25 TH

ANNIVERSARY
MARCH 2025
Vol. 26 No. 3
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ARTICLES
Gastrointestinal Motility Disorders
in the Neonate

Congenital Diarrhea and Enteropathies

Functional Infant Formula Additives

Nutritional Considerations in Neonates

Requiring Gastrointestinal Surgery

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VISUAL DIAGNOSIS
Term Infant With a Large Red-Purple Mass
in the Upper Thigh

EQUITY, DIVERSITY, AND INCLUSION CASE SERIES

Fostering Breastfeeding Equity in the
Neonatal Intensive Care Unit

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on, a proud supporter of the American Academy

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 NeoReviews
ARTICLES Editor-in-Chief: Dara Brodsky, Boston, MA
Associate Editor, IOS Cases: Elizabeth Schulz, Bethesda, MD
e141 Gastrointestinal Motility Disorders in the Neonate Associate Editor, IOS Cases: Jayasree Nair, New York, NY
Associate Editor, CME: Santina A. Zanelli, Charlottesville, VA
Kathryn Hawa, Shamaila Waseem, Joseph Croffie Associate Editor, NeoQuest: Rita Dadiz, Rochester, NY
Associate Editor, Perspectives: Mamta Fuloria, Bronx, NY
e154 Congenital Diarrhea and Enteropathies Associate Editor, Maternal-Fetal Medicine: Brett Young, Boston, MA
Associate Editor, Video Corner: Akshaya Vachharajani, Columbia, MO
Lina Diaz-Calderon, Runa Watkins, Atiye N. Aktay
Assistant Editor, CME: Theodore De Beritto, Los Angeles, CA
Associate Editor, Complex Fetal Care:
e163 Functional Infant Formula Additives Carl Backes, Columbus, OH
Kanika Puri, Courtney Svenstrup, Charles Vanderpool EDITORIAL BOARD
Jane E. Brumbaugh, Rochester, MN
e172 Nutritional Considerations in Neonates Requiring Anisha Bhatia, Canton, OH
Colby Day, Jacksonville, FL
Gastrointestinal Surgery Jennifer Hanford, Columbia, MO
Tony H. Tzeng, Sujir Pritha Nayak, Katie A. Huff Alison Chu, Los Angeles, CA
Corinne L. Leach, Buffalo, NY
Krithika Lingappan, Houston, TX
Sai Mukthapuram, Cincinnati, OH
Zeynep Salih, Carmel, IN
INDEX OF SUSPICION IN THE NURSERY Thomas E. Wiswell, Honolulu, HI
Clyde Wright, Aurora, CO
e186 Unilateral Facial Lesion in an Infant With Known Vermian
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e207 Fostering Breastfeeding Equity in the Neonatal Intensive
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 ARTICLE

Gastrointestinal Motility Disorders

in the Neonate
Kathryn Hawa, DO, Shamaila Waseem, MD, Joseph Croffie, MD

EDUCATION GAP

Clinicians caring for infants require a foundational knowledge of normal

gastrointestinal neuromuscular development and the role of congenital
anomalies in infants with gastrointestinal dysmotility.

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

1. Describe the normal gastrointestinal (GI) neuromuscular development

and motility in infants.
2. Discuss abnormalities of neuromuscular development in various con-
genital GI anomalies.

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3. Explain the role of motility testing in infants with clinical symptoms of GI
dysmotility.

ABSTRACT
Gastrointestinal (GI) motility disorders in term and premature infants may
occur at different times of gestation. Knowledge of normal neuromuscular
development can help clinicians determine the cause of GI dysmotility and
prognosis in infants born with congenital anomalies. Various developmental
abnormalities and premature gestational age can alter normal GI motility,
requiring further advanced testing and management. A multidisciplinary
approach is often needed to care for these patients.

INTRODUCTION
Disorders of gastrointestinal (GI) motility can have a significant effect on neonates
as efficient motility is necessary for digestion and absorption of nutrients needed
for growth and development. Knowledge of the pathophysiology, diagnostic
approaches, and management strategies for these disorders will provide the clini-
cian with tools needed for early intervention to improve outcomes for these

AUTHOR DISCLOSURE: Dr Croffie has received consulting fees from AbbVie and Johnson and Division of Gastroenterology, Hepatology,
Johnson and serves on an advisory board for Johnson and Johnson. Drs Hawa and Waseem and Nutrition, Riley Hospital for Children,
have disclosed no financial relationships relevant to this article. This commentary does not Indiana University Health, Indiana
contain a discussion of an unapproved/investigative use of a commercial product/device. University School of Medicine, Indianapolis,
Indiana
Accepted for Publication Date: October 15, 2024
[Link]
Copyright © 2025 American Academy of Pediatrics

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 neonates. This review summarizes the most common GI without an active swallow) does not occur until 32 weeks’
motility disorders that affect neonates, explores the underly- gestation.2–6 Premature infants (GA 25–36 weeks) have
ing pathophysiology, and discusses current diagnostic been shown to have increased numbers of noncoordi-
approaches and treatment options. nated esophageal contractions without true propaga-
tion.7–10 At birth, after 34 weeks’ gestation, healthy infants
can generate a coordinated, intact swallow with primary
ESOPHAGEAL/GASTRIC DEVELOPMENT and secondary peristalsis to obtain adequate nutrition
At week 4 of embryologic development, the foregut will orally.2,11
eventually develop into the esophagus, trachea, and lungs The stomach and the proximal duodenum begin as an out-
through complex cellular expression.1 Muscle differentia- pouching of the foregut at week 4 of gestation. During week 8
tion with circular and longitudinal muscle formation, as of gestation, physiologic rotation of the stomach and appro-
well as initial presentation of ganglion cells of the GI tract, priate proximal duodenal positioning occurs.2 Development
begins around week 6 of gestation. Eventually, the develop- of the stomach and duodenum is completed by 20 weeks’
ment of the striated and smooth muscle of the proximal gestation. Interstitial cells of Cajal are present in the longi-
and distal esophagus occurs, as does the formation of the tudinal layer of the stomach and are responsible for gastric
submucosal plexus over several weeks.1 Neuronal matura- pacing 3 times per minute. In neonates, intact antral motility,
tion and development continue throughout gestation and necessary for gastric emptying, initially appears between 14
postnatally.1 and 24 weeks’ gestation and matures around 30 to 35 weeks’
Suck and swallow patterns typically develop between gestation.2,12 With ingestion of a solid or liquid meal, mecha-
weeks 10 and 14 in utero. Primary propulsion of food or noreceptors and osmoreceptors in the stomach and duo-
liquid in the esophagus following swallow (primary peristal- denum initiate the release of various hormones, including

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sis) is intact at 26 weeks’ gestation and improves with cholecystokinin, nitrous oxide, and serotonin, which pro-
increasing gestational age (GA) (Figure 1A and 1B).2 mote appropriate gastric and antroduodenal coordination.12
Secondary peristalsis (esophageal response to distention Intact neuromuscular integrity is characterized by the

FIGURE 1. (A) Normal high-resolution esophageal manometry tracing with intact relaxation of the upper (black arrow) and lower (red arrow)
esophageal sphincter and propulsion of the food bolus throughout the esophagus. (B) Abnormal esophageal manometry. The red arrow
denotes initiation of a swallow. The black arrow indicates lack of lower esophageal relaxation. Note the panesophageal pressurization after
swallowing (black box).

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presence of an organized propagated contraction sequence SMALL BOWEL AND COLON DEVELOPMENT
during fasting, which begins in the stomach and migrates The small bowel and colon begin to elongate and grow
into the small bowel; this occurs every 90 to 120 minutes around the 5th week of gestation. During the 6th and 10th
and is referred to as the migrating motor complex (MMC) weeks of gestation, the bowel performs a 90° and then 180°
(Figure 2A). Initiation of the MMC in the stomach is rotation, respectively, with a return to the abdominal cavity in
triggered by the hormone motilin.12 There are 3 phases of the correct anatomic position. Innervation of the colon is
the MMC: through the enteric nervous system (intrinsic innervation)
and sympathetic/parasympathetic nervous system (extrinsic
• Phase 1 is quiescence of the bowel and must be present innervation).12,13 There are limited data on when normal neo-
after phase 3. natal colonic motility begins, but normal passage of meco-
• Phase 2 is characterized by irregular contractions without nium is evidence for intact recto-anal motility. Although
propagation. traditionally normal passage of meconium in term neonates
• Phase 3 is characterized by regular high amplitude contrac- occurs within 48 hours of birth, infants less than 32 weeks’
tions lasting 3 to 10 minutes and is found to propagate gestation with a normal recto-anal inhibitory reflex on ano-
throughout the small intestine (Figure 2A).12 rectal manometry may have delayed meconium passage.14
Various motility patterns have been identified in colonic
Gastric antrum propagated MMCs begin around 32 weeks’ manometry in children, but the hallmark of neuromuscular
gestation and are absent in younger preterm infants. integrity is the presence of high-amplitude propagating

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FIGURE 2. This figure contains examples of antroduodenal manometry studies in children. (A) Normal phase 3 MMC. Note the antral response
of the stomach (red arrow) after erythromycin with increased amplitude contractions as well as propagation throughout the small intestines
(black arrow). (B) Abnormal phase 3 MMC consistent with myopathy. Although propagating contractions throughout the small intestine are
noted, amplitude of contractions is minimal (black arrow). (C) Abnormal phase 3 MMC consistent with neuropathy. No significant propagation
of MMC is observed despite adequate amplitude of contractions (black box).
Abbreviation: MMC, migrating motor complex.

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 FIGURE 3. (A) Normal colonic manometry study with visualized high-amplitude propagating contractions (black arrow). (B) Colonic pseudo-
obstruction due to neuropathy with simultaneous contractions and multiple peaks noted (black box).

contractions that move stool from the colon into the rectum nutritive swallows in preterm/term infants with and without
(Figure 3).2,15,16 congenital malformations.7,9–11 One recent study used high-
Appropriate neuromuscular development is critical for resolution esophageal manometry in over 50 neonatal inten-
normal esophageal and GI motility. Prenatal and neuromus- sive care unit infants with various congenital malformations,

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cular developmental abnormalities or preterm birth may including EA, or bronchopulmonary disease compared with
determine clinical significance and prognosis of esophageal healthy infants.11 This study found that infants with congeni-
and/or GI dysmotility in the neonate. tal malformations had similar motility issues as surgically
repaired EA including segmental dysmotility and failed
CONGENITAL ABNORMALITIES OF THE peristalsis.11
ESOPHAGUS Endoluminal functional imaging probe (EndoFLIP) is a
relatively new diagnostic tool used to evaluate esophageal
Esophageal Atresia
pressures and distensibility while assessing for secondary
Esophageal atresia (EA) is the failure of the foregut to recan-
alize during early gestation (week 8) and is most commonly peristalsis under sedation.21 Currently, there are minimal
seen as atresia with a distal tracheoesophageal fistula (EA/ data on the clinical utility of EndoFLIP in children with sur-
TEF) (type C).2,17,18 Infants may present clinically with a pre- gically corrected EA/TEF, but EndoFLIP has been shown to
natal history of polyhydramnios. There may be a history of be safe to use in children under 5 years of age.22 One small
excessive secretions soon after birth, failure to pass a naso- retrospective study evaluated 9 children (median age being
gastric tube, or inability to pass contrast into the stomach 9 years old) with EA/TEF repair using EndoFLIP and found
during an esophagram. Surgical intervention is the mainstay that the esophageal body had a higher distensibility com-
of management for infants to achieve enteral autonomy and pared with the esophagogastric junction; however, 6 of 9
has improved mortality in these patients. However, it is well patients had no secondary peristalsis with maximal pressures
known that esophageal dysmotility (including gastroesopha- on the esophageal wall.23 More studies are needed to deter-
geal reflux disease and dysphagia) may occur in virtually all mine the clinical utility of EndoFLIP and esophageal man-
infants and children with this disorder.2,17,18 The etiology of ometry in infants with EA/TEF repair and the potential
this dysmotility is disputed in the literature; it is unclear role in antireflux surgeries.
whether this is a primary disorder or a result of surgical dis- In addition to esophageal dysmotility, studies using
ruption.19,20 Previous studies in children after EA/TEF pH impedance planimetry showed transient lower esopha-
repair have described 3 major esophageal motility patterns geal sphincter relaxations in infants with EA/TEF
including distal contractions (47%), aperistalsis (38%), and repair.24,25 Furthermore, some evidence suggests that gastric
pressurization (15%).17 dysmotility/delayed gastric emptying is present in these
Esophageal manometry has been used in infants for fur- patients as well, which have been hypothesized to increase
ther evaluation of esophageal motility in nonnutritive and the risk for gastroesophageal reflux.24,26 Because of the

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high incidence and risks surrounding chronic untreated infants and children.38 Often, asymptomatic esophagitis
gastroesophageal reflux in patients with surgically corrected may be found on endoscopy with likely long-term chronic
EA/TEF, the North American Society for Pediatric complications, including increased risk of Barrett’s esopha-
Gastroenterology, Hepatology and Nutrition developed a con- gus or malignancy.38,39 There are no specific guidelines for
sensus statement for continued management of these follow-up endoscopy in patients born with congenital dia-
patients with acid suppression (ie, proton pump inhibitor) phragmatic hernia; however, because of the potential compli-
throughout infancy and beyond if symptoms persist or cations of asymptomatic reflux disease, some authors have
complications arise. This organization recommends close recommended routine assessment for acidic and nonacidic
monitoring with repeat upper endoscopies throughout reflux with pH impedance studies.40 Higher risk of reflux
childhood.27 has been observed in children aged less than 2 years with
patch surgical repair and a history of intrathoracic gastric
CONGENITAL ABNORMALITIES OF THE STOMACH anatomy. Unfortunately, there are no known predictive fac-
Gastroschisis tors to determine risks associated with persistent gastroeso-
Gastroschisis is typically diagnosed around week 20 of ges- phageal reflux in older children.41
tation, with the bowel visualized outside of the intraabdomi-
nal cavity on ultrasound.28 Gastroschisis is described as
CONGENITAL DISORDERS OF THE SMALL
simple or complex based on the presence of additional com-
INTESTINES
plications including bowel atresia, volvulus, malrotation,
Pediatric Intestinal Pseudo-Obstruction
and/or perforation.28,29 Complex gastroschisis has been
Pediatric intestinal pseudo-obstruction (PIPO) is a hetero-
reported in multiple studies to have worsening outcomes
geneous disorder that is mostly congenital and is a separate
related to overall GI motility and worsening morbidity and

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entity from chronic intestinal pseudo-obstruction found in
mortality with prolonged hospital stays.29,30 Conflicting the-
adults.42 Over 50% to 80% of affected patients present within
ories revolve around worsening outcomes and dysmotility in
1 to 12 months of age.43 The definition by the European
patients with gastroschisis. Although the exact mechanism
Society of Pediatric Gastroenterology, Hepatology and
for the development of GI dysmotility is unclear, bowel dila-
Nutrition (ESPGHAN) requires symptoms mimicking GI
tion and a history of atresia have been associated with worse
obstruction without evidence of mechanical obstruction
outcomes.29,31 Pinto et al have postulated that severe bowel
within 2 months of birth or 6 months thereafter. Two of
matting and subsequent worsening dysmotility is due to
the following 4 criteria must be met:
prolonged amniotic fluid exposure to meconium, as seen
in animal models.32 However, in 2015, Youseff et al pros-
• Objective measure of small intestinal neuromuscular
pectively evaluated over 650 infants born with gastroschisis
involvement (manometry, histopathology, transit)
and found decreased bowel matting and gastroschisis prog-
• Recurrent and/or persistently dilated loops of small intes-
nosis scores with increased GA.33,34 In addition, other stud-
tine with air fluid levels
ies have found decreased duration of nutrition support in
• Genetic and/or metabolic abnormalities definitively asso-
infants born at later GA and who had early abdominal clo-
ciated with PIPO
sure.35,36 Evidence that decreased numbers of interstitial
• Inability to maintain adequate nutrition and/or growth on
cells of Cajal in patients with gastroschisis compared
oral feeding (needing specialized enteral nutrition and/or
with age-matched controls may contribute to sustained GI
parenteral nutrition support)43
dysmotility.37

Congenital Diaphragmatic Hernia The incidence and prevalence of PIPO are mostly
Congenital diaphragmatic hernia results from a congenital unknown, but prior studies suggest the incidence may be
defect in the diaphragm and subsequent migration of GI con- up to 1/40 000 live births.43 The cases may be familial,
tents into the thoracic space. Depending on the size of the and genetic testing is often reserved for infants to determine
defect, other structures may also migrate into the thoracic prognosis42,44; however, the majority of genetic abnormal-
space, including the heart and/or lungs. Outcomes for ities are sporadic.42,45
infants born with congenital diaphragmatic hernia have GI histology in patients with PIPO can vary depending on
improved significantly; however, in addition to multiple sys- type and include neuropathies, myopathies, and mesenchy-
temic comorbidities, gastroesophageal reflux and feeding mopathies.42,46 Histology may be normal in some instances.
dysfunction remain as persistent issues for many of these Full thickness biopsies are often needed when the diagnosis

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 TABLE 1. Recommended Laboratory Testing and Imaging for Diagnosing Pediatric Intestinal Pseudo-obstruction
Testing
Recommendations Laboratory Testing Imaging Motility Testing
First line Complete blood count Abdominal radiograph
Complete metabolic panel (upright or decubitus)
Inflammatory markers (ESR/CRP)
Celiac screening (tissue transglutaminase,
total IgA levels)
Thyroid (TSH, free T4)
Second line Cortisol Upper GI series with small bowel Antroduodenal manometry
Lactate, urine organic acids follow through Esophageal manometry
Genetic screening Computed tomography Anorectal and colonic
Magnetic resonance imaging manometry
Gastric scintigraphy
Abbreviations: ESR/CRP, erythrocyte sedimentation rate/C-reactive protein; GI, gastrointestinal; T4, thyroxine; TSH, thyroid-stimulating hormone.
American Board of Pediatrics Neonatal-Perinatal Content Specification

is unclear and further evaluation with various histochemical urinary catheterization.45,47 Prenatal findings on imaging
stains is required to evaluate both the myenteric and sub- are most commonly megacystis (ie, a greatly enlarged, non-
mucosal nerve layers. Otherwise, recommendations by obstructed bladder) with or without hydroureteronephrosis
ESPGHAN include a tailored approach to patients for diag- (up to 88% of cases) and are most commonly detected in
nosis based on symptomatology. The evaluation should aim the second trimester of pregnancy. Only a quarter of GI
at looking for reversible causes of pseudo-obstruction and abnormalities are detected on prenatal imaging.48 When
should begin with basic laboratory testing.43 Further evalu- detectable on ultrasound, findings may include dilated stom-

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ation may be considered including genetic testing, metabolic ach and bowel loops. Because of their inability to tolerate
screening, endoscopy, and imaging. Radiographic studies adequate amounts of enteral feedings, patients with
including radiograph, magnetic resonance imaging, com- MMIHS often require long-term parenteral nutrition, which
puted tomography, and contrast studies may be used to has been shown to prolong survival rates. However, signifi-
evaluate for small bowel dilation or extraneous findings in cant associated complications can occur, including recurrent
the patient developing an obstruction.42,43 Of note, abdomi- central line-associated infections and liver injury.47 The diag-
nal radiographs may suggest evidence of small bowel dila- nosis of MMIHS is mostly clinical, but various manometric
tion, but contrast imaging is needed for further evaluation. studies, including gastroduodenal and colonic manometry,
Endoscopy may be indicated for further evaluation of the may be used to assist in further evaluating bowel motility.
mucosal lining to diagnose other conditions, including In addition, further evaluation may be determined with
eosinophilic disorders and celiac disease. Table 1 outlines biopsies.
suggested laboratory tests and imaging for diagnosis.
Antroduodenal manometry yields the highest results due Mitochondrial Neuro-Gastro-Intestinal-
to the increased incidence of small bowel involvement in Encephalomyopathy
PIPO. Manometry is often used to determine neuromuscular Symptoms of hearing loss and ophthalmoplegia along with
coordination and is strongly recommended by ESPGHAN PIPO should increase suspicion for a mitochondrial neuro-
consensus for diagnosis and to guide management gastro-intestinal-encephalomyopathy syndrome caused by
(Figure 2).43 an autosomal recessive mutation of the TYMP gene. A major-
ity of these patients have abnormal brain imaging with
Megacystis-Microcolon-Intestinal Hypoperistalsis leukoencephalopathy. Although the average age of presenta-
Syndrome tion is early adulthood (18.5 years old), the earliest recorded
Megacystis-microcolon-intestinal hypoperistalsis syndrome onset has been in infancy.43,49
(MMIHS) is a GI smooth muscle myopathy that has variable In summary, the diagnosis of PIPO should be considered
clinical severity and ultimately manifests as PIPO. Actin in neonates with megacystis or GI-obstructive symptoms
gamma 2 gene mutations are the most frequent abnormal- with bladder dysmotility, persistent/recurrent obstructive
ities seen with this disorder (44% of all MMIHS) and affected symptoms after a negative evaluation for Hirschsprung
patients have the most severe symptoms.45 Around 50% of disease, and hypothyroidism or obstructive symptoms
infants with MMIHS present shortly after birth with obstruc- after surgery for malrotation such as a Ladd procedure.
tive bowel symptoms and bladder dysfunction requiring Other considerations for PIPO include GI-obstructive

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symptoms with concordance of eye abnormalities (ptosis, of the vagina in girls compared with normal values.51 Mild
ophthalmoplegia), sensorineural deafness, and/or cardiac anatomic defects may be difficult to diagnose and may
abnormalities. present with medically refractory constipation symptoms
later in life.52,56
Anorectal manometry may be useful in infants with ano-
CONGENITAL DISORDERS OF THE COLON rectal malformations and difficulty with stooling to further
AND ANUS evaluate neuromuscular function. Previous evaluation of
Anorectal Malformations normative values in healthy infants between birth and
Anorectal malformations in neonates remain a relatively rare 2 months of age and 2 and 6 months of age has been
diagnosis with an incidence of 1 in 3000 to 5000 and may reported.57,58 An overall increase in baseline anorectal pres-
vary in severity.50 Although difficult to diagnose antenatally, sures has been found with increasing age with the lowest
a 20-week gestation fetal magnetic resonance imaging may pressures notable in premature infants, suggesting matura-
be used if there is strong suspicion because of the presence tion of anorectal tone over time.57 den Hollander et al studied
of other associated congenital malformations or chromoso- over 60 infants with high-resolution 3-dimensional (3D) ano-
mal abnormalities with known association with anorectal rectal manometry to further evaluate concerns for rectoper-
anomalies.50,51 Otherwise, diagnosis is typically made post- ineal congenital anorectal malformations. With the addition
natally and with a thorough physical examination for several of electrical stimulation during manometry, they were able to
key abnormalities, including an insufficient anal opening diagnose 35 patients with concerns for rectoperineal anorec-
(unable to place a size 12 Hegar dilater in the anus) and/or tal malformations with 100% sensitivity and specificity.56
abnormal anal location (anterior/posterior).50 In girls, close Studies using sitz markers have shown abnormal gener-
examination of the labia and perineal body is important to alized colonic transit time with age in infants with malforma-

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determine the presence of normal anatomic structures tions, including the genitourinary system, rectum, and/or
including the urethra, vagina, and anus as distinct entities. spine.59,60 There is a high concordance of fecal incontinence
Possible fistula in boys needs to be determined by close following anorectal malformation repair, which is postulated
inspection.50 Delay in meconium passage is a clinical presen- to be due to persisting anorectal dysfunction.55,61
tation that may raise suspicion for an anorectal anomaly but Ambartsumyan et al compared 3D high-definition anorectal
is not required for diagnosis depending on the area and manometry findings in 30 children of different ages who had
extent of anatomic structures involved. Affected areas may repaired anorectal malformations with age and sex-matched
include the anus, rectum, and/or the genitourinary tract. children diagnosed with chronic constipation.45 The authors
The spine may be involved when severe. More proximal found that children with repaired anorectal malformations
(“high”) anomalies, which may involve anal, rectal, or colonic had more abnormal sensation and lower pressures in the
atresias, often have more comorbidities associated with them anus. In addition, complete propagation of high-amplitude
than low malformations such as anal stenosis or anterior propagating contractions to the neorectum has been
anus.2,45,50,52,53 observed, which is similar to that reported in patients with
Almost all anorectal malformations are managed with Hirschsprung disease (Figure 3).54,62,63
surgery after birth; however, there are some controversies
with lower anorectal malformations regarding surgical tim-
ing and/or conservative management. All patients with ano- MEDICATIONS
rectal malformations should be screened for additional Currently, there are no US Food and Drug Administration–
congenital anomalies, including VACTERL association approved medications for infants to help with GI dysmotility
(Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal symptoms. However, the authors will review several studies
and Limb).54 Long-term complications in patients with sur- evaluating off-label medication use in infants and children.
gical anorectal repair include chronic constipation, fecal Erythromycin and azithromycin are macrolide antibiotics
incontinence, and sexual dysfunction.55 Anteriorly displaced with motilin agonist properties. These antibiotics increase
anus is a common anorectal malformation, although its exact gastric tone, phase 3 of the MMC, and the frequency of gas-
prevalence is not known. An anteriorly displaced anus may tric contractions.43,64–67 Erythromycin has been investigated
suggest the presence of a perineal fistula and is diagnosed in the past in very low birth weight preterm infants with
on examination, often with the use of Anal Position Index. notable improvement in faster tolerance of enteral feedings
This index measures the distance between the anus and and decreased need for parenteral nutrition.68,69 However,
the base of the scrotum in boys or the posterior fourchette infants born before 32 weeks’ gestation may not benefit

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 due to the lack of normal MMC at that time.70,71 Although monitoring of symptoms. Multidisciplinary care is often
concerns for side effects, including necrotizing enterocolitis, needed for infants and children with these disorders.
cardiac rhythm abnormalities, and an 8-fold increased risk of
pyloric stenosis have been raised in previous studies in
infants less than 2 weeks of age treated for pertussis or chla- American Board of Pediatrics
mydia exposure, no significant side effects were reported
Neonatal–Perinatal Content
with the use of erythromycin at lower doses in preterm
infants.68,72,73 However, larger studies and individual risk/
Specification
• Learn normal gastrointestinal motility development in
benefit ratios are needed.
the preterm and term neonate.
Metoclopramide is a dopamine receptor antagonist used
• Recognize conditions that disrupt normal gastrointes-
to improve gastric promotility.74 In the past, it was often pre- tinal motility.
scribed to premature infants for symptoms of gastroesopha- • Discuss the utilization of medications to help with
geal reflux during hospitalization; however, overall use improving gastrointestinal motility.
decreased significantly with increased awareness of concerns
for neurologic adverse events and subsequent black box
warning by the US Food and Drug Administration in
2009.75 Although erythromycin and metoclopramide have References
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849105 doi: 10.1542/peds.2017-0007

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 NEOREVIEWS QUIZ

NEO
QUIZ
1. Neonatal gastrointestinal motility disorders can significantly impact the
digestion and absorption of nutrients. During normal development,
esophageal primary peristalsis is present by 26 weeks’ gestation while
secondary peristalsis does not occur until 32 weeks’ gestation. Similarly, small
bowel migrating motor complexes (MMC), typically occurring every 90–
120 minutes, appear around 32 weeks’ gestation. Which of the following
hormones triggers MMC in the stomach?
A. Cholecystokinin
B. Serotonin
C. Ghrelin
D. Motilin
E. Gastrin
REQUIREMENTS: Learners can
2. Esophageal atresia (EA) is characterized by failure of recanalization of the take NeoReviews quizzes and
foregut during week 8 of gestation and is most often associated with a distal claim credit online only at:
[Link]
tracheoesophageal fistula (type C). Esophageal dysmotility, dysphagia and
neoreviews.
gastroesophageal reflux can occur in children with a history of EA repair.
Which of the following dysmotility pattern is most common in patients with a To successfully complete 2025
history of EA repair? NeoReviews articles for AMA PRA
Category 1 Credit™, learners must
A. Aperistalsis

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demonstrate a minimum
B. Distal contractions performance level of 60% or
C. Pressurization higher on this assessment. If you
D. Proximal esophageal spams score less than 60% on the
assessment, you will be given
E. Hypercontractility
additional opportunities to
3. Megacystis-microcolon-intestinal hypoperistalsis syndrome is a answer questions until an overall
gastrointestinal smooth muscle myopathy that can present in the newborn 60% or greater score is achieved.

period in 50% of cases. Clinically, patients present with bowel obstruction

This journal-based CME activity is
and bladder dysfunction, includingis some cases a diagnosis of megacytitis available through Dec. 31, 2027;
on prenatal ultrasound. Mutations in which of the following gene are most however, credit will be recorded
frequently identified in megacystis-microcolon-intestinal hypoperistalsis in the year in which the learner
syndrome? completes the quiz.

A. Actin gamma 2
B. Intercellular adhesion molecule-1
C. Myosin light chain kinase
D. Glial cell line–derived neurotrophic factor
E. Thymidine phosphorylase
2025 NeoReviews is approved for
4. Erythromycin is a macrolide antibiotic with promotility properties. Studies a total of 10 Maintenance of
indicate that erythromycin can improve feeding tolerance and decrease the Certification (MOC) Part 2 credits
by the American Board of
need for parenteral nutrition in very low birthweight infants. Which of the
Pediatrics (ABP) through the AAP
following is a possible side-effect of erythromycin in preterm infants? MOC Portfolio Program.
NeoReviews subscribers can claim
A. Maculopapular rash
up to 10 ABP MOC Part 2 points
B. Gastritis upon passing 30 quizzes (and
C. Pyloric stenosis claiming full credit for each quiz)
D. Hypokalemia per year. Subscribers can start
E. Supraventricular tachycardia claiming MOC credits as early as
October 2025. To learn how to
claim MOC points, go to: https://
[Link]/journals/
pages/moc-credit.

e152 NeoReviews

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5. Metoclopramide is a dopamine receptor antagonist shown to improve gastric
motility. The Food and Drug Administration (FDA) issued a black box warning
regarding the use of metoclopramide in infants. Which of the following side-
effects of metoclopramide triggered the FDA black box warning?
A. Prolonged QT interval
B. Hypercalcemia
C. Direct hyperbilirubinemia
D. Necrotizing enterocolitis
E. Tardive dyskinesia

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 ARTICLE

Congenital Diarrhea and Enteropathies

Lina Diaz-Calderon, MD, Runa Watkins, MD, Atiye N. Aktay, MD

EDUCATION GAPS

The causes of diarrhea in neonates and mechanisms to manage diarrhea in a

timely manner are critical because neonates are susceptible to dehydration and
electrolyte imbalances. The etiology could be due to infections or food protein
allergies but may also be secondary to congenital enteropathy requiring early
interventions to replace the fluid losses caused by the electrolyte disorders.

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

1. Recognize the differential diagnosis and initial evaluation of an infant

with diarrhea;
2. Describe the basic mechanisms responsible for congenital enteropathies;
3. Explain the diagnostic workup and management of congenital diarrhea; and

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4. Delineate the role of genomic testing to identify causative mutations of
congenital enteropathies and its impact on dietary management of spe-
cific conditions.
ABBREVIATIONS

ABL abetalipoproteinemia
ApoB apolipoprotein B ABSTRACT
CCD congenital chloride diarrhea
Diarrhea in neonates is usually secondary to an infectious process or a food
CE congenital enteropathy
CSD congenital sodium diarrhea protein allergy. Once the infection is treated or the allergen is removed, the
CTE congenital tufting enteropathy
EFA essential fatty acid diarrhea resolves without lifelong sequelae. On the contrary, infants with
EpCAM epithelial cell adhesion anatomical disorders such as intestinal atresia, gastroschisis, malrotation
molecule
GGM glucose-galactose with volvulus, or necrotizing enterocolitis can present with protracted diar-
malabsorption
rhea secondary to poor gut motility and short bowel syndrome. A small
HBL hypobetalipoproteinemia
HE hematoxylin-eosin group of infants who present with severe diarrhea shortly after birth can
IPEX immune dysregulation
polyendocrinopathy have a congenital enteropathy resulting from a monogenic disorder. This
enteropathy X-linked group poses clinical challenges that require intensive resuscitation and
IgA immunoglobulin A
MVID microvillous inclusion disease meticulous diagnostic evaluation aimed at optimizing interventions and
NEC necrotizing enterocolitis
outcomes. In this review, we will provide a diagnostic and management
SID sucrase-isomaltase deficiency
TPN total parenteral nutrition approach for infants with congenital enteropathies.
Treg T regulatory

Division of Pediatric Gastroenterology, AUTHOR DISCLOSURE: Drs Diaz-Calderon, Watkins, and Aktay have disclosed no financial
Department of Pediatrics, University of relationships relevant to this article. This article does not contain a discussion of an unapproved/
Maryland, Baltimore, Maryland investigative use of a commercial product/device.
Accepted for Publication Date: October 4, 2024
[Link]
Copyright © 2025 American Academy of Pediatrics

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INTRODUCTION Serum and Stool Testing
Diarrhea in neonates is usually secondary to an infectious Initial serum testing in infants with severe diarrhea soon
process or a food protein allergy. Once the infection is treated after birth includes a complete blood count, a comprehensive
or the allergen is removed, the diarrhea resolves without metabolic panel, coagulation studies, a lipid profile, and inflam-
lifelong sequelae. On the contrary, infants with anatomical matory markers. Additional laboratory tests such as immuno-
disorders such as intestinal atresia, gastroschisis, malrota- globulins, zinc levels, and T- and B-cell subset analysis may be
tion with volvulus, or necrotizing enterocolitis (NEC) can considered based on clinical suspicion for specific disorders.
present with protracted diarrhea secondary to poor gut motil- Stool analysis includes inspecting the stool to determine
ity and short bowel syndrome. A small group of infants who if it is watery or bloody or contains fat, as further investiga-
present with severe diarrhea shortly after birth can have a tions will be determined by the consistency of the diarrhea
congenital enteropathy (CE) resulting from a monogenic dis- (Table 1). A fasting trial (nil per os) of at least 24 hours is
order. This group poses clinical challenges that require inten- recommended before obtaining any stool testing. Diet-
sive resuscitation and meticulous diagnostic evaluation induced diarrhea, referred to as osmotic diarrhea with an
aimed at optimizing interventions and outcomes.1 In this elevated stool osmotic gap (ie, >100 mOsm), will improve
review, we will provide a diagnostic and management after a fasting trial. In contrast, in patients with defects in
approach for infants with CEs. electrolyte transport—namely, secretory diarrhea with a
low stool osmotic gap (ie, <50 mOsm)—diarrhea remains
unchanged despite a nil per os challenge. If there is suspi-
DIAGNOSTIC APPROACH TO INFANTS WITH cion of diet-induced diarrhea, nutritional consultation is
CONGENITAL DIARRHEA warranted to guide feeding trials with specialized carbohy-
drate-free formulas to elucidate if the infant has malabsorp-
CEs are a rare group of disorders that present with devastat-

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tion of a specific carbohydrate or a defect in absorbing other
ing chronic diarrhea in infants. The incidence of CE is
nutrients.1
unknown and varies widely among populations and geo-
graphic areas.2 For example, congenital chloride diarrhea Endoscopic Evaluation
(CCD), one of the most common causes of congenital diar- Infants with findings that are consistent with electrolyte
rhea, has a higher incidence in countries with high rates transport–related diarrhea and those in whom a selective
of consanguinity (eg, Kuwait, Saudi Arabia) or countries with carbohydrate malabsorption was not elucidated after a feed-
a high carrier rate of the same mutation (eg, Finland, Poland) ing challenge should undergo endoscopic evaluation with
due to the founder effect.3–5 esophagogastroduodenoscopy and flexible sigmoidoscopy
Diarrhea within the first days after birth can often be with biopsies, even if genetic testing is available.5 Intestinal
difficult to identify because watery stool can be mistaken biopsies should include samples for routine histology,
for urine. If there is clinical suspicion of high stool losses electron microscopy, and measurement of disaccharidase
causing dehydration or electrolyte derangements, placing a activity. Histological analysis evaluates intestinal epithelial
urinary catheter for a few days may allow accurate measure- architecture (villous to crypt ratio) and inflammatory infiltrates
ment of stool output. After daily stool volume has been accu- in the lamina propria and intraepithelial compartments.
rately measured, the diagnosis of diarrhea can be established Abnormal villous architecture may be associated with defects
if the infant has stool output of more than 20 mL/kg/d.1 in enterocyte structure, differentiation, and immune-
Key components in the initial evaluation of infants with mediated conditions.2 Immunohistochemical staining may
diarrhea include a review of prenatal history, family history, assist in the diagnosis of some disorders, as well. For example,
and ethnicity. The history of polyhydramnios, multisystem in infants with fatty diarrhea, a frozen section of intestinal
involvement, and family history of consanguinity should biopsy stained with oil red O may demonstrate fat-laden enter-
increase the clinician’s suspicion of a CE.1 For infants with ocytes, indicating lipid trafficking disorders.1
clinical findings consistent with a CE, an extensive evaluation
is recommended, which is described in this section. Infants Molecular Analysis
with extremely high stool output resulting in major hemo- Early genetic testing is advised when evaluating infants with
dynamic disorders soon after birth who require critical inter- a suspected CE. Genetic testing allows for the identification
ventions to replace fluid and electrolyte losses must also of mutations and a better understanding of the pathophysi-
undergo additional investigations to rule out other causes, ology of the CE. Most CEs are inherited in an autosomal
such as NEC and anatomical gastrointestinal anomalies. recessive fashion with a few having an autosomal dominant

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 TABLE 1. Stool Tests
Stool
Appearance Stool Test Interpretation Suspected Diagnosis if Abnormal Result
Watery Electrolytes • Normal osmotic gap: 50–100 mOsm • Congenital sodium diarrhea
(Na+, K+, and Cl−) • Osmotic gap calculation [290 − 2 × (Stool • Congenital chloride diarrhea
Na+ + K+)] helpful to differentiate between • Primary bile acid diarrhea
secretory and osmotic diarrhea
• High fecal Na+, K+, or Cl− reflects secretory
diarrhea
α-1-Antitrypsin Marker of intestinal protein loss • Intestinal lymphangiectasia (low albumin
and edema)
• DGAT1 deficiency with protein-losing
enteropathy
Reducing substances • Normal: <0.5% • Glucose-galactose malabsorption
• Product of bacterial fermentation of • Sucrase-isomaltase deficiency
luminal CHO • Congenital lactase deficiency
• Positive test results for reducing substances
are indicative of CHO malabsorption
pH • Normal: 7–7.5
• Lactic acid produced with bacterial
fermentation of luminal CHO
Fatty Elastase • Normal: >200 μg/g stool • Normal elastase: abetalipoproteinemia,
• Enzyme secreted by the exocrine pancreas hypobetalipoproteinemia, chylomicron
• Minimally degraded in the GI tract retention disease
Spot fecal fat test Normal: negative • Low elastase: suspect pancreatic
insufficiency (cystic fibrosis, Shwachman-
Diamond syndrome)

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Bloody Hemoccult • Hemoglobin in stool via peroxidase reaction • Positive test result indicative of colitis
• Caution: false positive with perianal skin • Caution is needed because not all cases of
irritation immune-mediated congenital enteropathies
present with hematochezia
Infectious stool PCR Detection of common enteric pathogens
panel
Abbreviations: CHO, carbohydrate; Cl−, chloride; DGAT1, diacylglycerol 0-acyltransferase 1; GI, gastrointestinal; K+, potassium; Na+, sodium; PCR,
polymerase chain reaction.
Adapted from Thiagarajah et al1 and Terrin et al.5

or X-linked recessive pattern of inheritance. To identify the tion, electrolyte abnormalities, ketoacidosis, and protein
potential causative mutation, targeted genetic testing can degradation.9
be considered when there is suspicion of a common genomic The calculation of an infant’s total volume requirement
variant, or whole-exome sequencing can be done as a broader must account for maintenance requirements per body
assessment.6 Commercially available panels are helpful to weight (100 mL/kg/d) in addition to replacement fluids
analyze targeted genes associated with conditions presenting based on estimated water and electrolyte deficits. Estima-
with congenital diarrhea, some of which can rule out up to tion of water deficit is calculated based on the infant’s physi-
121 disease phenotypes.7,8 cal examination evaluating for signs of dehydration, as well
as the percentage of weight loss, which determines the extent
of dehydration (ie, weight loss that is mild, 5%; moderate,
MANAGEMENT 10%; or severe, 15%).10 In infants with diarrhea, it is crucial
Fluid and Electrolytes to have continuous monitoring of intake and output to
Patients with a CE often have large stool losses requiring replace ongoing losses accordingly. Serum electrolyte levels
intensive fluid and nutritional management. Severe diarrhea and renal function should be assessed periodically to manage
may lead to significant dehydration and electrolyte derange- potential electrolyte derangements secondary to large vol-
ments that can be life-threatening. Considering that most umes of stool losses. Nutritional support is also critically
infants with CE undergo prolonged periods without enteral important in infants with CE to achieve normal growth
feedings, the best way to provide hydration and nutrition is and development, thereby preventing complications from
via total parenteral nutrition (TPN). TPN prevents dehydra- chronic dehydration, metabolic acidosis, and electrolyte

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abnormalities such as metabolic bone disease, renal dysfunc- with intestinal failure secondary to CE who require lifelong
tion, and micronutrient deficiencies.11 TPN or have complications from parenteral nutrition with
high mortality risk may be candidates for intestinal trans-
Diet Therapy plantation as a lifesaving opportunity in severe cases.12
Data from the Pediatric Congenital Diarrhea and Entero-
pathies Consortium (known as PediCoDE) suggest simplify- Consultations
ing the dietary manipulation in infants with CE by eliminat- For infants with suspected CE, gastroenterology, nutrition,
ing specific malabsorbed nutrients, supplementing electro- and genetics should be consulted for further evaluation
lyte and micronutrient deficiencies, or restricting full enteral and management guidance. Consultation with pediatric
intake based on the underlying diagnosis.11 surgery should also be considered depending on the clinical
In cases with carbohydrate malabsorption (glucose- condition and potential need for central venous catheter or
galactose malabsorption [GGM], sucrase-isomaltase defi- gastrostomy tube placement. Infants with suspected multi-
ciency [SID], and congenital lactase deficiency), the mainstay systemic involvement warrant evaluations from immunol-
in therapy is selective elimination (or reduction) of the mal- ogy and endocrinology services.
absorbed carbohydrate.
Defects in lipid absorption, assembly, or packaging cause CONGENITAL ENTEROPATHIES BY TYPE OF
fat malabsorption presenting with steatorrhea and increased DISORDER
risk of fat-soluble vitamin deficiency. A minimal-fat diet
Individuals with CE typically present with infantile-onset
(<10% of total calories from fat) is recommended for infants
profuse diarrhea requiring intensive fluid and electrolyte
with CE secondary to fat malabsorption (abetalipoproteine-
resuscitation upon initial presentation. At least 30 mono-
mia [ABL], hypobetalipoproteinemia [HBL], chylomicron
genic intestinal epithelial disorders have been described in

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retention disease, and diacylglycerol 0-acyltransferase 1
the literature presenting with congenital diarrhea.6 CEs
deficiency). However, long-term fat restriction increases a
can be classified into broad groups based on the epithelial
patient’s risk for essential fatty acid (EFA) deficiency, poor
type of defect (functional vs structural). In this section, we
growth, and micronutrient deficiencies, warranting close
focus on the most common disorders that represent each
monitoring of vitamin levels and supplementation with
type of intestinal epithelial defect.
medium-chain triglycerides and EFA.11
Infants with intestinal lymphangiectasia have lymph leak-
age, containing high amounts of protein and fats, into the DEFECTS IN THE ABSORPTION AND TRANSPORT
bowel lumen. Treatment for intestinal lymphangiectasia OF NUTRIENTS OR ELECTROLYTES
includes a diet high in protein and minimal fat intake to Congenital Chloride Diarrhea
decrease lymph production, thereby reducing osmotic load Alterations in epithelial electrolyte transporters are the most
and diarrheal output. prevalent causes of congenital diarrhea. Mutations in
CEs due to defects in electrolyte and micronutrient trans- SLC26A3 generate defects in the brush border Cl−/HCO3
port (CCD, congenital sodium diarrhea [CSD], and acroder- exchanger impairing luminal Cl− reabsorption in the ileum
matitis enteropathica with impaired zinc uptake) have high and colon, resulting in CCD. CCD is an autosomal recessive
requirements for intravenous supplementation of sodium, disorder with most cases having a positive family history of
chloride, bicarbonate, and potassium that later can be transi- congenital diarrhea or consanguinity.3 Infants with CE due to
tioned to enteral supplementation as mainstay therapy. abnormal electrolyte transport may present in utero with pol-
Lastly, more severe forms of CE, including enteric yhydramnios and intraluminal water visible throughout the
anendocrinosis, microvillous inclusion disease (MVID), con- small bowel and colon on fetal magnetic resonance imaging,
genital tufting enteropathy (CTE), and trichohepatoenteric suggesting the presence of large quantities of watery diar-
syndrome, have generalized intestinal malabsorption with rhea.13 Infants with CCD present with very large-volume
a profuse mixed (osmotic and secretory) diarrhea pattern that secretory diarrhea and metabolic alkalosis with high stool
almost universally requires lifelong strict restriction of chloride levels. Intestinal biopsies in patients with CCD
enteral intake and TPN support due to inability to achieve demonstrate normal villous and crypt architecture on hema-
enteral autonomy.11 Most of these patients have multisyste- toxylin-eosin (HE) staining and electron microscopy.
mic diseases, such as pancreatic insufficiency and endocri- Mainstay therapy of CCD is targeted at avoiding dehydration
nopathies, in addition to intestinal failure, placing and serum electrolyte derangements. Oral short-chain fatty acid
additional challenges in their dietary management. Patients butyrate and cholestyramine are candidate therapies to reduce

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 intestinal secretion with a moderate decrease in diarrheal out- Homozygous mutations in the SI gene lead to severe con-
put.4 However, most patients also need lifelong enteral (and genital presentations with early-onset diarrhea, in contrast
sometimes parenteral) hydration with electrolyte supplementa- with patients having heterozygous variants that develop clini-
tion to avoid complications from chronic diarrhea. Medical cal symptoms later in childhood.
management should also include close monitoring of extrain- The severity of symptoms in patients with SID depends on
testinal manifestations that can present in children and adults the amount of ingested oligosaccharides, the gut micro-
with CCD, including hyperuricemia, chronic kidney disease, biome, and the residual SI activity.16 Undigested enteral
inflammatory bowel disease, and male subfertility. sugar load is fermented in the gut lumen, increasing lactic
acid in stools, reflected by low pH on stool testing.
Congenital Sodium Diarrhea
Diagnosis can be established by genetic molecular testing
Sodium transport–related diarrhea may be secondary to
or low SI activity on duodenal biopsies that otherwise have
mutations in 3 different genes: SLC9A3 (coding for Na+/H+
normal architecture on HE staining. Therapeutic options
exchanger), GUCY2C (coding for guanylate cyclase), or
include dietary starch restriction along with sacrosidase
SPINT2 (a syndromic form due to alterations in serine pro-
(yeast-derived) enzyme replacement supplements.17
tease inhibitor). Infants may have a history of polyhydramnios
and significant bowel distention that can become complicated Enterokinase Deficiency
with volvulus. Multisystemic involvement of CSD, associated Infants with enterokinase deficiency have abnormal entero-
with mutation of SPINT2, presents with choanal atresia, kera- kinase production secondary to mutations in TMPRSS15,
titis, or bone malformations.6 Initial serum testing typically which results in impaired protein digestion6 and protein-
shows hyponatremia, metabolic acidosis, and high stool losing enteropathy. Affected infants present with diarrhea,
sodium with low osmolarity. Most patients with CSD have hypoalbuminemia, and edema when receiving a diet contain-
normal intestinal biopsies except for cases associated with

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ing intact proteins (or peptides). Symptoms usually resolve
SPINT2 mutation, which have biopsies consistent with villous after transitioning to an amino acid–based diet.5 Addi-
atrophy and crypt hyperplasia, similar to CTE, but with nor- tionally, there is a therapeutic role of enteral pancreatic
mal epithelial cell adhesion molecule (EpCAM) staining.14 enzyme replacement because enterokinase is also involved
Glucose-Galactose Malabsorption in the activation of pancreatic enzymes.
GGM is a rare autosomal recessive disorder of the intestinal
Abetalipoproteinemia and Hypobetalipoproteinemia
Na+/glucose/galactose cotransporter attributed to mutations
Conditions with fat malabsorption present with steatorrhea,
in SLC5A1. In this disorder, patients are unable to transport
vomiting, poor growth, and fat-soluble vitamin deficiencies.
monosaccharides, glucose, and galactose across the apical
ABL and HBL are autosomal recessive disorders resulting
border of the intestinal epithelium, resulting in osmotic diar-
from mutations in MTTP and APOB genes, respectively,
rhea.15 Stool analyses reflect diet-induced diarrhea with low
leading to abnormal microsomal triglyceride transfer pro-
pH, high osmolarity, and positive test results for reducing
tein.6,11 Apolipoprotein B (ApoB) is responsible for carrying
substances. Intestinal biopsies show normal villous and crypt
lipids to all cells and tissues across the body. Low levels of
architecture on HE staining and electron microscopy. Infants
serum total cholesterol, very low-density lipoprotein, and
with GGM require a lifelong restriction of glucose and galac-
low-density lipoprotein reflect abnormal production of
tose, with all patients taking a fructose-based formula
ApoB. ABL and HBL have the same clinical phenotype and
throughout the first year after birth.11 Close nutritional guid-
intestinal microscopic findings showing fat-laden entero-
ance is crucial for family education on maintaining a
cytes that stain with oil red O.6 Infants with CE due to fat mal-
restricted diet while incorporating other nutrients to avoid
absorption require close nutritional monitoring to avoid EFA
deficiencies.
and vitamin deficiencies secondary to lifelong treatment with
a very low-fat diet.
Sucrase-Isomaltase Deficiency
Patients with SID cannot digest oligosaccharides—namely,
sucrose, maltose, dextrins, and starches. They typically DEFECTS IN ENTEROCYTE STRUCTURE AND
present with diarrhea and bloating in infancy when sucrose FUNCTION
from fruit purees or juices is introduced into the diet. SID Congenital Tufting Enteropathy, Microvillous Inclusion
may also present during the neonatal period if the infant Disease, and Trichohepatoenteric Syndrome
ingests formula containing dextrins and isomaltose. CE due to defects in intestinal epithelial differentiation and
SID has an autosomal recessive pattern of inheritance. polarization include CTE, MVID, and trichohepatoenteric

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syndrome. Mutations in EpCAM gene lead to CTE, an DEFECTS IN THE MODULATION OF INTESTINAL
autosomal recessive disorder. EpCAM regulates the IMMUNE RESPONSE
composition and function of tight junctions, leading to dis- Immune Dysregulation Polyendocrinopathy
organization of villi appearing with intestinal villous atrophy Enteropathy X-linked Syndrome
and “tufts” near the tip of the villous.6 A syndromic form of Immune dysregulation polyendocrinopathy enteropathy X-
CTE associated with mutations in SPINT2 gene has been linked (IPEX) syndrome is an X-linked recessive uncurable
reported with superficial punctate keratitis and choanal disease of the immune system with immune dysregulation
atresia.18 due to mutations in FOXP3 altering the development and
MVID is caused by defective apical membrane recycling function of T regulatory (Treg) cells. Uncontrolled T-cell
due to disordered endosomal trafficking. The motor activity activation results in inflammation, autoimmunity, and met-
of myosin 5β and actin cytoskeleton control vesicular traffick- abolic disorders.22 Boys with IPEX syndrome present in the
ing in the epithelial apical recycling pathway. Myosin 5β is first year after birth with enteropathy (severe nonbloody
affected by mutations in MYO5B, STX3, UNC45A, or diarrhea), endocrinopathy (diabetes or thyroid disease),
STXBP2, all inherited in an autosomal recessive pattern, and dermatitis (severe eczema). Patients may also have
which are more frequently reported in Navajo and Arab pop- hematologic disorders, including hemolytic anemia,
ulations.6 Loss of function of myosin 5β results in an MVID thrombocytopenia, and neutropenia. Some cases have con-
phenotype characterized by severe persistent diarrhea from comitant autoimmune diseases including autoimmune
birth and abnormal intestinal biopsy findings with villous hepatitis and nephropathy. Laboratory testing is aimed at
atrophy and inclusion bodies in the apical cytoplasm of enter- assessing immune status with lymphocyte subsets, comple-
ocytes seen in electron microscopy.19,20 Mutations in ment, immunoglobulin A (IgA), IgG, IgM, and IgE levels.
MYO5B have also been associated with chronic liver disease; In cases with high clinical suspicion of IPEX syndrome, tar-

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therefore, it is crucial to be cautious when administering geted genetic testing may be done; however, whole-exome
TPN to minimize hepatotoxicity. sequencing may be recommended if other immunological
Syndromic diarrhea/trichohepatoenteric syndrome is an disorders are considered.
autosomal recessive disorder linked to mutations in TTC37 Due to its disease severity and multisystemic involve-
and SKI2VL. Affected infants present with mixed secretory ment, the only viable cure for IPEX syndrome is allogeneic
and malabsorptive diarrhea along with multisystemic hematopoietic stem cell transplantation.22 Immuno-
involvement, including intrauterine growth restriction, hair suppressive agents (steroids and calcineurin inhibitors)
abnormalities, facial dysmorphism, hepatomegaly, and and long-term nutritional support are the basis of treatment
immune abnormalities. Management of trichohepatoenteric for patients with IPEX syndrome in whom stem cell trans-
syndrome is based on parenteral nutrition and immuno- plant is not an option. Future options for patients with
globulin supplementation.21 IPEX syndrome involve gene therapy–based treatment with
Infants with MVID and CTE have predominantly secre- FOXP3-engineered Treg-like cells to control immune dysre-
tory diarrhea but also osmotic when they are fed. Profuse gulation and minimize the significant morbidity that is asso-
diarrhea usually starts within the first 4 weeks after birth, ciated with currently used therapies.23
rapidly requiring fluid, electrolyte, and nutrient supplemen-
tation with TPN. Most cases have an uneventful pregnancy PROGNOSIS AND OUTCOMES
without findings of polyhydramnios.5 Obtaining early Even though the initial clinical presentation of infants with CE
genetic molecular testing is vitally important in cases with is severe diarrhea associated with feeding intolerance, dehy-
suspected MVID or CTE to confirm the diagnosis and aid dration, and electrolyte abnormalities, some diet-induced con-
in multidisciplinary discussions with families regarding genital diarrheal disorders (GGM, SID, CCD, ABL, and HBL)
the infant’s potential outcome and treatment options.20 have better prognoses. This is because they often have a favor-
Treatment for MVID and CTE is particularly challenging able response to dietary modification and enteral electrolyte
due to the severely impaired ability to absorb nutrients supplementation with the potential of achieving enteral
and electrolytes resulting in early-onset high-volume autonomy during early childhood.11 Conversely, patients with
diarrhea even with minimal to no enteral feedings. Hence, epithelial structural abnormalities are notable for more severe
most patients have intestinal failure and require lifelong clinical presentation leading to intestinal failure, requiring
TPN to support their high electrolyte and fluid stool long-term TPN, with an overall mortality rate of up to 20%
losses.11 and a median age at death of 13.5 months.24 Patients with

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 severe forms of CE have very high morbidity and mortality 7. Congenital diarrhea panel. Genetic Testing Registry, National
risks with improved survival after undergoing intestinal trans- Center for Biotechnology Information, National Library of Medicine.
Updated July 26, 2018. Accessed August 16, 2024. [Link]
plantation. However, the reported survival of pediatric patients [Link]/gtr/tests/552661/
even after intestinal transplantation is 72.7% at 1 year and 8. Invitae congenital diarrhea panel. Genetic Testing Registry,
57.2% at 5 years, posing a complex decision-making dilemma National Center for Biotechnology Information, National
for families and health care providers.12 Library of Medicine. Updated July 15, 2021. Accessed
August 16, 2024. [Link]
593410/
CONCLUSIONS
9. Kliegman R, Nelson WE, eds. Nelson Textbook of Pediatrics. 18th
Infants with CE pose clinical challenges requiring intensive ed. Saunders; 2007.
initial fluid and electrolyte resuscitation followed by diagnostic 10. Jospe N, Forbes G. Fluids and electrolytes–clinical aspects.
evaluation to establish an early diagnosis. Molecular analysis is Pediatr Rev. 1996;17(11):395–403. PubMed doi: 10.1542/
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workup of CE, especially if the clinical diagnosis remains 11. Avitzur Y, Jimenez L, Martincevic I, et al. PediCODE
Consortium. Diet management in congenital diarrheas and
uncertain. Whole-exome or whole-genome sequencing is a enteropathies - general concepts and disease-specific approach, a
widely available and valuable tool to identify mutations associ- narrative review. Am J Clin Nutr. 2024;120(1):17–33. PubMed doi:
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medical team is crucial in the management of infants with 12. McNelis K, Rogers ME, Kocoshis S. Pediatric intestinal
transplantation management and outcomes. Neoreviews. 2023;
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24(7):e431–e439. PubMed doi: 10.1542/neo.24-6-e431
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10.1002/uog.7509
Neonatal-Perinatal Content 14. Holt-Danborg L, Vodopiutz J, Nonboe AW, et al. SPINT2 (HAI-
Specification 2) missense variants identified in congenital sodium diarrhea/
tufting enteropathy affect the ability of HAI-2 to inhibit prostasin
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testinal system PubMed doi: 10.1093/hmg/ddy394
• Recognize common inheritance patterns of genetic 15. Chan AP, Namjoshi SS, Jardack PM, et al. Long-term dietary
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13(4):4168–4185. PubMed doi: 10.3390/ijms13044168 C. Management of syndromic diarrhea/tricho-hepato-enteric
syndrome: a review of the literature. Intractable Rare
6. Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of
Dis Res. 2017;6(3):152–157. PubMed doi: 10.5582/irdr.2017.
monogenic intestinal epithelial disorders. Hum Genet. 2023;
01040
142(5):613–654. PubMed doi: 10.1007/s00439-022-02501-5

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22. Ben-Skowronek I. IPEX syndrome: genetics and treatment 24. Caralli M, Roman C, Coste ME, et al. Genetic enteropathies
options. Genes (Basel). 2021;12(3):323. PubMed doi: 10.3390/ linked to epithelial structural abnormalities and enteroendocrine
genes12030323 deficiency. J Pediatr Gastroenterol Nutr. 2021;72(6):
23. Borna S, Lee E, Sato Y, Bacchetta R. Towards gene therapy for 826–832. PubMed doi: 10.1097/MPG.0000000000003049
IPEX syndrome. Eur J Immunol. 2022;52(5):705–716. PubMed
doi: 10.1002/eji.202149210

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 NEOREVIEWS QUIZ

NEO
QUIZ
1. A 4-day-old infant born at 37 weeks’ gestation is noted to have high stool
losses causing dehydration and electrolyte derangements. Using accurate
measurements, the diagnosis of diarrhea can be made with a stool output of
greater than which of the following?
A. 5 mL/kg/d
B. 10 mL/kg/d
B. 15 mL/kg/d
D. 20 mL/kg/d
E. 25 mL/kg/d
2. A term infant is found to have abnormal stools. Before stool testing, the
infant is made nil per os (NPO) for at least 24 hours. Upon further
investigation, the infant is found to have a defect in electrolyte transport REQUIREMENTS: Learners can
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 ARTICLE

Functional Infant Formula Additives

Kanika Puri, MD, Courtney Svenstrup, MD, Charles Vanderpool, MD

EDUCATION GAPS

In certain scenarios, supplementation of formula becomes imperative.

Clinicians are well versed regarding the macronutrient composition of infant
formula including proteins, carbohydrates, and fats. However, less well-
known functional additives are becoming more common in infant formula.
These compounds may confer additional benefit in an infant’s growth and
overall development.

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

1. Explain the potential benefits of infant formula additives, including

human milk oligosaccharides, milk fat globule membrane, lactoferrin,
ABBREVIATIONS

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and long-chain polyunsaturated fatty acids.
2’FL 2’-fucosyllactose
2. Describe the current literature regarding the effect of infant formula 5HMO 5 different HMOs
additives in the overall health and development of the infant. AAP American Academy of
Pediatrics
ALA α-linolenic acid
ARA arachidonic acid
ABSTRACT BF breastfed
BPD bronchopulmonary dysplasia
Breastfeeding is the ideal initial feeding method for providing nutrition to DHA docosahexaenoic acid
full-term infants and is recommended by major health organizations, includ- EF experimental formula
FDA US Food and Drug
ing the American Academy of Pediatrics and the World Health Organization. Adminstration
FF formula-fed
Despite improvements in global breastfeeding rates, many infants still GRAS generally recognized as safe
receive formula. Significant advancements have been achieved in the safety HMO human milk oligosaccharide
LA linoleic acid
and nutritional content of modern formulas. Various functional additives, LC-PUFA long-chain polyunsaturated
such as human milk oligosaccharides, milk fat globule membrane, docosa- fatty acid
LF lactoferrin
hexaenoic acid, and lactoferrin, are used with the aim to replicate some of LNnT lacto-N-tetraose
MFG milk fat globule
the benefits of breast milk. These additives enhance formula by providing MFGM milk fat globule membrane
benefits beyond basic nutrition. The aim of this review is to summarize these NEC necrotizing enterocolitis
RCT randomized controlled trial
additives and their impact on infant nutrition and development. ROP retinopathy of prematurity
WHO World Health Organization

AUTHOR DISCLOSURE: Dr Svenstrup has attended meetings with the support of the North Indiana University School of Medicine, Riley
American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Drs Puri and Hospital for Children at Indiana University
Vanderpool have disclosed no financial relationships relevant to this article. This article does not Health, Indianapolis, Indiana
contain a discussion of an unapproved/investigative use of a commercial product/device.
Accepted for Publication Date: November 4, 2024
[Link]
Copyright © 2025 American Academy of Pediatrics

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 INTRODUCTION continue to be modified and updated with focus on nutri-
Breastfeeding is widely recommended as the optimal form tional adequacy and quality.
of feeding for term infants. Multiple organizations have Modern capabilities for human milk analysis have identi-
reinforced this recommendation with formal policy state- fied multiple functional components with potential impor-
ments, including the American Academy of Pediatrics tant health implications. Current formula companies have
(AAP) in their updated policy statement in 2022.1 The sought to modify infant formula in a way that more closely
AAP has also published recommendations for promoting resembles human breast milk. As a result, functional addi-
human milk and breastfeeding in very low birth weight tives to infant formula have increased and are also increas-
infants, focusing on provision of necessary education, ingly featured in infant formula marketing. A functional
access to lactation support, and transition to direct breast- additive is defined as a compound that provides a benefit
feeding when able.2 The World Health Organization beyond nutritional or caloric effects, providing specific health
(WHO) and the AAP both recommend that full-term infants or well-being benefits or reduction of disease risk. Functional
should be exclusively breastfeed for the first 6 months after additives to infant formula include human milk oligosaccha-
birth. Emerging science regarding the benefits of breast- rides (HMOs), milk fat globule membrane (MFGM), specific
feeding and human milk has spurred advocacy, education, fat content including docosahexaenoic acid (DHA) and other
and protection of breastfeeding practices through policy long-chain polyunsaturated fatty acids (LC-PUFAs), and lac-
decisions. In response, there has been an improvement in toferrin (LF) among others.
breastfeeding rates throughout the world. According to While modern science and human milk analysis have
the 2023 WHO breastfeeding scorecard, global rates of identified these functional components, and their addition
exclusive breastfeeding in term infants in the first 6 months to infant formula offers potential and theoretical benefits, cli-
of age have improved by 10 percentage points: up to 48% nicians will need to continue to understand limitations when

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globally for 2023 and close to the WHO target of 50% by these compounds are added to infant formula. Human milk,
2025.3 While the improved rates of breastfeeding are specifically a breastfeeding parent’s milk, is a dynamic nutri-
encouraging, most infants globally fall outside of this exclu- tion source. Human milk and its functional components
sive breastfeeding goal and have some exposure to infant change based on geographic location, lactation stage, and diet
formula. Breastfeeding rates can vary based on social, medi- of the breastfeeding parent. Functional additives within
cal, or physiologic limitations in the family unit. Many of infant formula are often bovine or synthetic in origin, are
these factors can be outside of parental control. While physi- static, and do not change. While their inclusion within infant
cians and policy makers should continue to advocate for formula represents an important advancement in the science
improved breastfeeding and access to breastfeeding sup- of infant formula feeding, human and breastfeeding parent’s
port, the use of infant formula will remain an aspect of neo- milk continues to remain the standard in infant nutrition.
natal health care. This review will highlight functional additives to infant for-
The history of infant formula production dates to the 19th mula with focus on the proposed function within health and
century with the advent of food preservation techniques and well-being along with available science regarding their health
the development of evaporated milk in the 1830s. By the benefit in formula-fed (FF) infants.
1880s, multiple brands of infant formula were available.
However, the use of artificial infant formula was associated FORMULA ADDITIVES
with many infant deaths, often in the summer due to likely HMOs
bacterial contamination.4 In the 1920s and 1930s, manufac- HMOs are non-nutritive sugar compounds that range from 3
turers began to develop infant formula with improved steril- to 32 sugars in size. They are highly abundant in human
ity as well as macronutrient and micronutrient content. The milk, representing the third largest component of human
first noncow milk-based formula was introduced in the milk after lactose and lipids. HMOs differ in composition
1920s, using soy as a protein source. In the 1940s, the first compared with milk oligosaccharides from any other mam-
hydrolyzed protein infant formula was introduced.5 As infant mal and are far more common in human milk compared
formula development and improvement continued, regula- with bovine milk.6,7 More than 200 HMO structures have
tions were developed to specify safety and quality standards. been identified in human milk, and HMO content can vary
Some of the first standards and regulations for infant for- based on maternal genetics, lactation stage, diet, and envi-
mula were established within the United States in the ronmental factors.8,9 The diversity of HMO content of the
1930s and 1940s. Regulations and formula standards breastfeeding parent’s milk highlights the potential for

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diverse effects on the health of infants with HMOs primarily microbial patterns that shifted closer to the BF group com-
affecting immune, antimicrobial, and microbiome modula- pared with the formula without HMOs.12 A similar study
tion. HMOs are thought to have antimicrobial and antiviral published in 2023 evaluated 5 different HMOs (5HMO)
activity through anti-adhesive properties. HMOs can selec- added to infant formula.13 The 5HMO formula was provided
tively bind pathogens or their toxins. HMOs are also thought to healthy term infants aged less than 14 days with compari-
to have a predominant prebiotic effect.7,8 They reach the distal son groups including BF infants and infants fed a standard
intestine and colon largely intact and can serve as a metabolic formula without HMOs. The 5HMO formula shifted the
substrate for commensal bacteria, including the Bifido- fecal microbiome content toward a population similar to
bacterium, Bacteroides, and Lactobacillus species. These pre- BF infants in as soon as 1 week with differences persisting
biotic effects can be HMO structure specific, and microbiome during the analysis period.13
effects may vary based on geographic location or maternal While data on HMO addition to term infant formula are
genetic factors.7,8 HMOs may also affect mucosal barrier func- encouraging, the role of HMO addition to preterm infant for-
tion as a byproduct of HMO metabolism, acting through mula is not well studied. A study published in 2022 evaluated
short-chain fatty acids.7,8 These fatty acids can stimulate the effect of an HMO supplement (2’FL and LNnT) given to
mucin release and may also exert trophic effects on epithelial infants of 27 to 33 weeks of gestational age.14 An isocaloric
cells. These effects may include modulation of cellular apop- placebo consisting of glucose was used as a comparison in
tosis, differentiation, and maturation.7,8 this randomized, double-blind trial. Infants within the study
Various methods have been used to obtain milk oligosac- consumed either their breastfeeding parent’s milk, donor’s
charides that have structure homology with HMOs including milk, or infant formula with the majority of infants being
isolation from bovine milk. However, bovine milk contains fed the breastfeeding parent’s or donor’s milk. While the
very little fucosylated oligosaccharides, which are predomi- authors commented on shorter time to full enteral feeding

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nant in HMOs. Synthetic processes have since been devel- in the HMO group, the difference of 2 days did not reach stat-
oped to create milk oligosaccharide structures with greater istical significance (P = .177).14 Although the HMO group
similarity to HMOs.10 The most common synthetic HMOs had higher length-for-age and head-circumference-for-age
used in infant formula include 2’-fucosyllactose (2’FL) and z scores, there was no difference in weight between groups.
lacto-N-tetraose (LNnT). Synthetic HMO use in infant for- Rates of adverse events were similar between the 2 groups,
mula requires regulatory approval, including the generally including a similar risk for necrotizing enterocolitis (NEC)
recognized as safe (GRAS) designation by the US Food in both groups.14
and Drug Administration (FDA). The first regulatory appro- While initial studies of HMO use in infant formula are
val of HMO use occurred in 2015.10 encouraging, their direct role in improving health outcomes
Intervention studies have evaluated the safety and efficacy remains less clear. Benefits seen by the addition of HMOs to
of adding HMOs to infant formula, and the general findings infant formula may be limited due to the inability to capture
indicate that HMO addition is safe with some potential ben- the type of HMO diversity seen in a breastfeeding parent’s
efits reported. However, studies are largely isolated to term milk. The safety, tolerance, and benefit of HMO addition
healthy infants, and methodologic variations among studies to preterm infant formula will need to be established prior
make generalizable conclusions difficult.7 A study published to widespread use. However, HMO addition to formula
in 2017 evaluated the addition of both 2’FL and LNnT to term remains a potential area of future research to bring formula
infant formula.11 The intervention was 6 months, and the feeding closer to breastfeeding when breastfeeding is not
control group was given standard intact term infant formula possible.
without HMOs. Weight gain was similar between formulas.
Infants fed the HMO containing test formula had fewer MFGM
night awakenings, softer stool, reduced risk of bronchiolitis Milk fat provides about 50% of the total calories in human
and other lower respiratory tract infections from 0 to milk with milk fat globule (MFG) as 1 of the principal com-
12 months of age and a reduced risk of antibiotic use from ponents.15 The MFG is synthesized in the endoplasmic
0 to 12 months of age.11 A study published in 2022 examined reticulum of the mammary epithelial cell, creating a cytosolic
healthy infants randomly assigned to a bovine formula con- phospholipid vesicle containing triglycerides. This MFG
taining the probiotic Limosilactobacillus reuteri DSM or the vesicle is secreted by the epithelial cells, and during this proc-
same formula with 2’FL added.12 A nonrandomized ess it takes on the epithelial cell bilayer, leading to a triple
breastfed (BF) group served as a control group. In this study, layer membrane structure called MFGM.15 Structurally, the
infants fed the formula with the probiotic and 2’FL had stool MFGM is a liquid lipid-protein mosaic with proteins

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 immersed in a liquid bilayer of lipids and is a heterogenous demonstrated an accelerated neurodevelopmental profile at
mixture of proteins, phospholipids, sphingolipids, ganglio- day 365 and improved language subcategories at day 545
sides, choline, sialic acid, and cholesterol.15 MFGM is consid- in those infants who received the supplemented formula.23
ered a functional component of human milk due to its high Another RCT with children aged 12 months who received
phospholipid, ganglioside, and protein contents. MFGM is MFGM and LF supplemented infant formula were found
thought to have beneficial effects on central nervous, cardio- to have better cognitive outcomes, like intelligence and exec-
vascular, metabolic, gastrointestinal, and motor systems.16 utive function, at 5.5 years of age when compared with stan-
Native MFGM is highly unstable and is damaged during dard formula.24
formula manufacturing, which may cause standard formulas A systematic review from 2024 involving 1352 neonates,
to be devoid of bovine MFGMs.17 Manufactured infant for- infants, and children aged up to 2 years showed similar
mula fat content is thus provided by vegetable oils, which results with improved cognitive development and significant
may account for some clinical differences observed between improvement in executive function. There was no significant
FF and BF infants. MFGM plays a unique role in immune difference in cognition compared with breast milk.25 In the
metabolism and maturation of the gastrointestinal tract of COGNIS study, neurocognitive tests and structural magnetic
the BF infant. This is thought to be secondary to its unique resonance imaging were studied in children aged 6 years.
structure.18 Two mechanisms have been proposed for its Children supplemented with MFGM, LC-PUFA, and synbi-
immunologic effects, including the ability to prevent the otics were found to have higher volume of brain matter in the
attachment of the pathogen to the intestinal epithelium left orbital cortex along with a higher IQ and better scores in
and direct bactericidal activity.19 Thus, multiple measures tasks based on attention as compared with the BF children.
have been used by adding bovine MFGM during production The study also found similar results with greater volumes in
to make it as close to human milk as possible, which can parietal regions than children receiving standard formula.26

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be produced commercially from either whey or cream The metabolic profiles differ between BF and FF infants,
concentrates.19 thought to be due to higher protein content and absence of
A meta-analysis from 2021 evaluated the safety and the MFGM in formula compared with breast milk. He et al27
benefits of MFGM supplementation in children.20 Infants found that the infants consuming MFGM supplemented for-
who received MFGM supplemented formula showed no mula had higher levels of fatty acid oxidation products, sim-
differences in mean weight, length, and head circumference ilar to BF infants, and represented a preference for fat
at 4 months of age when compared with use of the standard metabolism. This is in contrast with the FF infants who
formula; whereas, the measurements for mean body weight showed a balance geared more toward protein metabolism,
and head circumference were slightly lower compared with based on the higher levels of byproducts of amino acid
the BF infants. Overall, the MFGM formulas were found to catabolism.27 MFGM supplementation in formula can sup-
be noninferior to the standard formula with a good safety press degradation of proteins and can also facilitate fatty acid
profile.20 oxidation and ketogenesis.28 Similar results were obtained in
A double-blind randomized controlled trial (RCT), inves- a previous study with a significant reduction of several
tigating the addition of a cream-derived MFGM to a milk metabolites including lactate, succinate, amino acids and
formula in preschool children, found a decrease in the inci- their derivatives in MFGM supplemented infants compared
dence and duration of febrile episodes compared with the with those fed standard formula.27 MFGM supplementation
group without supplementation.21 In the TUMME RCT, in the earlier stages of life can have a positive cognitive
involving FF infants receiving experimental formula (EF) impact through modulation of the gut microbiome.18
supplemented with bovine MFGM from less than 2 months Overall, the majority of evidence on the addition of
until 6 months of age, an overall decreased incidence of acute MFGM to infant formula suggests that MFGM is safe, well
otitis media and lower use of antipyretic drugs were found in tolerated, and provides important potential benefits that
the EF group compared with the unsupplemented standard extend beyond caloric and fat supplementation. However,
formula group.22 In a study from China, the overall inci- methodology has varied among studies, and some EFs con-
dence of adverse respiratory events and diarrhea were found tained other potential functional additives beyond MFGM
to be significantly lower in infants who received formula with alone. While bovine MFGM/manufactured MFGM is
added bovine MFGM and bovine LF.23 thought to have significant structural similarity to human
Supplementation with bovine MFGM can be a valuable MFGM,29 differences may still exist. The full biological ben-
addition to infant formula for cognitive benefits. A RCT in efits of human MFGM may be difficult to replicate with
infants receiving bovine MFGM and LF in formula manufactured MFGM.

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LF LC-PUFAs
LF is a whey glycoprotein that comprises 15% to 20% of the LC-PUFAs (eg, arachidonic acid [ARA] and DHA) are essen-
total protein content in human breast milk.30 LF concentra- tial fatty acids that are derived from linoleic acid (LA) and α-
tion changes dynamically throughout lactation with the high- linolenic acid (ALA), respectively.40–42 LC-PUFAs are 15% to
est in colostrum (~7 g/L) and lowest in mature breast milk 30% of the total fatty acid profile in breast milk with varying
(2–3 g/L).31 Evidence suggests that LF plays a role in iron levels depending on maternal diet.40–43 Standard infant for-
homeostasis and host defense as well as promoting immune mulas contain LA and ALA from which infants will synthe-
system and intestinal development, brain and neurodevelop- size their own ARA and DHA.44 Recently, LC-PUFAs have
ment, and bone health.32 been added to infant formula at variable doses and marketed
LF has been shown to promote intestinal iron absorption as advantageous to infant development. Controversy exists
in animals with iron deficiency.33 However, there is over whether LC-PUFA supplementation is beneficial with
mixed evidence regarding LF on iron status in infants. some suggesting that it may be conditionally essential for
King et al34 conducted a double-blind, placebo-controlled preterm infants who may not be able to synthesize adequate
study showing that FF infants who were supplemented with amounts to meet their needs for development. Studies have
LF had higher hematocrit levels compared with the control investigated the effect of LC-PUFA supplementation on neu-
FF group. On the other hand, a study from 2020 showed that rodevelopment, visual acuity, physical growth, bronchopul-
adding LF to a low-iron fortified formula did not affect iron monary dysplasia (BPD), and retinopathy of prematurity
status.35 (ROP).
Studies have shown that LF can protect against bacterial, Fifty percent of a preterm infant’s energy needs come
viral, and fungal infections via immunomodulation and vari- from dietary fats. During the third trimester of pregnancy,
ous antimicrobial properties. LF can enhance the function ARA and DHA cross the placenta and accumulate in the fetal

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of immune cells, inhibit inflammatory responses,32 and brain. Studies have shown that preterm infants have lower
have direct cytotoxic effects against bacteria, viruses, and levels of ARA and DHA after birth, suggesting insufficient
fungi.36 Additionally, LF exhibits bacteriostatic activity by endogenous synthesis.39,45 ARA and DHA supplementation
competing with bacteria for iron, which prevents acquisition is considered a safe and reliable way to ensure adequate
and sequestration of the iron needed for growth and intake, even if the benefits are modest and transient.46
virulence.32,37 The 2022 European Society of Pediatric Gastroenterology,
Studies in animals have shown that LF improves bone Hepatology and Nutrition’s Committee of Nutrition enteral
formation and density, reduces bone resorption, and may nutrition guidelines recommended that preterm infants
act as a vitamin D receptor activator to regulate bone forma- should receive LA 38 to 1540 mg/kg per day, ALA at least
tion.32 However, there are no clinical studies in humans 55 mg/kg per day, DHA 30 to 65 mg/kg per day, and ARA
that have investigated the effects of LF on infant bone 30 to 100 mg/kg per day, with a goal ARA to DHA ratio
health. of 0.5 to 2.46
LF can be produced as bovine LF and recombinant human Lipids are about 60% of the dry weight of the human
LF with the former being commercially available.32 Bovine brain with LC-PUFAs comprising 35% of the lipids in the
and human LF share 70% sequence homology.38 Clinical tri- gray matter.40–43 Additionally, they are highly concentrated
als have shown that bovine LF is safe and has similar effects in the retina. Therefore, LC-PUFAs are considered important
as human LF.32 The FDA has determined that bovine LF is for neurodevelopment, cognitive functioning, and visual
GRAS, and the maximum amount allowed in infant formula acuity.47 Studies analyzing LC-PUFA supplementation on
is 100 mg per 100 g of infant formula, which is notably less long-term infant development have been mixed. A 2017
than the concentration of human LF in mature breast milk meta-analysis of all RCTs evaluating the effects of LC-
(2–3 g/L).39 The minimum dose at which LF can exert a ben- PUFA supplementation compared with nonsupplemented
eficial effect has not been determined, and the amount added formula milk on visual function, neurodevelopment, and
varies among the different commercial infant formulas, typ- physical growth revealed that “most of the trials reported
ically ranging from 20 mg per 100 g to 100 mg per 100 g.32 no benefits or harms of neurodevelopmental outcomes of
Additionally, the benefits of LF depend on the purity and bio- formula full-term infants and no consistent beneficial effects
activity of LF, which can be altered based on processing tech- on visual acuity.”44 Another meta-analysis in 2016 of all ran-
niques. Further studies investigating the clinical benefits, domized trials evaluating the effect of PUFA supplementa-
optimal dose, type of LF (human vs bovine), and manufactur- tion in enterally-fed preterm infants found that there may
ing processes are warranted. be benefits for preterm infants, but the overall quality of

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 evidence remains low.48 Recent studies have also not demon- supplementation, including the optimal ARA to DHA ratio,
strated improvement in neurodevelopment outcomes with are warranted.
LC-PUFA supplementation.49
BPD is a complication of preterm birth characterized by ROLE OF FORMULA ADDITIVES IN PREVENTION
atypical lung development. Studies have investigated the OF NEC IN PREMATURE NEWBORNS
effect of LC-PUFA supplementation on the development of
The premature infant population is unique owing to their var-
BPD with the thought that enriching diets with DHA would
iable nutritional demands based on their degree of prematu-
modulate the inflammatory process that may contribute to
rity. The benefits of breastmilk for premature infants are
BPD development.50 However, studies have shown that
numerous, including decreased incidence of infections, posi-
LC-PUFA supplementation may increase the risk of BPD
tive long-term impact on cognitive development, protective
development. Collins et al50 performed a multicenter RCT
effect against atopic disease, and improved gastric emptying.55
investigating the effect of enteral supplementation of DHA
NEC is multifactorial due to inadequate tissue oxygena-
in preterm infants compared with soy on the development
tion, bacterial overgrowth, and enteral feeding with immatu-
of BPD. They found that BPD was increased in the DHA
rity that leads to injury to intestinal mucosa.56 In preterm
group with no differences in secondary outcomes, including
newborns, the immature intestinal barrier is highly per-
ROP and NEC.50 In 2020, Marc et al51 published a multicen-
meable and may be a risk factor for developing NEC and res-
ter, randomized, placebo-controlled trial investigating mater-
piratory tract infections. In these cases, MFGM may be
nal DHA supplementation on BPD development in preterm
beneficial given its immune-metabolic properties.18 In a dou-
infants. The study was terminated early due to the interim
ble-blind RCT, premature infants fed the egg phospholipid
analysis showing an increased incidence of BPD in the inter-
supplemented formula developed significantly less NEC
vention group, suggesting that DHA supplementation may
overall compared with infants fed the standard formula.56

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be potentially harmful.51
Further studies are required to assess this potential benefit.
ROP is another complication of preterm birth character-
The concentration of HMOs in human milk is highly var-
ized by vascular disease of the eye that can lead to blindness.
iable. It has been proposed that supplemented HMOs may
Studies in mice have shown that increased intake of omega-3
confer a benefit in protection of the gastrointestinal tract.
protects against pathogenic neovascularization in oxygen
However, studies to date have demonstrated limited benefits
induced retinopathy.52 Hellström et al53 performed a multi-
of oligosaccharides or HMOs for NEC prevention.57,58
center RCT to determine whether enteral supplementation
Numerous studies have shown that LF may prevent
with ARA and DHA reduces ROP in extremely preterm
neonatal sepsis and NEC. However, a 2020 meta-analysis
infants. ARA and DHA were administered in a 2 to 1 ratio.
of all RCTs, which evaluated oral LF at any dose or duration
The authors found that LC-PUFA supplementation lowered
to prevent sepsis or NEC in preterm neonates, only showed
the risk of severe ROP by 50% in preterm infants.53
low quality evidence to suggest LF supplementation of
LC-PUFAs compete for the same enzymes in their meta-
enteral feedings decreased late-onset sepsis and NEC stage
bolic pathways, suggesting that there may be an optimal ratio
II or III in preterm infants without adverse effects.59
of ARA to DHA.54 Colombo et al45 published a randomized,
Despite promising outcomes in experimental models,
double-blind study evaluating the effects of varying levels of
several studies have failed to demonstrate any impact of
DHA supplementation on neural development in infants
LC-PUFAs on the prevention of NEC in preterm infants.60,61
while receiving the same amount of ARA supplementation.
Gut immaturity in preterm infants leads to difficulties in
The authors found that ARA levels showed an inverted-U
tolerating enteral feeding, which partly affects their response
function in response to increased DHA supplementation,
to different formula additives when compared with term
which means that ARA levels would rise as the DHA dose
infants. With the ambiguous outcomes, it is important to
increases and then plateau at higher DHA doses. The infants
emphasize that further clinical data are needed to elucidate
who received the highest DHA dose had the same cognitive
their benefits in prevention of NEC in premature infants.
performance as controls, suggesting that the ratio between
these 2 LC-PUFAs is important and may influence their
effect on neurodevelopment. The authors suggest a balance SUMMARY
of ARA to DHA of 1 to 1 or 2 to 1.45 Breastfeeding offers tremendous benefits and is the gold
Overall, the evidence regarding LC-PUFA supplementa- standard for infant feeding in term infants. Human milk
tion is controversial and potentially harmful. Further composition changes based on maternal genetics, diet,
studies investigating the benefits and safety of LC-PUFA geographic location, and lactation stage. These factors and

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TABLE. Summary of Formula Additives and Their and limitations of these additives when discussing nutri-
Potential Benefits tional plans for term and preterm infants and remain advo-
Formula cates for human milk and breastfeeding when possible for
Additive Structure Potential Benefits the breastfeeding parent and infant.
HMOs Carbohydrate Host defense
Microbiome modulation
Softer stools
Fewer nighttime awakenings

American Board of Pediatrics

MFGM Trilayer structure, mainly Host defense
comprised of Intestinal development
phospholipids and
proteins
Neurodevelopment
Cognitive development
Neonatal-Perinatal Content
LF Glycoprotein Host defense Specification
Intestinal development
Neurodevelopment • Understand the role of vitamins and nutritional supple-
Iron homeostasis ments in infant neonatal nutrition.
LC-PUFAs Fatty acids Neurodevelopment
Visual acuity
ROP prevention

Abbreviations: HMOs, human milk oligosaccharides; LC-PUFA, long-

chain polyunsaturated fatty acid; LF, lactoferrin; MFGM, milk fat References
globule membrane; ROP, retinopathy of prematurity.
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 ARTICLE

Nutritional Considerations in Neonates

Requiring Gastrointestinal Surgery
Tony H. Tzeng, MD, PhD,1 Sujir Pritha Nayak, MD,2 Katie A. Huff, MD, MS1,3

EDUCATION GAPS

Surgery in neonates induces a stress response that leads to overall catabo-

lism and breakdown of the body’s nutrient stores. During this catabolic
acute phase, growth may not occur even when excessive nutrition is pro-
vided; once the stress response resolves, catch-up growth for these neo-
nates may be needed. Neonates requiring gastrointestinal surgery remain
at risk for future poor growth. Neonates who require intestinal resection
are at risk of nutrient deficiencies, even once off parenteral nutrition.

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

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1. Describe the influence of surgery on the macronutrient needs and
growth of the neonate.
2. Explain the use of parenteral nutrition and associated complications in
the surgical neonate.
3. Describe enteral nutrition strategies in the neonate requiring gastrointes-
tinal surgery, including type, mode, and duration of feeding.
4. Describe nutritional deficiencies that occur in neonates requiring gastro-
intestinal surgery.

ABSTRACT
Neonates who require gastrointestinal surgery are a complex group of
patients that require special consideration with regard to nutritional supple-
mentation and growth. During the acute postoperative phase, a major stress
ABBREVIATIONS
response causes catabolism with degradation of the body’s nutrient stores
ASPEN American Society for Parenteral
and Enteral Nutrition
leading to poor growth. Following surgery, parenteral nutrition is often
ERAS enhanced recovery after surgery required to support the surgical neonate; although, enteral nutrition, if fea-
IFALD intestinal failure associated liver
disease sible, is critical because it helps improve intestinal adaptation. However, the
ILE intravenous lipid emulsion best type, mode, and duration of feeding is not established in the current
PN parenteral nutrition

1
Department of Pediatrics, Indiana University AUTHOR DISCLOSURE: Drs Tzeng, Nayak, and Huff have disclosed no financial relationships
School of Medicine, Indianapolis, Indiana; relevant to this article. This article does not contain a discussion of an unapproved/investigative
2
Department of Pediatrics, University of use of a commercial product/device.
Texas Southwestern Medical Center,
Accepted for Publication Date: November 18, 2024
Dallas, Texas; and 3Division of Neonatal-
Perinatal Medicine, Indiana University School [Link]
of Medicine, Indianapolis, Indiana Copyright © 2025 American Academy of Pediatrics

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literature. It is important to factor in the individual patient anatomy and site of intestinal resection when considering
intestinal absorptive ability because these patients are at high risk for nutrient malabsorption, with the risk persisting
even when enteral autonomy is achieved. The neonate undergoing gastrointestinal surgery requires close growth and
nutritional monitoring both during the neonatal period but also into later life because risks of abnormalities persist. In
this review, we summarize the impact of gastrointestinal surgery and postoperative intestinal changes on infant
growth and nutrition.

INTRODUCTION resistance, necessitating adjustment of glucose intake to

Neonates who require gastrointestinal surgery are a complex maintain euglycemia.8,14 With the decreased postoperative
group of patients that require special consideration regard- glucose use, lipids become an important source of energy.
ing nutritional supplementation and growth. Approximately The degree of lipid oxidation depends on the degree of
24% of admissions to level IV neonatal intensive care units stress.8,14 The protein degradation that occurs during the
are for surgical evaluations, with 72% undergoing a surgical acute phase often outweighs protein synthesis, leading to a
procedure.1 In this review, we outline the impact of the sur- negative nitrogen balance.14 In the setting of acute illness,
gical procedure itself as well as the postoperative intestinal it is unclear if a positive protein balance is possible or favor-
changes on infant growth and nutrition. Although all neo- able even for the preterm infant.8 Early administration of pro-
nates requiring surgery need special consideration of their tein is discussed later with early parenteral nutrition (PN)
nutritional needs, in this review we focus on neonates requir- considerations.
ing gastrointestinal surgery. During the recovery phase of the postoperative response,

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the patient shifts back into an anabolic state in which energy
needs are less variable, and growth again occurs.5,8 During
NUTRITIONAL NEEDS AND ALTERATIONS
this recovery phase, it may be reasonable to increase nutri-
Response to Surgery and Macronutrient Requirements tion and energy targets to account for any deficits accrued
The response to surgery directly influences macronutrient during the acute phase and to promote catch-up growth.8
requirements by causing a major metabolic stress reaction In the clinical setting, determining the timing of the transi-
that leads to cortisol, stress hormone, and cytokine release.2 tion from one phase to another can be difficult; however, the
The release of these compounds ultimately leads to energy acute phase corresponds to ongoing inflammation with
mobilization by increasing gluconeogenesis in the liver, pro- elevated inflammatory markers, such as C-reactive protein,
tein breakdown from muscle, and fatty acid release via lipoly- and an ongoing need for increased respiratory and cardio-
sis.2–4 Additionally, cortisol, glucagon, and catecholamines vascular support.5,8
counteract the anabolic hormones of insulin, growth hor- The exact caloric needs of the neonate during the postop-
mone, and insulin-like growth factor-1 leading to a predomi- erative period remain unclear. Study results have varied in
nance of catabolism during the early postoperative period.3,5 terms of the postoperative resting energy expenditure
In infants, the metabolic and hormonal response to surgery, because of inconsistent timing for measurement and dura-
which is often referred to as the acute phase of the postoper- tion of monitoring.5,6,8 The European Society for
ative response, peaks at about 4 hours and subsides by about Paediatric Gastroenterology, Hepatology and Nutrition, pub-
24 to 48 hours postoperatively.6–8 During this catabolic state, lished a review of the theoretical calorie and macronutrient
growth temporarily ceases, which can last days.8 The length goals during the phases of critical illness–induced stress
of this acute phase is shorter in neonates compared with response in preterm neonates and term neonates aged youn-
older children and adults and is influenced by prematurity, ger than 4 weeks (Table 1).8 However, given the lack of evi-
postnatal age, type of surgery, anesthesia, and presence of dence in the literature, calorie and macronutrient delivery
sepsis.6,9–13 should be based on individual patient’s needs with close
During the acute phase, neonatal calorie needs vary, monitoring of the stress response and clinical state to help
increasing the risk of inappropriate and excess calorie admin- guide true nutrient needs.
istration.5 Energy needs may be as low as the basal metabolic
rate and are influenced by the degree of stress response in Growth and Body Composition
addition to other factors.8 Hyperglycemia is common during Neonates who require gastrointestinal surgery are at high
this time because of increased gluconeogenesis and insulin risk for growth failure related to multiple factors, including

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 TABLE 1. Macronutrient and Micronutrient Needs and Recommendations Based on Theoretical Considerations8
and Baseline Neonatal Recommendations for Preterm Infants and Term Infants Aged Younger than 4 Weeks15,33
Needs and Recommendations Preterm Parenteral Preterm Enteral Term Parenteral Term Enteral
Macronutrients8
Acute phase
Nutrient
Energy (kcal/kg/d) 40–80 40–95 15–70 35–80
Glucose (mg/kg/min) 3.5–8.5 3.5–7.5 3–7 3–7
Protein (g/kg/d) 1–3 1–3 0–2.5 <1.5–2.5
Lipid (g/kg/d) 1–3 2–6 0–2.5 <3–4.5
Recovery phase
Energy (kcal/kg/d) 90–120 110–160 75–85 90–120
Glucose (mg/kg/min) 7.5–12 7.5–12.5 5.5–10 6–10.5
Protein (g/kg/d) 2.5–3.5 3.5–4.5 2–3 2–3.5
Lipid (g/kg/d) 3 5–8 3 4–6
Micronutrients33 15,101–104 16–19 /kg/d /kg/d /kg/d Daily
Vitamin
Vitamin A (IU) 700–1500 1332–3330 500–1000 1320
Thamin (B1) (mg) 0.35–0.5 0.132–0.275 0.35–0.5 0.2
Vitamin B12 (μg) 0.3 0.12–0.6 0.3 0.4
Vitamin C (mg) 15–25 16.5–41 15–25 40
Vitamin D 80–400 IU/kg/d or 400 IU/d 400–1000 IU/d 40–150 IU/kg/d or 400 IU/d 400–1000 IU/d
Vitamin E (mg) 2.8–3.5 2.2–11 2.8–3.5 4
Vitamin K (μg) 10 4.4–28 10 2

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Biotin (μg) 5–8 3.3–15 5–8 5
Folic Acid (μg) 56 22–100 56 65
Niacin (mg) 4–6.8 1.1–5.5 4–6.8 2
Pantothenic acid (mg) 2.5 0.6–2.1 2.5 1.7
Pyridoxine (mg) 0.15–0.2 0.07–0.275 0.15–0.2 0.1
Riboflavin (mg) 0.15–0.2 0.2–0.43 0.15–0.2 0.3
Trace element /kg/d /kg/d /kg/d Daily
Chromiuma (μg) Not routinely included 0.03–5 0.2 0.2
Copper (μg) 40 120 – 230 20 200
Iodineb (μg) Not available 10–55 Not available 110
Ironb (mg/kg/d) Not routinely included (0.2–0.25) 1–3 Not routinely included (0.05–0.1) 1–3
Manganesea (μg) 1 1–15 1 3
Molybdenuma (μg) 1 0.3–5 0.25 2
Selenium (μg) 7 7–10 2–3 15
Zinc (mg) 0.4–0.5 2–3 0.25 2
Abbreviation: PN, parenteral nutrition.
These are intended to be used as baseline considerations; true needs and supplementation should be based on individual patient growth,
laboratory, and clinical data.
a
Chromium, manganese, and molybdenum are present as contaminants in other PN products and often provided in sufficient doses in this setting to
provide adequate doses for neonates without additional supplementation needed.
b
Iodine and iron are not dosed as part of PN solutions in the United States; although there is an intravenous iron solution, it is given separate from PN.
There is no intravenous iodine formulation in the United States.

underlying diagnosis, degree of bowel resection, presence of surgical neonates. Studies have shown decreased fat mass
an ostomy, comorbidities or complications, and nutrition in newborns receiving gastrointestinal surgery compared
provided.20–23 As mentioned previously, in the early postop- with reference populations of normal infants.23,25
erative period, growth decreases because of the catabolic Notably, the changes in growth for newborns requiring
stress response irrespective of nutrition provided. Growth gastrointestinal surgery persist beyond the neonatal period
recurs with a shift back to an anabolic state after the stress with some showing altered growth into adolescence.22,26,27
response subsides8; however, compared with matched non- The etiology of this abnormal growth is likely related, at least
surgical neonates, neonates requiring surgery have lower in part, to changes in absorption of nutrients after intestinal
weight and length over time.24 In addition to anthropometric resection. In one study, patients with short bowel syndrome
growth measurements, body composition is also altered in had decreased growth when compared with those with no

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short bowel syndrome or prior necrotizing enterocolitis aged intestinal failure, with a ratio greater than 35 correlating with
at 18 to 22 months.28 Given the increased risk for growth fail- adequate weight gain.37
ure and changes in body composition, patients who require Micronutrients, including vitamins and trace elements,
gastrointestinal surgery as neonates should be closely moni- are important factors contributing to the growth of the neo-
tored for growth in the neonatal period and beyond. nate. However, levels of these nutrients can be altered by
multiple factors in the surgical neonate, and the exact doses
Fluid, Electrolyte, and Micronutrient Considerations
needed remain unclear. Surgery can lead to previously
Fluid management in the surgical neonate can be complex,
asymptomatic micronutrient deficiencies becoming sympto-
both intraoperatively and postoperatively. During surgery,
matic.15 Understanding the patient’s gastrointestinal
fluid is given to replace baseline deficits, provide mainte-
anatomy postoperatively will help determine the risk for
nance needs, and replace losses.29 One retrospective study
showed that increased intraoperative fluid volumes corre- inadequate nutrient absorption and possible deficiencies,
lated with decreased postoperative complications and length as discussed later (Fig 1). The trace elements zinc, copper,
of stay among patients undergoing surgery for necrotizing and selenium are excreted in the setting of high ostomy out-
enterocolitis, suggesting there might be a correlation put or diarrhea.40 In addition, prolonged PN has been asso-
between fluid volume delivered during the operation and ciated with deficiencies of zinc, copper, and selenium, as well
patient outcomes.30 Surgery can stimulate the release of anti- as elevations in manganese, chromium, and molybdenum.40
diuretic hormone, leading to fluid retention.29 In addition, Monitoring trace element levels in high-risk populations, in
surgical neonates are also at risk for drastic fluid shifts particular those on prolonged PN, is important because alter-
due to third spacing or capillary leak, abnormal fluid excre- ations including both deficiency and toxicity can occur with
tion due to immature renal function, and hypotension lead- or without associated symptoms (Table 2). It is important to
ing to the need for fluid resuscitation. It has also been shown

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consider, however, that measuring trace element levels can
that surgical neonates often receive more fluid than intended be difficult in the critically ill, postoperative neonate because
or prescribed postoperatively.31All of these factors can make inflammation can alter measured levels and cause falsely
maintaining fluid balance difficult. This balance is impor- high or low results.42 Other common deficiencies in gastro-
tant, however, because fluid overload in the neonate has been intestinal surgical neonates, especially those with high
associated with increased risk of death and need for mechani- ostomy output or prolonged PN dependence, include iron,
cal ventilation, whereas excessive restriction can worsen vitamin A, vitamin E, and vitamin D.43 These deficiencies
hypovolemia and lead to hypovolemic shock. 31,32 can persistent in the surgical neonate even once they are tran-
The choice of fluid during surgery and the immediate sitioned to full enteral nutrition, especially iron and vitamin
postoperative period should be individualized based on the
D deficiencies.43 Vitamin K deficiency is also important to
patient’s status and laboratory values. Administration of free
consider in surgical neonates because this can lead to bleed-
water and hypotonic fluids have been associated with hypo-
ing complications. In addition to malabsorption, vitamin K
natremia in the neonate.33,34 Evidence on which fluid should
levels can be affected by alterations in the intestinal micro-
be used for resuscitation in the immediate postoperative
biome, because intestinal bacteria act as an important vita-
period is limited, although crystalloid solutions are com-
min K source.15 Laboratory screening with an international
monly used in neonates. Some literature has shown that
normalized ratio may not be sensitive to diagnose vitamin
resuscitation with Ringer’s lactate may be beneficial in the
K deficiency. Thus, for patients undergoing gastrointestinal,
presence of metabolic acidosis.35 Electrolyte derangements
can be an ongoing issue, especially in patients with enteros- surgical, or invasive procedures, supplementing with vita-
tomies or colonic resection who may have increased electro- min K can be considered for abnormal intestinal absorp-
lyte excretion in their stool. In neonates with intestinal tion.15 Overall, micronutrient deficiencies can be subtle
resection, even when in continuity later, urinary sodium and asymptomatic until large or prolonged changes
losses are common. Targeting sodium supplementation occur, necessitating close monitoring in high-risk patients
to maintain urine sodium greater than 30 mEq/L such as neonates requiring intestinal resection or prolonged
(>30 mmol/L) in infants aged younger than 12 months with PN (Table 2). It is reasonable to consider starting micronu-
intestinal surgery is associated with improved growth.36 The trient supplements at doses recommended for the general
urine sodium to creatinine ratio has also been proposed to neonatal population unless known deficiencies exist
monitor growth in infants aged younger than 6 months with (Table 1).15

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 FIGURE 1. Nutrient absorption by intestinal site. Image partially created using [Link] and information adapted from sources.67,106,38,39

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NUTRITIONAL SUPPLEMENTATION infants aged up to 17 years who received early PN within
PN Considerations and Use 24 hours of pediatric intensive care unit admission, were
Neonates frequently need support with PN after gastrointes- compared with those who received late PN after 7 days of
tinal surgery until there is a return of bowel function or res- admission.45 The authors found that late PN was associated
olution of an ileus. Appropriate delivery of macronutrients with decreases in new-onset infections, length of mechanical
and micronutrients is important to address the metabolic ventilation, and length of stay.45 In the secondary analysis of
changes in this critical period, as previously outlined. the PEPaNIC trial population, higher protein doses was asso-
Many of the neonates who require gastrointestinal surgery ciated with new-onset infections, increased days of mechani-
will be on PN preoperatively for a variable length of time, cal ventilation, and higher mortality rate.46 In adults in the
dependent on their degree of prematurity and underlying intensive care unit, those treated with late PN also had
diagnosis. The timing of postoperative PN is controversial decreased days of mechanical ventilation and rates of infec-
and multiple factors influence its consideration. tion.47 A secondary analysis from the PEPaNIC trial, includ-
ing only term infants, noted a decreased rate of mortality and
Early vs Late Postoperative PN hospital-acquired infections with late PN.48 A Cochrane
Currently, evidence is lacking regarding the ideal time to review comparing late vs early PN in late preterm or term
start PN in the critically ill or postoperative neonate. infants found only this trial to be sufficient to include for out-
Providing early protein supplementation in extremely low come analysis, demonstrating the limited evidence in this
birth weight preterm infants helps mitigate the excessive pro- population.49 Although this study shows some potential ben-
tein losses that occur in this population compared with term efit to late PN initiation in the critically ill patient, more data
infants.44 However, as noted previously, during the acute are needed, including for the postoperative surgical neonate.
postoperative phase, the stress response–induced catabolism Another important issue is that preterm infants were not
causes muscle protein breakdown as an amino acid source. included in these studies. An American Society for
This endogenous protein breakdown is not reduced by exog- Parenteral and Enteral Nutrition task force recommended
enous protein supplementation, and concerns have been that PN be considered for the critically ill neonate when
raised about protein-calorie imbalance from excessive pro- enteral nutrition is unable to meet energy requirements
tein supplementation in this setting.8 In the Early versus for expenditure and growth; this group also notes that insuf-
Late Parenteral Nutrition in the Pediatric Intensive Care ficient evidence exists regarding the specific time frame to
Unit (PEPaNIC) trial, pediatric patients, including term initiate PN.50 Given the lack of evidence with regard to the

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TABLE 2. Monitoring Considerations in the Surgical Neonate Divided by Postoperative Phase
Parameter Monitoring Reason
Acute phase
CRP Trend phase and stress response8
Electrolytes Fluid status, supplementation adequacy
Glucose Glycemic control/trend
Triglyceride Fat tolerance
Weight Fluid status/growth
Urine output Fluid status
Recovery phase
Electrolytes Fluid status, supplementation adequacy
Urine electrolytes (Na, Cr) UNa >30 associated with improved growth31,36
UNa:UCr >35 associated with improved growth32,37
Triglyceride Fat tolerance
Weight Growth/fluid status
Urine output Fluid status
Stable but PN-dependent
Electrolytes Fluid status, supplementation adequacy
Liver function tests, direct bilirubin Monitor tolerance of nutrition, monitor for signs of IFALD
Triglyceride Fat tolerance
Urine electrolytes (Na, Cr) UNa >30 associated with improved growth31,36
UNa:UCr >35 associated with improved growth32,37
CBC Anemia
Weight Growth/fluid status

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Urine output Fluid status
Trace element Levels should be monitored monthly especially in the setting of concern for or known past
deficiency. Once on stable PNa levels can be every 3 months.15,33
Vitamin levels At minimum fat-soluble vitamins (D, E, A) should be monitored because of high risk of deficiency
over time. B12 monitoring should also be considered. Monitoring should be monthly if there are
concerns or past deficiencies. Once on stable PNa levels can be every 3 months.15,33
Essential fatty acid panel Consider in those on Omegaven, on lipid restriction, malnourished, with poor growth, or other
signs of deficiency.41,105
Abbreviations: CBC, complete blood count; Cr, creatinine; CRP, C-reactive protein; IFALD, intestinal failure associated liver disease; Na, sodium;
PN, parenteral nutrition; UNa, urine sodium; UNa:UCr, urine sodium to urine creatinine ratio
a
Stable PN: refers to PN that requires minimal adjustments over time with patient on goal macronutrient and micronutrient supplementation.

timing of PN initiation, consideration should be given to ear- complications in the neonate, in particular intestinal failure
lier supplementation in those with decreased nutrition associated liver disease (IFALD).55
stores, such as the preterm or malnourished infant. Complications associated with PN usage include nutri-
tional intolerance or disturbances (eg, hypertriglyceridemia,
Intestinal Failure and PN Complications hyperglycemia), thrombosis, phlebitis, IFALD, bloodstream
The length of time needed on PN after neonatal gastrointes- infection, and metabolic bone disease.56 Although some of
tinal surgery varies and is dependent on individual patient these complications could be avoided by giving peripheral
factors, including residual intestinal length, presence and PN and not placing a central line, peripheral PN is only
location of the enterostomy, presence of the ileocecal valve, meant to be used for a short duration; if PN needs are
and underlying diagnosis.51–53 If the postoperative neonate ongoing, the placement of a central line is necessary.50
requires prolonged PN, they may eventually be classified Strategies to reduce the rates of these PN-associated compli-
as having intestinal failure. Although the definition of intes- cations include close patient monitoring, use of standardized
tinal failure varies, the American Society for Parenteral and protocols and care bundles, and care by a multidisciplinary
Enteral Nutrition defines pediatric intestinal failure as the team.57,58
reduction of functional intestine resulting in dependence Approaches for prevention and treatment of IFALD
on parenteral support (PN or intravenous fluids) for a mini- include increasing enteral nutrition, prevention of sepsis,
mum of 60 days in a 74-day period.54 The length of time on and care by a multidisciplinary team, in addition to altering
PN is important to consider because increased PN length intravenous lipid emulsion (ILE) and PN dosing.59 ILEs—in
is associated with an increased rate of PN-associated particular, soybean oil-based ILEs—are thought to be one of

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 the biggest contributors to IFALD development. It is postu- data. Overall, enteral nutrition provides significant benefits
lated that soybean oil-based ILE is proinflammatory given its over PN by promoting intestinal adaptation and decreasing
high phytosterol content, increased omega-6-polyunsaturated the risk for the previously discussed PN-associated complica-
fatty acid content, and low level of vitamin E.60 Preventive ILE tions.59,70,71 The ultimate goals of enteral nutrition include
strategies include giving reduced doses of soybean oil-based facilitating intestinal adaptation and maintaining appropri-
ILE or using alternate, composite mixed oil ILE containing fish ate growth and minimizing complications. It is desired to
oil in high-risk patients.61,62 The results of studies using these start enteral nutrition as early as possible.68,72 However,
strategies, however, have shown mixed results. there remains a paucity of randomized controlled trials or
Treatment strategies for IFALD also include the use of other high-quality literature, and subsequently, clear and evi-
alternate lipid dosing strategies such as fish oil containing dence-based recommendations on achieving these aims.68,70
ILE as monotherapy or in mixed oil ILE.63,64 At this time, fish The introduction of enteral nutrition as early as tolerated
oil-based ILE as 100% fish oil is the only United States Food following surgery in pediatric patients has clear benefits, par-
and Drug Administration-approved lipid therapy for the ticularly with a significant impact on facilitating intestinal
treatment of IFALD in pediatric patients.65 Fish oil-based adaptation.73 One predictor of eventual enteral autonomy fol-
ILE is only approved at a dose of 1 g/kg/d, limiting the lipid lowing resection in neonates is the degree of early enteral
calories when used as monotherapy. The mixed oil ILE con- feeding tolerance.52 Intestinal adaptation includes a complex
taining soy, medium chain triglycerides, olive, and fish oils series of events that increase intestinal crypt depth and villus
should not be given to neonates who are entirely PN-depen- height, ultimately increasing functional intestine and absorp-
dent at restricted doses. Abnormal essential fatty acid levels tive ability.38 Questions surrounding the best strategy to
and concern for mild essential fatty acid deficiency in neo- maximize intestinal adaptation following gastrointestinal
nates receiving doses of less than or equal to 2 g/kg/d is surgery in the neonate, including type, duration, and route

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of concern.63 PN dosing strategies for IFALD prevention of delivery of enteral nutrition, are still unanswered because
and treatment include cycling PN over a shorter period dur- of insufficient clinical evidence.38,71
ing the day. This strategy has been associated with lower bili- Human milk is used as the first-line enteral nutrition in
rubin levels but described only in multiple case series and the preterm population because of evidence supporting its
retrospective studies, not in randomized studies in the sur- beneficial and protective effects. Specifically, this includes
gical neonate66–68 This method is often used in larger promotion of growth, immune modulation, and antimicro-
infants who are over 2 kg with the cycling time incrementally bial activity in the intestine.74 Studies in the surgical neonate
increased, and it has also been associated with complications population have shown decreased PN and length of stay with
such as hypoglycemia.67 breast milk use.53,75,76 In the gastroschisis population, one
The most important strategy overall to prevent complica- study showed that use of mother’s own milk was associated
tions associated with PN is to limit the time on PN. When it is with decreased length of stay.77 Another retrospective single
not possible to wean off PN, it is important to monitor the center study including postoperative preterm neonates older
patient’s clinical and laboratory parameters closely to assess than 33 weeks’ gestation and over 1500 g showed that infants
for tolerance and appropriateness of nutrition provided. who received donor milk had shortened length of stay and
Monitoring strategies vary and are often center-dependent.69 central line days compared with formula-fed infants.78
When determining the timing of laboratory monitoring, Maternal breast milk is considered the first line for the
important factors to consider include the reason for the test majority of infants; however, more data are needed on the
and the patient’s risk for an underlying abnormality. Table 2 use of donor breast milk in the term surgical neonate before
outlines important considerations for short and long-term its widespread use can be recommended.
monitoring of the neonate undergoing gastrointestinal sur- When human milk is not available, the general recom-
gery. The timing of the laboratory tests in relation to surgery mendation in the literature for the postoperative neonate
and patient recovery may influence the results. It is reason- with intestinal failure is the use of amino acid–based or
able to monitor the patient more frequently during the acute hydrolyzed formulas.79,80 Amino acid formulas have been
phase postoperatively, with any PN changes, and with any associated with decreased PN need.53 However, in a review
change in clinical status. comparing aggregate data from multiple studies, no differ-
ence was found in outcomes when comparing hydrolyzed
Enteral Nutrition Application and Considerations formulas with diets with a combination of hydrolyzed for-
In the neonate requiring gastrointestinal surgery, optimizing mula and human milk or amino acid–based formula and
enteral nutrition postoperatively is also complex with limited human milk.73 Based on this review and the lack of

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randomized trials comparing these formulas directly, amino perforation and a single death.88,89 A meta-analysis found no
acid–based and hydrolyzed formulas are considered equiva- significant complications associated with mucous fistula
lent in this population, although varying individual patient refeeding and noted decreased time to full feedings,
tolerance should be considered. These formulas are intended decreased length of PN, decreased cholestasis, and decreased
for term neonates and contain lower levels of minerals and length of stay.90 A small prospective randomized controlled
protein when compared with preterm formulas, so strong trial with mucus fistula refeeding in preterm infants found
consideration should be given to the use of preterm formula that mucus fistula refeeding was associated with larger colon
in the preterm surgical neonate, if tolerated.70 diameter and improved patient growth rate.91 The complica-
tions that were reported in this randomized study included
Route of Enteral Nutrition perforation with stoma prolapse reduction and culture-
The route of enteral nutrition following gastrointestinal sur- proven sepsis.91 Given the unclear data regarding mucous
gery in the neonate is primarily guided by expert opinion and fistula refeeding and the severity of some of the reported
consideration of potential benefits, with no clear evidence of complications, consideration for mucous fistula refeeding
superiority of one approach over the other.72,81–83 Oral feed- should weigh all risks and benefits for each individual patient
ings are generally favored to mitigate the risk of oral aversion, before use.
stimulate reflexes and oral motor development, and release
beneficial trophic compounds into the saliva.68,82 However, Intermittent vs Continuous Enteral Nutrition Feeding
a small study in adults with short bowel syndrome found that Regarding the duration of feedings, intermittent feedings are
tube feeding or combined tube feeding with oral feedings proposed to be beneficial given that they mimic the physio-
significantly improved absorption of proteins, lipids, and logic feeding cycles, with alternating fasting periods and
energy compared with oral feeding alone.84 An alternative gastric emptying along with corresponding cyclic enteral hor-

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option, particularly in infants who do not tolerate enteral monal changes—all of which may improve bile release,
nutrition, is sham feeding, which involves offering an oral improve gut motility, and enhance intestinal adaptation.68,82
feeding with removal before digestion. A single trial in neo- On the other hand, continuous feedings may provide better
nates after gastrointestinal surgery reported no significant nutrient absorption because of increased intestinal mucosal
complications with this approach and found an association contact time and decreased risk of osmotic diarrhea, but at
with decreased maternal stress.85 The use of sham feedings the expense of decreased gut motility and higher risk of small
should be based on the safety of oral feeding in each individ- intestine bacterial overgrowth.81,82 In a small clinical trial
ual patient, and consideration should be given to evaluation using a within subject design, patients with short bowel syn-
by speech or occupational therapy to determine oral feeding drome had improved weight gain on continuous feedings
readiness.86 Another consideration includes the intraopera- compared with intermittent feedings.92 This study, however,
tive placement of a transanastomotic feeding tube. A recent only included 2 patients with short bowel syndrome and
meta-analysis, including 2 prospective studies, reported that noted no difference in nutrient absorption between the 2
transanastomotic tube feeding resulted in decreased time to feeding duration time. An alternate approach is to integrate
full feedings and decreased length of PN in congenital both methods providing intermittent feeding during the day
duodenal obstruction.87 Although there are limited data, and continuous feeding at night.93 Even when evaluating
considering the use of a transanastomotic feeding tube feeding duration in older pediatric patients, a recent system-
seems beneficial in the duodenal obstruction neonatal atic review noted the significant heterogeneity of the data and
population. lack of evidence, which led to an inability to draw conclusions
Another enteral nutrition feeding strategy in infants with about the best feeding duration strategy.94 In clinical practice
enterostomies is mucus fistula refeeding, which involves col- it is reasonable to consider starting with intermittent feed-
lecting the proximal ostomy content and transferring it to the ings, extending to continuous feedings if concerns for mal-
distal mucus fistula to facilitate intestinal adaptation and sim- absorption, intolerance, or poor growth arise. In the setting
ulate physiologic feeding in otherwise unused distal intes- of anticipated malabsorption, such as those neonates with
tines.38 Retrospective studies evaluating mucous fistula ultra short bowel syndrome, starting with continuous feed-
refeeding have found mixed results. One study showed ings can be considered.38
improved outcomes, including decreased time to full feed-
ings and PN need with decreased peak bilirubin and no com- Role of Nutrition Protocols in Postoperative Neonates
plications reported, whereas another reported serious Although results have been mixed between studies, multiple
complications related to mucous fistula refeeding, including retrospective studies have shown that the use of a feeding

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 protocol in neonates following gastrointestinal surgery Anatomical Considerations for Postoperative Nutrition
improves outcomes, including decreased incidence and When considering enteral nutrition in the postoperative neo-
degree of cholestasis, decreased time to full feedings, and nate, the intestinal anatomy is an important factor, including
decreased central line-associated blood stream infec- the portion of bowel resected, location of the ostomy, and the
tions.95–97 Specifically, in neonates with gastroschisis, a presence of the ileocecal valve. At baseline, the gastrointesti-
meta-analysis found that a standard protocol following sur- nal tract is responsible for the absorption of multiple
gery led to significantly shorter days to first feedings and nutrients and fluid (Fig 1). When a portion of the intestine
decreased risk for necrotizing enterocolits.98 is removed or the intestine is in discontinuity, this absorp-
The improved clinical outcomes and decreased rate of tion is significantly altered. Consideration of the individual
complications with nutrition protocols illustrates the impor- patient anatomy and risk for nutrient malabsorption is
tance of postoperative nutrition, which can also be incorpo- important to determine both acute and possible long-term
rated into the framework of an interdisciplinary, multimodal need for supplementation. Even as patients wean off PN, they
approach, including enhanced recovery after surgery (ERAS) remain at risk for nutrient deficiencies. During the transition
protocols. ERAS protocols include pre-, peri-, and post- from PN to enteral nutrition, a wide variety of micronutrient
operative elements, designed to ameliorate the surgical deficiencies have been reported, including iron, copper, and
stress response. They are established in adult patients, with the fat-soluble vitamins A, D, and E, among others.43,104 In
increasing use in the pediatric population.99 Common ERAS one report, as many as 42% of children with a mean age of
protocol topics include judicious fluid administration, early 5 years had at least one vitamin deficiency and 80% had one
feeding, and early discontinuation of PN, among others.99 mineral deficiency during the transition off PN.104 Once off
A meta-analysis including 8 studies with a total of 943 PN and on enteral nutrition only, reports of micronutrient
patients studied ERAS protocols in pediatric gastrointestinal deficiencies have been as high as 87.5% in the previously

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surgery—with a diverse range of surgeries including small PN-dependent intestinal failure patient.105 Many deficiencies
bowel resection, intussusception reduction, cholecystec- have been reported in this setting, but the most common
tomy—and noted significantly decreased length of stay, time ones include iron, zinc, and vitamins A, D, E, and
to first bowel movement, and time to regular diet in children B12.43,103–105 The risk for deficiencies is associated with the
treated with the ERAS approach.100 length of previous PN need.43,104 Factors associated with
There is limited literature on the use of ERAS protocols in decreased risk for micronutrient deficiency include ileocecal
the neonatal population. A prospective, non-randomized valve presence and multivitamin supplementation.103 Given
study analyzed the effects of ERAS with a gradual increase the increased risk for ongoing micronutrient deficiencies
in feeding starting on postoperative day 1 compared with nor- even once on full enteral nutrition, it is reasonable to con-
mal postoperative care with an initial fasting period up to tinue to monitor micronutrient levels in patients who previ-
5 days; the authors found decreased length of stay and ously had gastrointestinal surgery, especially those who were
increased weight at one-month follow-up in infants treated PN-dependent. It is also reasonable to consider supplemen-
with ERAS.101 A randomized prospective study also demon- tation with a multivitamin in this population.
strated clinical improvement with significantly decreased Postoperative anatomy, particularly ostomy location, also
time to first postoperative bowel movement, days of PN, plays a role when considering gastrointestinal fluid and
and length of stay. However, notably, the ERAS protocol electrolyte losses, tolerance of enteral nutrition, and ability
that was used focused on early postoperative activity to advance feedings. With postoperative ileus, gastrointestinal
without any specific feeding goals reported.102 Consensus losses can be elevated and higher than normal. Thus, gastro-
guidelines using the Delphi method after systematic review intestinal output should be monitored closely and accounted
were published to apply ERAS for term infants aged younger for when considering electrolyte and fluid supplementation.
than 4 weeks who require intestinal surgery not related to As enteral nutrition is introduced and advanced, the gastro-
necrotizing enterocolitis with many of the recommendations intestinal output, electrolytes, and weight gain should be
based on low level evidence.103 More data are needed regard- closely monitored to determine tolerance (Table 2). Many cen-
ing the use and topics to include in ERAS protocols in the ters report using a threshold of 30 to 50 ml/kg/d of ostomy
postoperative period to determine their influence on out- output to consider enteral nutrition advancement.38,80
comes in the neonatal population, particularly in preterm However, growth and electrolyte levels should be considered
neonates. in individual patient enteral nutrition advancement.

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Summary severe complications such as intestinal perforation and
death.88
• The acute phase of surgical response includes a stress
• Postoperative care protocols, including nutritional
reaction with elevated stress hormones and cytokines
management, should be considered for the neonate
that peaks at 4 hours and lasts 24 to 48 hours.2,6–8
undergoing gastrointestinal surgery.
During the acute phase, body stores of macronutrients
• Micronutrient deficiencies are common in neonates
are broken down for fuel, and growth slows or may not
undergoing gastrointestinal surgery and the site of
occur.
intestinal resection can help with anticipating deficien-
• Growth and body composition are altered in the gas-
cies. Even as patients wean from parenteral to full
trointestinal surgical neonate. These alterations can last
enteral nutrition, micronutrient deficiencies are
into later childhood and adolescence.22–27
common, particularly deficiencies in iron, zinc, and vita-
• Fluid balance, including intake and all output (urine, mins A, D, E, and B12, which necessitates monitoring
stool/ostomy, insensible) and electrolytes, should be levels and supplementing as necessary.43,103–105
monitored closely after neonatal gastrointestinal sur-
• When an enterostomy is present following neonatal
gery because fluid balance is tied to patient outcomes
surgery, enteral nutrition should be advanced when
(death, hypotension) and influences electrolyte levels.
ostomy output is less than 30 to 50 mL/kg/d and
• PN is necessary in neonates requiring gastrointestinal growth and electrolytes are appropriate.38,80
surgery when they cannot tolerate complete enteral
nutrition. The timing of PN should be individualized
with early PN in preterm and malnourished neonates.
Time on PN should also be limited to help decrease
the risk for complications associated with its use,
including nutritional disturbances, line complications,
central line-associated bloodstream infection, IFALD, American Board of Pediatrics
and metabolic bone disease.56 Neonatal–Perinatal Content

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• Enteral nutrition helps facilitate intestinal adaptation
following neonatal gastrointestinal surgery, with early
Specification
tolerated enteral volume predicting later enteral • Know the indications and advantages of total PN and
autonomy.52 combined enteral and PN.
• Maternal human milk is the first-line choice of feeding • Know the difficulties in providing enteral nutrition to
for gastrointestinal surgical neonates unless contraindi- neonates with gastroschisis.
cated for another reason. Donor breastmilk should be • Know the clinical features, complications, and manage-
considered in preterm surgical neonates, although ment of short bowel syndrome.
more data are needed in the term neonate. When
human milk is not available, hydrolyzed or amino-
based formula should be considered equally in the
term surgical neonate.73
• The best route of enteral feeding has not been deter- References
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however, oral and/or sham feedings are associated 1. Murthy K, Dykes FD, Padula MA, et al. The Children’s Hospitals
with decreased oral aversion.68,82 Neonatal Database: an overview of patient complexity, outcomes
and variation in care. J Perinatol. 2014;34(8):582–586. PubMed
• Transanastomotic feeding tubes in those with duo-
doi: 10.1038/jp.2014.26
denal obstruction has been associated with decreased
2. Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN. The
time to full feedings.87
surgically induced stress response. JPEN J Parenter Enteral Nutr.
• It is reasonable to consider intermittent feeding dura- 2013;37(suppl 5):21S–29S. PubMed doi: 10.1177/0148607113496117
tion in neonates following gastrointestinal surgery
3. Gore DC, Jahoor F, Wolfe RR, Herndon DN. Acute response of
unless there is anticipated malabsorption (ie, ultra short
human muscle protein to catabolic hormones. Ann Surg.
bowel) and change to continuous feedings if malab- 1993;218(5):679–684. PubMed doi: 10.1097/00000658-
sorption or poor growth occurs because one has not 199321850-00015
been shown to be superior to the other.38
4. Srinivasan V. Stress hyperglycemia in pediatric critical illness:
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 INDEX OF SUSPICION IN THE NURSERY

Unilateral Facial Lesion in an Infant

With Known Vermian Hypoplasia
Callie Marshall, MD, MPH,1 Ekta Shah, DO,2 Liza Siegel, MD,3 Melissa Riley, MD,1 Leo Shmuylovich, MD, PhD,3
Ali Mian, MD,4 Christopher D. Smyser, MD, MSCI,5 Lindsay Peglar Marsala, MD5

PRESENTATION
A baby girl is born at 38 + 4 weeks via uncomplicated spontaneous vaginal delivery.
Prenatal course is significant for vermian hypoplasia and maternal Beckwith-
Wiedemann syndrome. Physical exam reveals an erythematous, blanchable, left-
sided facial patch in the distribution of the V1 and V2 branches of the trigeminal
nerve with clear demarcation at the midline (Figure 1). Per maternal report, a faint

[Link]/neonatology
lesion was present at birth but deepened in color over the first hours of life.
The baby has a reassuring neurologic exam and initiates breastfeeding without
difficulty. Brain magnetic resonance imaging (MRI) reveals left-sided cerebellar
hypoplasia (ipsilateral to facial lesion) and asymmetric enlargement of the left
Meckel’s cave (Figures 2 and 3). Ophthalmic evaluation finds no abnormalities of
the left eye aside from an extension of the facial lesion to the eyelid. Midline workup
reveals an aneurysmal atrial septum and small secundum atrial septal defect with no
abnormalities on the abdominal ultrasound. After consulting with ophthalmology,
cardiology, neurology, dermatology, and genetics, her medical team discharges her
on day 3 of life. She sees genetics outpatient but does not undergo germline testing
ABBREVIATIONS due to limited diagnostic yield with her ultimate diagnosis.
She returns to the dermatology clinic at 3 weeks of life by which point her patch
MRI magnetic resonance imaging
PHACES posterior fossa malformations, has thickened and deepened in color. She has mild left eye swelling leading to
hemangioma, arterial decreased spontaneous opening, and thus is readmitted for propranolol initiation.
anomalies, coarctation of the
Computed tomography angiogram identifies no additional vascular anomalies of
aorta/cardiac defects, and eye
abnormalities syndrome the head or neck.

1
Department of Pediatrics, Division of AUTHOR DISCLOSURE: Drs Marshall, Shah, Siegel, Riley, Shmuylovich, Mian, Smyser, and Marsala
Newborn Medicine, St. Louis Children’s have disclosed no financial relationships relevant to this article. This article does not contain a
Hospital, St. Louis, Missouri; 2Department of discussion of an unapproved/investigative use of a commercial product/device.
Pediatrics, Division of Pediatric Neurology,
Accepted for Publication Date: November 22, 2024
Children’s Hospital of Atlanta, Atlanta,
Georgia; 3Department of Pediatrics, Division [Link]
of Pediatric Dermatology, St. Louis Copyright © 2025 by the American Academy of Pediatrics
Children’s Hospital, St. Louis, Missouri;
4
Department of Pediatrics, Division of
Pediatric Radiology, St. Louis Children’s
Hospital, St. Louis, Missouri; and
5
Department of Pediatrics, Division of
Pediatric Neurology, St. Louis Children’s
Hospital, St. Louis, Missouri

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 Actual Diagnosis
After a discussion among multiple experts including derma-
tology and neurology, she is diagnosed with PHACES. This
conclusion hinged upon the diagnosis of her patch. While
the 2 can appear similar early in life, a fully formed red patch
at birth favors capillary malformation. On the other hand,
darkening and thickening over time suggests hemangioma.

The Condition
Infantile hemangiomas are the most common benign tumor
of childhood, occurring in approximately 5% of infants.1 In
about 50% of cases, there is no evidence of hemangioma
at birth, and it becomes apparent in the first few weeks. In
the other 50%, there is a visible precursor lesion: a faint ery-
thematous patch, telangiectatic red patch, bruise-like area, or
FIGURE 1. Erythematous facial patch in the distribution of the V1
and V2 branches of the trigeminal nerve with demarcation at the pale area of vasoconstriction. Infantile hemangiomas tend to
midline on second day of life. grow rapidly over the first months of life (typically complete
when aged 6 months) followed by a period of stability (until
DISCUSSION aged 1 year) and then slow resolution (complete in 90% of
Differential Diagnosis patients when aged 4 years).2.
The differential diagnosis of a segmental facial patch in a Coined by Frieden et al in 1996, PHACES is speculated to

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newborn includes capillary malformation (previously called be a vascular neoplasm caused by a cephalic neuroectoder-
a port wine stain) and infantile hemangioma precursor. mal defect in embryogenesis and overexpression of vascular
Given her unilateral cerebellar hypoplasia, a port wine stain growth factors.3 PHACES has a female predominance and
raises concern for Sturge Weber syndrome, whereas a includes a constellation of clinical findings seen in approxi-
hemangioma does so for PHACES (posterior fossa malfor- mately 30% of patients with large segmental facial
mations, hemangioma, arterial anomalies, coarctation of hemangiomas.3 The diagnostic criteria for PHACES include
the aorta/cardiac defects, and eye abnormalities syndrome). a facial hemangioma > 5 cm in diameter and 1 major or 2

FIGURE 2. Head ultrasound images obtained on second day of life demonstrating asymmetric left cerebellar size (*) and extra-axial space
(arrow).

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 FIGURE 3. Axial (C) and coronal (D) T1-weighted images obtained on third day of life demonstrating left-sided cerebral hemispheric
hypoplasia (*), which is ipsilateral to the patient’s facial patch.

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minor criteria involving abnormalities from the following resonance angiogram of the head, neck, and chest;
categories: cerebrovascular, brain structure, cardiovascular, echocardiogram; and ophthalmologic evaluation. PHACES
ocular, and midline.4,5 has a known association with endocrine abnormalities (most
Vascular anomalies—dysgenesis, agenesis, aberrant ves- commonly thyroid dysfunction and growth hormone defi-
sels, and retained embryonic vessels—are the most common ciency). Therefore, children with PHACES require ongoing
comorbidities in PHACES, typically affecting medium to vigilance for growth, developmental milestones, and symp-
large arteries of the chest, neck, and head.5–7 Vascular toms of hypothyroidism or adrenal insufficiency in addition
changes are considered progressive, including aneurysmal to early endocrine assessment if a patient has structural pitui-
and steno-occlusive changes, Moyamoya arteriopathy, and tary abnormalities.5 While most structural anomalies in
eventually, arterial ischemic stroke with a median age of PHACES are static, progressive hydrocephalus and posterior
onset around 8 to 18 months.8,9 Neurologic abnormalities fossa cysts warrant neurosurgical consultations. Vascular
include structural differences of the posterior fossa abnormalities are stratified by a risk for ischemic strokes with
(Dandy-Walker malformation, arachnoid cysts, cerebellar recommended follow-up ranging from none to routine bian-
atrophy/hypoplasia) and midline structures (corpus cal- nual imaging and possible secondary stroke prevention or
losum, septum pellucidum, optic nerve/chiasm) along with neurosurgical consultation.5
malformations of cortical development (polymicrogyria, gray
matter heterotopia, cortical dysplasia) and intracranial Management
hemangiomas (internal auditory canal, cerebellopontine Long-term differences in those with PHACES include a
angle).5,6,10–12 Reported rates of structural brain anomalies heightened risk for developmental delays, seizures, head-
range from 35% to 52%12–14 and are often ipsilateral to the aches, movement disorders, and hearing abnormalities
cutaneous lesions.5–7 Cardiovascular abnormalities often depending on their intracranial abnormalities.5,11,13,15
involve the arch or subclavian artery. Less common findings Patients with PHACES warrant close neurologic surveillance
are ophthalmic comorbidities (<20% of patients), including and early referrals to therapies, audiologists, and neurosur-
posterior segment anomalies and microphthalmia5 and geons if indicated.
extracranial midline abnormalities, most of which are sternal Large segmental facial hemangiomas associated with
defects.5 PHACES typically follow aggressive growth patterns. They
Evaluation of a large segmental facial hemangioma have a high risk for functional impairment (particularly with
should include an MRI of the brain and neck; magnetic eyelid involvement), ulceration, scarring, and disfigurement.

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Thus, systemic treatment with propranolol is • Understand common congenital anomalies (eg, dys-
recommended.2 morphisms, deformations, disruptions, malformations,
syndromes)
Patient Course
This baby successfully initiates propranolol with occasional
episodes of mild hypoglycemia that resolve with slower dose
increases. She is currently meeting developmental mile-
stones and sees physical and occupational therapists
monthly, who note only occasional postural asymmetry, a References
finding related to her unilateral cerebellar hypoplasia.16 Her 1. Krowchuk DP, Frieden IJ, Mancini AJ, et al. SUBCOMMITTEE
subspecialty follow-ups also include repeat echocardiogram ON THE MANAGEMENT OF INFANTILE HEMANGIOMAS.
Clinical practice guideline for the management of infantile
with cardiology, neurodevelopmental surveillance with neu-
hemangiomas. Pediatrics. 2019;143(1):e20183475. PubMed
rology, hemangioma management with dermatology, and doi: 10.1542/peds.2018-3475
ophthalmology exams that have found no structural changes. 2. Paller A, Mancini AJ, Hurwitz S. Hurwitz clinical pediatric
She does not follow with neurosurgery given her absence of dermatology: a textbook of skin disorders of childhood and
progressive structural brain changes. adolescence. 4th ed. Saunders; 2011.
3. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The
association of posterior fossa brain malformations,
LESSONS FOR THE CLINICIAN hemangiomas, arterial anomalies, coarctation of the aorta and
cardiac defects, and eye abnormalities. Arch Dermatol. 1996;
• The trajectory of a facial lesion over the first weeks of life
132(3):307–311. PubMed doi: 10.1001/archderm.1996.
can be pivotal in distinguishing hemangiomas from capil- 03890270083012
lary malformations, which, in turn, can differentiate asso- 4. Metry D, Heyer G, Hess C, et al. PHACE Syndrome Research

[Link]/neonatology
ciated syndromes. Conference. Consensus statement on diagnostic criteria for
• A large facial patch in a newborn should prompt further PHACE syndrome. Pediatrics. 2009;124(5):1447–1456. PubMed
doi: 10.1542/peds.2009-0082
evaluation including head and neck vascular imaging,
5. Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome:
echocardiogram, and ophthalmologic exam. consensus-derived diagnosis and care recommendations.
• Hemangiomas may or may not be present at birth but grow J Pediatr. 2016;178:24–33.e2. PubMed doi: 10.1016/[Link].2016.
thicker and darker in the first few weeks of life. 07.054

• A baby with PHACES requires long-term, multidiscipli- 6. Heyer GL, Dowling MM, Licht DJ, et al. The cerebral
vasculopathy of PHACES syndrome. Stroke. 2008;39(2):308–316.
nary follow-up because of the progressivity of the vascular
PubMed doi: 10.1161/STROKEAHA.107.485185
and dermal manifestations.
7. Hess CP, Fullerton HJ, Metry DW, et al. Cervical and
intracranial arterial anomalies in 70 patients with PHACE
syndrome. AJNR Am J Neuroradiol. 2010;31(10):1980–1986.
PubMed doi: 10.3174/ajnr.A2206

Summary 8. Burrows PE, Robertson RL, Mulliken JB, et al. Cerebral

vasculopathy and neurologic sequelae in infants with cervicofacial
This case highlights the necessity of maintaining a high hemangioma: report of eight patients. Radiology. 1998;207(3):
index of suspicion for associated cardiac and vascular 601–607. PubMed doi: 10.1148/radiology.207.3.9609880
anomalies in babies with segmental facial patches. This 9. Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with
baby demonstrates the importance of close follow-up posterior fossa brain malformations, hemangiomas, arterial
and interdisciplinary communication, as segmental infan- anomalies, coarctation of the aorta and cardiac defects, and eye
tile hemangiomas and capillary malformations can be ini- abnormalities (PHACE) syndrome: a systematic review of the
tially indistinguishable but reveal themselves over time, literature. Stroke. 2012;43(6):1672–1674. PubMed doi: 10.1161/
STROKEAHA.112.650952
guiding clinicians, in this case, to the diagnosis of
PHACES. 10. Pascual-Castroviejo I. Vascular and nonvascular intracranial
malformation associated with external capillary hemangiomas.
Neuroradiology. 1978;16(1):82–84. PubMed doi: 10.1007/
BF00395211
American Board of Pediatrics 11. Duffy KJ, Runge-Samuelson C, Bayer ML, et al. Association of

Neonatal–Perinatal Content hearing loss with PHACE syndrome. Arch Dermatol. 2010;
146(12):1391–1396. PubMed doi: 10.1001/archdermatol.2010.201
Specification 12. Steiner JE, McCoy GN, Hess CP, et al. Structural malformations
• Recognize signs of cutaneous manifestation of sys- of the brain, eye, and pituitary gland in PHACE syndrome. Am J
Med Genet A. 2018;176(1):48–55. PubMed doi: 10.1002/ajmg.a.
temic diseases
38523

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 13. Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study 15. Yu J, Siegel DH, Drolet BA, et al. Prevalence and clinical
of PHACE syndrome in infantile hemangiomas: demographic characteristics of headaches in PHACE syndrome. J Child
features, clinical findings, and complications. Am J Med Genet A. Neurol. 2016;31(4):468–473. PubMed doi: 10.1177/
2006;140(9):975–986. PubMed doi: 10.1002/ajmg.a.31189 0883073815599261
14. Haggstrom AN, Garzon MC, Baselga E, et al. Risk for PHACE 16. Bosemani T, Poretti A. Cerebellar disruptions and
syndrome in infants with large facial hemangiomas. Pediatrics. neurodevelopmental disabilities. Semin Fetal Neonatal Med.
2010;126(2):e418–e426. PubMed doi: 10.1542/peds.2009-3166 2016;21(5):339–348. PubMed doi: 10.1016/[Link].2016.04.014

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 INDEX OF SUSPICION IN THE NURSERY

Shining a TORCH on a Case of Blueberry

Muffin Rash in a Newborn Infant
Anisha Gopu-Gilboy, MD,1 Joshua R. Sheak, MD, PhD,2 Nagendra Monangi, MD,3,4 Andreas Damianos, MD,3,4
Lauren Pommert, MD, MS3,5

CASE PRESENTATION
A female infant born at 37 weeks gestation to a G2P1 (gravidity 2 para 1) woman via
cesarean section presents with hepatosplenomegaly and diffuse rash consisting of
the following: petechiae; macules of variable size on legs, back, arms, and head; and
violaceous firm, smooth nodules throughout the back, abdomen, and extremities,
with the largest on the left posterior elbow and left knee (Figure 1A–C) resembling a

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“blueberry muffin” rash. This term is usually used to describe numerous, scattered,
nonblanching, popular, or nodular blue to purple purpura in a neonate.1 The infant
was admitted to the neonatal intensive care unit for advanced management and care. ABBREVIATIONS

Pregnancy was significant for severe polyhydramnios (amniotic fluid index was AML acute myeloid leukemia
AST aspartate aminotransferase
42 cm) and maternal “flu-like” illness a couple of weeks prior to delivery. The mode
CNS central nervous system
of delivery was secondary to a former cesarean section and worsening polyhydram- CMV cytomegalovirus
nios of unknown etiology. Prenatal laboratory evaluation was reassuring with a FISH fluorescence in situ
rubella immune status and negative testing for HIV, syphilis, group B streptococ- hybridization
HSCT hematopoietic stem cell
cus, hepatitis B, chlamydia, and gonorrhea. The parents declined noninvasive pre- transplant
natal testing. HSV herpes simplex virus
Laboratory evaluation on admission (Table 1) was significant for pancytopenia KMT2A lysine-specific methyltransferase
2A
with an absolute neutrophil count of 0, coagulopathy, unconjugated hyperbilirubi-
PCR polymerase chain reaction
nemia, and elevated aspartate aminotransferase, ferritin, uric acid, and lactate dehy- SR spontaneous remission
drogenase. Infectious testing was obtained and included cultures, serologies for TORCH toxoplasma, other, rubella,
cytomegalovirus, herpes
HIV, toxoplasmosis, syphilis, and rubella, and polymerase chain reaction (PCR) test-
simplex virus
ing for cytomegalovirus (CMV), parvovirus, human herpesvirus 6, herpes simplex WBC white blood cells

1
AUTHOR DISCLOSURE: Drs Gopu-Gilboy, Sheak, Monangi, Damianos, and Pommert have Cincinnati Children’s Hospital Medical
disclosed no financial relationships relevant to this article. This article does not contain a Center Pediatric Residency Training
discussion of an unapproved/investigative use of a commercial product/device. Program, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio; 2Neonatal
Accepted for Publication Date: December 2, 2024
and Perinatal Fellowship Program,
[Link] Cincinnati Children’s Hospital Medical
Copyright © 2025 American Academy of Pediatrics Center, Cincinnati, Ohio; 3Department of
Pediatrics, University of Cincinnati College
of Medicine, Cincinnati, Ohio; 4Division of
Neonatology, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio; and
5
Division of Oncology, Cancer and Blood
Diseases Institute, Cincinnati Children’s
Hospital Medical Center, Cincinnati, Ohio

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 [Link]/neonatology
FIGURE 1. Representative images of the patient’s skin lesions. (A–C) Images on day of birth of the patient’s back, torso, and posterior surface
of the upper arm show multiple violaceous purpuric lesions. (D–F) Images on day of life 6 showing spontaneous regression of previously
visualized lesions prior to chemotherapy treatment. Ruler with units of measurement of inches on the top and centimeters on the bottom.

virus 1 and 2 (HSV 1 and 2), HIV, enterovirus, and adenovi- are commonly implicated, and timely treatment is crucial
rus. A head ultrasound was obtained given concerns for to prevent associated complications. In this case, TORCH
congenital infections and demonstrated lenticulostriate vas- infections, such as congenital CMV, were a strong possibility
culopathy.2,3 Given the clinical presentation, the infant given the maternal history of flu-like illness during the third
started treatment with antibiotic (ampicillin and gentamicin) trimester of pregnancy and the infant’s presentation with
and antiviral (ganciclovir) therapy while awaiting the results hepatosplenomegaly, pancytopenia, and findings on head
of the diagnostic workup. Initial consults were placed to ultrasound.2,3 Upon initial suspicion of congenital CMV,
infectious diseases and hematology followed by oncology empirical treatment with valganciclovir was started pending
and dermatology. testing results due to devastating complications of uncon-
trolled disease.4,5 Similarly, other TORCH infections can
DISCUSSION usually be diagnosed by serology or PCR testing and occa-
Differential Diagnosis sionally treated with antiviral therapies.
The differential diagnosis for blueberry muffin type rash is More rarely, hematologic disorders can result in such a
broad1 and includes infection, blood dyscrasias, and malig- rash including oncologic entities resulting in neoplastic infil-
nancies because these observed skin lesions can be caused tration. Biopsy of the lesion is crucial to differentiate and con-
by dermal erythropoiesis, vasculopathy or vascular malfor- firm these diagnoses to determine appropriate therapeutic
mations, or neoplastic dermal infiltration. TORCH (toxoplas- interventions in a timely fashion.6 In our case, a biopsy of
mosis, rubella, cytomegalovirus, HSV, syphilis) infections the lesion was performed on the second day of life.

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TABLE 1. Laboratory Evaluation leukemia is less than 1% of all childhood leukemias.8 AML is
Reference
the predominant type of neonatal leukemia10,11 and is asso-
Name Value Units Range25,26 ciated with KMT2A rearrangements (KMT2Ar) in approxi-
Blood type O+ mately 50% of cases, which leads to a monocytic AML
DAT Negative phenotype. In contrast, 75% of infants with acute lympho-
Complete blood count with differential blastic leukemia harbor KMT2Ar.8 Hyperleukocytosis (white
WBC 2.95a ×103/mcL 9.0–29.9
blood cells [WBC] >100 × 103/mcL) is the most consistent
Hgb 7.1a g/dL 13.5–19.5
Hct 22a % 42–60 hematologic feature associated with neonatal leukemia and
Platelets 17a ×103/mcL 135–466 occurs commonly in those with KMT2Ar, often causing res-
RDW 19.9a % ≤19.1 piratory distress, hypoxia, acidosis, and cardiac and renal fail-
MCHC 32.3a g/dL 30–36 ure due to hyperviscosity.7,8 Our patient presented with
ANC 0a ×103/mcL 6–28
pancytopenia, which is atypical and more suggestive of mar-
ALC 2.92a ×103/mcL 2–11
row suppression from possible infection. Extramedullary
Coagulation studies
PT 20.4a s 9.9–12.7 leukemic involvement including skin, liver, and/or central
INR 1.7a 0.9–2.7 nervous system (CNS) is common in infants with leukemia
PTT 42a s 24.7–33.1 and is also associated with KMT2Ar.11,12 Leukemia cutis, the
Fibrinogen 46a mg/dL 140–400 rash visualized in this case, is seen in two-thirds of babies
Liver function tests
with congenital AML and can occur in the absence of periph-
Total bilirubin 6.3a mg/dL 0.1–5.1
Conjugated bilirubin 0.8a mg/dL 0–0.4 eral blood and bone marrow involvement.8 Other clinical fea-
ALT 22a unit/L ≤49 tures include jaundice, hepatosplenomegaly, ascites, and
AST 146a unit/L 20–98 pleural effusions.11,12 Congenital AML is typically associated

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Oncologic screening with high-risk clinical and cytogenetic features leading to 5-
Ferritin 1160a ng/dL 50–501
year overall survival rates of around 50%.7,11–15 This is, in
Uric acid 8.7a mg/dL 1.2–5.4
LDH 1606a units/L 125–765
part, because infants are at increased risk of infectious and
pulmonary toxicities, early death, and treatment-related mor-
Abbreviations: ALC, absolute lymphocyte count; ALT, alanine
aminotransferase; ANC, absolute neutrophil count; AST, aspartate tality with therapy.7,16–18
aminotransferase; DAT, direct antiglobulin test; Hct, hematocrit; Hgb, A unique and rare feature of congenital AML is that it can
hemoglobin; INR, international normalized ratio; LDH, lactate
dehydrogenase; MCHC, mean corpuscular hemoglobin concentration; undergo spontaneous remission (SR) without cytotoxic
PT, protime; PTT, prothrombin time; RDW, red blood cell distribution therapy, similar to transient abnormal myelopoiesis seen
width; WBC, white blood [Link] outside of provided reference
ranges25,26 are bolded. with Down syndrome.8,11,19 This phenomenon is most com-
monly described in neonates with a specific KAT6A::
Final Diagnosis CREBBP gene fusion ([t(8;16)]) resulting in a monocytic or
Our patient’s infectious testing returned negative, and anti- myelomonocytic AML phenotype, and although some of
biotic treatment was transitioned to cefepime monotherapy these patients eventually relapse, there are cases of neonates
due to the patient’s persistent neutropenia. Given persistent who have sustained long-term remission without treat-
neutropenia, the infant was also started on antifungal (mica- ment.8,19 SR is very unusual in neonatal AML with
fungin and pentamidine) prophylaxis. Urine studies for KMT2Ar; however, a case series described 5 neonates with
neuroblastoma including homovanillic acid and vanillylman- KMT2Ar AML who had SR, 3 of whom experienced relapse
delic acid were also negative. by 6 months of age and 2 of whom remained in remission at
Biopsy results from a skin nodule revealed KMT2A the time the report was published (2 years and 7 months)
(lysine-specific methyltransferase 2A) rearrangement consis- without chemotherapy.8
tent with neonatal acute myeloid leukemia (AML) with sub-
cutaneous myeloid cell lineage infiltration.7 The infant’s Treatment/Management
fluorescence in situ hybridization (FISH) returned negative Prompt consultation with hematology/oncology colleagues is
for trisomy 21. crucial for diagnosing and treating neonatal and infantile
acute leukemias. Evaluation of neonatal leukemia typically
The Condition consists of a bone marrow aspiration and biopsy to confirm
Neonatal leukemia is defined as occurring within the first diagnosis, establish leukemia immunophenotype and cyto-
28 days of life, and nearly all cases are congenital.8,9 molecular genetic drivers, and better understand risk strati-
Excluding patients with trisomy 21, the incidence of neonatal fication and treatment. Obtaining bone marrow aspirates and

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 biopsies can be very challenging in this population, and for Patient Course
those for whom marrow samples are inadequate or unable to Following the diagnosis, the patient’s rash (confirmed as leu-
be obtained, peripheral blood flow cytometry can help to con- kemia cutis via histopathology and KMT2A FISH) began to
firm a diagnosis and determine immunophenotype. Biopsy spontaneously regress, and by day of life 6, the skin findings
of a leukemia cutis lesion, if present, is also diagnostic and had nearly resolved prior to any chemotherapy (Figure 1D–
can be sent for genetic studies, including FISH and next- F). However, there was worsening conjugated hyperbilirubi-
generation sequencing. A lumbar puncture is needed to nemia (maximum 9.7 mg/dL) concerning leukemic involve-
evaluate for the presence of leukemia in the CNS and to ment of the liver. Thus, the patient started low-dose
administer intrathecal chemotherapy. In patients with hyper- cytarabine treatment (1.5 mg/kg once daily for 7 days), result-
leukocytosis and/or coagulopathy, a lumbar puncture should ing in an improvement in cholestasis. Two weeks later, at age
be delayed until the WBC count has decreased and coagulop- 3 weeks of life, a repeat biopsy of the largest remaining skin
athy is corrected, so as not to contaminate the CSF by intro- lesion (Figure 1F) was negative for leukemia by morphology,
ducing peripheral leukemic cells. An echocardiogram is immunohistochemical staining, and FISH.
needed to establish heart function prior to giving anthracy- Two weeks after cytarabine completion, bone marrow
cline therapy. Lastly, baseline laboratories to assess renal evaluation revealed residual disease. Prior to proceeding with
and hepatic function and risk of tumor lysis syndrome are traditional intensive AML induction chemotherapy, the
also needed prior to chemotherapy initiation. patient developed bloody stools and was found to have exten-
Infants with AML are typically treated with the same sive neutropenic enterocolitis involving the cecum, ascend-
intensive anthracycline and cytarabine-based chemotherapy ing colon, and transverse colon. This intraabdominal
regimens used in older children, often with the addition of infection limited the escalation of chemotherapy, so low-dose
gemtuzumab ozogamicin, an anti-CD33 humanized anti- cytarabine was restarted. Unfortunately, during this treat-

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body conjugated with a cytotoxic antibiotic recently shown ment, the patient developed rapidly progressive AML with
to be safe and effective in this population.16,20 Hematopoietic CNS involvement. Chemotherapy was escalated to more
stem cell transplant (HSCT) is considered for those with intensive high-dose cytarabine, but despite this, the patient
high-risk disease based on leukemia genetics such as ultimately died at 3 months of age due to progressive
KMT2Ar and/or suboptimal response to induction chemo- leukemia.
therapy.16 Delivering intensive therapy to this population,
including HSCT, can be challenging due to differences in
drug absorption, distribution, hepatic metabolism, and renal LESSONS FOR THE CLINICIAN
excretion.21 Additionally, neonates experience increased • Blueberry muffin rash does not always indicate a TORCH
rates of life-threatening infections, organ toxicities, and over- infection. Considering a broad differential diagnosis is
all higher rates of treatment-related mortality.7,16–18,22 important, including malignant conditions such as con-
In clinically well-appearing, stable neonates, watchful genital leukemia. Prompt biopsy of the skin lesions may
waiting and serial disease evaluations may be considered be required to make a diagnosis.
due to the possibility of spontaneous regression, especially • The most common genetic mutation seen in infantile AML
in patients with KAT6A::CREBBP.19 Spontaneous regres- is KMT2Ar, which is typically characterized by a monocytic
sion can occur over the span of weeks to months and is char- AML phenotype and associated with hyperleukocytosis
acterized by the resolution of leukemia cutis lesions and/or and extramedullary involvement, especially skin and CNS.
decreasing absolute blast count in the peripheral blood with • Rarely, congenital leukemia can spontaneously regress
the eventual absence of marrow involvement. However, it is without treatment. This is most commonly described in
worth noting that KAT6A::CREBBP can also present with neonates whose AML harbors a t(8;16) KAT6A::CREBBP
more aggressive disease.23,24 Due to this and the rarity of this fusion. These patients remain at high risk of disease
phenomenon, there is no guidance as to which children can relapse and need eventual treatment; therefore, close mon-
be monitored without treatment vs immediately treated with itoring is required.
intensive therapy. This decision should be made in conjunc- • Infants with AML are treated with the same intensive cytar-
tion with oncology partners, and observation is only appro- abine and anthracycline-based chemotherapy regimens as
priate in neonates who are clinically well. Those patients older children with AML and are at increased risk of
with spontaneous AML remission remain at high risk of chemotherapy-related complications and death.
relapse and warrant close outpatient monitoring in the fol- • Ultimately, the decision to treat neonatal AML with inten-
lowing years. sive chemotherapy vs “watch-and-wait” for possible

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 spontaneous regression depends on the individual patient, 9. McCoy JP Jr, Overton WR. Immunophenotyping of congenital
their clinical status and organ involvement, and their AML leukemia. Cytometry. 1995;22(2):85–88. PubMed doi: 10.1002/
cyto.990220202
cytomolecular genetics. This decision should be made in
10. Vora A. Childhood leukaemia: an update. Paediatr Child Health
conjunction with oncology colleagues. Watchful waiting (Oxford). 2016;26(2):51–56. doi: 10.1016/[Link].2015.10.007
could be considered in well-appearing, clinically stable 11. Bresters D, Reus ACW, Veerman AJP, van Wering ER, van der
neonates, provided that close short- and long-term moni- Does-van den Berg A, Kaspers GJL. Congenital leukaemia: the
toring is available. Given the rarity of both neonatal Dutch experience and review of the literature. Br J Haematol.
2002;117(3):513–524. PubMed doi: 10.1046/j.1365-2141.2002.
AML and spontaneous regression, this population is
03459.x
unlikely to be studied in prospective clinical trials.
12. Zhang Q, Ren Z, Yang J, Yin A. Analysis of 59 cases of
congenital leukemia reported between 2001 and 2016. J Int Med
Res. 2019;47(10):4625–4635. PubMed doi: 10.1177/
0300060519872899

American Board Of Pediatrics 13. Pui CH, Raimondi SC, Srivastava DK, et al. Prognostic factors
in infants with acute myeloid leukemia. Leukemia. 2000;14(4):
Neonatal–Perinatal Content 684–687. PubMed doi: 10.1038/[Link].2401725

Specification 14. Webb DK, Harrison G, Stevens RF, Gibson BG, Hann IM,
Wheatley K; MRC Childhood Leukemia Working Party.
• Recognize different types of TORCH infection. Relationships between age at diagnosis, clinical features, and
• Know the signs of congenital leukemia. outcome of therapy in children treated in the Medical Research
Council AML 10 and 12 trials for acute myeloid leukemia. Blood.
• Know the signs of neonatal leukemia.
2001;98(6):1714–1720. PubMed doi: 10.1182/blood.V98.6.1714
15. Masetti R, Rondelli R, Fagioli F, et al. Infants with acute myeloid
leukemia treated according to the Associazione Italiana di

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Ematologia e Oncologia Pediatrica 2002/01 protocol have an
outcome comparable to that of older children. Haematologica.
References 2014;99(8):e127–e129. PubMed doi: 10.3324/haematol.2014.
106526
1. Mehta V, Balachandran C, Lonikar V. Blueberry muffin baby: a
16. Pollard JA, Guest E, Alonzo TA, et al. Gemtuzumab ozogamicin
pictoral differential diagnosis. Dermatol Online J. 2008;14(2):8.
improves event-free survival and reduces relapse in pediatric
PubMed doi: 10.5070/D353Q852NC
KMT2A-rearranged AML: results from the phase III children’s
2. de Jong EP, Lopriore E, Vossen ACTM, et al. Is routine TORCH oncology group trial AAML0531. J Clin Oncol. 2021;39(28):
screening warranted in neonates with lenticulostriate 3149–3160. PubMed doi: 10.1200/JCO.20.03048
vasculopathy? Neonatology. 2010;97(3):274–278. PubMed doi: 10.
17. Tomizawa D, Saito AM, Taga T, et al. Unexpected high mortality
1159/000255166
rate due to acute respiratory distress syndrome among infants
3. Nijman J, de Vries LS, Koopman-Esseboom C, Uiterwaal CSPM, with AML enrolled on JPLSG AML-05 trial. Blood. 2010;116(21):
van Loon AM, Verboon-Maciolek MA. Postnatally acquired 2146. doi: 10.1182/blood.V116.21.2146.2146
cytomegalovirus infection in preterm infants: a prospective study
18. Tomizawa D, Tawa A, Watanabe T, et al. Appropriate dose
on risk factors and cranial ultrasound findings. Arch Dis Child
reduction in induction therapy is essential for the treatment
Fetal Neonatal Ed. 2012;97(4):F259–F263. PubMed doi: 10.1136/
of infants with acute myeloid leukemia: a report from the
archdischild-2011-300405
Japanese Pediatric Leukemia/Lymphoma Study Group. Int J
4. Pesch MH, Schleiss MR. Emerging concepts in congenital Hematol. 2013;98(5):578–588. PubMed doi: 10.1007/s12185-013-
cytomegalovirus. Pediatrics. 2022;150(2):e2021055896. PubMed 1429-2
doi: 10.1542/peds.2021-055896 19. Coenen EA, Zwaan CM, Reinhardt D, et al. Pediatric acute
5. Kimberlin DW, Jester PM, Sánchez PJ, et al. National Institute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and
of Allergy and Infectious Diseases Collaborative Antiviral Study biological entity: a collaborative study by the International-Berlin-
Group. Valganciclovir for symptomatic congenital Frankfurt-Munster AML-study group. Blood. 2013;122(15):
cytomegalovirus disease. N Engl J Med. 2015;372(10):933–943. 2704–2713. PubMed doi: 10.1182/blood-2013-02-485524
PubMed doi: 10.1056/NEJMoa1404599 20. Hasle H, Abrahamsson J, Forestier E, et al. Nordic Society of
6. Cyr J, Langley A, Demellawy DE, Ramien M. A neonate with Paediatric Haematology and Oncology (NOPHO). Gemtuzumab
Langerhans cell histiocytosis presenting as blueberry muffin ozogamicin as postconsolidation therapy does not prevent
rash: case report and review of the literature. SAGE Open Med relapse in children with AML: results from NOPHO-AML 2004.
Case Rep. 2020;8. doi: 10.1177/2050313x20919616 Blood. 2012;120(5):978–984. PubMed doi: 10.1182/blood-2012-
03-416701
7. Creutzig U, Zimmermann M, Bourquin JP, et al. Favorable
outcome in infants with AML after intensive first- and second- 21. Lu H, Rosenbaum S. Developmental pharmacokinetics in
line treatment: an AML-BFM study group report. Leukemia. pediatric populations. J Pediatr Pharmacol Ther. 2014;19(4):
2012;26(4):654–661. PubMed doi: 10.1038/leu.2011.267 262–76. doi: 10.5863/1551-6776-19.4.262.
8. Roberts I, Fordham NJ, Rao A, Bain BJ. Neonatal leukaemia. 22. Orbach D, Sarnacki S, Brisse HJ, et al. Neonatal cancer. Lancet
Br J Haematol. 2018;182(2):170–184. PubMed doi: 10.1111/bjh. Oncol. 2013;14(13):e609–e620. PubMed doi: 10.1016/S1470-2045
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 23. Daifu T, Kato I, Kozuki K, et al. The clinical utility of genetic Sci. 2010;25(6):945–949. PubMed doi: 10.3346/jkms.2010.25.
testing for t(8;16)(P11;P13) in congenital acute myeloid leukemia. 6.945
J Pediatr Hematol Oncol. 2014;36(5):e325–7. doi: 10.1097/MPH. 25. Wong ECC, Brugnara C, Straseski JA, Kellogg MD, Adeli K.
0000000000000099 Pediatric Reference Intervals. 8th ed. Elsevier; 2021.
24. Sung TJ, Lee DH, Kim SK, Jun YH. Congenital acute myeloid 26. Kuhle S, Male C, Mitchell L. Developmental hemostasis:
leukemia with t(8;16) and t(17;19) double translocation: pro- and anticoagulant systems during childhood. Semin Thromb
case presentation and literature review. J Korean Med Hemost. 2003;29(4):329–338. PubMed doi: 10.1055/s-2003-42584

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 VISUAL DIAGNOSIS

Term Infant With a Large Red-Purple

Mass in the Upper Thigh
Alexander Guh-Siesel,1 Elizabeth Oh, MD2

CASE
A term female twin infant presents at birth with a large red-purple mass in the left
upper thigh.

PRENATAL AND BIRTH HISTORIES

• Born to a 30-year-old gravida 3, para 1–0–1–1 woman with gestational

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hypertension
• Conception by in vitro fertilization resulting in a dichorionic diamniotic
pregnancy
• Prenatal laboratory tests: blood type A negative, antibody negative, group B
Streptococcus negative, hepatitis B surface antigen negative, rapid plasma reagin
nonreactive, rubella equivocal, and HIV negative
• Prenatal course benign with normal fetal survey at 20 weeks’ gestation, low-risk
cell-free DNA assessment
• Maternal medications: prenatal vitamins, ferrous sulfate, baby aspirin
• Gestational age: 37 weeks and 3 days
• Born by repeat cesarean birth; routine resuscitation; Apgar score of 9 and 9 at 1
and 5 minutes, respectively; a left upper thigh mass is noted (Figure 1)
• Birthweight: 2960 g (27%), birth length 48.5 (36%), birth head circumference
34 cm (54%)

PRESENTATION AFTER BIRTH

Vital Signs ABBREVIATIONS
• Heart rate: 123 beats per minute
CH congenital hemangioma
• Respiratory rate: 44 beats per minute PDGFRB platelet-derived growth factor
• Axillary temperature: 36.7 °C (98.1 °F) receptor beta

AUTHOR DISCLOSURE: Mr Guh-Siesel and Dr Oh have disclosed no financial relationships 1

Harvard University, Cambridge,
relevant to this article. This article does not contain a discussion of an unapproved/investigative Massachusetts; and 2Beth Israel Deaconess
use of a commercial product/device. Medical Center, Department of
Neonatology, Harvard Medical School,
Accepted for Publication Date: October 4, 2024
Cambridge, Massachusetts
[Link]
Copyright © 2025 by the American Academy of Pediatrics

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 • Fibrinogen: 356 mg/dL (10.4 μmol/L)
• D-dimer: 2223 (elevated)
• Total bilirubin: 5.8 mg/dL; direct bilirubin: 0.2 mg/dL
• Reticulocyte count: 6%

DIFFERENTIAL DIAGNOSIS
• Congenital hemangioma
• Infantile myofibroma
• Infantile hemangioma
• Infantile fibrosarcoma
• Rhabdomyoscarcoma

ACTUAL DIAGNOSIS
• Infantile myofibroma

FIGURE 1. A large 8 cm × 4 cm firm, rubbery, nodular mass with a

red-purple discoloration on the infant’s left anterior thigh was noted CLINICAL COURSE, EVALUATION, AND
at birth.
MANAGEMENT
An ultrasonography is obtained, and results show a uniform

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Physical Examination solid minimally vascular soft tissue with overall measure-
• General: well appearing infant in no distress ments of approximately 6 × 3 × 4 cm. There is likely a small
• Head, Eyes, Ears, Nose, Throat: Normocephalic; normal, feeding vessel coming from the adjacent left femoral artery.
open, flat fontanelles; no atypical facial features; patent The surgical team is consulted, and the infant is trans-
nares; intact palate; no neck mass or crepitus ferred to the local children’s hospital for further evaluation.
• Lungs: Clear, equal breath sounds; no tachypnea, no chest A magnetic resonance imaging of the pelvis (Figure 2) with
retractions and without contrast shows a well-circumscribed exophytic
• Cardiovascular: Normal heart sounds; regular rate and solid mass measuring 5.6 × 5.2 × 2.9 cm arising from the
rhythm; no murmurs or gallop, femoral pulses 2+ subcutaneous tissue of the left anterior thigh. There appears
bilaterally to be a vascular pedicle arising from the common femoral
• Abdomen: Soft, no hepatomegaly or splenomegaly, bowel artery and vein. There does not appear to be any involvement
sounds present; patent anus of the underlying osseous structures or muscle. Chest radio-
• Genitourinary: Normal female genitalia graph is unremarkable with no mediastinal mass or lymph
• Extremities: Hips with negative Barlow and Ortolani nodes. The infant continues to be hemodynamically stable.
maneuver. Spine appears normal. There is a 8 cm × 4 cm
firm, rubbery, nodular mass with a red-purple discolor-
ation on the left anterior thigh
• Skin: No icterus, no rash, no other lesions or masses
besides mass on thigh
• Neurologic: Rooting and sucking reflex present, symmet-
ric Moro reflex, normal strength and tone. No abnormal
movement, focal neurological deficit or cranial nerve palsy

Laboratory Studies
• White blood cell count: 16.7 × 103/μL (16.7 × 109/L); hemo-
globin 14.0 g/dL (8.7 mmol/L); hematocrit 40.3%; platelets
318 × 103/μL (318 × 109/L)
• Prothrombin time 12.6 seconds; partial thromboplastin FIGURE 2. Axial T2 image of mass in left anterior thigh. (Image
time 39.4 seconds; international normalized ratio 1.2 obtained with assistance from Dr Emily Whitesel.)

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 At 4 days of age, the mass is surgically removed with no NOTCH3 have been identified in the development of infan-
complications. Pathology report showed a rubbery, nodular tile myofibroma.3
well-delineated neoplasm with biphasic morphology com- Infantile myofibroma is diagnosed by the distinct histopa-
posed of immature appearing plump cells associated with thology of a biphasic pattern of dark-stained round small
branching vasculature. The periphery of the lesion consists spindle cells with enlarged hyperchromatic nuclei located
of nodules of spindled cells. There are areas of necrosis in the center and light-stained spindle-shaped myofibroblasts
and ulcerations seen. The lesion appears to be com- arranged along the periphery.5,7 Immunohistochemistry can
pletely excised. Findings are consistent with an infantile be used to confirm an infantile myofibroma diagnosis with
myofibroma. strong positivity for α-smooth muscle actin and vimentin
The infant is admitted to the neonatal intensive care unit and negativity for S100, a marker for neurofibroma, and glu-
postoperatively and is discharged after 3 days with no com- cose transporter 1, a marker for infantile hemangioma.5,8
plications, with follow-up appointments with general surgery A solitary or multicentric infantile myofibromas can
and genetics. resolve spontaneously, but treatment is often surgical exci-
The infant continued to do well after surgical excision. At sion, especially with visceral involvement or if symptomatic
6 weeks of age, a whole-body magnetic resonance imaging is due to compression of other organs. Patients with solitary
performed to evaluate for other myofibromas with no evi- and multicentric lesions have a good prognosis. Visceral
dence of other solid masses in the brain, torso, or extremities. involvement, particularly pulmonary involvement, has a poor
The infant is referred for genetic testing. An oncopanel prognosis with mortality rate as high as 33% to 75%.2,5
genetic test shows a mutation in the platelet-derived growth Chemotherapy has been used in patients with visceral
factor receptor beta (PDGFRB) variants within the mass, but involvement but with little success.2
germline testing is negative for PDGFRB variants. Despite Recurrence is possible with multicentric and generalized

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the negative germline test, there was a potential risk of forms, and therefore, surveillance is recommended every
somatic mosaic pathogenic variant. As a result, the infant 6 months for 2 years.2
continues to have surveillance with abdominal and pelvic
ultrasonography every 3 months for the first year of age with
no current evidence of disease. DIFFERENTIAL DIAGNOSIS
Congenital hemangioma (CH) is a benign vascular tumor
fully formed at birth and often detected on prenatal ultra-
DISCUSSION sonography due to its high vascularity. These lesions typically
Infantile myofibromas are the most common fibrous tumor present as red-purple lesions but can also present as a solitary
of infancy, occurring in approximately 1 out of every 150 000 tumor.9 They are divided into 3 subgroups:
infants.1 It is more common in boys, with a 55∶1 male/female
ratio.1,2 Infantile myofibroma is characterized by a firm, rub- 1. rapidly involuting CH, which regresses once the infant is
bery nodule that is flesh-colored, yellow, or blue-purplish in born and typically disappears within 1 to 1.5 years;
color, and it can present in 3 different forms: 2. noninvoluting CH, which remains stable and continues
to grow; and
1. solitary form, single cutaneous nodule; 3. partially involuting CH, which initially regresses but
2. multicentric form, involving skin, subcutaneous tissues, eventually stabilizes around 1 year.9
muscle and bone; and
3. generalized form, with visceral involvement.2 For this infant, ultrasonography of the lesion did not show
significant vascularity outside of a single vessel feeding the
Solitary lesions are more common, representing 70% to mass.
80% of cases, and have a good prognosis.3–5 Multicentric Infantile hemangiomas are the most common benign
lesions are rarer (20% 30% of all cases), more common in tumor of infancy, resulting from abnormal endothelial pro-
girls (63% of female cases), and are generally benign.2–5 liferation and are commonly referred to as “strawberry
The generalized form has poor prognosis and can be fatal marks.”10 These lesions present as precursor lesions at birth
due to visceral involvement.2,6 Patients with suspected infan- and typically proliferate within the first few weeks after
tile myofibroma should have additional radiographic evalu- birth.9 Infantile hemangiomas are more common in female
ation to evaluate for visceral involvement.2 Although most infants and those who are white, preterm, or born from
cases arise spontaneously, mutations in PDGFRB and multiple gestations.11 They can be identified by specific

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 markers such as glucose transporter 1 overexpression, as well References
as positivity for Lewis Y antigen, merosin, and FcRII.10 Most 1. Infantile myofibromatosis. National Cancer Institute website.
infantile hemangiomas resolve on their own and can be 2020. Accessed January 21, 2025. [Link]
treated with beta-blockers (topical or oral), corticosteroids, pediatric-adult-rare-tumor/rare-tumors/rare-soft-tissue-tumors/
infantile-myofibromatosis.
or surgical excision.10 Because infantile hemangiomas typi-
2. Mashiah J, Hadj-Rabia S, Dompmartin A, et al. Infantile
cally present as smaller lesions that then grown postnatally,
myofibromatosis: a series of 28 cases. J Am Acad Dermatol.
the infant’s skin lesion is not consistent with an infantile 2014;71(2):264–270. PubMed doi: 10.1016/[Link].2014.03.035
hemangioma. 3. Arts FA, Sciot R, Brichard B, et al. PDGFRB gain-of-function
Infantile fibrosarcoma is the most common nonrhabdo- mutations in sporadic infantile myofibromatosis. Hum Mol
Genet. 2017;26(10):1801–1810. PubMed doi: 10.1093/hmg/
myosarcoma soft tissue tumor in infants. It typically presents
ddx081
within the first 2 years of age, with about 40% of cases evi-
4. Machado Morais J, Castro C, Ferraz C, Lima J, Barroca H,
dent at birth.12 This tumor is characterized by rapid growth Bom-Sucesso M. Congenital infantile myofibroma: the
and is often poorly circumscribed, potentially involving sub- importance of molecular diagnosis. Cureus. 2023;15(3):e35885.
cutaneous fat, fascia, and tendons, particularly in the distal PubMed doi: 10.7759/cureus.35885

extremities.13 Histologically, infantile fibrosarcoma is charac- 5. Shahzad F, Chappell AG, Purnell CA, Aldulescu M, Chamlin S.
Infantile myofibroma presenting as a large ulcerative nodule
terized by spindle cells with fusiform oval nuclei and lance- in a newborn. Case Rep Pediatr. 2019;2019:3476508. PubMed
shaped, tapered cells.12,14 The management of infantile fibro- doi: 10.1155/2019/3476508
sacrcoma generally involves surgical excision, and the prog- 6. Wiswell TE, Davis J, Cunningham BE, Solenberger R, Thomas
nosis is typically favorable.13 Like infantile hemangioma, in PJ. Infantile myofibromatosis: the most common fibrous tumor
of infancy. J Pediatr Surg. 1988;23(4):315–318. PubMed
this case, the size of the mass at birth makes infantile fibro- doi: 10.1016/S0022-3468(88)80196-9
sarcoma less likely. 7. Narayen V, Ahmed SA, Suri C, Tanveer S. Myofibroma of the

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Rhabdomyosarcoma is the most common soft tissue sar- gingiva: a rare case report and literature review. Case Rep Dent.
coma in childhood, originating from rhabdomyoblasts, 2015;2015:243894. PubMed doi: 10.1155/2015/243894
which are primitive mesenchymal cells with varying degrees 8. Hegde U, Sheshanna SH, Doddawad VG, Nitin P.
Immunohistochemistry: an indispensable aid in diagnosis and
of skeletal muscle differentiation. This type of sarcoma
management of infantile myofibroblastoma. J Oral Maxillofac
accounts for approximately 50% of pediatric soft tissue sar- Pathol. 2021;25(3):558. PubMed doi: 10.4103/jomfp.
comas.14 Rhabdomyosarcomas can occur in various loca- jomfp_388_20
tions, with those arising from the genitourinary tract, such 9. Braun V, Prey S, Gurioli C, et al. Congenital haemangiomas: a
single-centre retrospective review. BMJ Paediatr Open. 2020;4(1):
as the vagina or bladder wall, being particularly common
e000816. PubMed doi: 10.1136/bmjpo-2020-000816
in infants.14 Head and neck rhabdomyosarcomas are also fre-
10. Chamli A, Aggarwal P, Jamil RT, Litaiem N. Hemangioma.
quently observed in young children. Tumors in the extrem- In: StatPearls. StatPearls Publishing; 2023.
ities are less common in newborns but can appear in 11. Haggstrom AN, Drolet BA, Baselga E, et al; Hemangioma
adolescents.15 Investigator Group. Prospective study of infantile hemangiomas:
demographic, prenatal, and perinatal characteristics. J Pediatr.
2007;150(3):291–294. PubMed doi: 10.1016/[Link].2006.12.003
12. Han Y, Lian K, Zhang D. Treatment of infantile fibrosarcoma:
CONCLUSION
a tertiary care center experience. Front Pediatr. 2022;10:1015185.
A large, red-purple nodular lesion in a healthy newborn may PubMed doi: 10.3389/fped.2022.1015185
be a scenario that a pediatrician will encounter in the new- 13. Chung EB, Enzinger FM. Infantile fibrosarcoma. Cancer.
1976;38(2):729–739. PubMed doi: 10.1002/1097-0142(197608)
born nursery. An accurate diagnosis can begin with ultra-
38:2<729:AID-CNCR2820380216>[Link];2-Z
sound imaging to determine vascularity of the lesion,
14. Davis DD, Shah SJ, Kane SM. Fibrosarcoma. In: StatPearls.
biopsy or excision with histologic stains, possible imaging StatPearls Publishing; 2023.
of other organs to assess for systemic disease, and consulta- 15. Kaseb H, Kuhn J, Babiker HM. Rhabdomyosarcoma. In: StatPearls.
tion with pediatric surgery or pediatric dermatology. StatPearls Publishing; 2022.

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 COMPLEX FETAL CARE

COMPLEX
FETAL CARE

Navigating Prenatal Diagnosis of Fetal

Agnathia: A Complex Case and
Diagnostic Journey
Kelly S. Sulo, DNP, MSN-Ed,1 Megan Kraemer, DO,1 Mindy Li, MD,2 Anatoli F. Karas, MD,3,4 Xavier Pombar, DO,5
Esther Lee, MD, MPH1

CASE PRESENTATION
A 27-year-old Gravida 7 Para 1142 woman received a second opinion referral to our
maternal-fetal medicine (MFM) center at 31 1/7 gestational weeks for a palliative
induction of labor for fetal agnathia. Maternal history was significant for recurrent

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first-trimester spontaneous abortions, and no other significant maternal medical,
surgical, or family history was reported. Although the pregnancy was initially
uneventful, imaging at 29 weeks’ gestation showed possible fetal agnathia. At this
time, the amniotic fluid index (AFI) was markedly high at 39.5 cm (>97th percentile,
normal AFI >5 to 24 cm, severe polyhydramnios AFI ≥24 cm), indicating severe
polyhydramnios, with the largest pocket noted at 14.9 cm (normal depth 2 to
8 cm).1 Ultrasound imaging additionally noted no visible mandible or lower lip,
which is concerning for agnathia. Magnetic resonance imaging was recommended
and completed at the referring hospital. This was described as challenging to deter-
mine with certainty the presence of a mandible. Genetic testing, including chromo-
somal microarray analysis with reflex testing to an agnathia-otocephaly complex
(AOC) panel (Prevention Genetics), was initiated following amniocentesis/amnior- ABBREVIATIONS

eduction. The patient was subsequentially referred to our MFM center for a second 2D two-dimensional
opinion and consideration of a palliative induction of labor. 3D three-dimensional
AFI amniotic fluid index
The patient received a comprehensive ultrasound examination at 31 1/7 weeks’ AOC agnathia-otocephaly complex
gestation with our MFM specialist. At this time, a two-dimensional (2D) grayscale EXIT ex utero intrapartum treatment
and three-dimensional (3D) reconstruction of the fetal face, including profile and MFM maternal-fetal medicine
VUS variant of uncertain significance

1
AUTHOR DISCLOSURE: Dr Pombar serves on the ethics comittee for the Society of Maternal Neonatal Intensive Care Unit, Department
Fetal Medicine. Drs Sulo, Karas, Kraemer, Lee, and Li have disclosed no financial relationships of Pediatrics, Rush University Medical
relevant to this article. This article does not contain a discussion of an unapproved/investigative Center, Chicago, Illinois; 2Division of
use of a commercial product/device. Genetics, Department of Pediatrics, Rush
University Medical Center, Chicago, Illinois;
Accepted for Publication Date: August 9, 2024 3
Department of Pediatrics, Rush University
[Link] Medical Center, Chicago, Illinois;
4
Copyright © 2025 American Academy of Pediatrics Department of Otorhinolaryngology, Head,
and Neck Surgery, Rush University Medical
Center, Chicago, Illinois; and 5Maternal and
Fetal Medicine, Silver Cross Hospital,
New Lenox, Illinois

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 coronal views, were conducted. The 2D ultrasound and
3D reconstructions failed to visualize the fetal mandible
(Figures 1 and 2), although the fetal maxilla was present.
The ears were low-set on 2D and 3D images (Figures 3
and 4), and the mouth appeared small, indicative of

FIGURE 4. Prenatal 3-dimensional reconstruction ultrasound imaging

of small mandible, left sagittal view.

FIGURE 1. Prenatal 2-dimensional ultrasound imaging of small

mandible, right sagittal view.

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FIGURE 5. Prenatal 3-dimensional reconstruction ultrasound imaging
of low-set left ear.

microstomia (Figures 5 and 6). Polyhydramnios was recon-

firmed, with the deepest vertical pocket measuring 10.4 cm
FIGURE 2. Prenatal 2-dimensional ultrasound imaging of low-set (Figures 7 and 8). The stomach bubble remained small
left ear.
throughout the examination (Figure 9). The estimated fetal
weight was 2176 g, consistent with the 95th percentile. The
MFM team detected no other fetal abnormalities.

EXPERT OPINION
MFM
The 2D and 3D reconstruction fetal ultrasound images in this
case supported the diagnosis of agnathia. Normally, man-
dibular formation occurs in the embryo around the third ges-
tational week.2 Goenka et al explain that detection of AOC
can occur as early as 11 to 14 weeks of gestation.3 If a nor-
mal-appearing mandibular arch is not visualized by the start
of the second trimester, repeat imaging should be obtained at
FIGURE 3. Prenatal 2-dimensional ultrasound imaging of
15 to 16 weeks’ gestation to exclude agnathia.3 On the other
microstomia, frontal. hand, fetuses severely affected by the AOC may have other

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FIGURE 6. Prenatal 3-dimensional reconstruction ultrasound imaging
of microstomia, frontal view.
FIGURE 9. Two-dimensional grayscale ultrasound imaging with small
stomach.

abnormalities, including central nervous system, skeletal,

renal, or cardiac anomalies, that prompt an earlier diagnostic
evaluation.4 Most cases of agnathia are diagnosed in the sec-

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ond or third trimesters.3 Although several different facial
ultrasound screening methods have been proposed, no uni-
versal facial ultrasound screening exists.5 Later in gestation,
ultrasound may fail to clearly detect the fetal stomach
because of swallowing difficulties secondary to the agnathia
and microstomia. Other syndromes in the differential diag-
nosis for agnathia include Goldenhar syndrome, Nager
syndrome, Pierre Robin syndrome, and Treacher-Collins
FIGURE 7. Two-dimensional Doppler ultrasound imaging syndrome.5
demonstrating polyhydramnios. Polyhydramnios commonly occurs in the third trimester.
Abbreviation: MVP, maximum vertical pocket.
Importantly, the absence of polyhydramnios in early gesta-
tion does not exclude agnathia.5 Different imaging modal-
ities during pregnancy can help characterize the spectrum
of involvement in AOC. Initially, 2D and 3D ultrasound
are used. As the pregnancy advances, the lower part of the
jaw may be difficult to fully visualize.5 At this point, helical
computerized tomography or magnetic resonance imaging
scans may be used later in pregnancy to better monitor
the fetus. Intrauterine management of agnathia may in-
clude amnioreduction for severe polyhydramnios.6 Families
require interdisciplinary care throughout the pregnancy.
Overall, AOC carries a very poor, if not lethal, prognosis.5
The outcome worsens for individuals with agnathia and asso-
ciated defects, especially abnormalities of the central nervous
syndrome.6 Without treatment immediately following deliv-
ery, infants with agnathia die from respiratory failure due to
airway obstruction.7 Survival beyond the intrapartum period
FIGURE 8. Two-dimensional grayscale ultrasound imaging with
requires perinatal tracheostomy and gastrostomy place-
polyhydramnios. ment.4 An individualized plan of care for each family must

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 be established during the pregnancy to optimize manage-
ment during delivery.

Genetics
The AOC represents a spectrum of malformation of the first
branchial arch that occurs in early embryogenesis and is usu-
ally lethal.1,8 Current genetic testing options for congenital
malformations include chromosomal microarray, single-
gene testing, panel gene testing, and whole-exome sequenc-
ing. Genetic testing may identify a molecular cause in either
of the two genes known to be associated with AOC, PRRX1 or
OTX2. Despite advances in technology, more than half of
individuals with AOC do not have an identifiable genetic eti-
ology. This makes counseling families on recurrence risk
extremely challenging. Diagnostic rates may increase as
newer technologies such as whole-genome sequencing are
increasingly used, but data on this have not been published
to date on patients with AOC. Families should still be offered FIGURE 10. Postnatal photographs of the small mandible and low-
set, posteriorly rotated right ear, downslanting palpebral fissure.
genetic counseling when agnathia is identified prenatally
given the complexity of clinical findings and likely poor
lip, inability to open the mouth, low-set ears that were
outcome.
posteriorly rotated, and downslanting palpebral fissures

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Otolaryngology (Figure 10). The infant never had an audible cry. The family
From an otolaryngology perspective, intrauterine manage- lovingly held the baby, and he died at 70 minutes after birth.
ment of agnathia is expectant. Based on prognosis and the With parental consent, a pediatric otolaryngologist per-
family’s requests, the interdisciplinary team caring for the formed bedside endoscopy shortly after death. A photograph
infant with agnathia can plan intrapartum management. of the external mouth showed microstomia and absent lower
Parents requesting full resuscitation for milder cases of agna- lip (Figures 11 and 12). The scope was then passed into the
thia may be offered the option of ex utero intrapartum treat- mouth opening. A photograph obtained just within the oral
ment (EXIT).5 An EXIT procedure may be planned so that the cavity revealed an abnormally narrow hard palate with a mid-
otolaryngologist can evaluate the severity of airway obstruc- line groove superiorly and a triangular bud inferiorly, pre-
tion and possible treatment options.6 Intrapartum manage- sumed to be a part of the unformed mandible (Figure 13).
ment with an EXIT procedure remains controversial due to The posterior oropharynx beyond this had a mucosal mem-
the overall poor outcome associated with AOC.6 When brane that did not allow the scope to pass into the oropharynx
parents elect for aggressive treatment and resuscitation, an or larynx. The scope was then passed through the naris,
airway is established, usually via tracheostomy, during deliv-
ery while the neonate is still on placental support. Nutrition
requires a nasogastric tube or gastrostomy tube. Patients
with agnathia surviving past infancy typically require multi-
ple surgeries for craniofacial, and specifically mandibular,
reconstruction.9,10

OUTCOME
In this case, the family declined the EXIT procedure and
decided to pursue palliative induction due to the confirmed
agnathia on multiple imaging modalities. The male infant
was born without a spontaneous cry and was apneic. The
infant exhibited pallor and mottling with minimal spontane-
ous movements. Notable physical examination findings FIGURE 11. Postnatal photographs of severe microstomia and
included agnathia, absent lower lip, presence of the upper posteriorly set ears.

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FIGURE 12. Images from the postmortem bedside endoscopy by FIGURE 15. Images from the postmortem bedside endoscopy by the
the otolaryngologist: external mouth and upper lip. otolaryngologist: closer view of what appears to be a tongue bud.

secretions (Figures 16 and 17). The scope was also passed

through the vocal cords. The trachea was filled with secre-
tions but otherwise appeared to be intact with normal rings
and carina.

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FIGURE 13. Images from the postmortem bedside endoscopy by
the otolaryngologist: appearance of hard palate.

which was connected to the nasopharynx, oropharynx, and

larynx. A smooth, ovoid structure on the inferior aspect
mouth represents a presumed, rudimentary tongue, or FIGURE 16. Images from the postmortem bedside endoscopy by
the otolaryngologist: epiglottis.
microglossia (Figures 14 and 15). The visualized vocal cords
and epiglottis appeared unremarkable other than clear

FIGURE 17. Images from the postmortem bedside endoscopy by

FIGURE 14. Images from the postmortem bedside endoscopy by the otolaryngologist: vocal cords; circular structure at 6’o’clock is a
the otolaryngologist: appearance of rudimentary tongue. bubble formed by secretions.

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 The infant’s clinical features appeared most consistent report to be able to spread knowledge of this condition to
with PRRX1-related AOC. Chromosome microarray per- the medical community and families facing similar circum-
formed on amniotic fluid cells was nondiagnostic and stances. We are forever grateful for your strength, love, and
dedication.
revealed an 18.4-kb deletion at 14q11.2, classified as a variant
of uncertain significance (VUS). This VUS is not known to be
associated with agnathia. The AOC panel, which included
References
sequencing and deletion/duplication analysis of OTX2 and
1. Reddy UM, Abuhamad AZ, Levine D, Saade GR; Fetal Imaging
PRRX1, was negative. Trio exome analysis later identified
Workshop Invited Participants*. Fetal imaging: executive
maternal inheritance of the 14q11.2 deletion without other summary of a joint Eunice Kennedy Shriver National Institute of
additional findings. Child Health and Human Development, Society for Maternal-
Fetal Medicine, American Institute of Ultrasound in Medicine,
American College of Obstetricians and Gynecologists, American
DISCUSSION College of Radiology, Society for Pediatric Radiology, and Society
Agnathia is a rare congenital craniofacial defect with a preva- of Radiologists in Ultrasound Fetal Imaging workshop. Obstet
Gynecol. 2014;123(5):1070–1082. PubMed doi: 10.1097/AOG.
lence of less than 1 in 70 000 live births. The condition is 0000000000000245
primarily characterized by severe underdevelopment or 2. Schiffer C, Tariverdian G, Schiesser M, Thomas MC, Sergi C.
absence of the mandible, resulting in a missing lower jaw, Agnathia-otocephaly complex: report of three cases with
restricted mouth opening, and an underdeveloped chin. involvement of two different Carnegie stages. Am J Med Genet.
2002;112(2):203–208. PubMed doi: 10.1002/ajmg.10672
Agnathia encompasses a spectrum of severity, ranging from
3. Goenka S, Sahithi K, Ratha C. Prenatal diagnosis of otocephaly:
partial mandibular agenesis to complete absence of the man- a rare facial anomaly. J Obstet Gynaecol India. 2022;72(4):
dible. When agnathia occurs concurrently with other cranio- 364–368. PubMed doi: 10.1007/s13224-021-01494-x
facial anomalies involving the first pharyngeal arch, such as 4. Alexander NL, Chandy B, Barton G, Liu YCC. A case of rare

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auricular fusion (synotia), microstomia with oroglossal hypo- isolated agnathia and literature review. Am J Med Genet A.
2020;182(10):2409–2416. PubMed doi: 10.1002/ajmg.a.61784
plasia, or aglossia, it forms the AOC. The AOC presents com-
5. Tantbirojn P, Taweevisit M, Sritippayawan S,
plex medical challenges due to upper airway obstruction.
Tanawattanacharoen S, Uerpairojkit B. Prenatal three-
Most cases of AOC occur sporadically. Genes associated with dimensional ultrasonography in a case of agnathia-otocephaly.
AOC in humans include OTX2 and PPRX1 as previously J Obstet Gynaecol Res. 2008;34(4 Pt 2):663–665. PubMed
mentioned; however, most affected individuals do not have doi: 10.1111/j.1447-0756.2008.00904.x

mutations in OTX2 or PPRX1, suggesting the involvement 6. Suemitsu T, Takesawa A, Hosokawa M, et al. Isolated agnathia-
otocephaly complex diagnosed prenatally for ex-utero
of other genes or multifactorial or nongenetic factors. intrapartum yreatment: a case report. Am J Case Rep. 2023;24:
Survival with AOC necessitates perinatal tracheostomy and e939016. PubMed doi: 10.12659/AJCR.939016
gastrotomy placement. 7. Donnelly M, Todd E, Wheeler M, Winn VD, Kamnasaran D.
This case underscores the importance of multidisciplinary Prenatal diagnosis and identification of heterozygous frame-
shift mutation in PRRX1 in an infant with agnathia-otocephaly.
collaboration in neonatal care to further the understanding of Prenat Diagn. 2012;32(9):903–905. PubMed doi: 10.1002/
congenital anomalies. A team consisting of MFM physicians, a pd.3910
pediatric otolaryngologist, geneticists, and neonatal specialists 8. Dubucs C, Chassaing N, Sergi C, et al. Re-focusing on agnathia-
partnered to provide comprehensive support to a family with otocephaly complex. Clin Oral Investig. 2021;25(3):1353–1362.
PubMed doi: 10.1007/s00784-020-03443-w
antenatal diagnosis of agnathia. Further investigations and
9. Gonzalez SR, Jones JK, Golinko MS. Surgical approach in a
ongoing genetic counseling may provide additional insights
patient with agnathia-otocephaly complex: three-stage
into the underlying factors contributing to this rare condition. mandibular distraction protocol. J Craniofac Surg. 2020;31(1):
e84–e89. PubMed doi: 10.1097/SCS.0000000000005945
Acknowledgments 10. Golinko MS, Shetye P, Flores RL, Staffenberg DA. Severe
We would like to give a special thanks to baby F and his loving agnathia–otocephaly complex. J Craniofac Surg. 2015;26(8):
parents who eagerly awaited the publication of this case 2387–2392. PubMed doi: 10.1097/SCS.0000000000002150

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 EQUITY, DIVERSITY, AND INCLUSION CASE SERIES

Fostering Breastfeeding Equity in the

Neonatal Intensive Care Unit
Keadrea Wilson, MD, FAAP,1 Bhuvaneshwari Jagadesan, MD, FAAP,1 Karis Browder, MD, FAAP,1
Jennifer M. Davidson, DO, FAAP,1 Joni Rose, MS, RD, LDN, IBCLC, RLC,2 Michelle-Marie Peña, MD, FAAP3

PRACTICE GAP

Clinicians should be aware of the benefits and challenges of breastmilk pro-

vision in the neonatal intensive care unit (NICU) as well as the evidence-
based strategies to mitigate the barriers to breastfeeding.

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

1. To describe the intangible and tangible costs of breastfeeding

2. To identify unconscious biases regarding breastfeeding
3. To cultivate a trauma-informed approach and be curious when commu-
nicating with parents about breastfeeding
4. To explain ways to mitigate barriers to parents providing milk within the
hospital setting

ABSTRACT
The benefits of mother’s milk are abundant and well known for both term
and preterm infants (Note: Not everyone who provides human milk identi-
fies as a woman or relates to the term “breastfeeding,” but because this
accompanies the majority of infant feeding experiences, we have made ABBREVIATIONS
the decision to phrase it this way while also acknowledging that this NICU neonatal intensive care unit
HCP health care provider
language can be exclusionary). The American Academy of Pediatrics now
TIA trauma-informed approach
supports longer breastfeeding duration through the first 2 years of age.1 VLBW very low birth weight

1
AUTHOR DISCLOSURE: Dr Pena works under grants from the National Institutes of Health and Department of Pediatrics, Division of
The March of Dimes and has attended meetings with the support of the AAP. Drs Wilson Neonatology, University of Tennessee
Jagadesan, Browder, Davidson, and Ms Rose have disclosed no financial relationships relevant to Health Science Center, Memphis, Tennessee;
2
this article. This commentary does not contain a discussion of an unapproved/investigative use LeBonheur Children’s Hospital, Memphis,
of a commercial product/device. Tennessee; and 3Department of Pediatrics,
Division of Neonatology, Emory University
Accepted for Publication Date: November 8, 2024
School of Medicine and Children’s
[Link] Healthcare of Atlanta, Atlanta, Georgia
Copyright © 2025 American Academy of Pediatrics

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 United States legislation in the last 2 decades has made progress in supporting breastfeeding, with policies such as
improved access to antenatal and postpartum lactation support, some improvements in double electric breast pump
access, and protected time and private spaces to pump at work for many employees.2,3 Despite this progress, sustained
breastfeeding beyond the early postpartum period remains challenging. Among all infants born in 2021, 84.1% received
breast milk for some time after birth, but this rate fell to 59.8% by 6 months and 39.5% at 1 year.4 There are also striking
disparities in which infants receive mother’s milk, with fewer non-Hispanic Black infants (75.4%) ever breastfeeding com-
pared with Asian infants (92.7%), non-Hispanic white infants (86.2%) and Hispanic infants (83.4%).4 Young mothers aged
20 to 29 years were also less likely to ever breastfeed than mothers 30 years and older.4 Similar disparities have been
shown among racial and ethnic groups who have been marginalized, with lower prevalences of any human milk at dis-
charge for non-Hispanic Black and Native American very low birth weight (VLBW) infants compared with white VLBW
infants.5,6 7Through the case reviews we present, we will discuss the underlying drivers of these breastfeeding inequities
in neonatal intensive care units (NICUs) by understanding the inherent costs of breastfeeding as well as the individual and
institutional level factors that impact mother’s milk provision.

MEET THE EXPERT CLINICAL VIGNETTES

Dr Michelle-Marie Peña serves as a clinical neonatologist 1. A 23 6/7 week gestational age female infant is born to a 15-
and Assistant Professor of Pediatrics at Emory University year-old Gravida 1 Para 1 adolescent from Guatemala with

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and Children’s Healthcare of Atlanta. Her health equity limited prenatal care. The mother is in middle school at
research agenda centers on supporting high-risk mother- the time of delivery, is Spanish-speaking, and lives in the
infant dyads in the NICU through action-oriented method- United States with multiple relatives, one of whom is
ologies. She uses equity-focused quality improvement and interested in obtaining custody of the infant. Soon after
implementation science to address inequities in parents’ birth, the lactation team from the birthing hospital gave
milk provision and lactation support practices, including the infant’s mother a double electric pump, and she
skin-to-skin care and breast pump access, both locally and reports pumping once per day because she is in school.
statewide. After a month of receiving her mother’s milk, the infant
receives donor breast milk feedings and later is transi-
tioned to a diet of infant preterm formula because her
KEY TERMS mother has stopped pumping and is unable to visit often
Implicit bias is a negative attitude toward a specific social to breastfeed. Otherwise, the infant’s NICU course is
group of which one is not consciously aware.22 complicated by osteomyelitis, cystic kidneys, retinopathy
A trauma-informed approach (TIA) involves realizing of prematurity, early signs of bronchopulmonary dyspla-
the widespread impact of trauma, recognizing the sia, and intraventricular hemorrhage.
signs and symptoms of trauma (eg, in patients or their 2. A 22 4/7 week gestational age female infant is born to a
parents), responding by integrating this knowledge 30-year-old Gravida 1 Para 1 Black woman whose preg-
in all areas of organizational functioning, and actively nancy is complicated by cervical insufficiency, tobacco
resisting retraumatization or creating stress without sup- use, chronic hypertension, marijuana use, bipolar disor-
porting patient coping. The TIA encompasses the funda- der, domestic abuse, and poverty. Additionally, the father
mental principles of safety, trustworthiness and of the baby has a history of hydrocephalus with shunt place-
transparency, peer support, collaboration and mutuality, ment. Shortly after delivery, the mother was hospitalized
empowerment, and acknowledgment of cultural, historical for pneumonia. She received lactation support at the birth
and gender issues.23 hospital and level 4 NICU where the infant was transferred
Opportunity costs include investment in pumping sup- for patent ductus arteriosus closure. The mother had been
plies at the expense of other items, the monetary value of collecting drops of breast milk several times per day with
time spent navigating insurance or reimbursements, or a manual breast pump for the first 2 months after delivery
monetary value of time spent pumping.24 due to preference. She desires to stop pumping due to

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 multiple stressors like physical weakness after having In addition to support, a mother’s decision to continue
pneumonia, physical abuse from the infant’s father, and expressing her milk will also be influenced by her success
difficulty securing a job and secure housing. or perceived success of milk expression. Mothers of preterm
infants often have comorbidities and delivery histories that
place them at risk for delayed lactogenesis. Stress and poor
PERSPECTIVE-TAKING nutrition can also hinder lactation success. Thus, lan-
Vignette 1: If you were the mother described in Vignette 1, guage-appropriate, longitudinal, and trauma-informed lacta-
what may influence your decision to initiate and continue tion support is critical, especially counseling that is adapted
breastfeeding? to the mother’s context—school and home in this case.8
Dr Michelle-Marie Peña [M.M.P.], who identifies as a Encouraging breastfeeding support practices, such as skin-
Hispanic, cis woman, responds: to-skin care and involving parents in oral care, can also
As an adolescent in middle school who emigrated from a empower parents at the bedside.
foreign country and prefers a language other than English, It is also important to emphasize that there is still a dose
I would feel overwhelmed by not only the pregnancy but also response to breast milk, so every drop counts.14,15 Being told
now the unexpected delivery and need to care for an extremely to pump 8 times a day may not help someone who is cur-
preterm infant. I am curious about the circumstances that led rently pumping once a day—we have to be realistic and
to her pregnancy at such a young age. One consideration use motivational interviewing and trauma-informed
includes trauma of sexual assault or abuse, which would be approaches. Our goal is to provide parents with information
important to know as we support her as a new mother. and support them in how they desire to feed their infant,
Breastfeeding initiation for this mother is likely influ- “meeting them where they are.” We, as providers, are there
enced by her prenatal exposure and education on infant to support them to be the best parents they can be.

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feeding choices, which includes education in schools, com- Vignette 2: As the neonatologist, how might you tailor
munity and family experiences and opinions on breast- your conversation around breastfeeding to the mother in
feeding, and education on infant feeding choices in the second case, given the infant and mother’s medical
prenatal visits. Having an extremely preterm infant may and social history?
push her to initiate providing her milk even if that had not Dr Keadrea Wilson, who identifies as a Black, cis woman,
been her plan. responds:
In fact, mothers of preterm infants, including Hispanic When I review the clinical vignette of this dyad, I quickly
and non-Hispanic Black mothers, have high breastfeeding understand that the journey to the NICU has already been
initiation rates and often provide their infants with at least fraught with difficulty. The mother has multiple chronic dis-
some of their milk, likely due to in-hospital counseling eases and mental health concerns, threats to her life by a vio-
and education on the clinical benefits of breast milk for pre- lent partner, and even unmet physical needs owing to
term infants’ brains, lungs, gut, and overall health.5,8,9 poverty. These multiple levels of adverse experiences and
Support to continue expressing milk is critical starting stress compound to influence lactogenesis and the decision
with the hospital team (especially longitudinal lactation sup- to initiate and continue breastfeeding.16,17 Further complicat-
port) as well as support from the mother’s family and, in this ing the postnatal experience is the trauma inherent to having
case, the mother’s school. The first 14 days postpartum are a preterm infant in the NICU.18 The crisis of preterm birth
especially critical to establish milk supply.10 Mothers quickly alters parents’ perception of parenting, strains their ability to
encounter challenges during this period, as they must use a cope, and triggers a wide array of physical, emotional, and
breast pump for hours per day and have resources to be able behavioral changes such as disorientation, fear, anxiety,
to visit their infant and ferry their milk to the NICU. In addi- depression, and guilt that may lead to changes in sleep pat-
tion, this mother is a postpartum adolescent with a higher terns, changes in diet, and social withdrawal.18 This infant
risk for feelings of fear and self-doubt while in school.11,12 was also born extremely premature, which places his health
We know that stress negatively impacts parents’ psychologi- in a precarious place from the beginning of his life and sub-
cal state and milk supply. It is not surprising that, over time, jects his parents to prolonged uncertainty and likely cycles of
studies have shown that provision of breast milk declines in crisis and adaptation.18 Additionally, the infant already has
the NICU, and this trend is magnified for Hispanic and non- the need to transfer to another unit for a cardiac procedure,
Hispanic Black infants often due to intersectional factors further separating the infant from his parents. Clinicians
including social determinants of health such as poverty must be aware of these complexities prior to approaching
and other social stressors.6,13 conversations on breastfeeding.

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 Having acknowledged the marked trauma in this case, own milk costs $0.95 to $1.55 when maternal opportunity
I would then frame my conversation using a trauma- costs (eg, time spent pumping or forgone wages while doing
informed approach, prioritizing psychological and physical something other than paid work) are excluded and $2.60 to
safety from the beginning.19 This means choosing to have $6.18 when opportunity costs are included.24 Although
this conversation unrushed, in person, if possible, within authors found that this is inexpensive compared to donor
the infant’s room or another quiet space and at the mother’s milk and formula, these early costs may still be prohibitive
preferred time. I then would move to validate her as a for mothers, especially those with lower income and/or less
parent—specifically, a good parent. Studies of NICU parent psychosocial support.24 Other authors also deeply consid-
experiences reveal that parents need to hear several empow- ered the direct costs of breastfeeding (equipment costs,
ering messages about being a good parent.20 This mother lactation-related nutritional requirements, and opportunity
has reached a point in her breastfeeding journey where costs), and they estimated that the annual costs of breast-
she wants to stop pumping. While I would ideally desire a feeding to be between $8640.07 and $11 611.32.25 More-
longer duration of mother’s milk, I must “meet this mother over, they explained that breastfeeding, unlike formula feed-
where she is” and acknowledge the successes of her breast- ing, is relegated to mothers only and that the opportunity
feeding journey up to this point. Despite the challenges of costs may be highest in low-income mothers whose jobs
her own health and well-being in addition to the infant’s may be less flexible or more physical, preventing simultane-
health, she initiated pumping and has been providing milk ous working and pumping.25 Beyond this, mothers must
over the last 2 months. This is commendable and deserving consider the timing of when to return to work, if, when,
of praise for her positive contribution to her child’s health and how to reduce hours at work, maternal leave duration,
and the sacrifice she endured. Because of the mother’s duties related to infant care after discharge from the
expressed physical and mental health challenges, I would NICU, educational pursuits, and unpaid domestic and care

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not probe “why” further or attempt to motivate her to recon- work at home—all of which affect economic stability and
sider her decision. After all, as neonatal clinicians we must the health of their preterm infant.25,26
prioritize both the infant and mother’s well-being. I would Outside of the supplies and time needed for breast-
offer additional lactation support if she changed her mind feeding, breastfeeding is physically and mentally taxing,
but also provide instructions on how to safely stop her supply. especially in those who are fully or partially pump
Once a parent stops breastfeeding, feelings of guilt or dependent, as are most mothers of preterm infants.
even relief may occur. Validating that there are still other Although some researchers have found that breastfeeding
ways to parent and have agency is important. In this case, this can provide a sense of agency for parents who suddenly
is especially important since mothers with greater exposure may experience shattered expectations, helplessness and
to traumatic events have lower visitation rates.21 Other prolonged uncertainty, others acknowledge both the physi-
common reported barriers to visiting that may affect this cal and mental rigors of breastfeeding.18,27 Breastfeeding
mother include the commute to the hospital, problems with mothers may experience mastitis, bleeding nipples, and
hospital parking, and job/employment.21 Perhaps in this painful uterine contractions.28 In addition, mothers may
conversation or the next, it would be important to underline experience symptoms of depression or have feelings of
ways that this parent could still have a parenting role through “inadequacy, incompetency and isolation” if there is per-
engagement at the bedside, which may include skin-to-skin ceived poor progress or there are challenges with the initia-
care, diaper changes, reading, and peer support.18,20 tion and continuation of breastfeeding.27 Thus, the physical
and mental health impacts are additional indirect costs that
mothers must pay during their breastfeeding course in
DISCUSSION the NICU.
Understanding the Inherent Costs of Breastfeeding
to the Parent Mitigating the Costs Through Individual and
Although it is historically thought that breastfeeding is cost- Institutional Strategies
effective, the provision of a mother’s own milk has many Health care professionals can play an essential role in pro-
costs—both direct and indirect. From equipment to time viding education and counseling to support breastfeeding
spent pumping to the emotional toll, mothers bear much initiation and continuation. In practice, our implicit biases
of the costs of breastfeeding while an infant is hospitalized influence our actions, especially toward patients of racial, eth-
in the NICU. A retrospective analysis of mothers of hospital- nic, or cultural minorities, and can drive health disparities
ized VLBW infants showed that providing 100 mL of their and the deepening of health inequities.22,29 In a study of

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TABLE 1. Implicit Bias Mitigation Techniques When Discussing Breastfeeding in the NICU
Example of Breastfeeding-Related Implicit Bias Mitigation Strategy Example of Reframing
The HCP was involved with a code in the NICU, and Emotional regulation Before entering the room, the HCP should stop and
the HCP’s next task is to discuss breastfeeding consider what they are doing and thinking, take a
with a mother. slow, deep breath, and contemplate their thoughts,
feelings, and assumptions. If they have a gut feeling
about how the conversation will go, that is a sign of
implicit bias.32
A mother states she doesn’t want to breastfeed but Partnership building The HCP should purposefully frame the encounter
doesn’t offer reasons why. emphasizing that the parent and the HCP both share
the goal of providing the best care for the infant.32
A mother approaches an HCP in tears and wants to Perspective-taking The HCP should purposefully think about what the
discuss discontinuing breastfeeding. parent is thinking and feeling by trying to imagine
how they would feel in their shoes. This will help
stimulate feelings of compassion and caring.32
You are rounding on a baby, and the mother is at Stereotype The HCP should reflect on their negative reactions,
the bedside, and she appears young. Your gut replacement acknowledge whether they are stereotypical
instinct is that she will never breastfeed due to responses, and consider the reasons for these
her age. It is not worth the effort to have this feelings.32 The response can then be replaced with an
conversation. unbiased response in the present and be avoided in
future conversations. In this instance, the HCP may
acknowledge that young mothers can also have a
strong resolve, and that it can be channeled to
successfully breastfeed.
Abbreviations: HCP, health care provider; NICU, neonatal intensive care unit.

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International Board-Certified Lactation Consultants, authors supporting breastfeeding in the NICU. Generally, having a
found 3 subthemes of implicit bias: baby in the NICU can be stressful for any parent, and the
myriad experiences in the NICU (eg, receiving an unex-
1. an unconscious bias in which a patient receives less care pected, complicated, and/or life-threatening diagnosis for
and attention than their other racial counterparts; their baby with subsequent feelings of hopelessness or help-
2. when educational information is produced, a tendency to lessness) can be perceived as a traumatic event itself.33 Thus,
have images of certain mothers ignored or made invisible; a TIA is important in the care of infants and their parents in
and the NICU.33
3. race-based referrals to social services where formula was Regarding breastfeeding in the NICU, a TIA replaces
offered.30 “What’s wrong with this parent?” and goes beyond by asking
“What happened to this parent?” or even “What are they
Patients who experience these types of implicit bias by experiencing at this moment?” This approach aims to pro-
health care providers (HCPs) are less likely to initiate breast- vide physical and psychological safety and trust.19 A parent’s
feeding and, if they do initiate, have a shorter duration of sense of physical safety, for example, may be supported by
breastfeeding.30,31 giving privacy screens in an open unit or shared patient
As clinicians, we must recognize and develop strategies to room. Psychological safety can be fostered by the provider
mitigate implicit biases around breastfeeding if we want to maintaining an empathetic demeanor and avoiding judg-
improve breastfeeding success, especially among margin- mental language as parents share their breastfeeding opin-
alized groups. This work begins with paying attention to ions and goals.19,23 Additionally, the medical team should
one’s instincts when approaching a family to discuss breast- demonstrate trustworthiness and transparency with parents
feeding and acknowledging any discomfort, anxiety, or fear by actively listening to parents’ questions and concerns about
that may signal an implicit bias.32 Next, we must use differ- breastfeeding. An additional step is to provide information
ent strategies, like emotional regulation, partnership build- about the benefits of breastfeeding in an approachable man-
ing, perspective-taking, and stereotype replacement to ner without the use of medical jargon and in media that fits
mitigate implicit bias in our breastfeeding conversations different learning styles (pamphlets, online resources, con-
(Table 1).32 nection to support groups, etc).19,23
Beyond recognizing and mitigating implicit bias, HCPs An awareness of the potential for stressors or trauma
should consider incorporating a TIA and remain curious could help HCPs approach breastfeeding in a more open,
about possible parental needs and perspectives when nonjudgmental and supportive way. For example, an

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 adolescent mother in the NICU is more likely to have limited mother’s milk at discharge.40 One ongoing study is testing
knowledge of breastfeeding compared to older, more experi- the effectiveness of not only providing parents with a hospi-
enced parents.34 Adolescent mothers may face unique bar- tal-grade pump but also transportation of pumped milk from
riers to breastfeeding because of their age, including home to the NICU and payment for time spent pumping
return to school, limited transportation, the social stigma (opportunity costs).41 When considering racial and ethnic
attached to being an adolescent parent who is also lactating, disparities, tracking data, including stratified data on milk
the physical demands of lactation, and unease with the act of provision over time (eg, within 6 hours of age and 7, 14,
breastfeeding.34 After an individualized assessment of needs and 28 days of age as well as at discharge) and breastfeeding
and context, mothers may benefit from more in-depth teach- support practices, is foundational to target efforts. One state-
ing and coaching that is context specific. Studies show that wide quality improvement initiative found disparities in any
this focused support from partners and medical profession- mother’s milk provision emerging after the first 3 weeks of
als has led to more positive attitudes toward breastfeeding hospitalization, such that Hispanic and Black mothers had
and the initiation of breastfeeding in adolescent mothers.35 significantly lower percentages of any mother’s milk provi-
Additionally, to encourage continuation of breastfeeding, sion compared to white mothers at the time of discharge.5
health care professionals should focus on helping adolescent The group targeted these disparities by conducting qualita-
mothers balance maternal identity with developmental needs tive interviews of Black and Hispanic mothers to identify
like personal freedom. 35 facilitators and barriers to sustained breastfeeding. They also
Although perinatal breastfeeding education and counsel- conducted family engagement practice surveys, created mul-
ing provided by health care professionals are likely to result tilanguage education materials, and improved family engage-
in improvements in breastfeeding initiation among mothers ment practices overall.5
with lower incomes and of ethnic minorities, breastfeeding

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continuation beyond the perinatal period requires that HCPs
and NICUs address issues like hospital-grade or hospital- CONCLUSION AND MOVING FORWARD
strength pump access and maternal opportunity costs.36,37 Through these cases, we highlight the complex factors that
Access to breast pumps positively affects exclusivity and contribute to mothers’ desire and ability to provide their
duration of breastfeeding among mothers with premature own milk when they have an infant admitted to the NICU.
delivery, early return to work, and mothers with preg- Although legislation has made some progress with improv-
nancy-related complications because they can effectively ing pump access and early lactation support in some hospi-
extract milk to maintain and increase milk supply.38 tals, breastfeeding remains challenging for many mothers
Specifically, pumping helps these mothers “come to volume” with infants in the NICU, especially among those with young
or reach the critical volume (≥500 mL/d) within the first age, low socioeconomic status, mental and physical health
14 days. Mothers achieving this volume by 14 days are more problems, and among those belonging to marginalized racial
likely to provide human milk at NICU discharge compared to and ethnic groups. Maintaining supplies and adequate nutri-
mothers who did not.10,39 Additionally, in cases of preterm tion are only small parts of what is required to initiate and
delivery, the demand for human milk is lower initially as continue providing breast milk for longer durations success-
feeding volumes are low, and maternal milk supply may fully. Mothers must weigh the time spent pumping rather
appear artificially high, which can result in not reaching than pursuing education, care work, self-care, or working
the critical volume and inadvertently lessen the urgency outside of the home as well as the physical rigors of breast-
for continued lactation support.39 Thus, helping mothers feeding, the emotional effects of having a baby in the NICU,
secure double electric hospital-grade pumps paired with and competing priorities in their lives like caring for other
regular audits of human milk volumes are crucial, as routine children and themselves.
pumping is essential for maintaining breastfeeding in a pre- As NICU clinicians, we can foster breastfeeding equity
term infant who may not latch directly initially.37,39 amid these costs by advocating for innovative breastfeeding
Innovative and hospital-level solutions are essential for support and through self-reflection to limit bias in conversa-
sustaining breastfeeding in the NICU. Quality improvement tions about breastfeeding with parents. Clinicians must
bundles that include increased access to breast pumps within acknowledge these implicit biases, especially those toward
the NICU, a multidisciplinary team, parental and staff edu- racial, ethnic, and cultural minorities, that may negatively
cation, evidence based interventions like early human milk shape how we interact with breastfeeding parents and coun-
expression and tracking of milk volumes by lactation teams sel about breastfeeding. NICU clinicians should employ
are integral to promoting sustained breastfeeding and techniques like partnership-building and perspective-taking

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to improve our care around breastfeeding. We also can use a 6. Parker MG, Greenberg LT, Edwards EM, Ehret D, Belfort MB,
TIA approach to prioritize safety, listening, nonjudgment, Horbar JD. National trends in the provision of human milk at
hospital discharge among very low-birth-weight infants. JAMA
and accessibility to support families through their current Pediatr. 2019;173(10):961–968. PubMed doi: 10.1001/
breastfeeding journeys. Lastly, we must use equity-focused jamapediatrics.2019.2645
quality improvement in our hospitals to mitigate barriers 7. Patel AL, Johnson TJ, Meier PP. Racial and socioeconomic
and test interventions, supporting breastfeeding beyond disparities in breast milk feedings in US neonatal intensive care
units. Pediatr Res. 2021;89(2):344–352. PubMed doi: 10.1038/
the early postpartum period.42
s41390-020-01263-y
8. Parker MG, Lopera AM, Kalluri NS, Kistin CJ. “I felt like I was
a part of trying to keep my baby alive”: perspectives of Hispanic
American Board of Pediatrics and Non-Hispanic Black mothers in providing milk for their
very preterm infants. Breastfeed Med. 2018;13(10):657–665.
Neonatal-Perinatal Content PubMed doi: 10.1089/bfm.2018.0104

Specification 9. Parker MG, Patel AL. Using quality improvement to increase

human milk use for preterm infants. Semin Perinatol. 2017;
• Realize common problems associated with breast milk 41(3):175–186. PubMed doi: 10.1053/[Link].2017.03.007
production in the NICU and their management
10. Hoban R, Bigger H, Schoeny M, Engstrom J, Meier P, Patel AL.
• Know the issues in the organization of perinatal care Milk volume at 2 weeks predicts mother’s own milk feeding
(eg, regionalization, transport, practice guidelines, at neonatal intensive care unit discharge for very low birth-
benchmarking data, quality improvement). weight infants. Breastfeed Med. 2018;13(2):135–141. PubMed
• Understand health equity and health disparities doi: 10.1089/bfm.2017.0159
(eg, access, social determinants of health, implicit bias, 11. NICHQ. Building Resiliency in Teen Moms Can Improve
systemic racism) Breastfeeding and Save Babies. Published May 30, 2018.
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resiliency-teen-moms-can-improve-breastfeeding-and-save-
Acknowledgments

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babies#:~:text=There%20are%20no%20physiological%
The authors would like to thank the NeoReviews Equity,
20reasons,same%20thing%20as%20feeling%20capable
Diversity, and Inclusion consultant group, Daria Murosko,
12. Leclair E, Robert N, Sprague AE, Fleming N. Factors associated
MD, MPH, FAAP, and Kathryn Paul, MD.
with breastfeeding initiation in adolescent pregnancies: a cohort
study. J Pediatr Adolesc Gynecol. 2015;28(6):516–521. PubMed
Suggested Readings doi: 10.1016/[Link].2015.03.007
13. Parker MG, Gupta M, Melvin P, et al. Racial and ethnic
Parker MG, Stellwagen LM, Noble L, Kim JH, Poindexter BB, Puopolo disparities in the use of mother’s milk feeding for very low birth
KM; SECTION ON BREASTFEEDING, COMMITTEE ON weight infants in Massachusetts. J Pediatr. 2019;204:134-141.e1.
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Promoting Human Milk and Breastfeeding for the Very Low Birth
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Weight Infant. Pediatrics. 2021;148(5):e2021054272. PubMed doi: 10.
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jmwh.13058 doi: 10.1016/[Link].2021.101198

ANSWER KEY FOR MARCH 2025 NEOREVIEWS

Gastrointestinal Motility Disorders in the Neonate:
1. D; 2. B; 3. A; 4. C; 5. E
Congenital Diarrhea and Enteropathies:
1. D; 2. B; 3. C; 4. A; 5. E

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