nutrition, stress gut microbiome, toxic
response to medication, or some combination thereof contrib-
ute to disease development. One or a combination of such
factors affects the developing immune system, resulting in
an abnormal response to inflammatory mediators. (21) A
Vol. 24 No. 3 MARCH 2023 e145
 Table 1. Criteria for Diagnosis of GDM
Screening
IADPSG approach (supported by the WHO)
2-hour 75-g OGTT
Two-step approach (supported by ACOG)a
1. 1-hour 50-g oral glucola drink
2. 3-hour 100-g OGTT
a
Although ACOG supports the 2-step approach, they do acknowledge that the 1-step approach may be appropriate for certain populations.
b
Most centers use a blood glucose level greater than or equal to 135 mg/dL (7.5 mmol/L), but this cutoff is associated with a higher false-
positive rate. (16)
ACOG5 American College of Obstetricians and Gynecologists, GDM5gestational diabetes mellitus, IADPSG5 International Association of
Diabetes in Pregnancy Study Groups, OGTT5 oral glucose tolerance test, WHO5World Health Organization.
synergistic response to genetic and epigenetic environmental
risk factors results in type 1 DM. (22) A father’s history of
type I DM imposes a higher risk that his offspring will inherit
type I DM than the risk to the offspring if the mother is af-
fected. (23)
Similar to type I DM, type 2 DM results from a syner-
gistic response to genetic and epigenetic environmental
risk factors and exposures. However, patients with type 2
DM have adequate insulin secretion with increased resis-
tance to insulin. (22) Ultimately, in response to this in-
creased insulin resistance, there is a progressive loss of
insulin secretion. There is really no standard to diagnose
type 2 DM during pregnancy and patients are traditionally
not labeled as such until postpartum confirmation. Bengt-
son et al developed a model that has 80% sensitivity for
predicting patients who are diagnosed with DM during
pregnancy who are most likely to be diagnosed with type
2 DM after delivery. This model is based on a combina-
tion of clinical indicators such as HbA1C levels, BMI,
family history of diabetes, and an early diagnosis of GDM
(<24 weeks’ gestation). (24) If validated, this approach
may help diabetes prevention efforts among persons with
GDM.
IMPACT OF DM ON PREGNANT PERSONS
Comorbidities such as obesity and hypertension play a role in
the impact of DM during pregnancy. In addition, the impact
is transgenerational as will be discussed further below. DM is
a risk factor for pregnancy-associated hypertension complica-
tions, and chronic hypertension compounds that risk. DM is
associated with an increased risk for infections and poor
wound healing during pregnancy as it is in the nonpregnant
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Diagnosis of GDM
One of the following required:

Fasting blood glucose $92 mg/dL (5.1 mmol/L)

1-hour blood glucose $180 mg/dL (9.9 mmol/L)

2-hour blood glucose $153 mg/dL (8.5 mmol/L)
Blood glucose $135-140 mg/dL (7.5–7.7 mmol/L)b
At least 2 abnormal values:

Fasting blood glucose $95 mg/dL (5.3 mmol/L)

1-hour blood glucose $180 mg/dL (9.9 mmol/L)

2-hour blood glucose $155 mg/dL (8.6 mmol/L)

3-hour blood glucose $140 mg/dL (7.7 mmol/L)
state. Glucose levels in patients with DM are also more erratic
during pregnancy with traditionally higher glucose peak levels
and lower glucose trough levels, respectively. The lower glu-
cose trough levels pose increased risk for DKA with a lower
glucose threshold to trigger this complication.
Public health issues associated with DM during preg-
nancy include worse outcomes in those affected patients
who are socially disadvantaged. (25) In addition, DM in preg-
nancy correlates with long-term cardiovascular and metabolic
risks for pregnant persons and their offspring. (26) Good
glucose control should lessen this effect, though the impact
of treatment during pregnancy on the long-term metabolic
health of the treated patient’s offspring is currently un-
known. (18)
IMPACT OF DM ON THE FETUS
Overall, DM during pregnancy is associated with a 2- to
5-fold increased risk of all fetal anomalies, stillbirth, and
neonatal death, with 50% of infants experiencing compli-
cations such as NICU admission, prematurity, and/or
macrosomia. (1)(25)(27) There is an increased risk for mis-
carriage and structural abnormalities in pregnancies com-
plicated by pregestational diabetes. Poor glycemic control
(as reflected by elevated HbA1C levels at conception and in
the beginning of the first trimester) is associated with an in-
creased risk for miscarriage and major anomalies. (28) The
risks for anomalies are complex and multifactorial. Growth
abnormalities may also affect pregnancies complicated by
either GDM or pregestational DM.
Animal studies have identified the molecular mecha-
nisms of hyperglycemia-induced birth defects, which in-
clude a negative impact on lipid metabolism, excess free-
 radical generation, and aberrant cell death. (29) Fetal
anomalies and growth abnormalities result from epige-
netic alterations (with changes in gene expression) as well
as oxidative stress. (6) Anomaly risk is increased in gen-
eral but particularly for cardiac and neural tube defects.
(6) In a cohort study of pregnant patients with type 1 DM,
an HbA1C of 8.5% or above carried a 33% risk of miscar-
riage or anomalies. (28) An HbA1C above 10.4%, regard-
less of type 1 or 2 DM, has been associated with an
anomaly risk of over 10%. (6)(29) Patients with GDM are
not immune to the increased risk of anomalies if they
have elevated fasting blood glucose values, high BMI, and/
or an early pregnancy diagnosis. (9) If the patient’s
HbA1C is less than 6.9%, the level of risk approaches that
in the general population. (6)
Growth abnormalities are also more common in preg-
nancies complicated by DM, particularly when glucose
control is poor, but this is not always true. Causative un-
derstanding of the determinants and assessment of fetal
growth and development in pregnancies complicated by
DM remain limited. For example, first-trimester HbA1C is
a good predictor of fetal macrosomia, as is the dietary gly-
cemic index (calculated based on carbohydrate intake) and
the glycemic load in early pregnancy but we do not know
exactly why this is the case. (30)(31) It is known that fetal
hyperinsulinemia will develop early in pregnancy if ex-
posed to a high glucose load, resulting in an exaggerated
fetal glucose steal phenomenon and resultant macroso-
mia, which explains why even good maternal glucose con-
trol in the third trimester can still be associated with fetal
macrosomia. Hyperinsulinemia increases lipoprotein li-
pase activity, which results in increased incorporation of
lipids into fetal adipocytes. (32) Macrosomia, defined by
ACOG as a birthweight greater than 4,500 g, correlates
with degree of diabetic control during pregnancy (33);
however, this is challenging to separate from obesity,
which is often associated with DM. (34) Macrosomia im-
poses risk for birth injury, cesarean section, postpartum
hemorrhage, and maternal trauma as well as overall peri-
natal morbidity and mortality. (35) Risk of accelerated fetal
growth persists even when microvascular disease is pre-
sent, but diabetic pregnancies complicated by severe vas-
cular disease and/or preeclampsia have an associated risk
for fetal growth restriction (FGR). (36)(37)
The rate of spontaneous or indicated preterm birth is in-
creased in pregnant persons with type 1 DM. (38) Iatrogenic
preterm delivery may result from preeclampsia and/or FGR.
There is a 5-fold increased risk for intrauterine fetal death
(IUFD) due to fetal hyperglycemia and hyperinsulinemia,
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which leads to increased fetal oxygen consumption that may
in turn lead to fetal hypoxemia and acidosis. (39) Additional
microvascular disease in diabetic pregnant patients can affect
uteroplacental perfusion, further increasing the risk of IUFD.
Polyhydramnios may complicate diabetic pregnancies. The
etiology of this association is not clearly defined but may be
explained by fetal polyuria from maternal and/or fetal hyper-
glycemia. However, because congenital anomalies are in-
creased in diabetic pregnancies in general, an evaluation for a
specific cause of polyhydramnios is important.
IMPACT OF DM ON THE NEONATE/INFANT
Pregnancies complicated by DM pose a risk to the newborn
as a consequence of fetal anomalies, birth injury, and prema-
turity. Macrosomia is associated with an increased risk for
electrolyte disturbances and hypoglycemia in the newborn.
However, newborn hypoglycemia, hypocalcemia, hypomagne-
semia, polycythemia, and indirect hyperbilirubinemia are in-
creased in all diabetic pregnancies even if macrosomia is not
present. In addition, these risks as well as risk for respiratory
distress syndrome (RDS) may occur despite excellent glucose
control during pregnancy.
Inadequate blood glucose control during pregnancy and
obesity contribute to infant/childhood obesity. Neonatal
adiposity correlates with adiposity of the pregnant person
(based on BMI and plasma triglycerol levels) but nega-
tively correlates with cord serum triglycerol, which sug-
gests an increase in fetal tissue lipid uptake. (18)
Both pregestational DM and GDM during pregnancy
correlate with long-term cardiovascular risks and meta-
bolic risks for pregnant persons and their offspring. (26)
Good glucose control should lessen this impact but the effect
of therapy during pregnancy on the long-term metabolic
health of the treated patient’s offspring is unknown. (18) DM
in pregnancy may also have a negative impact on cognitive
dysfunction in offspring and potentially increases the risk of
attention-deficit/hyperactivity disorder and autism spectrum
disorders; however, other confounders may be affecting these
risks. (40)
PRECONCEPTION AND GESTATIONAL
MANAGEMENT FOR PERSONS WITH DM
The need for promotion of good health and wellness be-
fore, during, and after pregnancy cannot be understated.
Lifestyle counseling, optimization of glucose control, and
management of comorbidities, along with frequent self-
monitoring of glucose levels, are essential for all patients
with DM.
Vol. 24 No. 3 MARCH 2023 e147
 Preconceptual
The current leading cause of perinatal mortality in pregnancy
complicated by type 1 or type 2 DM is fetal malformations,
and the level of glucose control during the periconceptual pe-
riod correlates directly with the risk of malformations. Because
most pregnancies are not planned, it is challenging to optimize
preconceptual health. So, instead of waiting until a person is
thinking about becoming pregnant, frequently educating pa-
tients with DM about the importance of good glucose control
is critical; this approach not only decreases risks in a future
pregnancy but also correlates with better overall outcomes for
the patient. Promoting awareness, increasing education, im-
proving access to care, and empowering patients with DM is
imperative to improve outcomes in pregnancies complicated
by DM.
To date, achieving excellent glucose control before preg-
nancy has been the best validated means of improving
outcomes of pregnancies with DM. Indeed, preconceptual
glucose optimization has been found to reduce the risk of
fetal anomalies and decrease perinatal mortality in pa-
tients with type 1 and 2 DM and is also cost-effective. (41)
Good glucose control in patients with DM in the first and
second trimesters reduces the risk of preeclampsia, macro-
somia, and prematurity. (25)(42) The ideal HbA1C level is
less than 6.5% in early pregnancy. An elevated first-tri-
mester HbA1C correlates strongly with poor pregnancy, fe-
tal, and infant outcomes. (43)(44)
The ideal approach for patients with DM is to provide
preconceptual assessment counseling about potential risks,
offer the opportunity for shared decision-making regarding
pursuing pregnancy, and focus on achieving the best glyce-
mic control possible before proceeding with pregnancy. Pa-
tients with both type 1 and type 2 DM may have end-organ
involvement so it is important that they be evaluated for ne-
phropathy, retinopathy, atherosclerotic cardiac disease, neu-
ropathy, and gastroparesis. In addition, an assessment of
other related comorbidities such as hypertension, obesity,
and thyroid disease is essential.
In addition to optimizing glycemic control and assessing for
diabetic complications and comorbidities, preconceptional care
should also include initiation of folic acid and review of medica-
tions, with discontinuation of those that are potentially harmful
to a developing fetus. Folic acid supplementation at a dose of
400 mg/day before conception for 2 to 3 months with continua-
tion during the rest of the pregnancy, in addition to a balanced
diet that includes folate-containing foods, is important as it has
been found to decrease the risk of anomalies. (45)
Discontinuation of medications that are teratogenic
(such as angiotensin-converting enzyme inhibitors) and
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replacement with medications that have better safety pro-
files during pregnancy is advised.
Insulin is the first-line medical therapy for DM during
the preconception period and during pregnancy. Neither
insulin nor analog insulins that were introduced in the
late 1990s cross the placenta. (9) Metformin is the most
studied oral hypoglycemic medication and it has not been
found to increase fetal anomalies. (6) Gliclazide is a sulfo-
nylurea for patients with type 2 DM, but safety data on its
use in pregnancy are limited. However, a small study com-
paring gliclazide with metformin did not show any differ-
ence in hypoglycemia, fetal anomalies, or birthweight.
(6)(46) Because of limited safety data, discontinuation of
gliclazide before conception is advised.
BMI should be optimized before any pregnancy, ideally
to a level below 30. Obesity is increasing worldwide (47)
and obesity independently increases the risk of cesarean
section, prematurity, fetal anomalies, stillbirth, and macro-
somia. (48) Lifestyle changes with increased exercise and
weight optimization has to be well thought out and long-
term, as short-term changes before pregnancy have not
improved outcomes thus far. (49)
Antepartum Medical Treatment
As a result of increased risk of pregnant patients with
DM having hypertensive complications, low-dose aspirin
(81 mg daily) is recommended after 12 weeks’ gestation,
starting ideally between 13 and 16 weeks, and continued
until delivery. (16)(17)
For patients with GDM, the overall risks include a 30%
risk of cesarean delivery, 50% risk of hypertension, 70%
risk of prematurity, and 30% risk of macrosomia. (1)
Treatment of GDM to achieve glucose control decreases
the risk of shoulder dystocia, macrosomia, cesarean sec-
tion, and hypertension. (50) Therefore, universal screening
is advised between 24 and 28 weeks’ gestation to have a
reasonable amount of time to initiate treatment for glu-
cose control. One-third of patients with GDM will need
medication for adequate glucose control. (6)(51) ADA and
ACOG recommend insulin as the first-line medication for
those who need treatment. Half of patients with GDM
treated with oral hypoglycemics such as glyburide or metfor-
min achieve adequate glucose control and then require a
change to insulin. (52) Patients treated with metformin are
twice as likely to need insulin compared to patients treated
with glyburide. However, due to concerns about increased
macrosomia and neonatal hypoglycemia risks with glyburide,
the Society for Maternal-Fetal Medicine opined that although
insulin is considered the first-choice treatment, metformin is
 a reasonable and safe alternative. (52) However, Barbour et al
disagree with widespread adoption of metformin given that fe-
tal concentrations of metformin are equivalent in the pregnant
patient and fetus. (53) Metformin could impose epigenetic
modifications on gene expression and also affect postnatal glu-
coneogenic responses. (53)
For persons with type 1 or type 2 DM, insulin or an
insulin analog is first-line treatment during pregnancy. Sul-
fonylureas cross the placenta and are associated with
neonatal hypoglycemia. (19) Glyburide is no longer recom-
mended given the higher rates of neonatal hypoglycemia
and macrosomia compared with metformin or insulin. (54)
For patients with type 2 DM who have been treated with
metformin before pregnancy, it is recommended to discon-
tinue metformin at least during the first trimester. An
exception to this approach is when a patient’s insulin resis-
tance is so substantial that large amounts of insulin are re-
quired and then, the addition of metformin is considered
reasonable after counseling the patient about the risks.
Additional Prenatal Care
A multidisciplinary team approach to the care of pregnant
patients with DM is ideal and includes a certified diabetic
educator, endocrinologist, nutritionist, maternal-fetal spe-
cialist, and obstetrician; however, it is often not feasible.
Virtual telehealth care has been extremely helpful in this
approach.
For preconceptual or overt DM, a recommended clinical
management approach is outlined in Table 2. (16)(17)(39)
(48)(55)(56)(57)(58)(59)(60) DM does not increase the risk of
aneuploidy, but noninvasive screening for aneuploidy should
be offered to all who are pregnant. Ultrasonography should be
performed in the first trimester not just for dating and viabil-
ity assessment but also to screen for abnormalities that may
be detected in the first trimester (eg, nuchal translucency en-
largement, anencephaly, anterior abdominal wall defect). This
should be followed by a detailed anatomy scan at approxi-
mately 20 weeks’ gestation and fetal echocardiography at 22
to 24 weeks’ gestation.
Assessing fetal growth with ultrasonography is a chal-
lenge, particularly in the presence of obesity when the sen-
sitivity of weight estimates is off by as much as 20%. It
appears that 3D fractional thigh volume is the best predic-
tor of neonatal body fat stores in those with suspected fetal
macrosomia, but this technique is not widely available out-
side of academic medical centers. (57) Fetal magnetic reso-
nance imaging is more specific but not more sensitive
than 2D ultrasonography in predicting macrosomia and is
much more costly. (58) Therefore, neonatal clinicians must
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understand the limitations of antenatal fetal weight assess-
ments and that the only true measure for macrosomia will be
on assessment/measure of the newborn.
The frequency of fetal growth assessment in pregnan-
cies complicated by DM is based on expert opinion, with
some recommending serial (every 3–4 weeks) if medica-
tions such as insulin or metformin are needed regardless
of whether the patient has GDM, overt DM, or pregesta-
tional DM, though this approach is often not practical in
low-resource areas. For patients with GDM who do not re-
quire medication, the current recommendation is for a
growth ultrasound scan in the third trimester. (17)
Recommendations for antenatal surveillance also vary
for pregnant patients with DM. The most common ap-
proach is for antenatal testing beginning at 32 weeks’ ges-
tation for those requiring medication for glucose control;
this is accomplished with either twice-weekly nonstress
tests or weekly biophysical profiles. For patients with
GDM who do not require medication, antenatal testing is
not recommended for that diagnosis alone. (17)
GLUCOSE MONITORING AND GLYCEMIC
CONTROL/THERAPY DURING PREGNANCY
The goal for pregnant patients with DM is to avoid DKA
and hypoglycemia, both of which lead to substantial risks
to the pregnant person and the developing fetus. Tradi-
tionally, patients with type 1 DM, type 2 DM, or GDM are
advised to obtain a fasting glucose measurement and a
1- or 2-hour postprandial glucose measurement via finger-
stick every day with the following goals:
• Fasting glucose 5 70–95 mg/dL (3.9–5.3 mmol/L)
• 1-hour postprandial glucose 5 110–140 mg/dL (6.1–
7.8 mmol/L), or
• 2-hour postprandial glucose 5 100–120 mg/dL (5.5–
6.6 mmol/L)
All pregnant persons may have nausea, vomiting, and loss
of appetite in the first trimester. In addition, insulin sensitivity
increases and thus, the risk for hypoglycemia increases in the
first trimester in all pregnancies. (11) Therefore, for patients
with DM, target glucose levels may need to be relaxed in the
first trimester until gastrointestinal symptoms resolve. There-
after, patients with DM should meet their target glucose
levels.
The type of insulin used in pregnancy depends on the
clinician’s experience and preference and includes either a
split-mix subcutaneous injection approach or an insulin
pump. There is no clear evidence that an insulin pump is
Vol. 24 No. 3 MARCH 2023 e149
 Table 2. Clinical Management of Patients with Preconceptual Diabetes or Overt DM during Pregnancy
Initial Assessment
HbA1C level
Genetic
Other baseline testing
Physical examination
Ultrasound
Antenatal surveillance
Fetal echocardiography
BMI5body mass index, BP5blood pressure, DKA5diabetic ketoacidosis; DM5diabetes mellitus, HbA1C5hemoglobin A1C
superior to the split-mix approach. (19) With the split-mix
subcutaneous insulin approach either an intermediate- or
long-acting insulin is used in combination with either in-
sulin lispro or insulin aspart, the latter for meal coverage.
The safety and efficacy of newer insulin analogs and con-
centrated insulin preparations need to be validated.
Continuous glucose monitoring, with a target goal glucose
range of 63 to 140 mg/dL (3.5–7.8 mmol/L) with more than
70% of measures in goal range, appears promising for use in
pregnancy. However, this is not regularly or readily available
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Relevance and Clinical Approach

Reflects average blood glucose level over prior 3 months

Used to assess degree of glucose control as well as risk of
anomalies, preeclampsia, and other complications

Declines naturally in all pregnancies so can be a challenge to
determine risks if obtained later in pregnancy (55)

Offer screening for aneuploidy

Renal function and urine protein excretion

Thyroid-stimulating hormone level (given risk of autoimmune
thyroid dysfunction)

Urine culture and sensitivity (higher risk of asymptomatic
bacteriuria and if left untreated, increased risk of
pyelonephritis, sepsis, preterm birth, and DKA)

12-lead electrocardiography (screen for cardiac involvement)

Echocardiography (if hypertension, or history of cardiac disease)

BMI

Ophthalmology examination

BP:
o Goal of systolic BP <140 mm Hg and diastolic BP <40
mm Hg (similar to pregnancies not complicated by
DM); reduces risk for preeclampsia, preterm birth prior
to 35 weeks’ gestation, and fetal or neonatal death (56)
o Antihypertensive medications include labetolol (Note:
this may have a negative impact on glucose control) or
nifedipine
First trimester for dating, viability, anomaly screen

Detailed fetal anatomy scan at approximately 20 weeks’
gestation

Recommended timing of growth scans varies:
o If any DM treated with insulin

without vascular involvement ! growth scan in third
trimester starting at 28 weeks’ gestation and every
4 weeks

with vascular involvement or other comorbidities !
consider growth scan earlier, potentially after anatomy
scan at 20 weeks’ gestation

Start at 32 weeks’ gestation until delivery (can consider earlier
in gestation based on other comorbidities or complications in
pregnancy such as fetal growth restriction) (16)(17)(59)

Twice weekly nonstress tests or weekly biophysical profiles

Imaging at approximately 22–24 weeks’ gestation

Cardiac anomalies account for 50% of fetal anomalies (48)
o Risk correlates with HbA1C (>8% risk if HbA1C $8.5% vs
3.9% risk if HbA1C < 8.5%) (28)
o Most common defects: ventricular septal defects and
conotruncal defects
o Potential of septal hypertrophy if uncontrolled
hyperglycemia (60)

If poor glucose control, some recommend a second
echocardiogram in the third trimester
to date. A recent randomized controlled clinical trial that com-
pared continuous to capillary glucose monitoring in pregnant
patients with type 1 DM showed that the continuous monitor-
ing increased the percentage of time that the blood glucose
was in target range and reduced neonatal complications (50%
reduction in macrosomia, NICU admissions, and neonatal hy-
poglycemia). (61) Combining an insulin pump with continu-
ous glucose monitoring has also shown promise in selected
pregnant patients with more stable glucose measurements
noted in the pregnant person and newborn. (62)
 For pregnant persons with DM who are candidates to re-
ceive corticosteroids before 34 weeks’ gestation to improve fe-
tal lung maturity, it is important to note that this medication
may result in severe hyperglycemia even if glucose control is
good. If it occurs, the hyperglycemia typically lasts 5 days. Be-
cause pregnant patients with diabetes were considered high
risk, they were not included in the only trial in which cortico-
steroids were provided at late preterm gestational age (ie,
34–37 weeks’ gestation) and thus, corticosteroid administration
in pregnant patients with diabetes is not recommended dur-
ing this period. (63)(64)
DELIVERY MODE AND DELIVERY TIMING OF
PREGNANT PERSONS WITH DM
For pregnant patients with well-controlled DM, delivery is rec-
ommended between 39 0/7 and 39 6/7 weeks’ gestation.
(16)(17) Expectant management beyond 39 6/7 weeks’ gesta-
tion is not recommended. If there is concern for impending
macrosomia, no added benefit has been shown for delivery
before 39 0/7 weeks’ gestation and this approach may impose
an increased risk of RDS because of the delayed fetal lung
maturity as a result of fetal hyperglycemia and its impact on
cell maturation and function. (65)(66) Timing of delivery for
uncontrolled hyperglycemia, noncompliance, prior stillbirth,
and/or vascular disease in patients with DM should be consid-
ered on an individual basis. (15)(59)(67)
Cesarean section is recommended for estimated fetal
weights greater than or equal to 4,500 g in pregnant patients
with diabetes because the risk of shoulder dystocia is 20% to
50%. (68) For pregnant patients with diabetes with an esti-
mated fetal weight between 4,000 and 4,499 g, the risk of
shoulder dystocia is lower but still substantial, at up to 15%,
therefore counseling with shared decision-making is impor-
tant and care should be individualized. (68)
Intrapartum Approach
Ideally, it is best to schedule cesarean sections or inductions
for pregnant patients with DM early in the morning because
euglycemia is much easier to achieve when a patient is in a
fasting state. Typically, on the day before delivery, the bedtime
insulin dose is halved and the morning insulin dose is held; if
insulin is needed intrapartum, it is provided via an insulin
drip. For patients in active labor, the target glucose should be
70 to 125 mg/dL (3.9–6.9 mmol/L) because higher glucose
levels have been associated with fetal acidemia and neonatal
hypoglycemia. (17)(69) Patients who are being treated with
metformin should not receive metformin during labor, and if
necessary, intravenous insulin can be administered. It is im-
portant to realize that insulin requirements dramatically
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decline after delivery of the placenta and thus, any insulin in-
fusion should be stopped after the infant is delivered. There
are no contraindications to regional anesthesia, though dex-
trose-free solutions for intravenous boluses should be used.
Postpartum Approach
The amount of subcutaneous insulin that a patient needs is
typically much lower in the first 48-hour postpartum period,
and this may continue indefinitely, particularly if the patient
is breastfeeding. For those who had DM before the pregnancy,
a reasonable approach is to restart their subcutaneous insulin
regimens at half the predelivery dose, with adjustments as
needed. Breastfeeding should be encouraged as insulin re-
quirements are about 20% lower compared with women who
do not breastfeed. (70)(71) Both insulin and metformin are
considered safe for breastfeeding. After delivery, patients with
GDM often have normal glucose values without insulin treat-
ment even if they required substantial insulin before or dur-
ing delivery.
Other morbidities are associated with DM in pregnancy.
Postpartum depression is more common in patients with pre-
gestational DM and GDM. Patients with GDM are at in-
creased risk for developing diabetes later in life (>50% risk
compared with 20% in patients without GDM) and should be
formally retested 6 weeks after delivery. (72) The Diabetes
Prevention Program Outcomes Study (a multicenter trial that
evaluated the effects of an intensive lifestyle program or met-
formin treatment to prevent or delay type 2 DM in patients at
high risk) found that metformin treatment reduced the risk of
type 2 DM by 35% compared with placebo for those at risk.
(1)(9)(73)(74) Consideration should therefore be given to start
metformin in GDM patients after delivery given that potential
benefit.
EPIGENETICS AND DM
Epigenetics is implicated in intrauterine exposure to hypergly-
cemia, potentially affecting the long-term metabolic health of
offspring of pregnancies complicated by DM. (1)(75) DM can
change genes involved in pathways essential for embryogene-
sis including oxidative stress, apoptosis, folate metabolism,
and proliferation. (6) With oxidative stress, there is an imbal-
ance between nitric oxide and reactive oxygen species, leading
to an increased risk of developing anomalies in the fetus. (6)
Oxidative stress directly damages the DNA, causing protein/
lipid oxidation. (6)
Evidence suggests that exposure to smoking, certain in-
fections, and endocrine disruptors (discussed next) can
lead to developmental programming in the fetus leading to
both obesity and type 2 DM later in life. (76) Indeed,
Vol. 24 No. 3 MARCH 2023 e151
 epigenetic modifications of DNA methylation and microRNA
interactions have been linked casually to obesity and type 2
DM. (76) Interventions like diet and exercise can reverse epi-
genetic changes and therefore, affect future generations.
An endocrine disruptor is a substance that can interfere
with the action of a hormone, with 15 such disruptors defined
to date. Examples include bisphenol-A (BPA) and phthalates,
which are food and water contaminants found in plastics that
are easily absorbed and can increase the risk of obesity and
GDM. (77) The exact mechanism is not defined but appears
to alter adipose cells and pancreatic islet B cells, causing dys-
function and transgenerational damage. (77) Endocrine dis-
ruptors alter organ development, immunity, metabolism, and
behavior. (78) They interfere with the developing epigenome
of the fetus, resulting in conditions such as obesity, diabetes,
and cardiovascular disease later in life. (78) They also affect
placental health in the current pregnancy, posing a risk for
GDM, preeclampsia, and FGR. (78) A child who was exposed
to endocrine disruptors in utero can be at increased risk
for cognitive dysfunction and attention-deficit disorders. (79)
Thus, eliminating such exposures is an important public
health measure. Data on the impact of BPA on the pregnant
patient are conflicting. A recent meta-analysis by Taheri et al,
for example, did not find an association with BPA exposure
and risk of GDM in a concurrent pregnancy. (80)
Arsenic exposure during pregnancy has been associated
with GDM, but the evidence does not clearly point to an ad-
verse impact on postpartum insulin resistance of pancreatic is-
let B cell function. (81) The association between environmental
phenol and paraben exposures and GDM has been demon-
strated but the impact of a mixture of such chemicals in expo-
sures has not been clearly delineated. (82)
In summary, epigenetic impact of DM in pregnancy in-
cludes an increased incidence of childhood obesity, and insu-
lin resistance/diabetes and neurocognitive issues in offspring,
which appear to extend to all forms of DM complicating preg-
nancy. (1)(73)(83) Epigenetic changes are modifiable and re-
versible, in that they do not change the innate DNA sequence,
but rather change how the body reads a DNA sequence and
how the genes are expressed. This is an area of active research
as well as an opportunity to modify outcomes and improve
health during pregnancies.
Summary
Despite improvements in perinatal care in pregnancies
complicated by DM, poor glucose control increases the
risk of complications for both the pregnant patient
and fetus. The risks include poor outcomes for the
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neonate as well as future risk of obesity, neurocogni-
tive dysfunction, and/or type 2 DM in offspring. There
is increasing evidence that a preconceptual approach
is optimal in improving outcomes. Promoting aware-
ness, increasing education, improving access to care,
and empowering women to engage in the same is im-
perative to improve outcomes in pregnancies compli-
cated by DM.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the impact of pregestational and gesta-
tional diabetes on maternal, fetal, and neonatal
outcomes
• Know the goals of management of diabetes in
pregnancy to reduce risks of complication for
mother and baby
• Know the impact of poor glycemic control on
perinatal morbidity and mortality
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66.Piper JM, Xenakis EM, Langer O. Delayed appearance of pulmonary
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2001;14(8):1085–1091
Vol. 24 No. 3 MARCH 2023 e155
 NEOREVIEWS QUIZ

NEO
QUIZ
1. Diabetes in pregnancy has been increasing over time. Screening and testing
strategies vary, including timing and technique. According to American
Diabetes Association criteria, which of the following test results would be
categorized as indicating a diagnosis of pregestational diabetes mellitus?

A. Hemoglobin A1C of 6%.

B. Fasting blood glucose 115 mg/dL (6.9 mmol/L).
C. 2-hour postmeal glucose 180 mg/dL (9.9 mmol/L).
D. Diabetic ketoacidosis.
E. Symptoms of diabetic ketoacidosis with a random glucose of
175 mg/dL (9.7 mmol/L).
2. A pregnant person is diagnosed with diabetes mellitus during pregnancy. REQUIREMENTS: Learners can
Positive testing includes an abnormally high 2-hour postmeal glucose as well take NeoReviews quizzes and
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D. The degree of glycemic control is important for maternal health overall 60% or greater score is
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3. A fetus is diagnosed with macrosomia as the pregnancy nears term the learner completes the quiz.
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A. Glycemic control in the third trimester is the key to avoiding macrosomia
and good control is virtually 100% effective in prevention of macrosomia.
B. Hyperinsulinemia leads to decreased lipoprotein lipase activity and
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 4. A pregnant person is diagnosed with gestational diabetes mellitus. Her care
team is discussing the treatment plan. Which of the following statements
concerning preconceptual treatment is correct?
A. Thiamine and high-dose vitamin C supplementation are key aspects of
standard treatment starting in the second trimester.
B. When used, insulin analogs that cross the placenta are recommended
to moderate fetal glucose levels.
C. Metformin is the most studied oral hypoglycemic and has not been
found to increase fetal anomalies.
D. Gliclazide is considered a first-line treatment for both pregestational
and gestational diabetes mellitus in pregnancy, regardless of the use of
insulin.
E. Aspirin is contraindicated for all patients with gestational diabetes
mellitus.
5. A pregnant patient with well-controlled diabetes mellitus is at 36 weeks of
gestation. The delivery plan is being discussed. Which of the following
statements concerning an appropriate treatment plan is correct?
A. For pregnant patients with well-controlled diabetes mellitus, delivery is
recommended between 39 0/7 and 39 6/7 weeks’ gestation.
B. Delivery is recommended before 38 weeks to avoid complications of
macrosomia.
C. Cesarean section delivery is recommended for all pregnancies if gestation
progresses beyond 40 weeks.
D. Induction is indicated between 35 and 37 weeks’ gestation if the
estimated fetal weight reaches 3,500 g during that period.
E. Antenatal steroids should be administered at 24 weeks and then again
at 32 weeks to decrease the risk of respiratory distress syndrome.

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 ARTICLE

Small and Mighty: Micronutrients at the

Intersection of Neonatal Immunity and
Infection
Laura G. Sherlock, MD,* Nancy F. Krebs, MD†
*Perinatal Research Center, Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
†
Section of Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO

PRACTICE GAPS

Neonatal clinicians should be aware that micronutrient deficiencies are

common in preterm and term infants and increase the risk for infection and
immune dysfunction. Micronutrient deficiencies are likely underrecognized
in the NICU, as micronutrient status is not routinely assessed.

OBJECTIVES After reviewing this article, readers should be able to:

1. Identify populations that are at risk for micronutrient deficiencies in the

neonatal period.
2. Explain that micronutrient status affects the risk for infection during infancy.
3. Summarize dynamic changes in micronutrient status that occur during
an infection.

AUTHOR DISCLOSURES Dr Krebs works

under research grants from the National
ABSTRACT
Institutes of Health, Eunice Kennedy Micronutrients are essential dietary components that regulate many
Shriver National Institute of Child Health
biologic functions, including the immune response, and are required in
and Human Development (UG1HD/
076474-06), and National Institute of small amounts (typically milligrams or less) in humans. Examples of
Diabetes and Digestive and Kidney micronutrients known to affect immune function include several trace
Diseases (DK126710-01) and has been a minerals (such as zinc and selenium) as well as vitamins (including vitamins
consultant for Nurture, Inc. Dr Sherlock
has disclosed no financial relationships
A and D). Deficiencies of specific micronutrients are associated with an
relevant to this article. This commentary increased risk of infection in infants in the NICU. Identifying micronutrient
does not contain a discussion of an supplementation strategies during this period may result in low-cost
unapproved/investigative use of a
commercial product/device.
interventions to reduce the burden of neonatal infectious disease. Many
replacement trials thus far demonstrate conflicting results about whether
micronutrient supplementation decreases the incidence or severity of
ABBREVIATIONS
sepsis in the neonatal period. The baseline incidence of micronutrient
APP acute phase protein
deficiency is important to consider but is often unknown as clinical
IDA iron deficiency anemia
LMIC low- and middle-income assessment of micronutrient status occurs infrequently. Future research is
countries needed to clarify the clinical scenarios in which optimizing micronutrient
NNT number needed to treat status in term and preterm infants may prevent infection or improve
RCT randomized controlled trial
TPN total parenteral nutrition
outcomes in those patients who become infected.
VLBW very low-birthweight infants

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 INTRODUCTION
Infections are the most common cause of death in chil-
dren younger than 5 years, and 600,000 neonates youn-
ger than 28 days die each year from infections. (1)(2) For
those neonates who survive, the immune system dysfunc-
tion that occurs after an infection contributes to an addi-
tional increase in morbidity and mortality. (3) Several
factors regulate the neonatal immune response, including
host nutritional status, (4) specific macronutrients, and
importantly, several micronutrients. (5)
Micronutrients are an essential component of nutri-
tional immunology. In the neonatal period, the risk of mi-
cronutrient deficiency is high for both preterm and term
infants. Preexisting micronutrient deficiencies are recog-
nized to impair both innate and adaptive immune re-
sponses, potentially contributing to an increased incidence
of, and poor outcomes following, sepsis. (4) Furthermore,
illness increases nutritional needs, which may result in an
acute increase in micronutrient requirements to support
host response. (4)(6) Finally, dynamic alterations in micro-
nutrient homeostasis after an infection are increasingly
identified as part of the acute phase response. (7)(8)(9)
Optimizing micronutrient status in patients in the
NICU is a compelling clinical objective, as nutritional in-
terventions are often low in cost and potentially easier to
disseminate compared to pharmaceutical interventions.
Historically, this approach has been successful with both
zinc and vitamin A supplementation in the prevention or
treatment of neonatal and pediatric infections on a global
scale. (10)(11) In this review, we summarize current knowl-
edge about the intersection of neonatal micronutrient sta-
tus and infection.
PART 1: MICRONUTRIENT DEFICIENCIES AND
NEONATAL SEPSIS
Nutritional status contributes to immune health across all
ages, including in the neonatal period. (4)(12) The first
1,000 days, from conception to 2 years of age, is consid-
ered a critical window for optimizing nutrition. (13)(14) In-
sufficient nutrition during fetal and neonatal development
contributes to the risk for neonatal infection. (5) Emerging evi-
dence suggests that both overnutrition and undernutrition af-
fect immunocompetence and may also program the immune
system, influencing immune health beyond infancy. (4)(5)(15)
Nutritional immunology investigates the roles of caloric in-
take, macronutrients, and specific micronutrients on immune
health. (4)(12)(16)
Humans require micronutrients in small quantities, in-
cluding trace minerals (such as zinc, selenium, iron, and
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copper) as well as fat-soluble and water-soluble vitamins. Mi-
cronutrients function as antioxidant scavengers, cofactors for
antioxidant enzymes, proteins required for cell proliferation
and energy metabolism, and transcription factors. (4)(16)(17)
Micronutrient deficiencies impair the innate and adaptive
immune responses. (4)(12) Clinical studies have associated
micronutrient deficiencies with an increased risk of viral,
parasitic, and bacterial infections in the neonatal period.
(5)(12) Within these clinical studies, micronutrient deficiency
frequently coexists with overall malnutrition. Furthermore,
the immune system exhibits considerable redundancy, with
overlap and sparing function among micronutrients, for ex-
ample, antioxidant functions of vitamins E and C. This com-
plicates our understanding of how a specific micronutrient
contributes to immune function. Animal and cell culture
models provide some insight into the specific impact of vari-
ous micronutrients on the immune system and have been
reviewed elsewhere (Table 1).
Globally, it is estimated that nearly half of children un-
der age 5 years have at least 1 micronutrient deficiency,
and that undernutrition contributes to 3.1 million child-
hood deaths per year. (14) However, determining the true
incidence of micronutrient deficiencies in the neonatal pe-
riod is challenging as levels are not routinely measured.
Neonatal micronutrient status is primarily influenced by
intake of the mother during pregnancy and lactation.
Table 2 summarizes our current knowledge of the regulation
of micronutrient status during pregnancy and lactation. There
is a high prevalence of micronutrient deficiencies in pregnant
women and children in low- and middle-income countries
(LMIC), where access to nutrient-rich foods is poor, as is food
diversity, and environmental conditions potentially limit mi-
cronutrient bioavailability. (5)(14)(18)
Multiple factors contribute to the increased risk of mi-
cronutrient deficiency observed in preterm infants. First,
fetal acquisition of many micronutrients occurs by placen-
tal transfer during the third trimester. (5) Preterm infants
born without late second or third trimester placental trans-
port are thus at risk for low total body micronutrient
stores. (19) Second, dietary recommendations are often ex-
trapolated from those established for term infants, which
may not be sufficient for the preterm population. (19) In-
fants born preterm are undergoing rapid growth, poten-
tially increasing micronutrient demands. Preterm infants
have variability in the tolerance of enteral intake and often
receive donor breast milk, in which micronutrient status
is incompletely understood. (19) It remains unclear if ab-
sorption or bioavailability of micronutrients is similar in
the preterm intestine. Factors such as immature intestinal
Vol. 24 No. 3 MARCH 2023 e159
 Table 1. Suggested Review Articles
Topic Article
Maternal nutrition during gestation and Prentice S. They are what you eat: can nutritional factors during gestation and early infancy
immune function in the offspring modulate the neonatal immune response? Front Immunol. 2017;8:1641
Zinc Hojyo S, Fukada T. Roles of zinc signaling in the immune system. J Immunol Res. 2016;
2016:6762343
Selenium Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from
molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2012;16(7):705–743
Iron Haschka D, Hoffmann A, Weiss G. Iron in immune cell function and host defense. Semin Cell
Dev Biol. 2021;115:27–36
Vitamins A and D Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D
take centre stage. Nat Rev Immunol. 2008;8(9):685–698

tract, lower enterocyte transporters, and shorter gut length
all contribute to lower absorption capacity. Higher urinary
excretion of essential trace minerals, such as zinc and cop-
per, occurs in early postnatal life and varies with degree of
prematurity, further contributing to the risk of deficiency.
(20)(21) Finally, because some micronutrients are antioxidant
scavengers or cofactors for antioxidant enzymes, (20)(22)(23)
and hospitalized preterm infants frequently experience in-
creased oxidative stress, these patients may have relatively in-
creased micronutrient utilization. (23) Within the preterm
population, infants requiring prolonged total parenteral nu-
trition (TPN) and neonates with an ostomy are at higher risk

Table 2. A Summary of Evidence Showing Regulation of Micronutrient Status During Pregnancy and Lactation
Evidence that Circulating Evidence that Maternal Evidence that Maternal
Levels in Preterm Infants Micronutrient Status Diet or
are Lower than Term Affects Neonatal Supplementation Affects Preterm versus Term
Micronutrient Infants? Levels at Birth? Levels in Breast Milk? Breast Milk Content
Zinc Yes (93) Yes (94) No (95)(96) Less zinc in preterm
Levels initially high and breast milk compared
sharply decline over to term when
first 3 months corrected for
postpartum postmenstrual
age (97)
Selenium Yes (93) Yes (48) Yes (95)(96) Less selenium in
Levels in milk decrease preterm breast milk
through lactation (95) compared to term
when corrected
for postmenstrual
age (97)
Copper Yes (93) Unclear No (95) Less copper in preterm
Levels in milk are low breast milk compared
and decrease through to term when
lactation (95) corrected for
postmenstrual
age (97)
Iron Yes (5) Neonatal iron levels are No (95)(96) Mixed results; some
preserved over Levels in milk are low studies demonstrate
maternal (5) and relatively stable no difference; others
Maternal supplementa- through lactation report slightly higher
tion decreases (95)(97) iron levels in preterm
maternal anemia (5) breast milk in early
lactation (97)
Vitamin A Yes (69)(98) Yes (98) Yes (95)(96)
Vitamin C No; higher levels Neonatal cord blood Yes (95)(96)
observed in preterm levels can be higher Levels in milk decrease
infants than term (76) than maternal levels through lactation (95)
(75)
Vitamin D Yes (82)(99)(100) Yes (101)(102) Yes (95)(101)(102)
Levels in milk are low (95)
Vitamin E Mixed results; some Yes (88) Yes (95)(96)
studies demonstrate
levels increase across
gestation (88)

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 for micronutrient deficiencies. (24)(25) Deficiencies may also
occur with suboptimal parenteral dosing, altered physiologic
processing, or increased losses (eg, via an ostomy).
Neonates born to mothers with overnutrition are also
at risk for micronutrient deficiencies. Excessive gestational
weight gain, maternal diabetes, rapid fetal growth, and
chronic low-grade inflammation are all possible contributing
factors. (26) Despite an increased caloric intake, multiple
studies demonstrate a higher incidence of micronutrient de-
ficiencies in obese individuals. (14)(27) Prepregnancy obesity
is associated with an increased risk for deficiencies in iron,
vitamin D, vitamin B12, and folate during pregnancy. (15)
Given the high prevalence of women of reproductive age
with obesity before and during pregnancy (
40%), and with
rates of gestational diabetes at approximately 6% of the pop-
ulation in the United States, future research should examine
the effects of these conditions on micronutrient status in the
offspring. (28) For example, offspring of women with gesta-
tional diabetes have been found to have low concentrations
of ferritin at birth, reflecting both altered utilization due to
chronic in utero hypoxemia and reduced transfer of iron to
the fetus. (29)
Micronutrient status is infrequently assessed clinically.
Normative values may be established on data from term in-
fants. It is poorly understood what micronutrient levels in
preterm infants predict optimal health or disease, and this is
an important area for future research. Circulating micronu-
trient concentrations are also dynamic in the early weeks of
postnatal life, so age-adjusted norms may be appropriate but
often are not available in clinical settings. Table 3 provides
information on which laboratory tests assess micronutrient
status clinically as well as values that are currently consid-
ered normal in the neonatal population.
Zinc
Nutrient Function and Risk of Deficiency. Zinc is a trace ele-
ment with diverse roles in human health, affecting cellular
differentiation and growth, innate and adaptive immune
health, and wound healing. (30) Zinc exerts its biological
effect by binding as a cofactor to different metalloproteins.
(31) Zinc binds to over 300 proteins in the body, and se-
quencing has identified zinc-binding patterns in roughly
10% of human proteins. (31) Functionally, zinc stabilizes
protein structure, increases enzymatic activity, and con-
tributes to transcription factor activity.
Zinc deficiency is common worldwide, especially in
LMIC where the intake of zinc-enriched foods is limited.
(10) Risk factors are compounded in premature infants,
including high requirements, limited absorption capacity,
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and renal wasting. (32) In addition, early aggressive pro-
tein-energy nutrition support has been associated with
high, but often unmet, zinc demands. (33) Serum zinc
concentration is the most common and clinically available
biomarker, but its primary limitation is low sensitivity.
Low serum zinc concentration is associated with moderate
to severe deficiency, whereas mild, potentially growth-
limiting deficiency is often not reflected in a low serum
zinc concentration. (34) Infection and inflammation also
decrease circulating zinc levels, further obscuring the as-
sessment of overall zinc status. (10)(35) The gold standard
for assessment of zinc status is evaluation of a growth re-
sponse to a trial of supplementation. Given the low risk of
toxicity, an empiric trial of supplementation (eg, 1 mg
zinc/kg per day) is warranted in clinical circumstances
that support a risk of deficiency.
Evidence for Role in Immune Function. The critical role
played by zinc in multiple cellular processes supports the
hypothesis that subclinical deficiency could affect immune
function and growth, but this has not been rigorously
tested in controlled trials. Multiple studies implicate zinc
status as a modifiable risk factor for infectious disease in
children under 5 years of age. Zinc deficiency increases
overall morbidity and mortality in this population, and
specifically worsens outcomes after diarrheal infections,
malaria, and respiratory infections. (10) Preclinical data
support these clinical associations, as zinc deficiency in
animal and cell culture models have a negative impact on
innate and adaptive immune function, and in some stud-
ies results in increased proinflammatory and prooxidative
signaling pathways. (36) Limited preclinical studies have
been conducted in neonatal preclinical models to explore
these mechanisms, a potential area for future research.
Postnatal Supplementation in Term Infants. Animal models
clearly demonstrate incremental growth impairment with
mild to moderate zinc deficiency. This is reinforced by multi-
ple clinical studies demonstrating beneficial effects of supple-
mentation on neonatal and pediatric growth, (37) providing
evidence of preexisting deficiency. (37) A Cochrane meta-anal-
ysis concluded that zinc supplementation improves weight-
for-age Z score and weight-for-length Z score in term infants
younger than 6 months. (37) However, no reductions in over-
all mortality, diarrheal illnesses, or respiratory tract infections
were observed. (37)(38) A more recent meta-analysis evaluated
11 randomized controlled trials (RCTs) on whether zinc sup-
plementation prevented or improved outcomes during neona-
tal sepsis in term infants younger than 4 months and found a
significant decrease in infant mortality with zinc
Vol. 24 No. 3 MARCH 2023 e161
 Table 3. Laboratory Tests that Assess Micronutrient Status and Values Currently Considered Normal in the
Neonatal Population
Clinical Test(s)/Biomarkers to
Micronutrient Evaluate Micronutrient Status Levels Indicating Sufficiencya
Zinc Serum/plasma zinc 0–10 years: 75–120 lg/dL
(11.47–18.36 lmol/L) (103)
Selenium Serum/plasma selenium 0–2 months: 45–90 lg/L
(0.57–1.14 lmol/L) (104)
Copper Serum/plasma copper 1.10–1.45 lg/dL
(0.17–0.23 lmol/L) (103)
Iron CBC – Hb(#), MCV(#), RDW(") Ferritin: >15 ng/mL
Serum ferritin (# for age) 1 CRP (15 lg/L) (103)
(or ESR) % Transferrin saturation:
%Transferrin saturation(#) >16% (103)
Vitamin A Serum/plasma vitamin A (retinol) Infant: 13–50 lg/dL
(0.45–1.75 lmol/L) (103)
Vitamin C Serum/plasma vitamin C 0.2–2.0 mg/dL (11.36–113.56
lmol/L) (103)
Vitamin D Serum/plasma 25-OH-vitamin D <10 ng/mL (24.96 nmol/L)
(severe deficiency)
10–29 ng/mL
(24.96–72.38 nmol/L) (mild
to moderate deficiency)
30–50 ng/mL (74.88–124.80
nmol/L) (optimum levels)
(103)
Vitamin E Serum/plasma a-tocopherol Preterm infant: 0.5–3.5 lg/mL
(1.16–8.13 lmol/L) (103)
Infants and children: 0.7–10 lg/mL
(1.63–23.22 lmol/L) (103)
a
From the AAP’s Pediatric Nutrition Handbook. (103)
CBC5complete blood cell count, CRP5C-reactive protein, ESR5erythrocyte sedimentation rate, Hb5hemoglobin, MCV5mean corpuscular
volume, RDW5red cell distribution width.
Review Article on
Micronutrient Biomarkers
King J, Brown K, et al.
Biomarkers of Nutrition for
Development (BOND)-Zinc
Review. J Nutr.
2015;146(4):858S–885S
Combs G. Biomarkers of
selenium status. Nutrients.
2015;7(4):2209–2236
Harvey LJ, Ashton K, et al.
Methods of assessing of
copper status in human: a
systematic review. Am J Clin
Nutr. 2009; 89(6):2009S–2024S
Lynch S, Pfeiffer C, et al.
Biomarkers of Nutrition for
Development (BOND)- Iron
Review. J Nutr. 2018;148
(suppl 1): 1001S–1067S
Tanumihardjo S, Russell R, et al.
Biomarkers of Nutrition for
Development (BOND) Vitamin
A Review. J Nutr.
2016;146(9):1816S–1848S
Elsori D, Hammound M. Vitamin
D deficiency in mothers,
neonates, and children. J
Steroid Biochem Mol Biol.
2018;175:195–199
Assuncao DGF, Silva LTPD, et al.
Vitamin E levels in preterm
and full-term infants: a
systematic review. Nutrients.
2022;14(11):2257

supplementation. (39) An RCT conducted in India random-
ized approximately 650 infants between 7 and 120 days of age
with probable serious bacterial illnesses to receive adjuvant en-
teral zinc supplementation or placebo. (40) The addition of
zinc decreased the episodes of treatment failure, with a num-
ber needed to treat (NNT) of 15. (40) In this study, zinc sup-
plementation also resulted in a nonsignificant trend toward
improved mortality, but the study was not powered to evaluate
this outcome. (40) An ongoing multicenter RCT in India of
term infants between 3 and 59 days of age admitted to the
hospital for suspected sepsis is evaluating the impact of em-
piric zinc supplementation on mortality during the hospital
stay or for 12 weeks after the sepsis episode. (41)
Studies of zinc supplementation to prevent infection or
improve outcomes during infection in older children have
not consistently demonstrated benefit, and results can vary
depending on preexisting zinc status. (42) Thus, when inter-
preting research that tests if zinc supplementation improves
outcomes for term infants with sepsis, it is important to con-
sider if the study was performed in an area with a high or
low incidence of zinc deficiency and the inherent risk factors
for zinc deficiency, such as conditions that would impair
zinc status including prematurity, prolonged TPN, or poor
nutritional status of the mother. (32) Future research is
needed to confirm the results of earlier studies and test if
the benefit of zinc supplementation varies by geographic re-
gion or preexisting nutritional status.
Postnatal Supplementation in Preterm Infants. Zinc accre-
tion occurs primarily in the third trimester, thus preterm

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 infants exhibit lower zinc levels than term infants and are
at high risk for zinc deficiency. (19)(43) A Cochrane review
including 482 infants concluded that enteral zinc supple-
mentation in hospitalized preterm infants may decrease
all-cause mortality (relative risk 0.55, 95% confidence interval
0.31 to 0.97). (44) Within this meta-analysis, no differences
were found between the incidence of bacterial sepsis or nec-
rotizing enterocolitis. (44) Additional research is needed to
determine if zinc supplementation would improve outcomes
for preterm infants during active infection, which is incom-
pletely tested at this time.
Selenium
Nutrient Function and Risk of Deficiency. Selenium is a mi-
cronutrient that has typically been recognized for its role
in regulating the redox state. (45) Selenium is cotransla-
tionally incorporated into 25 selenium-containing proteins,
referred to as selenoproteins. (46) Several of these are anti-
oxidant enzymes, including the glutathione peroxides, thi-
oredoxin reductases, and methionine sulfoxide reductase
B. (46) The presence of selenium enhances the catalytic
ability of these antioxidant enzymes; thus, selenium defi-
ciency can increase the risk of oxidative stress under phys-
iologic conditions or after oxidative challenge. (46) Other
selenoproteins are important for regulating thyroid func-
tion, the inflammatory response, endoplasmic reticulum
stress, and intracellular calcium influx. (46)
Selenium content varies considerably in soil, and there are
vast geographic differences in the risk for selenium deficiency.
(47) Selenium status of infants at birth is determined by sele-
nium status of the mother during pregnancy. (48) While it is
unknown how many total infants are selenium deficient, it is
estimated that 500 million to 1 billion individuals are sele-
nium deficient globally, affecting 20% to 66% of pregnant
women in high-risk regions. (47)(49) Preterm infants are also
at risk for selenium deficiency, given decreased duration of
placental transfer. (47)
Evidence for Role in Immune Function. Clinical and preclini-
cal evidence supports the importance of selenium in immune
health. (50) Selenium deficiency in critically ill children and
adults is associated with an increased risk for mortality, multi-
organ failure, and longer intensive care unit stays. (51)(52)
Selenium deficiency in term infants is associated with an in-
creased risk of respiratory viral infections. (53) Selenium defi-
ciency in preterm infants increases the risk for late-onset
sepsis. (54) Finally, decreased total body or organ-specific activ-
ity of selenium-containing antioxidant enzymes results in exac-
erbated oxidative stress, an increased inflammatory response,
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and worsened mortality after viral and bacterial infection in
animal models. (17)(50)
Postnatal Supplementation in Term Infants. Studies exam-
ining whether selenium supplementation improves or pre-
vents infections in term infants are lacking.
Postnatal Supplementation in Preterm Infants. Multiple
RCTs have evaluated selenium supplementation in pre-
term infants. (54)(55) The largest RCT was conducted by
Darlow et al, in which 534 very low-birthweight (VLBW)
preterm infants were randomized to parenteral selenium
followed by enteral selenium versus no selenium in paren-
teral nutrition followed by enteral placebo. (54) This trial
was originally designed to test the hypothesis that sele-
nium supplementation would decrease the incidence of
bronchopulmonary dysplasia, and no difference was found
for this outcome. (54) Interestingly, selenium supplemen-
tation significantly decreased the incidence of late-onset
sepsis compared with placebo, with an NNT of 10. (54) Al-
though this is a compelling observation, this study was
conducted in a geographic location with a high incidence
of selenium deficiency, and it is unknown if the findings
would translate to populations where selenium deficiency
is less endemic.
Notably, most commercial human milk fortifier prod-
ucts do not contain selenium, and data on typical sele-
nium content of donor human milk are lacking. For the
typical high-risk NICU population with the combination
of low tissue levels at birth and potentially high require-
ments, this may be an additional risk for selenium defi-
ciency. Additional research is clearly needed to evaluate if
late-onset sepsis similarly reduced in VLBW infants born
in westernized countries with less likelihood of geochemi-
cal depletion, or for infants born at the limits of viability,
who are at very high risk for selenium deficiency.
Iron
Nutrient Function and Risk of Deficiency. Iron is an essential
trace mineral with multiple physiologic roles for cellular and
metabolic function. Proteins with iron atoms are referred to
as hemoproteins. (56) Iron is integral for oxygen transport and
delivery, as hemoglobin is the most abundant hemoprotein.
(56) Other important hemoproteins include antioxidant en-
zymes such as catalase and peroxidases, cytochrome oxidase
within the electron transport chain, cytochrome P450, and
myoglobin. (56) Collectively, these hemoproteins affect cellular
growth, differentiation, and metabolism. Iron requirements are
higher during periods of rapid growth and development, in-
cluding pregnancy and early childhood. (56) Iron homeostasis
Vol. 24 No. 3 MARCH 2023 e163
 is elegantly controlled by hepcidin, a protein synthesized in
hepatocytes in response to signals that reflect iron status and
inflammation. In individuals with iron deficiency, hepcidin
secretion is inhibited and allows transfer of iron from entero-
cytes into circulation. In the setting of inflammation or iron
sufficiency, hepcidin synthesis is stimulated and blocks trans-
fer from enterocytes and from macrophages. (29)
Iron deficiency is the most common micronutrient defi-
ciency worldwide and is highly prevalent in pregnant
women, infants, and young children. (56) Iron deficiency
is particularly common in LMIC where food diversity and
availability of nutrient-rich foods is low. (56) It is esti-
mated that there are 32 million pregnant women and
273 million children with anemia globally, with about 50%
of these cases caused by iron deficiency. (57) Iron defi-
ciency and iron deficiency anemia (IDA) are common in
preterm infants. (58) Iron acquisition occurs during the
third trimester, thus preterm infants are born with low to-
tal body iron stores. (58) Furthermore, hospitalized pre-
term neonates require frequent blood draws to assess
their biochemical state, increasing iron losses. (58) De-
layed cord clamping is an important, low-cost intervention
to prevent iron deficiency and IDA; however, this has not
been adopted universally and is not recommended in cer-
tain circumstances. (58)
Evidence for Role in Immune Function. Iron affects the cellu-
lar proliferation of immune cells, including macrophages, B
cells, and T cells. (59) Iron deficiency has been demonstrated
to diminish the antibody response to certain vaccines. (59)
However, iron supplementation is not beneficial during active
sepsis and host defense has developed numerous mecha-
nisms to restrict iron availability to pathogens. (59)
Postnatal Supplementation in Term and Preterm Infants.
Iron deficiency and IDA have an adverse impact on neuro-
logic development. (60) Screening for IDA and supple-
menting with enteral iron is thus a regular part of clinical
practice in breastfed infants and preterm infants, in
whom the incidence of iron deficiency and IDA are
higher. (60) A meta-analysis of oral iron supplementation
in low-birthweight and preterm infants demonstrated that
oral iron improved hematologic parameters with no con-
sistent differences in adverse outcomes. (60)
Of note, routine iron supplementation may not be with-
out harm, particularly in iron-replete individuals (59) or in
the setting of systemic inflammation. (29) Two of the indi-
vidual studies included in the meta-analysis previously re-
ferred to demonstrated increased respiratory infections in
infants in the iron treatment groups, and not all trials
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reported infectious outcomes. (60) A high rate of neonatal
sepsis, and in particular Escherichia coli sepsis, was noted
during the late 1960s and early 1970s in Polynesia, when
intramuscular iron was routinely delivered to newborns.
(61) When this intervention was stopped, the incidence of
neonatal sepsis dropped from 17 per 100 to 2.7 per 1,000
neonates. (61) In addition, iron deficiency is protective
against malaria and gastrointestinal infections in children,
demonstrating a complex interplay (mediated by hepcidin)
between iron status and infectious risk. (59)
Currently, the benefit of enteral iron supplementation is
considered to outweigh potential risk in this population. How-
ever, strategies to minimize risk are being evaluated, including
assessment of iron and clinical status before administration of
enteral iron. High-dose ($6 mg/kg per day compared with
3 mg/kg per day) enteral iron supplementation has been
shown to alter the enteric microbiome of premature infants,
and future research is needed to determine the clinical signifi-
cance of different doses and routes of iron supplementation
on the developing microbiome. (62) Furthermore, several
strategies to limit iron availability to pathogens have been con-
sidered to prevent or treat neonatal sepsis, including the iron-
binding protein, lactoferrin. A recent large multicenter RCT
randomized 2,203 preterm infants to oral lactoferrin or pla-
cebo to test if lactoferrin would prevent neonatal sepsis and
found no reduction. (63) Future research is needed to test if
lactoferrin or other intestinal iron sequestration therapies
would improve outcomes during active infection in neonates.
Copper
Nutrient Function and Risk of Deficiency. Copper is a trace
mineral that is important in regulating redox state, as it is
a cofactor for several antioxidant enzymes. (64) It is also a
cofactor for proteins required for oxygen transport, angio-
genesis, neurotransmitter synthesis, and immune func-
tion. (64) Copper homeostasis is normally maintained by
copper absorption from the intestine and copper release
by the liver into bile. Copper deficiency in the neonatal pe-
riod is rare, though preterm infants are at risk due to the
loss of third trimester accretion in utero. Deficiency has
been recognized in individuals receiving prolonged TPN
without added copper, including preterm infants with cho-
lestasis for whom copper had been reduced or withheld in
TPN. (65) A small retrospective study of 7 preterm infants
with ostomies receiving prolonged TPN reported a high
incidence of copper deficiency (71%), indicating that this
may be a particularly vulnerable population. (25)
Rationale for Role in Immune Function. Copper deficiency
is well described to affect the immune system by causing
 neutropenia. (66) In clinical reports of copper deficiency
in preterm infants, neutropenia was part of the clinical
presentation. (65) Whether copper deficiency increases the
susceptibility to infection in humans is poorly understood.
Preclinical data indicate that copper deficiency decreases
neutrophil number and function by decreasing phagocytic
capacity and antibacterial ability. (66) Copper is reported
to accumulate intracellularly in phagocytes during certain
bacterial and fungal infections, and this may act as a pro-
tective component of host defense by increasing oxidative
stress to the pathogen. (66)
Postnatal Supplementation in Term and Preterm Infants.
Copper supplementation studies for the prevention or
treatment of sepsis in term and preterm infants are lack-
ing. Few clinical or preclinical data support the hypothesis
that copper supplementation is warranted in most term or
preterm infants, as the risk of deficiency is low. Neonatal
clinicians should consider copper deficiency in their differ-
ential for infants receiving prolonged TPN who develop
neutropenia, especially for those who have an ostomy or
are very preterm.
Vitamin A
Nutrient Function and Risk of Deficiency. Vitamin A refers
to a collection of fat-soluble compounds including retinol,
retinoic acid, retinaldehyde, retinyl esters, as well as pro–
vitamin A carotinoids. (67) Vitamin A is critical for embry-
onic development, contributing to respiratory epithelial
growth and regeneration, intestinal epithelial growth and
regeneration, and retinal development.
Vitamin A deficiency is common in LMIC, affecting
over 19 million pregnant women and 190 million children
less than 5 years of age globally. (11) Public health initia-
tives and food supplementation interventions have altered
the frequency of vitamin A deficiency in some parts of the
world; however, it remains very common in South Asia
and sub-Saharan Africa. (68) Although vitamin A defi-
ciency is uncommon in developed countries, fetal vitamin
A acquisition increases across gestation, and thus preterm
infants have lower hepatic and circulating vitamin A levels
compared with term infants and are frequently vitamin A
deficient. (69) Zinc deficiency frequently occurs in con-
junction with low levels of the vitamin A carrier protein,
retinol-binding protein. (70) As zinc deficiency is common
in preterm infants, it is plausible that deficiencies of these
micronutrients may coexist, and that zinc deficiency may
exacerbate vitamin A deficiency in this population.
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Evidence for Role in Immune Function. Vitamin A is impor-
tant for multiple aspects of immune health, including pro-
moting mucosal integrity, adequate function of neutrophils,
macrophages, and natural killer cells, and supporting the
adaptive immune response. (4) Vitamin A deficiency in the
neonatal and childhood period is associated with increased
mortality from all causes, as well as increased death second-
ary to diarrheal illnesses, respiratory infections, and measles.
(11) Vitamin A supplementation in the 6-month to 5-year-old
population has been extensively studied and a Cochrane sys-
tematic review of over 1 million children demonstrated a
12% reduction in all-cause mortality, as well as a decrease in
the incidence of diarrheal episodes and diarrhea-associated
mortality. (11) The World Health Organization recommends
vitamin A supplementation to infants 6 months to 5 years of
age in regions where vitamin A deficiency is common.
Postnatal Supplementation in Term Infants. In contrast to
the 6-month to 5-year-old population, studies of vitamin A
supplementation in younger infants have not consistently
demonstrated benefit. There have been 12 large multicen-
ter RCTs of more than 160,000 neonates evaluating the
effects of vitamin A supplementation in term infants on
mortality or prevention of infection. (71) A meta-analysis
demonstrated no significant improvement in survival at 6
or 12 months of age. (71) The results were heterogeneous
and there appeared to be geographic differences; studies
that occurred in South Asia demonstrated benefit (de-
creased mortality) and most studies conducted elsewhere
found no difference in mortality or even evidence of
harm. (71) Consequently, vitamin A supplementation in
infants younger than 6 months is not routinely recom-
mended at this time.
Postnatal Supplementation in Preterm Infants. Vitamin A
supplementation in preterm infants has been extensively
studied for its role in respiratory epithelial growth and the
prevention of bronchopulmonary dysplasia. (72) Two of
these RCTs also reported the incidence of late-onset sepsis
as a secondary outcome measure. (72) These trials had
considerable heterogeneity in the delivery route, dose, and
frequency of vitamin A regimens, and mainly evaluated paren-
teral and intramuscular formations. A meta-analysis demon-
strated a nonsignificant trend toward decreased culture-proven
sepsis in preterm infants receiving vitamin A supplementa-
tion versus placebo. A newer RCT that was not included in
the Cochrane review compared postnatal enteral vitamin A
versus placebo in 196 VLBW infants. VLBW infants receiving
vitamin A supplementation exhibited fewer episodes of late-
onset sepsis (NNT 5 6.686). (73) Thus, some rationale exists
Vol. 24 No. 3 MARCH 2023 e165
 to consider vitamin A to prevent sepsis in preterm infants;
however, currently this approach cannot be recommended
without further research.
Vitamin C
Nutrient Function and Risk of Deficiency. Vitamin C is a
water-soluble vitamin also known as ascorbic acid. Vitamin
C is an important antioxidant, functioning as a free-radical
scavenger. (74) It also functions critically in the biosynthe-
sis of collagen, L-carnitine, and certain neurotransmitters.
(74) Severe vitamin C deficiency in the neonatal popula-
tion is rare, as breast milk and formula provide adequate
ascorbic acid. Vitamin C levels in cord blood have been re-
ported to be higher than the maternal circulation and to
decrease after birth. (75) Levels in preterm infants have
been demonstrated to be higher than in term infants. (76)
Interestingly, high vitamin C levels in preterm infants
measured shortly after birth have been associated with in-
creased mortality and lower total antioxidant capacity.
(77)(78) The redox milieu in neonates is unique compared
with adults and children, and vitamin C can act as a proox-
idant in certain settings. (23) Thus, future study of vitamin
C in the neonatal period will need to carefully assess risk
as well as benefit.
Evidence for Role in Immune Function. Vitamin C adjuvant
therapy at high doses may contribute to antibacterial defense.
(74) Vitamin C has been evaluated in several multicenter
RCTs as an adjuvant therapy for critically ill adults, including
those with sepsis. (74) There is recent interest in using vita-
min C to promote optimal immune and metabolic function
during pediatric sepsis, often in conjunction with hydrocorti-
sone and/or thiamine. (79) Extension of these studies to the
neonatal population has not been reported.
Postnatal Supplementation in Term Infants. Studies evaluat-
ing vitamin C supplementation to prevent or support treat-
ment of neonatal sepsis are lacking.
Postnatal Supplementation in Preterm Infants. Studies eval-
uating vitamin C supplementation to prevent or support
treatment of sepsis in preterm neonates are also lacking.
An RCT of VLBW infants evaluated 3 different vitamin C
dosing regimens and no differences in mortality were ob-
served between treatment groups. (77) Sepsis was not re-
ported as a secondary outcome in this study. (77)
Vitamin D
Nutrient Function and Risk of Deficiency. Vitamin D is a
fat-soluble vitamin that is typically recognized for its role
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in calcium homeostasis and bone metabolism. (17) It has
received considerable investigation for its nonclassic bio-
logical functions over the last decades, including the regu-
lation of innate and adaptive immune function. (80)
Vitamin D status depends on intake from diet as well
as skin exposure to ultraviolet irradiation. Vitamin D in-
sufficiency is very common in pregnant women and chil-
dren. (81) Vitamin D insufficiency ranges considerably
depending on the geographic region sampled and season
of year evaluated. (81) Across studies in different geo-
graphic locations, vitamin D insufficiency is present in
10% to 80% of pregnant women. (81) Vitamin D acquisi-
tion occurs during the third trimester, rendering preterm
infants at high risk for vitamin D deficiency. One report
found that 67% of infants born before 28 weeks’ gestation
had vitamin D levels less than 20 ng/mL (49.92 nmol/L),
suggesting deficiency. (82) Severe vitamin D deficiency re-
sults in clinical rickets and is more common in extremely
preterm infants. (81)
Evidence for Role in Immune Function. Vitamin D has
been demonstrated to influence macrophage activity, T-
lymphocyte number and function, and the susceptibility to
respiratory infections. (80) In children younger than 5
years, vitamin D deficiency is associated with increased
respiratory illnesses and gastroenteritis. (83) Despite this,
a Cochrane review of vitamin D supplementation in this
population did not show a significant reduction in mortal-
ity, pneumonia, or diarrhea. (83) Term and preterm in-
fants with sepsis exhibit lower vitamin D levels than
healthy controls. (84)(85) Lower vitamin D levels at birth
are also associated with increased risk for late-onset sepsis
in preterm infants.
Postnatal Supplementation in Term Infants. A single-center
study randomized term infants with sepsis to vitamin D
and antibiotics versus antibiotics alone and found that vi-
tamin D as an adjuvant therapy improved sepsis severity
score and lowered C-reactive protein levels. (84) There are
currently no known multicenter RCTs of vitamin D sup-
plementation for the prevention of sepsis during infancy.
An ongoing randomized trial, the VITALITY study, will
compare 400 IU of vitamin D with placebo in breastfed
infants ranging in age from 6 to 8 weeks to 12 months of
age. (86) The study design includes a secondary outcome
of respiratory viral infections. (86)
Postnatal Supplementation in Preterm Infants. A small
study randomized preterm infants with late-onset sepsis to
1 of 2 doses of vitamin D. (30) Both doses were effective at
 correcting vitamin D levels but did not differ in impact on
cytokine levels or clinical parameters. (30) Thus, the role
of vitamin D to prevent or improve infectious outcomes
for preterm infants is incompletely understood.
Vitamin E
Nutrient Function and Risk of Deficiency. Vitamin E refers
to a group of 8 lipid-soluble molecules that include to-
copherol and tocotrienols. These compounds are antioxi-
dants known to scavenge free radicals. (4)(17) They also
exhibit anti-inflammatory properties and promote epithe-
lial barrier integrity and T-cell proliferation. (87)(88) As-
sessing vitamin E status is complicated, as plasma levels
often correlate with levels of cholesterol and triglycerides,
and do not necessarily reflect tissue stores. (87) Vitamin E
levels increase as gestation progresses, thus there is a ra-
tionale that preterm infants may be vitamin E deficient.
(88) Cord blood vitamin E levels are typically less than
half maternal values in term infants. (88)
Rationale for Role in Immune Function. A few studies have
evaluated vitamin E as an adjuvant therapeutic in adults
with sepsis, primarily with the rationale that increased an-
tioxidant capacity may improve outcomes. (89) Several of
these have been in combination with other vitamin antiox-
idants. (89) Studies of vitamin E supplementation in the
pediatric population to improve immune function or sep-
sis are lacking. However, vitamin E in the neonatal period
warrants discussion, as it has been extensively investigated
as an antioxidant therapy in preterm infants.
Postnatal Supplementation in Term Infants. Studies evaluat-
ing vitamin E supplementation to prevent or support treat-
ment of neonatal sepsis are lacking.
Postnatal Supplementation in Preterm Infants. Several RCTs
have evaluated vitamin E versus placebo as an intervention
to decrease bronchopulmonary dysplasia, retinopathy of pre-
maturity, or intraventricular hemorrhage in preterm infants.
(87) More than 1,500 randomized infants have been evalu-
ated. (87) Unexpectedly, several of the individual trials and
meta-analyses of these studies demonstrated an increased
risk of sepsis for infants in the vitamin E supplementation
groups. Subgroup analysis demonstrated that rates of sepsis
were increased in infants with birthweights less than 1,500 g;
infants receiving a total dose of vitamin E more than 30 IU/kg
per day; infants receiving intravenous vitamin E; infants
with a serum a-tocopherol level greater than 3.5 mg/dL;
and infants initiated on vitamin E therapy before 48 hours
of age. Two of the studies using an enteral form of vitamin
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E demonstrated an increased risk of necrotizing enterocoli-
tis. (88) It has since been recognized that this preparation
included a polyoxyethylated castor oil carrier, which may it-
self be toxic to the neonatal intestines. (88)
These studies emphasize the importance of carefully
conducted RCTs to investigate micronutrient supplemen-
tation, as undesired side effects can occur. a-tocopherol
and g-tocopherol are the most evaluated supplements in
the neonatal period. There are differences in the bioavail-
ability, antioxidant, and anti-inflammatory properties of
each. Heterogeneity in the isoform being studied, route of
administration, and dose may affect meta-analysis of vita-
min E efficacy in the neonatal period. (88) Future research
of vitamin E therapy in preterm infants will need to con-
sider immunomodulatory effects.
PART 2: DYNAMIC CHANGES TO
MICRONUTRIENT HOMEOSTASIS DURING
ACTIVE INFECTION
Host response to infection requires rapid identification
and coordination between the innate and adaptive im-
mune systems, as well as metabolic adaptations to support
the body during illness. (9) Alterations in micronutrient
status are increasingly recognized as part of the metabolic
response to infection and inflammatory stimuli. (4) Dy-
namic changes in micronutrient homeostasis have been
identified during clinical sepsis in humans and experi-
mental sepsis in adult models for many trace minerals
and vitamins. (12)(17)
Circulating levels of micronutrients may decrease be-
cause of multiple etiologies, including 1) increased meta-
bolic demands, 2) greater uptake for utilization within
injured tissues and organs, 3) increased consumption/uti-
lization in the circulation, 4) decreased intake, or 5) altered
production of carrier proteins for specific micronutrients.
Although increased micronutrient metabolic demands are
plausible, a growing body of literature implicates several
micronutrients as part of the acute phase response.
The acute phase response describes a series of pro-
teins and reactants that change in the circulation after in-
fection or inflammatory stimuli. (7) It is an important
component of the host response and is orchestrated in
the liver, specifically within hepatocytes. (7)(9) Positive
acute phase proteins (APP) and reactants significantly in-
crease in the circulation after illness, including C-reactive
protein, serum amyloid a, ferritin, and ceruloplasmin.
(7) Negative APPs and reactants exhibit a significant de-
crease in the circulation, including albumin, transferrin,
and selenoprotein P. (7)(8) The mechanistic implications
Vol. 24 No. 3 MARCH 2023 e167
 for the change in each of the APPs and acute phase reac-
tants are still being elucidated; however, the acute phase
response is considered an adaptive response. (7) Several
of the positive APPs and reactants exhibit antibacterial
and anti-inflammatory properties. (7) Negative APPs and
reactants may limit utilization from invading pathogens.
(7) Zinc, iron, and selenium are well established as negative
acute phase reactants across the age span, including in neo-
nates. (7)(90)(91)(92) Observational studies demonstrate that
patients with sepsis exhibit lower levels of vitamins A, C, D,
and E than healthy controls. (17) Notably, many of the carrier
and transport proteins for trace minerals and vitamins are
made in the liver and have been established as negative APPs.
(17)(92) Table 4 summarizes evidence for each micronutrient
that may be a component of the acute phase response.
The rationale for several nutritional replacement trials
during sepsis has been based on the hypothesis that if
micronutrient status declines during illness, providing
more of that micronutrient would restore the body to ho-
meostasis, thus improving biological functions and abil-
ity to combat infection. Adding to the scientific premise
for replacement during illness, infection and sepsis incite
oxidative stress and a proinflammatory response, and
many trace minerals and vitamins have antioxidant and
anti-inflammatory properties. However, it is essential to
consider the alternative hypothesis that a transitory de-
cline in micronutrient status confers a survival benefit to
the host, either by limited use of the pathogen or facilitat-
ing an increase in oxidative stress or inflammation for in-
fection control. Future preclinical and clinical work should

Table 4. Micronutrients that may be Components of the Acute Phase Response

Micronutrient Evidence of Altered Micronutrient Levels During Sepsis/Illness
Zinc Infection and critical illness (adult) (92): Decrease in plasma zinc levels
Infection and critical illness (pediatric) (91): Decrease in plasma zinc levels
Necrotizing enterocolitis (neonatal) (91): Decrease in plasma zinc levels
Mechanisms include:
 Redistribution of zinc (to support hepatic synthesis of multiple positive APP) (91)
 Increased calprotectin (zinc binding protein) (92)
 Decreased albumin (zinc transport protein) (91)
Selenium Infection (adult) (12): Decrease in plasma levels of selenium
Infection and critical illness (pediatric) (91): Decrease in plasma levels of selenium
Infection (neonatal) (90): Decrease in plasma levels of selenium
Mechanisms include:
 Decreased selenoprotein P (selenium transport protein) (8)
Copper Infection (adult) (105): Increase in circulating copper levels
Infection (neonatal) (90): Increase in circulating copper levels
Mechanisms include:
 Increased ceruloplasmin (copper transport protein) (90)
Iron Infection (adult) (59)(92): Decrease in circulating iron levels
Infection (pediatric) (91): Decrease in circulating iron levels
Infection and critical illness (neonatal) (91): Decrease in circulating iron levels
Mechanisms include:
 Increased hepcidin (91) (restricts iron absorption from intestines and inhibits iron export from macrophages)
 Increased ferritin (91) (storage protein for iron)
 Decreased transferrin (91) (iron transport protein)
 Neutrophil release of lactoferrin (92) (iron scavenger)
Vitamin A Infection (adult) (91): Decrease in circulating retinol levels
Infection (pediatric) (91): Decrease in circulating retinol levels
Inflammation (neonatal) (106): Decrease in circulating levels of two vitamin A transport proteins
Mechanisms include:
 Decreased retinol binding protein (transport protein for vitamin A) (91)
 Decreased transthyretin (transport protein for vitamin A) (106)
 Increased urinary excretion during illness (91)
Vitamin C Infection (adult) (12): Decrease in vitamin C
Infection (neonatal foals) (107): Decrease in vitamin C
Mechanisms poorly understood, may reflect oxidation of ascorbic acid
Vitamin D Infection and post-operative (adult) (12)(91): Decrease in 25(OH)D
Infection and burn (pediatric) (91): Decrease in 25(OH)D and vitamin D–binding protein
Infection (neonatal) (84)(85): Decrease in 25(OH)D
Mechanisms include:
 Decreased vitamin D binding protein (91)
Vitamin E Infection and inflammation (adult) (91): Decrease in a-tocopherol; cholesterol levels may confound
Mechanisms include:
 Redistribution of cholesterol during inflammatory response (91)

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 explore these hypotheses, with appropriate balancing meas-
ures tested.
CONCLUSION
Micronutrients are powerful dietary components that al-
ter innate and adaptive immune function. Specific micro-
nutrient deficiencies are associated with increased risk
for neonatal infection, including zinc, selenium, vitamin
A, and vitamin D. There is a strong rationale to test if mi-
cronutrient supplementation in high-risk infants may
prevent infection or improve outcomes during active sep-
sis. However, many neonatal micronutrient supplementa-
tion trials have yielded conflicting results. The benefit of
micronutrient supplementation may vary based on the
nutrient status of the infant before the intervention, as
several studies demonstrated improved outcomes in pop-
ulations with a high incidence of preexisting nutrient de-
ficiencies. It is also essential that future research evaluate
the alternative hypothesis that during active infection,
low circulating micronutrient levels may be an adaptive
response to limit micronutrient availability to pathogens.
Finally, micronutrient deficiencies often coexist clinically,
and animal models may provide insight into the impact
of specific micronutrients on neonatal immune function.
Cumulatively, abundant research opportunities exist at
the intersection of micronutrient status, immune func-
tion, and neonatal sepsis. Carefully conducted studies are
needed to inform future nutritional strategies, with the
goal of improving neonatal outcomes.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the requirements for vitamins in newborn
infants, and the differences between preterm
and full-term infants.
• Know the potential adverse effects of pharmaco-
logic use of fat-soluble vitamins.
• Know the clinical manifestations, diagnosis, man-
agement, and prevention of zinc, copper, selenium,
manganese, and chromium deficiency.
• Know the clinical and laboratory manifesta-
tions of deficiencies of fat-soluble vitamins.
• Know the clinical and laboratory manifestations
of deficiencies of water-soluble vitamins.
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 NEOREVIEWS QUIZ

NEO
QUIZ

1. Micronutrients have been shown to regulate multiple biological functions

including innate and adaptive immune responses. Multiple factors contribute
to an increased risk of micronutrient deficiency in preterm infants, including
decreased placental transfer with a shortened third trimester, increased
demand, and possibly diminished bioavailability. Infants born to mothers
affected by obesity are also at increased risk for micronutrient deficiency.
Prepregnancy obesity is associated with increased risk for deficiency for all of
the following micronutrients EXCEPT:

A. Vitamin D.
B. Iron.
REQUIREMENTS: Learners can
C. Folate. take NeoReviews quizzes and
D. Copper. claim credit online only at:
E. Vitamin B12. https://publications.aap.org/
neoreviews.
2. Which of the following micronutrient exerts its effect by binding to metalloproteins?
A. Selenium. To successfully complete 2023
NeoReviews articles for AMA PRA
B. Zinc.
Category 1 Credit™, learners
C. Vitamin A. must demonstrate a minimum
D. Iron. performance level of 60% or
E. Vitamin D. higher on this assessment. If
you score less than 60% on the
3. Vitamin A is a fat-soluble vitamin important for immune function, including assessment, you will be given
promotion of mucosal integrity, neutrophil, macrophage, and natural killer additional opportunities to
cell function as well as adaptive immune response. Studies have shown that answer questions until an
overall 60% or greater score is
preterm infants have lower hepatic and circulating vitamin A levels
achieved.
compared with term infants. Which of the following statements regarding
vitamin A supplementation in preterm infants is correct? This journal-based CME activity
is available through Dec. 31,
A. A Cochrane review of vitamin A supplementation versus placebo
2025, however, credit will be
demonstrated decrease in the incidence of early-onset sepsis in very recorded in the year in which
low-birthweight (VLBW) infants. the learner completes the quiz.
B. Parenteral vitamin A supplementation has been shown to decrease all-
cause mortality in VLBW infants.
C. In a recent randomized controlled trial, enteral vitamin A supplementation
resulted in decreased episodes of late-onset sepsis in VLBW infants.
D. Enteral vitamin A supplementation is the most studied route of administration
in preterm infants. 2023 NeoReviews is approved
E. A Cochrane review of vitamin A supplementation versus placebo for a total of 30 Maintenance of
Certification (MOC) Part 2
demonstrated a trend toward a decrease in clinical late-onset sepsis but credits by the American Board
not culture-proven sepsis in VLBW infants. of Pediatrics (ABP) through the
AAP MOC Portfolio Program.
4. Vitamin D is a fat-soluble vitamin important for calcium homeostasis and
NeoReviews subscribers can
bone metabolism. Which of the following immune functions is modulated by claim up to 30 ABP MOC Part 2
vitamin D? points upon passing 30 quizzes
(and claiming full credit for
A. Macrophage activity. each quiz) per year. Subscribers
B. B lymphocyte number. can start claiming MOC credits
C. Susceptibility to diarrheal illness. as early as October 2023. To
D. Neutrophil function. learn how to claim MOC points,
E. Susceptibility to fungal infections. go to: https://publications.aap.
org/journals/pages/moc-credit.

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 5. Dynamic changes in micronutrient homeostasis have been noted during
clinical sepsis in humans. Recent evidence suggests that several
micronutrients are part of the acute phase response and adaptive response
to infection and/or inflammation. Which of the following micronutrients is
increased during sepsis and critical illness in the neonate?
A. Zinc.
B. Vitamin A.
C. Iron.
D. Vitamin D.
E. Copper.

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 ARTICLE

Congenital Cutaneous Candidiasis in

Preterm Infants
Chelsea Shope, MSCR,* Alexandra Ritter, MD, MSCR,* Samantha Karlin, MD,† Lara Wine Lee, MD, PhD,†
Colleen H. Cotton, MD‡,§
*College of Medicine, Medical University of South Carolina, Charleston, SC
†
Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC
‡
Department of Dermatology, George Washington School of Medicine and Health Sciences, Washington, DC
§
Division of Dermatology, Children’s National Hospital, Washington, DC

EDUCATION GAPS

The signs and symptoms of congenital cutaneous candidiasis (CCC) are often sub-
tle in very low birthweight and preterm infants, thus making it difficult to diag-
nose. Without treatment, CCC is prone to disseminate, leading to pneumonia,
meningitis, sepsis, or death. Clinicians should be aware of the risk factors associ-
ated with CCC to identify neonates who may be at an increased risk. Early detec-
tion of CCC allows for systemic treatment before the disease progresses.

OBJECTIVES After completing this article, readers should be able to:

1. Identify the signs and symptoms of congenital cutaneous candidiasis

(CCC) infection.
2. Describe approaches to the diagnosis and treatment of CCC.
3. Recognize the risk of developing invasive Candida infection in infants
with CCC and the harmful sequalae associated with this systemic illness.

ABSTRACT
AUTHOR DISCLOSURES Dr Karlin
Congenital cutaneous candidiasis (CCC) is a rare condition, which typically participates in a Data Safety Monitoring
affects premature and very low birthweight neonates. Affected infants Board for Medical University of South
present with a diffuse rash of variable morphology, which can appear as Carolina. Drs Shope, Ritter, Lee, and
Cotton have disclosed no financial
peeling, sloughing desquamation; maculopapular lesions; or, less commonly, relationships relevant to this article. This
pustules, vesicles, or bullae. Due to the varied nature of the clinical commentary does not contain a
presentation, the diagnosis of CCC can be quite difficult but critically discussion of an unapproved/
investigative use of a commercial
important because early treatment with intravenous fluconazole can prevent
product/device.
disease progression. In this review, we summarize the epidemiology,
pathogenesis, clinical presentation, evaluation, and management of CCC.
ABBREVIATIONS

CCC congenital cutaneous

candidiasis
INTRODUCTION CSF cerebrospinal fluid
IV intravenous
Fungal infections are common in neonates, with infections due to Candida spe- KOH potassium hydroxide
cies occurring in both term and preterm infants. (1)(2)(3) However, congenital VLBW very low birthweight

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 cutaneous candidiasis (CCC) is a rare type of fungal infec-
tion, which most frequently occurs in premature and very
low birthweight (VLBW) neonates. (1)(4) Affected infants
present with a diffuse rash of variable morphology, which
can appear as peeling, sloughing desquamation; maculo-
papular lesions; or, less commonly, pustules, vesicles, or
bullae. (3)(5)(6)(7)(8)(9)(10) As the infection is acquired
antenatally, affected neonates most often present with a
rash on the first day of birth, but lesions have been re-
ported to appear as late as 7 days of age. (1)(6)(11)(12)(13)
Due to the varied nature of the lesions and presentation of
the disease, clinical recognition of CCC can be quite diffi-
cult but critically important because early treatment with
intravenous (IV) fluconazole can prevent disease progres-
sion. To illustrate this condition, we present a case of a 13-
day-old male infant with CCC. We also review the epide-
miology, pathogenesis, clinical presentation, evaluation,
and management of CCC.
THE CASE
A male neonate was born via spontaneous vaginal delivery
after preterm premature rupture of membranes (12 hours
prior to delivery) to a 27-year-old gravida 4, para 1112
woman at 23 weeks and 5 days’ gestation. His Apgar
scores were 1, 4, and 7 at 1, 5, and 10 minutes of age, re-
spectively, and he had a birthweight of 630 g (51st percen-
tile). He received surfactant, was placed on a ventilator,
and was admitted to the neonatal intensive care unit
(NICU). Of note, the maternal obstetrical history was sig-
nificant for cervical incompetence, which was treated with
a rescue cerclage placed at 23 weeks’ gestation in her first
pregnancy and a history-indicated cerclage placed in her
second pregnancy. She did not have a cerclage placed in
the third pregnancy, which resulted in a nonviable delivery
at 16 weeks’ gestation. Prior to delivery of the infant, she
had a cerclage placed at 13 weeks’ gestation.
At the time of birth, the infant’s mother was diagnosed
with chorioamnionitis in association with purulent vaginal
drainage. As a result, the infant underwent a sepsis evalu-
ation soon after birth and was started on ampicillin and
gentamicin. Umbilical venous and arterial catheters were
placed for access and blood pressure monitoring. He had
mild thrombocytopenia (107 × 103/mL [107 × 109/L]), with
otherwise reassuring laboratory results. At 2 days of age,
his white blood cell count was elevated (35 × 103/mL [35 ×
109/L]) with 49% neutrophils, his platelets had increased
to 186 × 103/mL (186 × 109/L), and he had hyperglycemia
(serum glucose 5 117 mg/dL [6.49 mmol/L]). Blood cul-
tures from the first day of birth showed no growth till
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48 hours, and he remained in a stable condition on pres-
sure support ventilation. His antibiotics were continued
for a 7-day course. The placenta was found to have severe
necrotizing chorioamnionitis in association with ascending
fluid infection, chronic vasculitis, and umbilical panvasculi-
tis with funisitis. The Giemsa stain was negative for fungal
organisms.
At 8 days of age, the infant underwent acute decompen-
sation while receiving synchronized intermittent manda-
tory ventilation and presented with hypotension requiring
dopamine and stress dose steroids, severe respiratory aci-
dosis requiring transition to the high-frequency jet ventila-
tor, and hyperglycemia (serum glucose 5 186 mg/dL
[10.32 mmol/L]). A peripheral arterial catheter was placed.
Blood cultures were redrawn, and ampicillin, gentamicin,
and IV fluconazole were empirically started. Ampicillin
was changed to nafcillin 1 day later. Blood cultures were
again negative at 48 hours, and the antibiotics and flucon-
azole were discontinued.
Three days after discontinuation of fluconazole, the der-
matology service was consulted for dry, scaly, “peeling” skin
that had been present for 2 days. Skin examination showed
diffuse pink scaly skin over the back and extremities, with
milder involvement of the face and neck and erosions on the
chest and abdomen (Fig 1). Potassium hydroxide (KOH)
preparation revealed numerous spores and pseudohyphae
(Fig 2). IV fluconazole was restarted along with wound care
with 2-sided wound contact layer dressings applied to eroded
areas. After 7 days of IV fluconazole administration, his clini-
cal condition improved, but due to persistent active skin
involvement, the dermatology service recommended an addi-
tional 7 days of antifungal treatment. He was tolerating full
gavage feedings and was doing well; therefore, after a total of
10 days of IV fluconazole administration, he was transitioned
to oral fluconazole. On day 13 of treatment, the infant’s respi-
ratory status worsened and he required fraction of inspired
oxygen of 1.0, which prompted transition from oral to IV flu-
conazole and discontinuation of his feedings. Although his
clinical condition improved again, the infant’s back and neck
remained pink and scaly, with evidence of active infection on
repeat KOH preparation at 14 days of treatment and then
again at 21 days.
Ultimately, due to a lack of response to 22 days of flu-
conazole and persistent lesions on the temple, back, abdo-
men, and leg, the infant was started on IV micafungin.
The lesions resolved following 7 days of treatment with
micafungin. At 5 1=2 months of age, the infant remains
hospitalized on pressure support ventilation because of se-
vere bronchopulmonary dysplasia.

Figure 1. Diffuse scale with erythema over the chest and abdomen of a
premature infant ultimately diagnosed with disseminated Candida infec-
tion secondary to congenital cutaneous candidiasis.
EPIDEMIOLOGY AND PATHOGENESIS
Although candidal vulvovaginitis affects up to 30% of preg-
nant women, a 2017 study by Kaufman et al reported that
CCC occurs in 0.2% of infants with a birthweight between
1,000 and 1,499 g and in 0.6% of infants with a birthweight
of <1,000 g. (1)(3)(6)(14) CCC is thought to occur in this pop-
ulation because of a complex interplay between ascending in-
fection from the vagina, the lack of functional maturation of
the skin at birth, and the immature immune system of pre-
term and VLBW patients. (1)(2)(5)(6)(15)(16) This unique set
of circumstances predisposes these neonates to invasion of
Figure 2. Numerous spores and pseudohyphae visible on microscopy of
skin scrapings and treated with potassium hydroxide, diagnostic for con-
genital cutaneous candidiasis.
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fungal organisms into both the epidermis and dermis, the hall-
mark of CCC. (1)(5)(6) While healthy term neonates commonly
acquire Candida infections postnatally, these are typically un-
complicated local skin infections, which resolve spontaneously.
(3)(17) Clinicians need to maintain a high index of suspicion
for CCC in extremely premature and VLBW infants during
the early newborn period because of increased morbidity and
mortality in case the local infection progresses to a systemic
fungal infection. (8)(14)(17)(18)(19)
While the pathogenesis of CCC is not fully understood,
it is believed that it occurs as a result of an ascending infec-
tion from the vagina. (1)(5)(20) Grossly, chorioamniotic pla-
ques associated with CCC are found at the inferior pole of
the amnion closest to the vagina, along with underlying
areas of vaginal inflammation. (1) It has been proposed that
Candida species use microscopic fissures within the am-
nion as an entry portal, allowing them to penetrate the am-
niotic sac without membrane rupture. (5)(6)(15)(20) This
entry approach is supported by the finding of mycelial fila-
ments in Wharton’s jelly without any detectable disturbance
of the overlying epithelium. (1) Once inside the amnion,
Candida species, most commonly C albicans, spread to the
fetal skin, which causes a rash to develop 36 to 72 hours af-
ter exposure. (1)(6) It is suspected that this subclinical infec-
tion may precipitate preterm labor and preterm premature
rupture of membranes, leading to a higher incidence of
CCC in preterm and VLBW neonates. (1)(6)(14)
Despite the high incidence of vulvovaginal candidiasis
in pregnancy, CCC is uncommon. (1)(3)(6) Current mater-
nal infection with vulvovaginal candidiasis at the time of
birth is only seen in approximately half of CCC cases,
though many case reports of CCC mention prior maternal
treatment for vulvovaginal candidiasis at some point dur-
ing the pregnancy. (1)(5)(6)(12)(14)(21) Intrauterine foreign
bodies, such as the presence of a cerclage (as described in
the case previously) or an intrauterine device during preg-
nancy, have been shown to be associated with an in-
creased risk for CCC. (1)(6) Maternal factors unrelated to
CCC risk include maternal age, parity, diabetes mellitus,
urinary tract infection, prolonged labor, prolonged rupture
of membranes, and the use of tocolytics, antibiotics, or ste-
roids. (1)
Candida species are common cutaneous commensals. (3)
In term infants, CCC is associated with a benign disease
course that spontaneously resolves. (3)(8)(17)(22) How-
ever, premature and VLBW infants, especially those born
less than 27 weeks’ gestation and those weighing less
than 1,000 g, have high rates of systemic infection and
death. (1)(6)(14)(15)(18)(23)(24)(25)(26) This population is
Vol. 24 No. 3 MARCH 2023 e177
 naturally more susceptible to cutaneous infection because of
the lack of functional maturity of the skin. (1)(3) Keratiniza-
tion, the process of epidermal maturation, does not begin un-
til 22 to 24 weeks’ gestation and continues until a few weeks
after birth. (3) This allows for skin penetration by Candida spe-
cies and invasive disease. (3) Interestingly, the gross epidermal
compromise seen with CCC-associated widespread erosions is
highly associated with invasive disease and carries the greatest
risk of death. (1)(8)
The lack of skin maturation in combination with an im-
mature immune system leaves VLBW and extremely prema-
ture infants prone to developing CCC. (1)(3) Skin occlusives
that are commonly used during NICU stays, such as tape,
monitor leads, and dressings, further increase the risk for
CCC. (3) The presence of a central catheter or endotracheal
tube, prior antibiotic use, and IV lipid emulsions are also as-
sociated with an increased risk of CCC. (25)
CLINICAL PRESENTATION
Neonates with CCC have cutaneous lesions of variable mor-
phology, which are often subtle at onset. (1)(6)(16)(27)(28)
CCC begins as mild scaling in flexural sites. (8)(10) This pro-
gresses to erythematous skin lesions with diffuse scale, most
commonly appearing as erythematous patches, sometimes re-
ferred to as “burn dermatitis.” (1)(3)(6) These lesions tend to
desquamate, peel, slough, and erode, as seen in the patient in
the case described previously. (1)(6)(29) Darmstadt et al found
that infants with lesions of burn dermatitis had a mortality
rate of 55%. (1) Less commonly, the lesions of CCC can pre-
sent with widespread papular, pustular eruptions that may
progress to vesicles or bullae; multiple denuded areas at birth;
yellowish plaques or secretions; or dry, flaking, scaling skin.
(1)(6) The sites with the greatest degree of involvement are
the back, extensor surfaces, and skin folds. (1) CCC may in-
clude pustules on the palms and soles or, rarely, be limited to
the nail plate. (1)(3)(22)(27)
Due to the varied nature of lesions, the differential diagno-
sis of CCC is broad. It must be differentiated from acquired
cutaneous candidiasis, which is a cutaneous infection also
most commonly caused by C albicans. However, acquired cu-
taneous candidiasis presents after the first week of age and
mainly affects intertriginous areas. (8) Other similar skin le-
sions include impetigo, Listeria monocytogenes, erythema toxi-
cum neonatorum, congenital syphilis, neonatal lupus, and
Langerhans cell histiocytosis.
It is estimated that between 3% and 5% of newborns
with CCC weighing <1,500 g and up to 10% of newborns
weighing <1,000 g develop systemic candidal disease. (18)
Infants with CCC who weigh less than 750 g have a
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twofold higher risk of developing systemic infection than
their counterparts with higher birthweight. (23)(30) Early
recognition and diagnosis of CCC are crucial for the pre-
vention of disseminated Candida infection. (6) Early signs
of systemic candidal infection include respiratory distress
and leukocytosis with neutrophilia. (1)(17)(31) Persistent
hyperglycemia and glycosuria may also be seen. (1)(28)
Systemic fungal infection leads to severe consequences,
including pneumonia, meningitis, and sepsis, with an esti-
mated mortality rate of 30%. (1)(6)(8)(11)(17)(19)(23) Up to
70% of infants who survive a systemic fungal infection
during the newborn period have neurodevelopmental im-
pairment. (23)(24)(30)(32) Studies have found that earlier
initiation of antifungals in neonates with CCC with sys-
temic fungal infection is associated with reduced mortal-
ity. (3)
EVALUATION
CCC should be suspected in neonates with a diffuse rash
affecting multiple body sites within the first week of birth,
especially if the patient is premature or with VLBW. The
evaluation should begin with a KOH preparation of skin
scrapings. (1)(3)(6)(26)(33) Samples should be obtained
from 2 or more sites, especially if cutaneous sloughing is
already present. The KOH preparation of infants with a
candidal infection will demonstrate spores and pseudohy-
phae. (3) Another diagnostic option is to obtain a fungal
culture either from a skin swab or skin biopsy. (3)(6)(33)
Organisms from tissue culture are best visualized using
periodic acid-Schiff stain or Gomori methenamine silver
stain. (1) Aerobic culture either from a cutaneous swab or
from tissue culture will aid in the identification of the ex-
act fungal species, although cultures take significantly lon-
ger to provide results compared to KOH preparation. (6)
Empiric IV antifungal therapy should be started when high
clinical suspicion exists even if confirmatory testing is not
complete, especially if the patient is less than or equal to
26 weeks’ gestation and weighs less than 750 g. (6)(26)
Placental evaluation may also prove useful if chorioam-
nionitis or lesions on the umbilical cord (funisitis) are
identified, as was present in the case described previously.
(1)(3)(6) Grossly, lesions appear as discrete, round, yellow
lesions clustered along the cord or near its insertion into
the placenta, or as yellow exudate on the extraplacental
membranes. (1) On histologic evaluation of the placenta, a
mixed infiltrate of neutrophils, lymphocytes, and histio-
cytes is often seen, and the presence of Candida species
may or may not be present using Giemsa stain (in the
case previously, no fungal organisms were identified).
 (1)(3)(6)(14)(16) If deeper regions of the placenta are involved,
fewer organisms are typically present. (1) Overlying amniotic
membrane is usually intact, although affected areas of the pla-
centa may become necrotic as lesions evolve and the associ-
ated inflammatory infiltrate intensifies (as present in the case
described previously). (1)(15)(34)
As CCC is confined to the epidermal and dermal layers
of the skin, cultures of blood, urine, and cerebrospinal
fluid (CSF) are negative. (1) However, if there is a concern
for systemic infection, cultures from these sites should be
obtained. (1)(6)(8)(13)(34) It is important to weigh the risks
and benefits of obtaining CSF if there are candidal lesions
overlying the back. As CCC is an invasive infection, there
is a potential of inoculating the CSF with Candida during
a lumbar puncture in an infant with CCC. If CSF cultures
are not drawn, clinicians should treat empirically for fun-
gal meningitis with 14 to 21 days of treatment. (6)
MANAGEMENT
Systemic treatment with IV fluconazole should be provided
for a minimum of 10 days in neonates with CCC to prevent
systemic disease. (6)(26)(35) This approach is necessary be-
cause topical therapy for the treatment of CCC does not pre-
vent systemic spread. (31) Although the bioavailability of
fluconazole is similar in the oral and IV preparations in
adults, it is possible that oral fluconazole treatment may lead
to inadequate systemic levels in premature infants because
of the immature gastrointestinal tract. (36) Effective antifun-
gal treatment is especially important in infants with invasive
fungal dermatitis (characterized by burnlike erosions), given
its high mortality. (1)(8)(34) Although CCC is most fre-
quently attributable to C albicans, it can also be caused by C
parapsilosis (6)(16)(17)(36); isolates of both species have been
found to be susceptible to fluconazole. (6)(17)
Previously, most clinicians used amphotericin B for the
treatment of invasive fungal infection, including CCC, in in-
fants. (3)(17) More recent literature has led to a significant
shift in treatment strategies. In 1998, a small, randomized
prospective trial showed that fluconazole is equally effective as
amphotericin B for the treatment of invasive Candida infec-
tion. (37) It has subsequently been proven that fluconazole
can treat premature infants with C albicans septicemia and is
an effective monotherapy for VLBW infants with no need for
discontinuation because of side effects. (26)(36)(38) Given the
equivalent efficacy and excellent safety data of fluconazole, the
use of amphotericin B or liposomal amphotericin B is consid-
ered second-line treatment. (4)(23) While there has previously
been concern surrounding the development of resistant Can-
dida species with the use of fluconazole (specifically C glabrata
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and C krusei), these species are not known to cause CCC. (39)
As demonstrated in the case described previously, there may
also be a role for the use of echinocandins in the manage-
ment of CCC, especially with failed symptom resolution de-
spite extended courses of fluconazole. However, studies
evaluating the long-term safety profile of echinocandins in
premature and VLBW populations are lacking. (40)
Summary
• Key risk factors associated with CCC include preterm
birth, especially those with a birth gestational age of
less than 27 weeks, and VLBW (<1,000 g).
(11)(12)(14)(41)
• Factors associated with skin breakdown, such as
instrumentation and indwelling catheters, are also
associated with CCC, which is common in this
population. (1)
• Maternal factors, such as a history of an intrauterine
foreign body (such as a cerclage) and infection with
vulvovaginal candidiasis or chorioamnionitis, are
also associated with CCC. (6)
• CCC commonly leads to invasive candidiasis in
extremely preterm infants, which is associated with
significant morbidity and mortality. (4) Studies have
proven that earlier initiation of antifungals is
associated with reduced mortality in neonates. (3)
• The use of IV fluconazole is found to be safe and
effective in extremely preterm and VLBW infants
with CCC. (19)(23)(39)(42)(43)
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the treatment and complications of neo-
natal fungal infections.
• Know the cutaneous manifestations of severe
candidiasis.
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Infect Dis J. 1997;16(8):763–767
38. Huttova M, Hartmanova I, Kralinsky K, et al. Candida fungemia in
neonates treated with fluconazole: report of forty cases, including
eight with meningitis. Pediatr Infect Dis J. 1998;17(11):1012–1015
39. Manzoni P, Leonessa M, Galletto P, et al. Routine use of fluconazole
prophylaxis in a neonatal intensive care unit does not select natively
fluconazole-resistant Candida subspecies. Pediatr Infect Dis J.
2008;27(8):731–737
40. Manzoni P, Rizzollo S, Franco C, et al. Role of echinocandins in the
management of fungal infections in neonates. J Matern Fetal
Neonatal Med. 2010;23(Suppl 3):49–52
41. Jagtap SA, Saple PP, Dhaliat SB. Congenital cutaneous candidiasis: a
rare and unpredictable disease. Indian J Dermatol. 2011;56(1):92–93
42. Aruna C, Seetharam K. Congenital candidiasis. Indian Dermatol
Online J. 2014;5(Suppl 1):S44–S47
43. Aujard Y, Farnoux C, Lefevre S, Maury L, Delezoide AL, Mariani-
Kurkdjian P. [Candida infections in newborns] [in French]. Arch
Pediatr. 2003;10(Suppl 5):569s–574s
 INDEX OF SUSPICION IN THE NURSERY

Umbilical Cord Bleeding in a Neonate

Alina Ivashchuk, DO,* Wendy Sturtz, MD*
*Christiana Care Health System, Newark, DE

PRESENTATION
Neonatal Course
A 2-day-old twin girl born at 33 weeks by urgent cesarean delivery due to mater-
nal severe preeclampsia presents with umbilical cord bleeding. This twin A of a
40-year-old gravida 5, para 4 woman’s dichorionic/diamniotic pregnancy has Ap-
gar scores of 7 and 9 at 1 and 5 minutes, respectively. Subsequent mild respira-
tory distress is noted after delivery, requiring continuous positive airway
pressure (CPAP) and 30% fraction of inspired oxygen (FiO2). Prenatal history is
significant for mild maternal thrombocytopenia (platelet count of 139 × 109/L
[139 × 103/mL]; reference range: 150–450 × 109/L [150–450 × 103/mL]), unknown
group B Streptococcus status, and negative prenatal screening test result. There
is no significant family medical history. Her birthweight is 1,880 g (45th percen-
tile per Fenton preterm growth curve), and length and head circumference are
commensurate. The infant received vitamin K injection after delivery. In the
NICU, she transitions from CPAP to high-flow nasal cannula (HFNC), with
symptoms of respiratory distress syndrome improving by day 2. She receives
dextrose-containing intravenous (IV) fluids via a peripheral IV device and preterm
formula via a nasogastric tube. A blood culture is sent on admission to the NICU;
however, she is not started on antibiotics as delivery was due to maternal indica-
tions, and her initial clinical course was typical for a 33-week premature infant.
Cord bleeding is first noted at 36 hours after birth after her umbilical clamp
is removed and quickly resolves with pressure to the umbilicus. However,
2 hours later, she has significant rebleeding at her umbilicus, with a total esti-
mated blood loss of 24 mL. No bleeding is noted from her IV site or blood draw
sites; there is no oral mucosal bleeding and no gastrointestinal (GI) blood loss.
On examination, her vital signs are normal, with a blood pressure of 56/36 mm
Hg (mean arterial pressure of 43 mm Hg), heart rate of 160 beats/minute, and
respiratory rate of 47 breaths/minute. The infant’s neurologic examination find-
ings are unchanged and appropriate for a preterm infant. The anterior fonta-
nelle is soft and flat. There is no hepatosplenomegaly or abdominal tenderness
or distention, no bruising or petechiae, and no joint swelling; range of motion
AUTHOR DISCLOSURES Drs Ivashchuk
of the extremities is normal. The infant continues to receive 4 L/min of oxygen and Sturtz have disclosed no financial
via HFNC 21%, and her cardiorespiratory status remains stable. relationships relevant to this article. This
Complete blood cell count shows a platelet count of 202 × 109/L (200 × 103/mL) commentary does not contain a
discussion of an unapproved/
(reference range: 100–300 × 109/L [100–300 × 103/mL]) and a hematocrit of 28.9% investigative use of a commercial
(reference range: 45%–67%), which decreased from 50.9% 1 day prior. Prothrombin product/device.

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 time (PT) and heparin-extracted partial thromboplastin
time (PTT) are both prolonged at more than 150 seconds
(PT range: 9.5–15.2 seconds; PTT range: 22–60 seconds),
and fibrinogen is 137 mg/dL (1.37 g/L) (reference range:
180–410 mg/dL [1.80–4.10 g/L]). The blood culture that
was sent on admission returned negative. Her head ultra-
sonography shows a large hemorrhage within the right
temporo-occipital region. She undergoes transfusion with
packed red blood cells and fresh frozen plasma (FFP).
DISCUSSION
Differential Diagnosis
An inherited bleeding disorder, rather than an acquired bleed-
ing disorder, is suspected in this infant. She received vitamin
K at birth, is not thrombocytopenic, and has not received
medications known to interfere with coagulation; her improv-
ing respiratory distress symptoms are attributed to lung im-
maturity and not to an infectious cause. Although factor VIII
and IX deficiencies are the most common inherited coagulo-
pathies, those diagnoses are less likely in this female infant
given their typical X-linked inheritance patterns. Notably, she
has prolongation of both PT and PTT, signifying that either
multiple factors or a factor in the common pathway is respon-
sible for abnormal coagulation. To consider the potential ex-
planation for this infant’s bleeding, one must recall that the
clotting cascade is initiated with vascular injury, causing
platelet and procoagulant factor activation and ultimately re-
sulting in activation of the intrinsic (factors VIII, IX, XI,
XII) and extrinsic (factors III, VII) pathways. These path-
ways then converge in the common pathway (factors I, II,
V, VIII, X), leading to clot formation. PTT evaluates factors
in the intrinsic and common clotting pathways, whereas
PT evaluates factors in the extrinsic and common clotting
pathways. The differential diagnosis for this patient can
therefore be narrowed to rare clotting factor deficiencies in-
cluding prothrombin, fibrinogen, factor II, factor V, and
factor X deficiencies, as well as combined factor deficien-
cies. All of these factor deficiencies can present with intra-
cranial hemorrhage and umbilical bleeding in neonates and
are equally common in males and females. (1)
Actual Diagnosis
After further discussion with the infant’s mother, it is elu-
cidated that the infant’s 10-year-old sister had been diag-
nosed with severe factor X deficiency as an infant after
presenting with hemarthrosis. After consultation with the
hematology service, a factor X assay (also known as factor
X coagulant activity, FX:C) is ordered. A normal FX:C
level ranges from 19% to 79%, a level of 6% to 10%
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characterizes mild factor X deficiency, a level of 1% to 5% in-
dicates moderate deficiency, and level <1% indicates severe
factor X deficiency. (2) The infant’s FX:C level is 1%, and she
is diagnosed with moderate factor X deficiency. The infant’s
twin sister has a normal coagulation profile, and further evalu-
ation for factor X deficiency is not indicated.
The Condition
Factor X is a vitamin K–dependent coagulation factor pro-
duced by the liver. It is the first step in the common path-
way of coagulation and is necessary for the conversion of
prothrombin to thrombin. (3)(4) Inherited in an autosomal
recessive pattern, factor X deficiency is equally prevalent
in males and females and is caused by mutations in the
F10 gene located on chromosome 13q34-ter. (3)(5)(6) Pres-
ently, 160 F10 mutations have been identified. (5) It is rare
with an incidence of 1 per 500,000 to 1,500,000 in the
general population. (3)(5)(7)
Heterozygous F10 mutations usually result in mild or
moderate factor X deficiency, whereas homozygous muta-
tions result in severe factor X deficiency, leading to variable
bleeding tendencies. (5) Symptoms of bleeding may manifest
at any age, though severely affected individuals with less
than 1% factor X activity present in infancy or early child-
hood. (3) Presenting symptoms can be hemarthrosis, GI
bleeding, menorrhagia, mucosal tract bleeding such as epi-
staxis, hematomas, or hematuria. Furthermore, excessive
bleeding after trauma, after procedures such as circumcision,
or after surgical interventions are possible presentations.
Neonates with severe factor X deficiency are commonly iden-
tified because of umbilical cord bleeding or central nervous
system bleeding. (3)(8) Significant or unusual bleeding, such
as umbilical cord bleeding in neonates, is an indication to
evaluate for inherited coagulopathies.
Diagnosis is made by identification of low factor X lev-
els (FX:C). (3)(9) Prenatal diagnosis is recommended if
there is a sibling with a known severe factor X deficiency
or if both parents are known carriers (heterozygotes). (3)
In addition, neonates with a severely affected sibling
should be tested for factor X activity level ideally after
birth, and cord blood should be used if possible. (1) In the
case presented here, unfortunately, the family history of
factor X deficiency, although documented in outpatient
visits, was not communicated on initial hospital admission
and was therefore not known when the infant was admit-
ted to the NICU. Consequently, the factor X activity level
was obtained first at 2 days after birth when the infant be-
came symptomatic rather than immediately after birth.
Subsequently, there were identified areas for improvement
 in communication surrounding transition of care between
outpatient and inpatient providers, as well as patient and
health care team communication.
Management
If there is a known or suspected homozygous F10 muta-
tion, either because both parents are known to be carriers
or because there is a sibling with known inherited factor
X deficiency, cesarean delivery may be offered to decrease
the risk of intracranial bleeding secondary to vaginal deliv-
ery. If a vaginal delivery is planned, invasive monitoring
and instrumentation at delivery are avoided. (6) In this
case, although the family history of factor X deficiency was
not known, the patient was delivered via cesarean delivery
because of maternal complications.
There is a paucity of evidence to guide management for
this coagulation disorder. With an immediate unstable neo-
natal bleeding episode and suspected factor X deficiency,
FFP is used along with plasma-derived prothrombin complex
concentrate. Although single-factor factor X concentrates are
preferred for treatment, only 1 plasma-derived factor X con-
centrate (Coagadex, Bio Products Laboratory Limited, Bore-
hamwood, United Kingdom) has been approved in the
United States and Europe. Coagadex is approved for short-
term prophylaxis, such as preoperatively, and for acute bleed-
ing episode control in patients with moderate-to-severe he-
reditary factor X deficiency. (2) Recently, Coagadex has been
used as prophylactic treatment in patients with factor X defi-
ciency as it was for our patient after discussion with the he-
matology service, although there are no long-term data for
its use in the neonatal population. (2)
Patient Course
The infant receives several more transfusions of FFP due to
persistently prolonged PT and PTT and is started on
plasma-derived factor X concentrate intravenously. Subse-
quently, factor X level and coagulation studies are improved,
and there is no further bleeding. An MRI of the brain con-
firms the presence of a large subacute parenchymal hemor-
rhage in the right occipital lobe and also demonstrates
moderate breakthrough intraventricular hemorrhage. The
infant is ultimately discharged from the hospital in room
air, with appropriate increases in head circumference and
weight, without any adverse neurologic sequelae, and orally
feeding with a central venous catheter for Coagadex admin-
istration. On outpatient hematology follow-up visits, she is
reported to have a mild expressive speech delay but is other-
wise meeting developmental milestones.
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Lessons for the Clinician
• Consider factor deficiencies when infants present with
excessive bleeding.
• Neonates with severe factor deficiencies commonly pre-
sent with umbilical cord bleeding or central nervous sys-
tem (CNS) bleeding.
• Thorough examinations and CNS imaging should be
considered in infants with coagulopathies to identify po-
tential sites of bleeding.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the causes and pathophysiology of con-
genital defects in hemostasis.
• Know the clinical manifestations, laboratory find-
ings, and management of congenital defects in
hemostasis.
References
1. Luchtman-Jones L, Wilson DB. The blood and hematopoietic system.
In: Neonatal-Perinatal Medicine Diseases of the Fetus and Infant, Volume
2. 9th ed. St. Louis, MO: Elsevier; 2011:1340
2. Shapiro A. Plasma-derived human factor X concentrate for on-
demand and perioperative treatment in factor X-deficient patients:
pharmacology, pharmacokinetics, efficacy, and safety. Expert Opin
Drug Metab Toxicol. 2017;13(1):97–104
3. Menegatti M, Peyvandi F. Factor X deficiency. Semin Thromb Hemost.
2009;35(4):407–415
4. Girolami A, Cosi E, Sambado L, Girolami B, Randi ML. Complex
history of the discovery and characterization of congenital factor X
deficiency. Semin Thromb Hemost. 2015;41(4):359–365
5. Mitchell M, Gattens M, Kavakli K, et al. Genotype analysis and
identification of novel mutations in a multicentre cohort of patients
with hereditary factor X deficiency. Blood Coagul Fibrinolysis.
2019;30(1):34–41
6. Spiliopoulos D, Kadir RA. Congenital Factor X deficiency in women:
A systematic review of the literature. Haemophilia 2019;25(2):195–204
7. Kulkarni R, James AH, Norton M, Shapiro A. Efficacy, safety and
pharmacokinetics of a new high-purity factor X concentrate in women
and girls with hereditary factor X deficiency. J Thromb Haemost.
2018;16(5):849–857
8. Brown DL, Kouides PA. Diagnosis and treatment of inherited factor
X deficiency. Haemophilia. 2008;14(6):1176–1182
9. Dorgalaleh A, Zaker F, Tabibian S, et al. Spectrum of factor X gene
mutations in Iranian patients with congenital factor X deficiency.
Blood Coagul Fibrinolysis. 2016;27(3):324–327
Vol. 24, No. 3 MARCH 2023 e183
 INDEX OF SUSPICION IN THE NURSERY
Dry Gangrene of Feet in an Apparently
Well Neonate
Kumar Ankur, MD, DNB,* Aparna Prasad, DNB,* Gaurav Kharya, DNB,† Sanjeev Chetry, MD, DNB*
*Department of Neonatology, BLK Super Speciality Hospital, New Delhi, India
†
Center for Bone Marrow Transplant & Cellular Therapy, Indraprastha Apollo Hospitals, New Delhi, India
AUTHOR DISCLOSURES Drs Ankur,
Prasad, Kharya, and Chetry have disclosed
no financial relationships relevant to this
article. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial
product/device.
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PRESENTATION
An early term male infant is born via emergency cesarean section because of
placenta previa to a 30-year-old gravida 4, para 1, abortus 2 woman. The preg-
nancy was complicated due to gestational diabetes mellitus, and the mother’s
blood sugar was well controlled on oral hypoglycemic agents. The infant is born
vigorous with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively, and is
transferred to the mother’s side. Breastfeeding is started along with sugar moni-
toring, which remains within the normal range for age. His vital signs remain
normal until 28 hours after birth, when a sudden onset of bluish discoloration
of the digits of the left lower limb is noticed by the parents. It increases in inten-
sity over a few hours as the skin over the discoloration changes to bluish-black.
Moreover, similar new patches appear over the left buttock and scrotum (Figs 1
and 2). The infant is referred to our center for further evaluation and management.
Upon arrival, he looks alert, and his birthweight, length, and head circumference are
2,740 g (9th percentile), 47 cm (6th percentile), and 34 cm (12th percentile), respec-
tively. Initial physical examination is unremarkable, and all the peripheral pulses of
the upper and lower limbs are well palpable. Local examination findings are noted as
gangrene of the digits of the left lower limb and bluish discoloration (reticular in the
pattern) of the left buttocks and scrotal sac. There is no history of similar events in
the family. He is admitted to the NICU for further care.
His sepsis screening result is negative, and his blood culture is sterile. His
blood sugar, hemoglobin/hematocrit, platelet counts, liver function tests, and co-
agulation profile are unremarkable. He is started on intravenous heparin and
cryoprecipitate transfusion after conducting further blood investigations, which
revealed the diagnosis.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis for a neonate with this clinical picture includes:
• Disseminated intravascular coagulation
• Infection-associated venous thrombosis
• Thrombosis in an infant of a diabetic mother
• Vascular spasm due to catheterization
• Thrombophilia

Figure 1. Gangrene on the left foot and toes.
DISCUSSION
The neonatal hemostatic system is affected by gestational
age, that is, the higher the gestational age, the more effec-
tive and mature will be the hemostatic system. Despite
that, even a term neonate has several procoagulants, and
inhibitor levels are reduced when compared to an older
child or an adult. Thus, diagnosing a neonatal coagulation
disorder causing either hemorrhage or thrombosis is a
challenge. (1)
Disseminated intravascular coagulation is typically a co-
agulation disorder of sick neonates and is usually followed
by events such as asphyxia, metabolic acidosis, infection,
hypothermia, or thrombosis. However, critical clinical fea-
tures and laboratory findings of thrombocytopenia, abnor-
mal coagulation profile, and low levels of fibrinogen and
d-dimers are indicators of its diagnosis. In our case, the
Figure 2. Skin appearance after 24 hours of treatment.
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neonate was well-looking and hemodynamically stable with
unremarkable aforementioned laboratory findings. (2)
Few case reports of lower limb venous gangrene are as-
sociated with Staphylococcus aureus sepsis, which has been
successfully treated with antibiotics and heparin, leading
to complete resolution. (3) In our case, the sepsis screen-
ing test was negative, and all blood and tissue cultures
were sterile.
A similar case of lower limb gangrene has been reported
in an infant born to a mother with uncontrolled diabetes
mellitus, for which lower limb amputation was required. Al-
though the association of gestational diabetes and venous
thrombi in infants of a diabetic mother is well established,
in this case, reported by Long et al, the thrombi were arterial,
causing gangrene in fetal life itself. (4) Our case is also of an
infant born to a diabetic mother, but her sugar levels were
well controlled on oral hypoglycemic agents.
Transient vascular spasm can occur after arterial cath-
eterization and cause pallor and cyanosis of the extremity
because of arterial constriction. However, this is uncom-
mon in the absence of any central line or arterial line
catheterization. (5) In our case, no such procedure was
performed.
Thrombophilia, which is a prothrombotic disorder, can
be either congenital or acquired. A complete thrombophilia
profile should be investigated for any unusual manifesta-
tions of thrombosis. It also includes antithrombin III activ-
ity, protein C activity, protein S activity, free protein S,
activated protein C resistance, homocysteine levels, lipopro-
tein(a), factor V Leiden mutation, activated partial thrombo-
plastin time (aPTT), and diluted Russell viper venom time
for lupus anticoagulant and anticardiolipin antibodies in
the mother. (6) Severe compound heterozygous or homozy-
gous deficiencies of protein C or S typically present with
purpura fulminans with or without thrombosis. Neonates
who have transplacentally acquired maternal antiphospholi-
pid antibodies such as lupus anticoagulant and anticardioli-
pin antibodies may also have a clinical presentation similar
to purpura fulminans. Nearly 20% of neonatal thromboses
can have the underlying predisposing genetic trait. (6) Anti-
thrombin III deficiency is associated with an increased risk
of venous thromboembolism than arterial. (7) Pregnant pa-
tients with antithrombin III deficiency and their deficient
infants have been successfully treated with antithrombin III
concentrates and low-molecular-weight heparin (LMWH),
preventing thrombosis in the neonatal period. (8) In our
case also, the thrombophilia profile was investigated, which
revealed antithrombin III deficiency and protein C and S
deficiencies (Tables 1 and 2).
Vol. 24, No. 3 MARCH 2023 e185
 Table 1. Thromobophilia Profile and Other Investigations
Investigations Value (Reference Range) Interpretation
Hemoglobin 13.69 g/dL (136.9 g/L) Low
Platelet 193 × 103/lL (193 × 109/L) Normal
G6PD No deficiency Normal
CRP 0.14 mg/dL (1.39 mg/L) (up to 6 mg/L) Normal
Antithrombin activity (functional) 47.6% (80-120%) Low
Protein C (functional) 16.3% (70-140%) Low
Protein S (functional) 42% (60-130%) Low
Lupus anticoagulant DRVVT 32.5 seconds (36-50 seconds) Borderline low
Factor V Leiden mutation analysis (PCR) Not detected Normal
 Factor V Leiden mutation (R506Q) Not detected
 Prothrombin gene mutation Not detected
(G20210A)
 MTHFR gene mutation
(C677T)

CRP5C-reactive protein, DRVVT5diluted Russell viper venom time for lupus anticoagulant, G6PD5glucose-6-phosphate dehydrogenase,
MTHFR5methylenetetrahydrofolate reductase, PCR, polymerase chain reaction.

Diagnosis monitored every 4 hours or after any changes in the

The thrombophilia profile was investigated, which revealed
antithrombin III deficiency and low protein C and S levels.
Factor V Leiden, prothrombin gene, and methylenetetrahy-
drofolate reductase (MTHFR) gene mutations were not de-
tected. These results were consistent with the diagnosis of
thrombophilia because of antithrombin III and protein C
and S deficiencies.
Management
Antithrombin III concentrates may be beneficial in pa-
tients with hereditary antithrombin III deficiency. (9)
A retrospective analysis found that the success rate of
medical treatment with unfractionated heparin or war-
farin was 81%, with the remaining 19% of cases requir-
ing limb amputation surgery because of gangrene. (10)
Treatment with warfarin is usually not preferred in
neonates as it requires very close monitoring. A load-
ing dose of 75 U/kg intravenously followed by a main-
tenance dose of 28 U/kg per hour for infants younger
than 1 year of age, with adjustments in the heparin in-
fusion rate to maintain aPTT at 60 to 85 seconds, is
generally recommended. Levels of aPTT should be
dose of heparin. The treatment duration is usually con-
tinued for 5 to 14 days with monitoring of thrombus.
The suggested dose of LMWH is higher in neonates as
compared to older children. (5)
Patient Course
The infant was started on intravenous heparin and sup-
ported with cryoprecipitate for 2 days, with target aPTT
maintained between 60 and 85 seconds (Table 2). After
24 hours of treatment, the bluish discoloration of digits
started to improve gradually (Fig 2). Over the next
3 days, heparin infusion was stopped and replaced with
subcutaneous LMWH, which was continued for 2 more
months.
Lessons for the Clinician
• Early recognition of coagulation disorder causing either
hemorrhagic or thrombotic complications is crucial for a
better outcome.
• Acquired disorders are most often present in sick in-
fants; however, many inherited disorders manifest in
otherwise healthy infants.

Table 2. Progression of Coagulation Parameters

PT aPTT
(Reference Range: (Reference Range: Heparin
Day of Admission 10.1–14.7 seconds) INR 27.8–37.2 seconds) Hemoglobin (IV/SC)
1 12.8 1.03 55.4 13.69 g/dL (136.90 g/L) IV
2 11.7 0.94 91 13.05 g/dL (130.52 g/L) IV
3 11.2 0.90 49.8 12.89 g/dL (128.91 g/L) IV
4 11.1 0.90 52.3 12.08 g/dL (120.85 g/L) SC
5 11.0 0.89 58.3 12.08 g/dL (120.85 g/L) SC
aPTT5activated partial thromboplastin time, INR5international normalized ratio, IV5intravenous, PT5prothrombin time, SC5subcutaneous.

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 • Early aggressive management with anticoagulants is re-
quired to salvage the organ.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the causes and pathophysiology of con-
genital and acquired thrombotic disorders.
• Know the clinical and laboratory features, man-
agement, and potential adverse effects of treat-
ment of congenital and acquired thrombotic
disorders.
• Know the clinical and laboratory features and
management of acquired defects in hemostasis
including intravascular coagulation and hemor-
rhagic disease of the newborn.
10. Mousa A, Zakaria OM, Hanbal I, et al. Management of extremity
References
1. Chalmers EA. Neonatal thrombosis. J Clin Pathol. 2000;53(6):
419–423 doi:10.1136/jcp.53.6.419
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2. Chalmers EA. Neonatal coagulation problems. Arch Dis Child
Fetal Neonatal Ed. 2004;89(6):F475–F478 doi:10.1136/adc.
2004.050096
3. Ibrahim H, Krouskop R, Jeroudi M, McCulloch C, Parupia H,
Dhanireddy R. Venous gangrene of lower extremities and
Staphylococcus aureus sepsis. J Perinatol. 2001;21(2):136–140
doi:10.1038/sj.jp.7200496
4. Long DK, Lorant DE. Multiple arterial thrombi and in utero leg
gangrene in an infant of a diabetic mother. J Perinatol.
2002;22(5):424–427 doi:10.1038/sj.jp.7210741
5. Ramasethu J. Management of vascular thrombosis and spasm
in the newborn. NeoReviews. 2005;6(6):e298–e311 doi:10.1542/
neo.6-6-e298
6. Manco-Johnson M, Nuss R. Neonatal thrombotic disorders.
NeoReviews. 2000;1(10):e201–e205 doi:10.1542/neo.1-10-e201
7. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review.
Haemophilia. 2008;14(6):1229–1239 doi:10.1111/
j.1365-2516.2008.01830.x
8. Shiozaki A, Arai T, Izumi R, Niiya K, Sakuragawa N. Congenital
antithrombin III deficient neonate treated with antithrombin III
concentrates. Thromb Res. 1993;70(3):211–216 doi:10.1016/
0049-3848(93)90127-a
9. Lechner K, Kyrle PA. Antithrombin III concentrates–are they
clinically useful? Thromb Haemost. 1995;73(3):340–348
venous thrombosis in neonates and infants: an experience from a
resource challenged setting [published online ahead of print
December 6, 2018]. Clin Appl Thromb Hemost. doi:10.1177/
1076029618814353
Vol. 24, No. 3 MARCH 2023 e187
 INDEX OF SUSPICION IN THE NURSERY
An Infant with Intrauterine Growth
Restriction, a Single Umbilical Artery,
and Abdominal Wall Defect
Senthil Kumar Arumugam, MD, DNB (Neonatology),* Ramalingam Rangasamy, MD, DCH, FAAP,*
Raeshmi Ramalingam, MD (Paediatrics),* Maheshwari Doreraju, DCH, DNB, MRCPCH*
*Department of Neonatology, Ramalingam Hospital, Salem, Tamil Nadu, India
AUTHOR DISCLOSURES Drs Arumugam,
Rangasamy, Ramalingam, and Doreraju
have disclosed no financial relationships
relevant to this article. This commentary
does not contain a discussion of an
unapproved/investigative use of a
commercial product/device.
e188 NeoReviews
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PRESENTATION
A male infant is born through emergency cesarean section at 39 weeks’ gesta-
tion for severe oligohydramnios. He has a normal transition with Apgar scores
of 9 and 10 at 1 and 5 minutes, respectively, and a birthweight of 1,510 grams
(<3rd percentile). The infant’s parents had a nonconsanguineous marriage, and
the gravid 3, para 2 mother had a history of a previous spontaneous abortion.
The length and head circumference of the infant measures 39 cm and 29 cm,
respectively. The ponderal index is 2.54, suggestive of symmetrical intrauterine
growth restriction. The mother is asthmatic and takes an inhaler twice daily, as
well as drugs for thyroid illness. The antenatal scans showed a single umbilical
artery, oligohydramnios, and fetal growth restriction.
The newborn has mild tachypnea, a heart rate of 108 beats/min, and satura-
tion of 93% with 1 L of oxygen through nasal prongs. Physical examination
shows skin wrinkling, low-set ears (Fig 1), supraumbilical abdominal defect mea-
suring 3 cm  2 cm (Fig 2), an umbilical hernia, and a single umbilical artery.
Stretched penis length (SPL) is 1.5 cm.
Investigation shows a hemoglobin level of 15.6 g/dL (156 g/L), packed cell vol-
ume of 43%, leukocytes of 14.5 × 103/mL (14.5 × 109/L), platelet count of 64 × 103/mL
(64 × 109/L), C-reactive protein of 0.50 mg/dL (5 mg/L), prothrombin time of
16 seconds, and partial thromboplastin time of 41 seconds. Smear study shows
10 normoblasts per 100 white blood cells. Serum calcium is 8.9 mg/dL (2.23 mmol/L).
Total serum bilirubin is 8.1 mg/dL (138.54 mmol/L), with a direct bilirubin of 1.1 mg/dL
(18.81 mmol/L). Blood culture is sterile. Thyrotropin on day 3 of life is 13.5 mIU/L. Plate-
let count reaches the nadir of 29 × 103/mL (29 × 109/L) on day 4 of life, and he receives
a platelet transfusion.
Echocardiography is suggestive of severe pulmonary hypertension. He re-
ceives oxygen through nasal prongs for 2 days. He receives gavage feeding from
day 1 after birth. He develops abdominal distention with visible loops and signif-
icant bilious aspirate 4 days after birth. Feed intolerance improves after keeping
the infant nil per oral for 48 hours. Ultrasonography of the abdomen shows nor-
mal findings.

Figure 1. Features of intrauterine growth restriction.
DIFFERENTIAL DIAGNOSIS
• Chromosomal anomalies
• Congenital intrauterine infection
ACTUAL DIAGNOSIS
Carbimazole Embryopathy
The mother had tested positive for antithyroid peroxi-
dase antibody and was diagnosed with Graves’ disease
2 years before conception. She continues to take oral car-
bimazole 10 mg twice daily even during pregnancy. She
Figure 2. Abdominal wall defect.
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takes salmeterol 50 mg and fluticasone 250 mg metered-
dose inhaler twice daily. She has euthyroid during preg-
nancy. The combined first-trimester screening predicts the
risk of Down syndrome and Edward syndrome to be low.
The antenatal scan at 20 weeks’ gestation shows a single
umbilical artery, and subsequent ultrasonographic scans
reveal fetal growth restriction and oligohydramnios.
Karyotyping of the infant shows normal study. Level of
IgM for toxoplasmosis, cytomegalovirus (CMV), rubella,
and herpes viruses are negative, urine CMV PCR testing
is negative, and VDRL tests of both the mother and infant
are negative.
Maternal platelet count is normal. The infant's platelet
count reaches 161 × 103/mL (161 × 109/L) after 11 days of
birth. Antinuclear antibody profile is negative. Thrombocy-
topenia is self-limiting, confirming that it is due to placen-
tal insufficiency. Thyroid profile after 12 days of birth
shows a thyrotropin level of 6.24 mIU/L and a free thyrox-
ine (T4) level of 1.47 ng/dL (18.92 pmol/L). Thyrotropin
receptor antibody testing is negative.
DISCUSSION
Graves’ hyperthyroidism is an autoimmune disease caused
by antibodies stimulating thyrotropin receptors (thyrotro-
pin-stimulating immunoglobulin [TSI]). It is seen in 0.2%
of pregnant women. (1) It carries high fetal/neonatal mor-
tality and morbidity in untreated cases.
Fetal effects due to Graves’ disease include neonatal
thyrotoxicosis, which occurs due to transplacental passage
of TSI, and hypothyroidism, which occurs due to excessive
use of antithyroid drugs. (2) Thyroid receptor antibodies
(TRAb) is a general term that includes stimulatory, inhibi-
tory, and neutral antibodies acting at the thyrotropin re-
ceptor. TRAb levels persistently elevated during pregnancy
carry a higher risk of fetal thyroid dysfunction. Thyroid
peroxidase antibodies are a nonspecific marker of autoim-
mune thyroid disease with no prognostic value. (1)
Antithyroid drugs have teratogenicity if given during the first
trimester, especially between 6 and 10 weeks of gestation. (3)
The available antithyroid drugs include propylthiouracil (PPU)
and methimazole. Carbimazole is a prodrug that is converted
in the body into an active drug, methimazole. These drugs in-
hibit thyroid hormone synthesis by interfering with thyroid per-
oxidase–mediated iodination and coupling. Methimazole has
better pharmacokinetics and lesser side effects compared to
PPU, which, in turn, can cause serious hepatotoxicity. (4) PPU
is the preferred drug in the first trimester, as it causes lesser
birth defects than methimazole, which can be switched after
first-trimester pregnancy. (5) Antithyroid drugs in lower doses
Vol. 24, No. 3 MARCH 2023 e189
 should be given to maintain the free T4 index in the upper ref-
erence range.
In a case series, 6 cases of embryopathy were reported
following exposure to carbimazole during the first trimes-
ter, which included 2 cases of abdominal wall defect, 2
cases of aplasia cutis, 1 case of patent omphalomesenteric
duct, and 1 case of bilateral choanal atresia with coarcta-
tion of the aorta. (6) The other birth defects seen in carbi-
mazole embryopathy are facial dysmorphism, esophageal
atresia, urinary tract malformation, coloboma, and ventric-
ular septal defect.
Bilateral renal agenesis with severe oligohydramnios
was documented in a newborn girl born to a hyperthyroid
mother receiving methimazole during early pregnancy. (7)
Our infant presents as a case of severe IUGR with a
single umbilical artery, abdominal wall defect, umbilical
hernia, and facial dysmorphism. Single umbilical artery in
association with the use of carbimazole has not been re-
ported till now. Carbimazole intake during the first trimes-
ter is known to cause diverse congenital malformation.
Isolated single umbilical artery is associated with an in-
creased risk of fetal growth restriction, oligohydramnios,
polyhydramnios, placental abruption, cord prolapse, and
perinatal mortality, as compared to the group of fetuses
with 3-vessel cord in a large cohort study. (8)
Progression
The infant weighs 3 kg, with a head circumference of 32
cm and SPL of 2.5 cm at 2 months of age. The parents are
reassured to wait for umbilical hernia and abdominal wall
defect repair.
Lessons for the Clinician
• Infants born to mothers with Graves’ hyperthyroidism
are at a risk of neonatal thyrotoxicosis.
• TRAb should be checked between 20 and 24 weeks’ ges-
tation. High levels predict an increased risk of fetal thy-
roid dysfunction. Thyroid function should be tested in
neonates at 3 to 5 days after birth and again at 10 to 14
days after birth.
• Antithyroid is to be given at the lowest dose to maintain
free T4 index at the upper reference level.
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• The preferred antithyroid during the first trimester is
PPU, which can be switched to methimazole after first-
trimester pregnancy.
• The clinician needs to be aware of the diverse congenital
birth defects associated with carbimazole embryopathy.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Identify the etiology, clinical manifestations, lab-
oratory features, and management of neonatal
thyrotoxicosis.
References
1. Nguyen CT, Sasso EB, Barton L, Mestman JH. Graves’
hyperthyroidism in pregnancy: a clinical review. Clin Diabetes
Endocrinol. 2018;4:4
2. Patil-Sisodia K, Mestman JH. Graves hyperthyroidism and pregnancy:
a clinical update. Endocr Pract. 2010;16(1):118–129
3. Laurberg P, Andersen SL. Therapy of endocrine disease: antithyroid
drug use in early pregnancy and birth defects: time windows of
relative safety and high risk? Eur J Endocrinol. 2014;171(1):
R13–R20
4. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N.
Comparison of methimazole and propylthiouracil in patients with
hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab.
2007;92(6):2157–2162
5. Andersen SL, Andersen S. Antithyroid drugs and birth defects.
Thyroid Res. 2020;13:11
6. Koenig D, Spreux A, Hieronimus S, et al. Birth defects observed
with maternal carbimazole treatment: six cases reported to Nice’s
Pharmacovigilance Center. Ann Endocrinol (Paris). 2010;71(6):
535–542
7. Rodrıguez-Garcıa R. Bilateral renal agenesis (Potter’s syndrome) in a
girl born to a hyperthyroid mother who received methimazole in early
pregnancy [in Spanish]. Ginecol Obstet Mex. 1999;67:587–589
8. Ebbing C, Kessler J, Moster D, Rasmussen S. Isolated single
umbilical artery and the risk of adverse perinatal outcome and third
stage of labor complications: a population-based study. Acta Obstet
Gynecol Scand. 2020;99(3):374–380
 VISUAL DIAGNOSIS

Unilateral Neck Swelling in a Newborn

elder Morgado, BS,† Jo~ao Pinheiro de Amorim, MA,‡
Juliana da Silva Cardoso, MA,* Cristina Godinho, BS,* H

Sara Leite, MA,* Isabel Mendes, BS*
*Neonatology Unit, Centro Materno-Infantil do Norte, Centro Hospitalar Universita
rio do Porto, Porto, Portugal
†
Pediatric Surgery Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universit

ario do Porto, Porto, Portugal
‡
Radiology Department, Centro Hospitalar Universit

ario do Porto, Porto, Portugal

THE CASE
A 3-day-old term female infant presents with right cervical swelling.

Prenatal and Birth Histories

• Born to a 25-year-old gravida 3, para 3 woman.
• Maternal history of psoriasis. The father was healthy, and the family history
was unremarkable. The parents had a nonconsanguineous marriage.
• Poorly supervised pregnancy with a single prenatal ultrasonography performed
at 120/7 weeks’ gestation.
• Estimated gestational age: 400/7 weeks.
• Vaginal delivery, cephalic presentation. No maternal fever or rupture of mem-
branes at delivery.
• Prenatal maternal laboratory evaluation: negative hepatitis B surface antigen,
human immunodeficiency, and syphilis tests, rubella immune, no immunity
to Toxoplasmosis. Unknown group B Streptococcus status.
• Apgar scores: 9 and 10 at 1 and 5 minutes, respectively.

Presentation
At birth, the newborn’s physical examination was normal, and she was admitted
to the postnatal ward for routine care. She was exclusively breastfed, with no re-
spiratory or gastrointestinal problems. At 3 days of age, a right cervical swelling
was noticed (Fig 1). Transillumination was not performed. Neck ultrasonography
with Doppler demonstrated a large macrocystic lesion with thin internal septa,
measuring approximately 45 × 14 × 35 mm at the greatest length (Fig 2).
AUTHOR DISCLOSURES Dr de Amorim
has attended an ESGAR (European
PROGRESSION Society of Gastrointestinal and
Abdominal Radiology) course with the
Vital Signs
support of Bayer. Drs da Silva Cardoso,
• Heart rate: 110 beats/min. Godinho, Morgado, Leite, and Mendes
• Respiratory rate: 50 breaths/min. have disclosed no financial relationships
relevant to this article. This commentary
• Blood pressure: 60/40 (mean 48) mm Hg.
does not contain a discussion of an
• Oxygen saturation: 99% (in room air). unapproved/investigative use of a
• Temperature: 97.7 F (36.5 C). commercial product/device.

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 Figure 1. Clinical presentation of an acute-onset soft right neck mass
measuring 40 × 30 mm (green arrow).

Figure 2A and B. Neck ultrasonographic images. In the right laterocervi-

Physical Examination (Day 3) cal region, lateral to the right common carotid artery (A), there is a large
• Birthweight of 3,180 g (45th percentile), birth length of multicystic lesion (white stars), measuring 45 × 14 × 35 mm at the greatest
length, which is compressible during the examination. It is a macrocystic
47 cm (12th percentile), and birth head circumference of lesion, with thin internal septa (yellow arrows), without mural nodules and
34 cm (54th percentile). with no vascularization on Doppler imaging.
• General appearance: Without facial dysmorphisms; skin
without rashes, nevi, or hemangiomas.
• Cystic hygroma
• Head: Normal configuration of the skull, open and flat
• Dermoid cyst
fontanelles, hair with texture and normal implantation.
• Neck: Right cervical swelling located in the anterior triangle
ACTUAL DIAGNOSIS
of the sternocleidomastoid, soft and nonadherent to deep tis-
Cystic hygroma.
sues; dimension of approximately 40 × 30 mm; without ery-
A poorly delineated cervical mass without signs of in-
thema, warmth, drainage, or pain on touching.
flammation and an ultrasonographic image with collec-
• Oral cavity: Pink mucosae, intact palate.
tions that are most likely cystic and lined by internal septa
• Lungs: No respiratory distress, equal breath sounds.
are consistent with the diagnosis of cystic hygroma.
• Cardiovascular: S1 and S2 present and rhythmic; no
The pediatric surgery service was consulted, which
murmurs or gallops.
recommended conservative management as the infant
• Abdomen: Normal umbilical cord; no discomfort with
was asymptomatic. The infant was discharged from the
palpation, no organomegaly.
nursery 4 days after birth with close follow-up by the sur-
• Genitourinary: Normal term female genitalia; patent anus.
gery service. After discharge, the lymphangioma grew
• Skeletal: No visible skeletal changes.
slowly. At 7 months of age, the infant presented with a
• Neurologic: Active, adequate tone and posture, primitive
superinfection of the cystic hygroma (Figs 3A and 3B), re-
reflexes present and normal.
quiring hospitalization and intravenous antibiotic therapy
with good response. The infant continues to be moni-
DIFFERENTIAL DIAGNOSIS tored outpatient by the general pediatrics and pediatric
• Branchial cleft cyst surgery services.

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Figure 3A and B. Neck ultrasonographic images. In the right laterocervi-
cal region, the same lesion is found but now has a more complex cys-
tic appearance, including multiple septa (arrows) and internal
echogenic debris (asterisks), probably corresponding to intracystic
complications and as a result of bleeding or superinfection in the
preexistent lymphangioma.
WHAT THE EXPERTS SAY
Cystic hygroma is a rare entity, accounting for approximately
6% of benign childhood anomalies. Despite this, it is the
most common subtype of lymphangiomas. Half of the cases
present at birth, and the remaining are noted at around 2
years of age. The most common location is the neck (75 to
90% of cases) followed by the axilla (20% of cases). (1) A cys-
tic hygroma can present as an isolated entity or as an integral
part of a syndrome. (2) Its embryological etiology is not yet
well known, but the cystic mass appears to result from
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occlusion of embryonic jugular lymphatic channels or abnor-
mally sequestered lymphatics. (3)
Clinically, a cystic hygroma is usually described as a large,
diffuse, doughy, and compressible mass covered by normal
skin that may increase in size with straining or crying. Most
cystic hygromas transilluminate. Symptoms depend on size
and location and can include symptoms related to airway ob-
struction and/or compression of nearby structures, with asso-
ciated difficulty in breathing, hoarseness, and dysphagia. (1)(4)
Cystic hygromas can be detected early in the first trimester of
pregnancy by ultrasonography or postnatally by a physical ex-
amination. Imaging will demonstrate multicystic lesions with
internal septations.
The decision to treat an infant with cystic hygroma de-
pends on several factors, such as location, size, and associ-
ated clinical symptoms. If an infant is asymptomatic, the
cystic hygroma does not need treatment as it is a benign
mass. Kato et al reported that spontaneous regression oc-
curred in macrocystic or mixed type and regression was
most frequent in patients who, at the time of onset, were
older than 2 years. (5) Associated findings of infection,
hemorrhage, respiratory distress, dysphagia, or disfigure-
ment are indications to treat, usually with surgical exci-
sion. Other therapeutic alternatives include sclerotherapy,
drainage, radiofrequency ablation, and cauterization. (1)
Cystic hygromas that are diagnosed prenatally generally
have a poorer prognosis than those diagnosed after birth.
Other factors associated with a worse prognosis include the
presence of chromosome abnormalities, hydrops fetalis,
thickness of cystic hygroma $6 mm, septated cystic hy-
gromas, nuchal cystic hygroma, and association with other
major malformations. (6) Alpman et al reported 18 cases of
cystic hygroma detected by prenatal ultrasonography, of
which 44.4% were found to have a 45,X karyotype, 16.7%
were found to be mosaic Turner syndrome, 27.7% had a
normal karyotype, 5.6% had a 47,XX,113 karyotype, and
5.6% had a 47,XX,121 karyotype. (7)
Branchial arch anomalies contribute to 20% of the cervi-
cal masses in neonates and are the second most common
cause of congenital head and neck lesions. Second arch
anomalies are the most common type and often present as
branchial cysts. Most commonly, branchial arch anomalies
are painless masses found between the sternocleidomastoid
muscle and the submandibular gland. On ultrasonographic
imaging, these lesions are well-circumscribed, thin-walled,
and anechoic. (8) In this case, the location of the mass
would not help much in the differential diagnosis, as both
branchial arch anomalies and a lymphangioma can be
found in the neck region. Imaging evaluation would be the
Vol. 24, No. 3 MARCH 2023 e193
 best tool to distinguish the diagnosis. Branchial arch anomalies
are usually well-defined and unilocular lesions, unlike our case,
in which there was a multilocular lesion with several septa.
Dermoid cysts may present as painless masses in the
neck; however, the most common location is in the outer
third of the eyebrow. Only 7% of dermoid cysts are pre-
sent in the head or neck, and if this occurs, the 2 most
frequent locations are the parahyoid region and the
suprasternal area. Imaging is important to distinguish it
from other differential diagnoses. (1)(9) In this infant,
the location of the mass in the anterior triangle of the
sternocleidomastoid, rather than the parahyoid region or
suprasternal area, makes the diagnosis of dermoid cyst
unlikely. On ultrasonography, dermoid cysts are typically
homogeneous hyperechoic oval lesions, unilocular and
more echogenic, different from what we found in this
case. (10)
Summary
• Cystic hygroma, although rare, is the most common
lymphangioma subtype in children.
• Prognosis is worse when there is a prenatal
diagnosis or up to 2 years of age.
• The presence of a neck mass should raise the
suspicion of this entity, with ultrasonographic
imaging being important for the initial evaluation.
• If cystic hygroma is not associated with any symptoms
or complications, treatment is conservative, with
outpatient follow-up.
• Prognosis of a cystic hygroma depends on several
factors such as the timing of the diagnosis, location,
thickness, the presence of septa, and the presence
of other malformations or chromosomal abnormalities.
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American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the clinical manifestations and approaches
to therapy of neck masses in the newborn infant.
• Recognize the clinical features of extrapulmo-
nary causes of respiratory distress.
References
1. Auerbach N, Gupta G, Mahajan K. Cystic hygroma. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2022
2. Pan M, Liu YN, Xu LL, Li DZ. First-trimester cystic hygroma and
neurodevelopmental disorders: the association to remember. Taiwan
J Obstet Gynecol. 2020;59(6):960–962
3. Behera S, Bawa M, Kanojia RP, Saha PK, Singh T, Samujh R.
Outcome of antenatally diagnosed cystic hygroma - lessons learnt.
Int J Pediatr Otorhinolaryngol. 2020;138:110227
4. Guruprasad Y, Chauhan DS. Cervical cystic hygroma. J Maxillofac
Oral Surg. 2012;11(3):333–336
5. Kato M, Watanabe S, Kato R, Kawashima H, Iida T, Watanabe A.
Spontaneous regression of lymphangiomas in a single center over
34 years. Plast Reconstr Surg Glob Open. 2017;5(9):e1501
6. Chen YN, Chen CP, Lin CJ, Chen SW. Prenatal ultrasound
evaluation and outcome of pregnancy with fetal cystic hygromas and
lymphangiomas. J Med Ultrasound. 2017;25(1):12–15
7. Alpman A, Cogulu O, Akgul M, et al. Prenatally diagnosed Turner
syndrome and cystic hygroma: incidence and reasons for referrals.
Fetal Diagn Ther. 2009;25(1):58–61
8. Adams A, Mankad K, Offiah C, Childs L. Branchial cleft anomalies:
a pictorial review of embryological development and spectrum of
imaging findings. Insights Imaging. 2016;7(1):69–76
9. Choi JS, Bae YC, Lee JW, Kang GB. Dermoid cysts: Epidemiology
and diagnostic approach based on clinical experiences. Arch Plast
Surg. 2018;45(6):512–516
10. Bansal AG, Oudsema R, Masseaux JA, Rosenberg HK. US of
pediatric superficial masses of the head and neck. Radiographics.
2018;38(4):1239–1263
 VIDEO CORNER

VIDEO
CORNER

A Neonate with Obstructed

Nasal Breathing
Juniper Lyra Burch, MD,*† Emily Whitesel, MD,*† Brian Manzi, MD,‡ Eelam Adil, MD‡
*Department of Pediatrics, Cambridge Health Alliance, Cambridge, MA
†
Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA
‡
Department of Otolaryngology, Boston Children’s Hospital, Boston, MA

THE CASE
A female infant is born at term gestation after an uncomplicated vaginal delivery
to a 31-year-old gravida 1 para 1 woman with normal prenatal laboratory tests.
The pregnancy was notable for diet-controlled gestational diabetes mellitus with
no concerning prenatal imaging. The infant was vigorous at delivery with Apgar
scores of 8 at 9 at 1 and 5 minutes after birth, respectively.
Shortly after delivery at approximately 1 hour of age, the pediatrician was called to
the bedside because the infant developed respiratory distress with grunting, flaring,
retractions, and stertor. The pediatrician admitted the infant to the special care nurs-
ery for further evaluation. When crying, the infant had oxygen saturations of greater
than 92% while breathing room air. However, with a closed mouth or when sucking
on a pacifier, she had an increase in respiratory distress, loud nasal breathing, and ox-
ygen desaturations to as low as 60%. Although the opening of both her nares ap-
peared narrow, the team was able to pass a 5F catheter through her nares bilaterally.
The infant was started on intranasal prednisolone 1% solution (2 drops in each
naris every 6 hours). Due to worsening respiratory distress at 12 hours of age, she was
given oxymetazoline 0.05% nasal spray in each naris, which was repeated at 24 hours
of age. Subsequently her respiratory distress improved, but on the first day after birth,
while she was still receiving the intranasal medications, she had return of increased
work of breathing as shown in the Video. The infant was transferred to a tertiary care
center where a computed tomography (CT) scan (Figs 1–3) confirmed the diagnosis.
Of the following the most likely diagnosis for this infant is:

A. Choanal atresia
B. Congenital nasal pyriform aperture stenosis
C. Deviated nasal septum
D. Nasal mucosal edema
AUTHOR DISCLOSURES Drs Burch,
E. Nasolacrimal duct cyst
Whitesel, Manzi, and Adil have disclosed
no financial relationships relevant to this
DISCUSSION article. This commentary does not
contain a discussion of an unapproved/
Bilateral nasal narrowing or obstruction is most likely the cause of this infant’s respi- investigative use of a commercial
ratory findings because her symptoms worsened when her mouth was closed (Video). product/device.

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Video. Following, her respiratory distress improved, but on the first day af-
ter birth, while she was still receiving the intranasal medications, she had
return of increased work of breathing.
The infant’s CT images are most consistent with congenital
nasal pyriform aperture stenosis (CNPAS) because of the nar-
row pyriform aperture that was measured at 4 mm by CT im-
aging (Fig 2, green measurement).
Figure 1. Computed tomography scan demonstrating the infant’s choanae
(orange arrows) and a single central maxillary megaincisor (blue arrow).
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Figure 2. Computed tomography scan showing the width of the pyriform
aperture (green measurement).
This patient was initially treated at the tertiary care center
with a 2.5-mm nasal airway and continuous positive airway
pressure. Due to continued respiratory distress and inability to
orally feed, she underwent a transnasal endoscopic balloon dila-
tion at 13 days of age (Figs 4 and 5). Following this procedure,
her respiratory distress significantly improved. She was placed
on continuous positive airway pressure for 48 hours postopera-
tively and then was given cool mist via aerosol. From postopera-
tive day 1 to 3, she was treated with a regimen of oxymetazoline
Figure 3. Computed tomography scan demonstrating a single central
maxillary megaincisor (blue arrow).

Figure 4. Nasal cavity before balloon dilation.
nasal spray (twice per day), normal saline drops, and ciprofloxa-
cin/dexamethasone drops. From postoperative day 4 to 7, she
was treated with normal saline drops and ciprofloxacin/dexa-
methasone drops. The cool mist was discontinued on postoper-
ative day 10. She was subsequently able to maintain appropriate
oxygen saturations in room air and was able to orally feed. She
was discharged from the NICU at 25 days of age.
She has continued to do well with appropriate weight
gain in the outpatient setting. At the most recent otolaryn-
gologist visit at 3 months of age, the family reported that
the infant is doing well with appropriate weight gain.
Figure 5. Nasal cavity after balloon dilation.
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However, they report that she has noisy breathing when
agitated. The parents are continuing to use nasal saline
drops multiple times during the day. The otolaryngologist
does not anticipate that another procedure will be needed.
CNPAS is an uncommon cause of nasal obstruction oc-
curring in approximately 1 in 25,000 live births. (1) The
underlying etiology is thought to be excessive bone growth
of the nasal process of the maxilla. (1)(2) Diagnosis is
made with CT scan demonstrating a pyriform aperture
width of 11 mm or less. (1)
CNPAS is associated with midline defects such as solitary
median maxillary central incisor (SMMCI) and holoprosence-
phaly. The CT scan of our patient demonstrated an SMMCI
(Figs 1 and 3, blue arrows). SMMCI is found in 35% to 65%
of patients diagnosed with CNPAS (1) and can be an isolated
finding or associated with other midline developmental anom-
alies. (1) Brain magnetic resonance imaging (MRI) is required
in all patients with CNPAS or SMMCI to evaluate for holopro-
sencephaly. This patient had a normal brain MRI scan (Figs 6
and 7) and normal karyotype and microarray. Interestingly,
in one series of 20 cases of CNPAS, 55% of the mothers of
affected patients had a diagnosis of diabetes mellitus. (3) The
biologic etiology of this association, similar to other strong cor-
relations between multiple congenital anomalies and maternal
diabetes mellitus, is not fully understood. (4)
Bilateral choanal atresia is a relatively common cause of na-
sal obstruction in newborns, occurring in approximately 1 in
5,000 to 7,000 live births. (5) In choanal atresia, there is a
bony or combined membranous and bony blockage of the
posterior nasal opening. (5) The infant in this vignette does
not have bilateral choanal atresia because a 5F catheter was
passed through both nares. In addition, the CT scan showed
patent choanae bilaterally (Fig 1, orange arrows).
Another possible cause of obstructed nasal breathing is a de-
viated nasal septum. This finding is relatively common, occur-
ring in approximately 20% of all newborns, and is often due to
compression and rotation during delivery. (6) Nasal endoscopy
is required to evaluate for a deviated nasal septum. This find-
ing was not apparent on this patient’s endoscopic examination.
The infant initially responded to intranasal steroids and oxy-
metazoline, suggesting a component of nasal mucosal edema.
Oxymetazoline is an adrenergic agonist that causes vasocon-
striction. (7) If systemically absorbed, oxymetazoline can cause
adverse cardiovascular effects and is not approved by the
United States Food and Drug Administration for pediatric pa-
tients less than 6 years of age. (8) However, the Section on
Anesthesiology and Pain Medicine and the Section on
Otolaryngology-Head and Neck Surgery note that “medical
professionals may elect to use it short term and off label for
Vol. 24 No. 3 MARCH 2023 e197
 Figures 6 and 7. Magnetic resonance imaging scans showing normal brain hemispheres.
younger children in particular clinical scenarios in which the
potential benefit may outweigh risks (eg, active bleeding, acute
respiratory distress from nasal obstruction, acute complicated
sinusitis, improved surgical visualization, nasal decongestion
for scope examination, other conditions, etc).” (8) Discontinuation
of oxymetazoline and steroids can have a rebound effect, (7) but
this infant had return of significant respiratory distress while still
undergoing treatment with both medications. This demonstrates
that nasal mucosal edema was not the only cause of the infant’s
respiratory distress.
Most infants with a dacrocystocele present with a unilateral
bluish swelling inferior to the medial epicanthus. (9) Less
commonly, the cysts can extend intranasally and, if bilateral,
can cause nasal obstruction evident by respiratory distress. (6)
The CT images did not show an intranasal cyst.
The infant in this vignette did not have excessive tear-
ing to suggest a nasolacrimal duct obstruction.
Correct response: B. Congenital nasal pyriform aperture
stenosis.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the clinical features of an infant with air-
way obstruction.
• Plan appropriate diagnostic evaluation and man-
agement for an infant with airway obstruction.
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• Know the incidence, clinical manifestations, and
management of bilateral and unilateral choanal
atresia.
References
1. Yang S, Orta P II, Renk EM, Inman JC. Congenital nasal pyriform
aperture stenosis in association with solitary median maxillary central
incisor: unique radiologic features. Radiol Case Rep. 2016;11(3):
178–181
2. Silva DP, Ribeiro D, Vilarinho S, Dias L. Congenital nasal pyriform
aperture stenosis: a rare cause of upper airway obstruction in
newborn. BMJ Case Rep. 2018;11(1):e227647
3. Shah GB, Ordemann A, Daram S, et al. Congenital nasal pyriform
aperture stenosis: Analysis of twenty cases at a single institution.
Int J Pediatr Otorhinolaryngol. 2019;126:109608
4. Wu Y, Liu B, Sun Y, et al. Association of maternal prepregnancy
diabetes and gestational diabetes mellitus with congenital anomalies
of the newborn. Diabetes Care. 2020;43(12):2983–2990
5. Kwong KM. Current updates on choanal atresia. Front Pediatr.
2015;3:52
6. Harugop AS, Mudhol RS, Hajare PS, Nargund AI, Metgudmath VV,
Chakrabarti S. Prevalence of nasal septal deviation in newborns and
its precipitating factors: a cross-sectional study. Indian J Otolaryngol
Head Neck Surg. 2012;64(3):248–251
7. National Center for Biotechnology Information. PubChem
Compound Summary for CID 4636, Oxymetazoline. https://
pubchem.ncbi.nlm.nih.gov/compound/Oxymetazoline. Accessed July
11, 2022
8. Cartabuke R, Tobias J, Jatana K. Topical nasal decongestant
oxymetazoline: safety considerations for perioperative pediatric use.
Pediatrics. 2021;148(5):e2021054271
 EQUITY, DIVERSITY, AND INCLUSION CASE STUDIES

Defining Gender in Infant Care

Kathryn J. Paul, MD,* Daria Murosko, MD, MPH,* Vincent C. Smith, MD, MPH,†
Diana Montoya-Williams, MD, MSHP,*,‡ Joanna Parga-Belinkie, MD, IBCLC*
*Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA
†
Division of Newborn Medicine, Boston Medical Center, Boston, MA
‡
PolicyLab, Children’s Hospital of Philadelphia, Philadelphia, PA

MEET THE EXPERT

Vincent C. Smith, MD, MPH, FAAP, is the Division Chief of Newborn Medicine
at Boston Medical Center and is a Professor of Pediatrics at Boston University
Medical School. He has done extensive work in the NICU to help families pre-
pare both physically and emotionally for hospital discharge with their infants.
He has investigated a range of factors including hospital readmissions, coping
strategies, and adaptation to parenthood. He has a special focus on families who
suffer from the effects of substance use disorders and LGBTQIA1 families.

CASE PRESENTATION
A term infant was born to a 26-year-old transgender man using he/him pronouns
who had received adequate prenatal care. His partner is a cisgender man. The in-
fant had a prolonged stay due to concern for early-onset sepsis requiring 48 hours
of monitoring and ampicillin/gentamicin. One of the health care professionals
caring for the infant commented to other members of the care team that she was
glad she did not have to go into the parent’s room. She stated, “I know I would
mess up her pronouns,” and reported she “couldn’t understand how the parent
identifies as a man with he/him pronouns and yet he had a baby.”

Perspective and Reflection

• Put yourself into the perspective of the infant’s birth parent. If you overheard
this conversation, how might you feel?
AUTHOR DISCLOSURES Dr Montoya-
○ Author perspective (KJP, who identifies as a non-Hispanic white, cis
Williams works under a Eunice Kennedy
woman): I might feel sad, misunderstood, and potentially afraid for myself Shriver National Institute of Child Health
and Human Development grant.
and my family. If the people caring for me and my baby don’t even want to
Dr Smith receives honoraria from Biogen.
interact with us – will something be missed? Are there updates I am not get- Drs Paul and Murosko received an
ting? I might also feel exhausted – I have been carrying the emotions and award in recognition of their work
in Equity and Diversity and Inclusion
confusions of others throughout the entire pregnancy. Now my baby is fi-
from the University of Pennsylvania.
nally here, and I want to celebrate. I want my health care team to see me as Dr Parga-Belinkie has disclosed no
a person and a parent, rather than get stuck on my pronouns. financial relationships relevant to this
○ Expert Commentary (Dr Vincent C. Smith [VCS]): It is likely a person over- article. This commentary does not
contain a discussion of an unapproved/
hearing that conversation would not feel safe. It would be natural to worry investigative use of a commercial
that they may be receiving less care and attention because the health care product/device.

Vol. 24 No. 3 MARCH 2023 e199

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 professional was uncomfortable with that situation. As
a new parent, it is also likely that the individual would
worry about the treatment their helpless newborn was
receiving. This could easily lead to distrust with the sys-
tem that may manifest itself as hypervigilance and
questioning of the medical decision making. From a
clinician’s standpoint, it is often better to talk with the
family directly. During this conversation, explain to the
family that as a clinician, your goal is to provide top-
quality medical care and ensure that the family has a
wonderful parenting experience. Still, it is possible that
you may make some mistakes. Apologize in advance
and encourage them to provide feedback when things
do not meet the quality standards that they expect. Em-
phasize that if you fail to use their preferred terminol-
ogy, it is not intentional and that you really want to be
the best clinician that you can be to their family.
CASE OBJECTIVES
• Describe unique challenges faced by transgender indi-
viduals in obtaining pregnancy and postpartum care
within a medical system.
• Reflect on our personal biases and systemic practices
that discriminate around gender identity, and in particu-
lar, around cis-normative perinatal care.
• Accurately apply key terminology around gender iden-
tity, gender expression, and sexual orientation, and rec-
ognize gender exists on a spectrum.
• Explore the challenges faced by transgender men who
gestate children and choose chest-feeding.
• Brainstorm strategies for practicing affirming and inclu-
sive medicine and identify opportunities to support fam-
ilies with diverse gender identities in newborn care.
KEY TERMS
• Stereotype: A reductive and generalized belief or attitude
toward members of a specific group, which does not ac-
count for individuality and has not been fully explored.
• Implicit bias: An example of personally mediated racism,
whereby beliefs and reactions toward certain individuals
are based on preconceived ideas and occur without one’s
awareness.
• Sex assigned at birth: “The assignment and classification
of people as male, female, intersex, or another sex as-
signed at birth often based on physical anatomy at birth
and/or karyotyping.” (1)
• Gender identity: “The internal sense of one’s gender”,
which may be man/male, woman/female both, neither,
or another gender. (2)
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• Cisgender: Cisgender people are those whose gender iden-
tity and assigned sex at birth correspond (ie, a person of
female sex who identifies their gender as a woman.)
• Gender expression/role: “The way a person acts, dresses,
speaks, and behaves (ie, feminine, masculine, androgynous).
Gender expression does not necessarily correspond to listed
sex at birth or gender identity.” (2)
• Transgender: “Transgender people are those whose gen-
der identity and assigned sex at birth do not correspond.
Transgender is also used as an umbrella term to include
gender identities outside of male and female. Transgen-
der is sometimes abbreviated as trans.” (2)
• Intersex: “Describing a person with a less common combina-
tion of hormones, chromosomes, and anatomy that are used
to assign sex at birth. There are many examples such as Kli-
nefelter syndrome, androgen insensitivity syndrome, and con-
genital adrenal hyperplasia. Parents and medical professionals
usually coercively assign intersex infants a sex and have, in
the past, been medically permitted to perform surgical opera-
tions to conform the infant’s genitalia to that assignment.
This practice has become increasingly controversial as intersex
adults speak out against the practice. The term intersex is not
interchangeable with or a synonym for transgender (though
some intersex people do identify as transgender).” (1)
• Asexual: A person with no sexual feelings or desires who
is not sexually attracted to anyone.
• Sexual orientation: “This refers to how people describe
their (romantic), emotional, (aesthetic), and/or sexual attrac-
tion to others. Sexual orientation is distinct from gender
identity. For example, transgender people can be any sexual
orientation (gay, lesbian, bisexual, heterosexual/straight, no
label at all, or some other self-described label).”
• LGBTQIA1: Acronym used to describe the community
of people who do not identify as cisgender and/or
straight. It stands for lesbian, gay, bisexual, transgender,
queer or questioning, intersex, asexual and plus (mean-
ing anyone whose gender identity or sexual orientation
is otherwise not defined in the acronym).
• Queer: “An adjective used by some people whose sexual
orientation is not exclusively heterosexual. Typically, for
those who identify as queer, the terms lesbian, gay, and
bisexual are perceived to be too limiting and/or fraught
with cultural connotations they feel do not apply to
them. Some people may use queer, or genderqueer, to
describe their gender identity and/or gender expression.
Once considered a pejorative term, queer has been re-
claimed by some LGBTQIA1 people to describe them-
selves; however, it is not a universally accepted term,
even within the LGBTQIA1 community.” (3)
 • Gender diverse, gender expansive, gender nonconforming:
“Describes a gender expression that differs from a given soci-
ety’s norms for males and females. A gender nonconforming
person is not necessarily transgender.” (2) Some in the field
believe gender nonconforming is less affirming language
than gender diverse or expansive. (4)
• Gender fluid: “Individuals whose gender varies over
time. A gender fluid person may at any time identify as
male, female, agender, or any other nonbinary identity,
or some combination of identities.” (4)
• Chest feeding: “A term used by many masculine-identified
(transgender) people to describe the act of feeding their
baby from their chest, regardless of whether they have had
chest/top surgery to alter or remove mammary tissue.” (5)
DISCUSSION OF RELEVANT LITERATURE
Health Disparities among Transgender People
From the moment we are born, we receive a “sex assigned
at birth.” When individuals are born cisgendered, the sex as-
signed at birth does not conflict with gender identity. But
for those individuals who do not identify with their assigned
sex, the health care system’s reliance on outdated ideas of
gender and biologic sex results in immediate tension.
Challenges in access to health care leading to disparities by
gender identity are a significant issue for the LGBTQIA1 com-
munity. In this article, we will focus on issues related specifi-
cally to the transgender or trans community and relate them to
this transgender man’s experience. According to a 2009 study
using data from a survey of almost 5,000 individuals in the
United States who were either LGBTQIA1 or living with hu-
man immunodeficiency virus (HIV), an estimated 27% of
trans individuals have been refused medical care. (6) At the
time of writing, bills restricting gender-affirming care have
been passed or proposed in 15 states, (7) with some states such
as Texas classifying this type of health care in pediatrics as child
abuse. For individuals who can obtain health care, additional
barriers exist in the receipt of that care. In a US survey con-
ducted in 2008, “50% of transgender people reported having
to teach a health care professional about providing appropriate
care”. (8) Until 2013, the Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition, identified transgender individuals
as suffering from mental illness. (9) Many individuals feel that
the new diagnosis of “gender dysphoria” continues to stigma-
tize members of the community and may cause them to avoid
seeking needed care altogether. (10) Fear of being stigmatized
and not receiving knowledgeable care represents an appropri-
ate, adaptive response to a noninclusive health care system.
These disparities are further compounded for individu-
als who are both LGBTQIA1 and black, indigenous, or
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people of color. (11)(12) Thus, patients who experience the
intersection of transphobia as well as racism, must be ad-
vocated for in all arenas, from clinical care to research.
Expert Commentary (Dr. Smith)
Many LGBTQIA1 individuals have had health care system
interactions that were less than ideal. These types of inter-
actions erode trust and can lead to some well-deserved
skepticism about the health care system, medical profes-
sionals, and support staff, and a heightened sensitivity to
mistreatment in clinical settings. This means that many
LGBTQIA1 individuals will need additional reassurances
to be trusting of health care professionals. Health care
professionals need to be empathic to this potential need
and explicitly work to ensure the individual’s comfort.
The Family Planning and Perinatal Care Experience
for Transmasculine Parents
Health care professionals should be aware of the chal-
lenges that families with transgender parent(s) face when
making the decision to parent, (13) beginning with family
planning. Options for trans individuals to have children
include fostering, adoption, surrogacy, egg donors, sperm
donors, and using their biological sex organs. However,
many of these options are expensive, with the costliest op-
tion (ie, gestational surrogacy) averaging approximately
$60,000, while egg donors cost approximately $25,000,
and sperm donors cost approximately $300. (14) In addi-
tion, several organizations including The World Profes-
sional Association for Transgender Health (2011), and the
Ethics Committee of the American Society for Reproduc-
tive Medicine (2015) have recommended that “healthcare
professionals counsel their trans patients about fertility
preservation options before commencing transition.” (15)
This may also be a cost-prohibitive process as sperm freez-
ing is estimated to cost approximately $250 and egg freez-
ing approximately $7,000. (14)
Adoption and fostering are also possible, but families
may face legal challenges, given that the federal government
and at least 7 states allow “taxpayer-funded child welfare
agencies … to refuse to place children with parents with
whom the agency has a religious objection.” (16) Such poli-
cies likely discourage families with transgender parent(s),
and potentially families within the larger LGBTQIA1 com-
munity who wish to foster and/or adopt children.
The limited and costly options available for transgender
individuals who wish to become parents help contextualize
why someone who identifies as a man might choose to use
their uterus to carry a pregnancy. However, the experience
Vol. 24 No. 3 MARCH 2023 e201
 of reproductive care also represents a challenge with respect
to inhabiting a cultural and medical world that is built for 1
type of cisgendered body. Pregnancy is inextricably tied with
femininity in Western culture. A 2017 qualitative study from
Sweden exploring fear of childbirth in lesbian, bisexual, and
transgender people assigned the female sex at birth explains
“pregnancy may disrupt notions of a coherent butch identity
or may require a redefinition of masculinity” given the bodily
changes associated with pregnancy and the fact that such
changes run directly counter to expressed gender identity.
Such changes may cause pregnancy-associated gender dys-
phoria in transgender men and nonbinary people. (17) Thus,
even if a trans man is able to overcome the barriers to access-
ing reproductive health care, there may be additional sociocul-
tural barriers to a healthy, positive pregnancy experience. (15)
Studies of transmasculine people’s pregnancy and child-
birth report that such patients often feel excluded, isolated,
and lonely. (17) This may be due at least in part to discrimi-
nation experienced within health care settings. Moreover,
many health care professionals lack the expertise and experi-
ence to adequately provide gynecological care to transgender
men. (14) As documented in a systematic review of the
health experiences of transgender men, many participants re-
ported experiencing “episodes of both verbal and nonverbal
discrimination and micro-aggressions while seeking [ … ]
care. This leads to a sense of being rejected, devalued, and
mistreated.” (18) Encouragingly, when trans men did en-
counter health care professionals who were knowledgeable
about their unique needs they felt “supported to make em-
powered decisions about their gynecological and reproductive
healthcare.” (7)
Such negative experiences may lead trans men to
choose alternative birth routes or settings, with recent re-
ports estimating that 22% of trans men give birth outside
of the hospital and up to 30% opt for an elective cesarean.
(19)(20) This has implications for the health of the birth
parent and newborn, given known complications and in-
creased risk of morbidity and mortality to both members
of the dyad associated with home births (21) and cesarean
sections in the United States. (22)
Finally, trans men face additional barriers and challenges
in postpartum care that lead to marginalization in health
care systems and settings, including newborn nurseries and
NICUs. An important issue in this period is infant feeding.
For cis-women, the decision on how to feed is personal, var-
ied, and dynamic. However, trans men must also contend
with resources and health care professionals that often exclu-
sively use “breastfeeding” and other female-centered lan-
guage. The Academy of Breastfeeding Medicine (ABM) itself
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notes that health professional education is lacking with re-
spect to patients who identify as LGBTQIA1. In addition,
certain physical aspects of human milk provision are unique
to this population and remain underappreciated by health
care professionals. For instance, if a trans person has under-
gone chest masculinization surgery, which will reduce, but
not eliminate, breast tissue, they may be able to experience
engorgement and provide their infants with human milk.
RECOMMENDATIONS MOVING FORWARD
The clinical vignette highlights some, but certainly not all,
of the challenges of being a trans person in a perinatal
health care setting. The experience of both positive and
negative interactions with the health care system vary
widely among transgender and other LGBTQIA1 individ-
uals, thus no vignette can capture the entirety of the pa-
tient experience. However, in general, most health care
professionals lack training and expertise in gender-affirm-
ing care, likely amplifying and further exacerbating the
challenges that LGBTQIA1 individuals face when obtain-
ing health care. Given this, it falls on all health care pro-
fessionals who practice within the perinatal space to create
a more inclusive health care setting that ameliorates the
disparities such parents are at risk of experiencing.
Language considerations are essential, given the way that
words surrounding reproductive and perinatal health and
health care are largely cis-normative and potentially isolating
and/or triggering. Readers will note our use of the words
“birth parent” or “person” rather than “mother” or “woman.”
Similarly, “chest feeding” and “nursing” are terms that have
been recently recommended by the American College of Ob-
stetricians and Gynecologists as a way to be inclusive when
caring for transgender parents in the perinatal setting. (23)
Rioux et al offer a comprehensive primer on gender-inclusive
language for epidemiologic research about pregnancy that
can also inform the language that clinicians use in health
care settings. (24)
In addition, some health care professionals struggle to use
a person’s preferred pronouns, such as using “they/them” to
refer to an individual. One way to handle this situation is to
simply use the person’s name and avoid pronouns altogether.
Health care professionals can also become more comfortable
using preferred pronouns by practicing using the pronouns
out loud so it does not sound foreign to either speakers or lis-
teners. One activity that may help is to read a children’s book
out loud but to change the pronouns to “they/them.”
Other recommendations include education of health
care professionals around specific supports for transgender
men who chose to gestate a pregnancy, including halting
 lactogenesis (by inhibiting milk production and breast en-
gorgement) and testosterone resumption. In addition, the
ABM recommends highlighting the benefits of bonding as
a goal when discussing chest feeding, which can be
Table. Suggested Activities to Improve Care for Gender Diverse Individuals and Their Newborns
Level Personnel Involved
Individuals Any person caring for expectant
parents and newborns (including
physicians, nurses, social workers,
pharmacists, etc).
Clinical Multidisciplinary teams caring for
teams newborns consisting of a variety
of health care professionals.
Institutions A dedicated interdisciplinary group
responsible for optimizing and
improving policies around caring
for LGBTQIA+ headed families.
Members should include: unit
leadership, clinicians (both those
caring for newborns and those
caring for expectant parents),
nurses, social workers,
pharmacists, case managers, and
family representatives and/or
community council members.
EMR5electronic medical record
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especially helpful for parents who wish to provide human
milk but experience low milk production. (5)
Providing the most equitable care requires an openness to
learning new ways of asking essential questions, and an
Suggested Activities
Reflect on the case:
 How would you have approached uncertainty with pronouns?
 How does avoiding the family change their postpartum experience?
 Would you have done anything differently?
Commit to avoid stigmatizing language in your care practices:
 Ask a person about their preferred pronouns and name.25
 If you use the wrong pronouns, apologize and move on. Do not attempt to
explain your biases to the individual you are caring for unless they invite you to.10
 Use “baby” when describing the newborn or “they” to avoid assigning a gender to
the infant
 Follow the lead of the parents – use the pronouns they use to refer to their
own infant
Be sure that all team members are aware of and educated on proper
pronouns:
 Document family member’s preferred pronouns in the EMR and educate
team members on where to find this information. This may require edits to
EMR flowsheets.
Discuss how best to partner with the family in feeding:26
 Clearly identify feeding plans and the terminology the family prefers to
support their needs.
 Ask about surgeries or manipulations to the chest.
 Offer lactation support regardless of desired feeding method. For families
who want to feed with human milk, support the dyad. For families who
prefer formula, explain changes in breast tissues and strategies for lactation
cessation.
Reflect on the care provided, and whether it aligned with unit policies and
best practices.
Recognize families may have lost trust in the medical system and provide
education for all staff members to improve the experience:27
 If staff have not already had training in working respectfully with LGBTQIA+
headed families, consider introducing this topic to anchor understanding
and buy-in.
 Familiarize staff with local laws regarding gender-affirming care.
 Advocate on an institutional level (e.g., by holding discussions, informing
others about calling politicians, bringing awareness from institutional
leadership) allowing for individuals to better care for their patients with the
backing of their hospital system.
EMR optimization:
 Ensure that EMR allows for documentation of preferred name and pronouns
 Work toward removal of assigned sex at birth for infants as a part of the
EMR, if important to family
Recognize intersectionality of health care needs:11
 LGBTQIA+ headed families of color will experience intersectional barriers to
accessing quality care. Identify best practices institutionally to support such
families.
 Make mental health care services available to all families.
 Fund research to support needs assessments and qualitative or quantitative
improvement projects on family planning for LGBTQIA+ headed families.
Medical education reform:
 Revise curricula and educational materials for all health care professionals and
trainees who will practice in the reproductive and perinatal space to include
inclusive language such as breast/chest feeding and human (vs. breast) milk
 Create continuing education materials for existing health care professionals
about pregnancy-related changes in chest tissue, resources for support if
chest feeding is desired, along with other lactation-related information
geared to trans men.
Vol. 24 No. 3 MARCH 2023 e203
 understanding of the resources available for gender-di-
verse families, especially regarding options for infant
feeding practices.
Expert Commentary (Dr. Smith)
Here are a few further thoughts for health care professio-
nals when approaching all LGBTQIA1 headed families:
• At baseline, void assumptions.
• No 2 LGBTQIA1 individuals are exactly alike. When in
doubt, let the LGBTQIA1 individual take the lead on
how they would like to be referred to, treated, and cared
for.
• Avoid relying on physical appearance and/or manner-
isms to give one any insight into the individual.
• Refrain from applying a heteronormative (male/female)
paradigm to LGBTQIA1 individuals.
• Keep in mind that LGBTQIA1 individuals really appre-
ciate kindness and a genuine desire on the behalf of
staff to provide them with the highest level of quality
health care. Many LGBTQIA1 individuals can overlook
some missteps when it is clear that the health care pro-
fessional has good intent as well as a caring, compas-
sionate, and kind approach.
• Have an open and honest dialogue about what you do
not know and express a willingness to learn.
• Learn and understand what the LGBTQIA1 individual
volunteers to share, without insisting that the individual
educate you about LGBTQIA1 culture at large.
CONCLUSION
Our case represents a conscious decision by one family to
become parents despite unique and complex challenges.
Our role as health care professionals is to educate our-
selves about these challenges and arm ourselves with the
tools to provide excellent care to such families. We must
work to recognize our biases, to make the experience less
difficult for our patients. Given that transgender men are
more likely than cisgender women to face bias and dis-
crimination when seeking obstetric and postpartum care,
health care professionals must be prepared to support the
unique needs of these parents and their infants. This in-
cludes understanding gender diversity, accepting chosen
gender identities, and appropriately using pronouns for all
individuals. Outside of these individual interactions, we,
as health care professionals, can also advocate within our
health care systems, and on state and national levels, to
change policies and laws that discriminate against our
patients’ families. The Table outlines these and other
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suggested activities that can be undertaken by individuals,
clinical teams, and institutions at large to further health
equity for this particular marginalized community.
References
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3. The Center. What is LGBTQIA1? https://gaycenter.org/about/lgbtq/.
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4. The Stonewall Center, University of Massachusetts, LGBTQIA1
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