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 PERSPECTIVES

A Call for Early Detection of Cerebral

Palsy
Faith Kim, MD,* Nathalie Maitre, MD, PhD,† on behalf of the Cerebral Palsy Foundation
*Department of Pediatrics, Columbia University Irving Medical Center/NewYork-Presbyterian Children’s Hospital of New York, New York, NY
†
Department of Pediatrics, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA.

PRACTICE GAPS

Clinicians caring for infants who are at risk of developing cerebral palsy
(CP) should be familiar with standardized assessment tools including the
General Movements Assessment and the Hammersmith Infant Neurological AUTHOR DISCLOSURES Dr Maitre has
worked under grants from the National
Examination. Clinicians trained in these tools can use them to make an
Institutes of Health and the Cerebral
early, accurate diagnosis of CP to allow for earlier intervention and Palsy Foundation; owns a patent, care of
improved outcomes. Enlighten Mobility and Thrive
Neuromedical; and is a cofounder of
Thrive Neuromedical. Dr Kim receives
support as a principal investigator for the
OBJECTIVES After completing this article, readers should be able to: Cerebral Palsy Foundation Early Detection
Initiative and has received honoraria for
being a guest speaker, courtesy of
1. Describe the changing spectrum of cerebral palsy (CP) diagnosis in Hackensack University and Morristown
infants treated in NICUs. Medical Center. This commentary does
not contain a discussion of an
2. Describe the development and implementation of clinical guidelines for unapproved/investigative use of a
early detection of CP. commercial product/device.

3. Recognize the utility of General Movements Assessment, Hammersmith

Infant Neurological Examination, and neuroimaging in the early ABBREVIATIONS

detection of CP. AIMS Alberta Infant Motor Scale

ASD autism spectrum disorder
CP cerebral palsy
CS cramped synchronized
ABSTRACT cUS cranial ultrasound
Cerebral palsy (CP) is the most common physical disability across the DAYC Developmental Assessment of
Young Children
lifespan, but historically, CP has not been diagnosed before the age of 2
EDI Early Detection and
years. Barriers to early diagnosis ranged from lack of available biomarkers, Implementation
absence of curative treatments, perceived stigma associated with a lifelong ELGAN Extremely Low Gestational Age
Newborn Study
diagnosis, and a desire to rule out other diagnoses first. Most importantly,
FM fidgety movement
the fundamental question that remained was whether children would GMA General Movements
benefit from earlier detection and intervention given the paucity of Assessment
research. However, evidence-based guidelines published in 2017 GMFCS Gross Motor Function
Classification System
demonstrated that the General Movements Assessment, the Hammersmith HIE hypoxic-ischemic
Infant Neurological Examination, and neuroimaging can be combined with encephalopathy
other elements such as a clinical history and standardized motor HINE Hammersmith Infant
Neurological Examination
assessments to provide the highest predictive value for diagnosing CP as
HRIF high-risk infant follow-up
early as age 3 months in high-risk newborns. Implementation of these IVH intraventricular hemorrhage
guidelines has been successful in decreasing the age at CP diagnosis, MRI magnetic resonance imaging
PVL periventricular leukomalacia
particularly in high-risk infant follow-up clinics with expertise in performing
TIMP Test of Infant Motor
these assessments. Early detection of CP allows for clinical and research Performance

Vol. 25 No. 1 JANUARY 2024 e1

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 opportunities investigating earlier interventions during a critical period of neuroplasticity, with the goal of
improving developmental trajectories for children and their families. New guidelines and research are now being
developed with a focus on early, targeted interventions that continue to be studied, along with global detection
initiatives.
INTRODUCTION
Cerebral palsy (CP) is the most common physical disabil-
ity across the lifespan, with approximately 10,000 infants
with a new diagnosis of CP every year in the United
States. (1)(2)(3)(4)(5)(6) Although the prevalence of severe
forms of CP has declined, the overall prevalence of the dis-
order has remained unchanged despite advances in obstet-
ric and neonatal care. (7)(8)(9) Children with CP can be
broadly categorized into groups based on their level of risk
at birth:
1. Term infants with hypoxic-ischemic encephalopathy
(HIE)
2. Preterm infants
3. Infants with identifiable and diverse risk factors such
as stroke, intrauterine drug exposure, cytomegalovirus,
and other infectious diseases
4. Infants with no identifiable risk factors (10)(11)(12)(13)
Among infants with moderate to severe HIE, 19% de-
veloped CP by 2 years of age despite therapeutic hypother-
mia, compared with 31% of nontreated infants. (14)(15)
(16)(17)(18)(19)(20)(21) Furthermore, it is well-established
that the risk of CP increases with decreasing gestational
age. (7)(22)(23)(24) A large systematic review demonstrated
a pooled prevalence of CP of 59 in 1,000 live births in in-
fants weighing 1,000 to 1,499 g at birth and 112 in 1,000
live births in infants born at less than 28 weeks’ gestation.
(9) Approximately 15% of preterm infants born between 24
and 27 weeks’ gestation develop CP, and as more infants at
younger gestational ages (22–23 weeks’ gestation) are sur-
viving, the rates of CP have increased to more than 20% in
the most premature infants. (23)(25)(26)(27) However, even
late preterm (34 to <37 weeks’ gestation) and moderately
preterm (32 to <34 weeks’ gestation) infants who comprise
the majority of infants born prematurely have higher odds
of developing CP compared with term infants, with white
matter injury representing the predominant type of abnor-
mal neuroimaging found in this subgroup of patients. (28)
Although the American Academy of Pediatrics recom-
mends motor development surveillance at ages 9, 18, 30,
and 48 months, a large proportion of term newborns who
develop CP may be undetected initially. (2)(29)(30)(31) A
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recent Canadian study used a prognostic bedside tool inte-
grating risk factors in the neonate and pregnant person
(eg, tobacco use, diabetes, preeclampsia, intra-amniotic in-
fection) and identified twice as many children with CP in
low-risk term infants compared with those who presented
with neonatal encephalopathy; however, this algorithm
has not yet been proven to be generalizable across popula-
tions. (32)
Standardizing practices to facilitate early detection of
CP across all groups of infants based on scientific evi-
dence will optimize identification and support the develop-
ment of additional effective interventions for affected
infants. In this article, we review the definition and risk
factors for CP as well as the history of early detection, in-
troducing readers to the basic elements and principles be-
hind assessment tools being implemented in high-risk
infant programs across the world.
OVERVIEW OF CP
The definition of CP has been debated dating back to 1861
when William Little first described a condition as “cerebral
paresis” that started in childhood and persisted across a
person’s lifespan. (33) The most cited definition in the lit-
erature reflects a large international consensus and reads
as follows: “[CP] describes a group of disorders of the develop-
ment of movement and posture, causing activity limitation that
is attributed to non-progressive disturbances that occurred in
the developing fetal or infant brain. The motor disorders of
[CP] are often accompanied by disturbances of sensation, cogni-
tion, communication, perception, and/or behavior, and/or by a
seizure disorder.”(34) This definition does not imply a single
etiology or discrete lesion but rather describes a spectrum of
disease with a common phenotype but possible broad origins,
or “disturbances.”(33) Mechanisms underlying the development
of CP are often attributed to 1) intrauterine factors (eg, placental
pathology, congenital anomalies, fetal growth restriction, drug
exposure), 2) peripartum events (eg, HIE, stroke, or intra-amni-
otic infection), 3) postnatal complications, most commonly due
to prematurity-related morbidities (eg, intraventricular hemor-
rhage [IVH] or periventricular leukomalacia [PVL]), or 4) identi-
fiable genetic factors. (35) However, the etiology of CP remains
unknown in half of affected children. Recent studies have
highlighted a more prominent role for genetic factors in the
 development of CP. Among 250 parent-offspring trios, of
which the majority (63%) were classified as having no identifi-
able cause associated with CP, whole-exome sequencing identi-
fied newly implicated genes in those with CP and estimated
that 14% of cases were related to a causative genomic mutation.
(36) A meta-analysis that included exome or genome sequenc-
ing in individuals with CP found an overall diagnostic yield of
8% to 16% in those with risk factors for CP versus 14% to
48% in those without risk factors; this finding is similar in pa-
tients with an intellectual disability or autism spectrum disorder
(ASD). (37) Thus, a genetic assessment is now included in a
systematic approach to an evaluation of CP.
The definition of CP acknowledges the complexity of
this disease beyond that of a physical disability. Almost
75% of children with CP experience another comorbidity,
which may worsen the impact of the disorder on func-
tional limitations and quality of life. (10)(38)(39) A meta-
analysis using data from CP registers found that most
children with CP experienced pain, 1 in 2 had an intellec-
tual disability, 1 in 3 could not walk or had a hip displace-
ment, and 1 in 4 could not talk; epilepsy and other
neurosensory impairments were common. (39) Children
with CP are also at high risk of developing behavioral dis-
orders. One study found that 7% of children with CP had
ASD compared with 1% of the general population; ASD
was most prevalent in children with nonspastic forms of
CP. (6) The added burdens of comorbidities are further
unevenly distributed amongst different subtypes of CP, of-
ten lesser in those with spastic hemiplegic or diplegic var-
iants. (39) Despite CP being a life-long disability, almost
all affected children are expected to have a normal life ex-
pectancy. The lowest survival rates are reported in those
with more severe disabilities, particularly if they have
other disorders such as epilepsy, severe cognitive disabil-
ity, or gastrostomy-tube dependence. (40)(41)(42)
CP can be conceptualized in different frameworks, but
the most globally accepted is the World Health Organiza-
tion’s International Classification of Function, which places
disability and functioning as outcomes of interactions be-
tween health conditions and contextual factors. (43) Evalua-
tion of CP then encompasses medical, individual, social,
and environmental factors, which all contribute to health
and activity. Neonatologists are most familiar with the
Gross Motor Function Classification System (GMFCS), ini-
tially developed and validated for patients with CP aged 2 to
12 years, but sometimes used in neonatal research studies
for children without CP. (44) The GMFCS categorizes chil-
dren with CP into 1 of 5 levels (levels I–V depending on
support needed for ambulation and mobility, with level V
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requiring the most support) based on self-initiated move-
ment; the emphasis is on sitting, walking, and wheelchair
mobility, with the expectation that the classification remains
stable even into early adulthood. (44) One previous study
examining the validity of the GMFCS tool in children with
CP ranging from 16 months to 13 years old found that chil-
dren younger than 6 years who were initially classified as
level II to IV were more likely to be reclassified, often to a
lower functional level when they were older compared with
children who were first classified as level I or V. (45) This
was particularly true in children younger than 4 years, indi-
cating less reliability of this tool in predicting functional
abilities later in life for younger children. (45) Although the
GMFCS now contains a descriptive category for infants
with CP aged 0 to 2 years, it should be used with caution
as a valid indicator of functional abilities in early childhood.
In one small study including 77 children with CP younger
than 2 years, 42% required reclassification by the age of 4
years—two-thirds of them were reclassified to a better func-
tional GMFCS level. (46)
Description of CP type and distribution in the first 2
years can be challenging, especially for preterm infants.
The classification algorithms developed by Dr Kuban for
the Extremely Low Gestational Age Newborn Study (EL-
GAN) study are helpful for neonatologists as they acknowl-
edge the difficulties in tone assessment resulting from
prolonged medical stays and interrupted development.
(47) In general, hemiplegia involving 1 side of the body,
and diplegia involving bilateral lower limbs are the most
common subtypes of CP affecting more than 75% of chil-
dren; they are associated with lower GMFCS levels. (48)
Quadriplegia involves all 4 limbs and can manifest as
spasticity with more severe functional limitations. (48)
There are 3 main types of abnormal tone including spastic
(87%), dyskinetic (7.5%), and ataxic (4%) CP but different
types can coexist and are difficult to differentiate in the
first 2 years of age. (7)(49) Spastic CP often manifests af-
ter damage to the periventricular white matter, (44) dyski-
netic CP after damage to the subcortical gray matter (eg,
basal ganglia and thalamus), and ataxic CP is most often
due to cerebellar injury or malformations. (49)
HISTORY BEHIND EARLY DETECTION
Historically, CP was thought of as an “unseen handicap,”
not diagnosed due to the emerging nature of voluntary
movements in infancy and the delayed evolution of abnor-
mal tone. (50) The notion that CP was preceded by a neu-
rologically silent period prevailed, and clinicians adopted a
wait-and-see approach until recently, when the advent of
Vol. 25 No. 1 JANUARY 2024 e3
 diagnostic tools and international consensus backed by
mounting evidence has favored early detection.
BASIC PRINCIPLES AND EVIDENCE OF TOOLS
USED FOR EARLY DETECTION
In 2017, a set of clinical guidelines based on systematic re-
views and evidence-based guidelines was published, which
delineated an algorithm that used a combination of vali-
dated tools to provide an early, accurate diagnosis of CP as
early as 3 months in specific cases. (51) The guidelines in-
corporate several high-evidence assessment tools (the Gen-
eral Movements Assessment [GMA], the Hammersmith
Infant Neurological Examination [HINE], the Developmen-
tal Assessment of Young Children (DAYC)-2, and brain
magnetic resonance imaging [MRI]) that measure differ-
ent but complementary constructs in addition to a clinical
history and other standardized motor assessments. (51)
The GMA
General movements are part of a spontaneous motor rep-
ertoire that are endogenously generated and are present
from fetal life until about 5 months’ corrected age. In the
early 1990s, Dr. Prechtl first described the GMA, a novel
visual approach to characterize an infant’s pattern of spon-
taneous movements. (52) He observed that the quality of
these movements were altered in both preterm and term
infants who had an underlying brain injury compared
with healthy controls. (52) He described 2 distinct general
movement patterns that comprise the GMA and can be
seen in both term and preterm infants: 1) writhing move-
ments and 2) fidgety movements (FMs). (53) During the
writhing period, which begins around 36 weeks’ postmenst-
rual age and persists until 9 weeks’ corrected age, general
movements are categorized as normal writhing, poor reper-
toire, chaotic, or cramped synchronized (CS). (53) Normal
writhing movements involve the whole body in a variable,
complex sequence with fluent movements that start and
end gradually, occurring frequently while the infant is
awake or sleeping with no external stimuli whereas poor
repertoire movements are more monotonous in nature. (53)
The most significant abnormal general movements to rec-
ognize during this period are CS patterns, which are char-
acterized by synchronous contractions of all limbs followed
by a relaxation phase and are highly predictive of the devel-
opment of spastic CP, most notably if they are present at
term-postmenstrual age. (53) At about 7 to 8 weeks’ cor-
rected age, FMs start to emerge and replace writhing move-
ments, persisting until 5 months’ corrected age when they
are then replaced by goal-directed, voluntary movements in
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healthy infants. (53) FMs are small, circular, and multiplanar
rapid and continuous movements that involve all parts of
the body including the extremities, head, neck, and trunk.
The presence of FMs represents a normal finding whereas the
absence of FMs at 3 to 4 months’ corrected age is highly
predictive of CP. (53)
Given the need to rely on gestalt or perception of move-
ment pattern quality, the GMA involves short video re-
cordings lasting 3 to 5 minutes that are then interpreted
after filming at 2 different time points: at term postmenst-
rual age during the writhing period and 3 to 4 months’
corrected age during the fidgety period. Because the GMA
has become a standardized qualitative tool with high inter-
observer reliability and validity, clinicians can become cer-
tified as GMA basic and/or advanced readers after taking
a 31=2-day course offered by the General Movements Trust.
(54)(55)
The first study describing the predictive value of the
GMA was published by Dr. Prechtl when he evaluated gen-
eral movements during the writhing and fidgety periods in
130 preterm and term infants with both low-risk cranial ul-
trasound (cUS) findings (eg, grade 1 IVH) and high-risk
cUS deficits (eg, grade 2–4 IVH, PVL) and examined their
neurologic outcomes by age 2 years. (55) FMs had a higher
sensitivity and specificity of 95% and 96%, respectively, in
predicting neurologic outcomes compared with cUS, which
had a sensitivity and specificity of 80% and 83%, respec-
tively. (55) Most infants with CS movements during the
writhing period developed absent FMs, and all but 1 infant
(43/44) with absent FMs developed CP. (55) Several studies
replicated these findings, demonstrating that trajectories of
CS movements followed by absent FMs were highly predic-
tive of CP. (53)(54)(55)(56)(57)(58)(59) A systematic review
of 19 studies on high-risk populations including preterm
and low-birthweight infants demonstrated a pooled sensitiv-
ity of 98% and specificity of 91% of the GMA for CP, most
predictive during the fidgety period around 3 to 4 months’
corrected age, which was better than the use of cUS or
term-postmenstrual age brain MRI. (60)
The HINE
The HINE is a scorable neurologic examination consisting
of 26 items that assess cranial nerves, tone, posture,
movements, reflexes, and reactions. It can be administered
in infants between 2 months and 2 years of age. (61) It
was first described in 1999 by Dr Haataja and validated
for use in a cohort of 119 healthy term infants followed
until age 18 months, providing a distribution of scores
across each domain. (62) It allows trained examiners to
 derive global optimality scores ranging from 0 to 78 and a
separate asymmetry score. It can be performed in 5 to 10 mi-
nutes and has good interobserver reliability after training. (62)
Longitudinal assessments allow examiners to differentiate be-
tween transient versus permanent abnormalities. The HINE
can provide both diagnostic and prognostic information in
high-risk infants. In the largest single study to date of 1,541 in-
fants discharged from the NICU, Romeo et al performed the
HINE at different time points during the first 2 years of age
and reported cutoff scores for each age window from 3 to 12
months that had high prognostic value for later CP diagnoses.
(63) In those who had documented brain insults, HINE scores
could assist with severity prognostication. (63)
Since then, numerous studies have evaluated the HINE’s
predictive value in various populations. (61)(64)(65)(66)(67)
Romeo et al recently demonstrated that 50% of low-risk
preterm infants with a HINE score less than 73 at 12
months’ corrected age had normal neurologic outcomes by
age 2 years, thus providing more appropriate cutoff scores
for these patients. (68) The HINE may help assess the se-
verity of CP at 2 years of age in infants with documented
brain insults, and combinations of global and asymmetry
scores on the HINE may help categorize hemiplegic CP.
(61)(69)(70)
Other Standardized Motor Assessments
Several standardized motor assessments are available, which
can be performed in both preterm and term infants and
have been studied for their predictive value for CP, namely
the Alberta Infant Motor Scale (AIMS), the Test of Infant
Motor Performance (TIMP), and the DAYC. The AIMS is a
58-item standardized tool that evaluates gross motor develop-
ment from birth until 18 months of age or when indepen-
dent ambulation is achieved and requires direct observation
of the infant in prone, supine, sitting, and standing posi-
tions. (71) The TIMP is a 42-item standardized tool that can
be performed as early as 34 weeks’ gestational age until 4
months’ corrected gestational age and requires both direct
observation and items elicited such as cranial nerve function
and evaluation of antigravity control. (72) Both evaluations
can take from 20 to 30 minutes to administer, and the
AIMS can be administered over telehealth but the TIMP
should be conducted in person. The TIMP should be admin-
istered by clinicians such as physical and occupational thera-
pists in the NICU or early intervention programs who have
undergone training through workshops and online modules;
however, the AIMS has been shown to have good reliability
between both experienced and novice examiners because
it relies on direct observation. (71) The DAYC is a
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standardized assessment tool that evaluates development
from birth through age 5 years using an interactive ques-
tionnaire for parents that can also be administered over
telehealth. The physical development domain in the most
updated version measures both gross motor and fine mo-
tor skills based on parental report, direct observation, or
assessment and takes about 10 minutes to administer
with good reliability reported. (73)(74) Although the
AIMS, TIMP, and DAYC do not require highly special-
ized training and/or additional resources compared to
the GMA, clinicians should not use any tool in isolation
for the purpose of predicting or diagnosing CP; rather
these tools should be used to help identify at-risk infants
and follow the trajectory of motor development while
screening those who may require closer surveillance.
(51)(75)
Neuroimaging
Although neuroimaging is helpful in early identification
of CP, 10% to 15% of infants with CP have normal neuro-
imaging; therefore, similar to the other assessment tools
mentioned in this review, it should not be used in isola-
tion when making or excluding a diagnosis of CP. (51)(76)
In a systematic review with over 2,400 infants and a CP
prevalence of 9.4%, sequential cUS in the NICU had a
pooled sensitivity of 74% (95% confidence interval [CI],
63%–83%) and specificity of 92% (95% CI, 81%–96%) to
predict CP in both preterm and high-risk term infants, es-
pecially in cases of grade 3 or 4 IVH, cerebellar injury,
and cystic PVL. (60)(77)(78)(79) Periventricular hemor-
rhagic infarction, a more accurate term for grade 4 IVH,
confers a high risk for CP, and white matter injury confers
a 20-fold increased odds of developing CP. (80)(81)
Evidence to support the routine use of MRI in preterm
infants to predict CP is mixed, with poor sensitivity
(65%–71%) and good to excellent specificity (84%–95%).
(81)(82)(83) The Choosing Wisely campaign endorsed by
the American Academy of Pediatrics recommends avoid-
ing routine screening MRIs at term-equivalent age in pre-
term infants given the lack of data to suggest improved
prediction of long-term outcomes; however, MRI should
be considered in infants with HIE, stroke, brain malfor-
mations, PVL, or severe IVH. (84) Notably, the Kidokoro
scoring (MRI scoring system of abnormalities that is spe-
cific for preterm infants with IVH) performed in preterm
infants at term-equivalent age is used in Australia and pro-
vides strong evidence of predicting outcomes accurately.
(85) Newer imaging techniques and modalities may allow
more accurate prognostication of diagnosis, topography,
Vol. 25 No. 1 JANUARY 2024 e5
 and severity in the future. (86) Certainly, if CP is suspected,
clinicians should consider MRI as part of the diagnostic
evaluation in a term infant without risk factors, for cortical
or vascular malformations among possible etiologies. (87)
Evidence to Support the Combination of Multiple
Tools
None of the assessment tools described herein (GMA,
HINE, standardized motor assessments, and neuroimag-
ing) should be used in isolation for detection of CP as
they each offer a complementary construct:
1. The GMA evaluates the quality of spontaneous move-
ments and provides information on neural function and
integrity.
2. The HINE is a standardized neurologic examination.
3. Standardized motor assessments (eg, AIMS, TIMP, and
physical domain of the DAYC) are tools to evaluate fine
and gross motor impairment.
4. Neuroimaging (eg, brain MRI or cUS) detects brain ab-
normalities or injury associated with CP.
Serial HINEs between 3 and 24 months’ corrected age
and the GMA at 3 to 4 months’ corrected age in infants
with newborn-detectable risk factors have shown promise
in predicting CP, especially the combination of absent
FMs and HINE score of less than 50. (88) The pooled pre-
dictive power of HINE, GMA, and cUS or MRI in high-
risk term and preterm infants has shown sensitivity, spe-
cificity, and positive and negative predictive values greater
than 98% in predicting the development of CP by 2 years
compared to each tool alone. (76) The caveat in this study,
however, was that HINE examiners, GMA readers, and
neuroimaging readers were all experts in the field of CP.
Use of CP Early Detection Tools in Neonatal
Follow-Up
The international clinical practice guidelines published in
2017 were developed by a multidisciplinary panel of scien-
tific and clinical experts in CP and parent stakeholders,
and outlined 12 recommendations based on best evidence-
based assessments with an algorithm for early detection of
CP (Fig). (51) Early detection is feasible and accurate and
can lead to earlier CP-specific interventions whereas an in-
terim designation of “high risk of CP” should be used if
the clinician is concerned but cannot be certain of the di-
agnosis. (51) In general, infants younger than 5 months'
corrected age who have identifiable risks such as the neu-
ral insults previously mentioned, but also others such as
intrauterine growth restriction, intrauterine drug exposure,
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and cytomegalovirus infection, should have a GMA, HINE,
thorough medical history conducted including review of
any detectable risk factors for CP or parent-identified con-
cerns, review of imaging, and a standardized motor assess-
ment performed starting at 3 to 4 months’ corrected age; in
infants older than 5 months, the HINE, MRI, and standard-
ized motor assessments are recommended. (12)(13)(51)
IMPLEMENTATION OF CLINICAL GUIDELINES
Because of the inconsistent ways in which neurologic ex-
aminations were performed and documented in high-risk
infant follow-up (HRIF) clinics, the neonatal neurodeve-
lopmental team at Nationwide Children’s Hospital, which
has over 5,000 yearly visits, was trained in the HINE with
the help of a Hammersmith trained neurologist and by de-
veloping a preparation course work and on-site practice.
(89) Following the implementation of the HINE, which
was administered at the 3- to 4-month, 9- to 12-month,
and 22- to 26-month visits up until 2 years’ corrected age,
the age at diagnosis of CP was reduced from 28 months
to 15.7 months without an increase in the number of new
diagnoses while maintaining adequate inter-rater reliabil-
ity. (89) By successfully learning and implementing the
HINE and the GMA into clinical practice at a single site
while standardizing documentation in the electronic medi-
cal record, the team was able to demonstrate a reduction
in age at CP diagnosis, demonstrating the feasibility of us-
ing this tool in clinical practice. (90)
Following the publication of the clinical guidelines for
early detection in 2017, single centers started implement-
ing these recommendations, reducing the age at diagnosis
to 8.5 months in one cohort with 98% of those diagnosed
with CP being referred to CP-specific early intervention
programs. (89)(91)(92) The largest implementation study
to date included the formation of an Early Detection and
Implementation (EDI) Network composed of 5 diverse US-
based HRIF clinics. The network reduced the age at CP di-
agnosis using quality improvement methodology and im-
plementation science on a large scale by transitioning to
an earlier visit at 3 to 4 months and incorporating the
GMA, HINE, medical history, and standardized motor
function assessment. (93) Within 1 year, the network low-
ered the age at diagnosis from 19.5 months’ corrected age
to 9.5 months’ corrected age with no increase in the num-
ber of CP diagnoses. (93) Recent publications show that
they sustained their change 5 years later, even through the
addition of new sites and the challenges related to the
COVID-19 pandemic. (94)
 Figure. Pathway to early detection. A represents the best available evidence pathway per the international clinical guidelines published by Novak et al
in 201751; B is next best if some tools in A are not available. AIMS5Alberta Infant Motor Scale, CP5cerebral palsy, DAYC5Developmental Assessment of
Young Children, GMs5Prechtl Qualitative Assessment of General Movements, HINE5Hammersmith Infant Neurological Examination, IUGR5intrauterine
growth restriction, MAI5Motor Assessment of Infants, NSMDA5Neuro-Sensory Motor Development Assessment, TIMP5Test of Infant Motor Perfor-
mance. (Modified from “Early Recognition of Cerebral Palsy: A Pathway to Referral” published online in 2018. Reprinted with permission from the Cerebral
Palsy Foundation in New York, NY.)

CAREGIVER PERCEPTION OF EARLY DIAGNOSIS
Population data support the notion that delaying conversations
surrounding even the suspicion of CP can be detrimental to
parental well-being. The vast majority of caregivers already
suspect the diagnosis before being told, and in 1 study, more
than 40% of caregivers experienced dissatisfaction and resent-
ment about a delayed diagnosis, which correlated with later
depression. (95) On a large scale, the US-based implementa-
tion network found that 90% of parents reported receiving
empathy and support at the diagnosis visit. (95) This positive
perception of early CP diagnosis has been confirmed, with pa-
rents generally wanting more information on the next steps.
(81)(96)(97) Parents of children with CP have stated that ear-
lier diagnosis or use of a high-risk designation was beneficial
to their family and their child and was a priority in an honest
yet positive conversation with diagnosis-related education and
resources. (97)
To address starting conversations earlier, a consensus
statement was put forth by the EDI network and the Cana-
dian Neonatal Follow-Up Network in 2022 to adopt a “high-
risk for CP” designation when a diagnosis is suspected but
there is a missing diagnostic component or a negative result
(Table). (94)(97) During a focus group involving caregivers
of children with CP describing their experiences surround-
ing CP diagnosis and the concept of using a designation
early on, parents expressed that a designation was an accept-
able alternative to start these conversations and could be re-
visited even if a diagnosis was ultimately not made. (98)
Globally, clinicians who have shifted their practice toward
early detection of CP have adopted this designation to pro-
vide a framework for shared decision-making and establish-
ing a common language between families and high-risk
follow-up clinicians. Importantly, this shift to early detection
has allowed for the study of earlier interventions in children
with CP even younger than 2 years. The results are promis-
ing, and an increasing pipeline of studies testing new inter-
ventional approaches is actively underway. (99)(100)
CONCLUSIONS
Across NICUs and HRIF clinics around the world, a shift
toward early detection of CP to drive new early interven-
tions has evolved from decades of historical challenges

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 Table. Proposed criteria for diagnosis of cerebral palsy (CP) versus high-risk clinical designation.
Basic elements of diagnosis of CP
High risk for CP clinical designation
Clinical history consistent with the etiology of CP
Neurologic exam with evidence of impairment
Decrease in motor function on standardized motor assessment
Neuroimaging findings associated with CP (eg, MRI or cUS with evidence of stroke,
HIE, grade 3–4 IVH, hydrocephalus, periventricular leukomalacia)
Positive biomarkers for CP:
! Genetic condition associated with CP
! No underlying progressive disorder
! Hammersmith Infant Neurological Exam scores below threshold for age
! Cramped synchronized and/or absent fidgety movements on the General
Movements Assessment
A basic element is missing/an assessment is not performed
Basic element with negative results for predicting later CP but others are positive
First evaluation of child before age of 2 years with clinical concern but no previous
evaluations have demonstrated clear concerns

Adapted from Maitre NL, Byrne R, Duncan A, et al; CP EDI Consensus Group; Canadian Neonatal Follow-up Network. “High-risk for cerebral palsy”
designation: A clinical consensus statement. J Pediatr Rehabil Med. 2022;15(1):165–174.

and advances. The feasibility of decreasing the age at CP diag-
nosis on a large scale has been proven, starting with practices
in the NICU and followed by an HRIF visit at 3 to 4 months’
corrected age. (84) Early diagnosis and high-risk designation
are well-accepted by caregivers, and these conversations can
2. Noritz G, Davidson L, Steingass K; Council on Children with
Disabilities, American Academy for Cerebral Palsy and
Developmental Medicine; Council on Children with Disabilities,
American Academy for Cerebral Palsy and Developmental Medicine.
Providing a primary care medical home for children and youth with
cerebral palsy. Pediatrics. 2022;150:e2022060055

and should start early, even while in the NICU when a fu-
ture diagnosis of CP is suspected. Through the implementa-
tion of evidence-based international clinical guidelines, after
receiving training in the use of these new assessment tools,
we can optimize the developmental trajectories of children
with CP. We can refer these children earlier to interventions
during a critical period of neuroplasticity to reduce motor
deficits and secondary impairments. All this can happen
while promoting better support, education, and well-being
for former NICU families—a goal that has always been cen-
tral to NICU follow-up programs.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the evolution of neurodevelopmental
impairments during development and the
difference between transient and permanent
impairments in NICU graduates (eg,
developmental delay vs. intellectual disability;
3. Herskind A, Greisen G, Nielsen JB. Early identification and
intervention in cerebral palsy. Dev Med Child Neurol. 2015;57(1):29–36
4. Maenner MJ, Blumberg SJ, Kogan MD, Christensen D, Yeargin-
Allsopp M, Schieve LA. Prevalence of cerebral palsy and intellectual
disability among children identified in two U.S. National Surveys,
2011-2013. Ann Epidemiol. 2016;26(3):222–226
5. McIntyre S, Goldsmith S, Webb A, et al; Global CP Prevalence
Group. Global prevalence of cerebral palsy: a systematic analysis.
Dev Med Child Neurol. 2022;64(12):1494–1506
6. Christensen D, Van Naarden Braun K, Doernberg NS, et al. Prevalence
of cerebral palsy, co-occurring autism spectrum disorders, and motor
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• Know the significance of persistent neuromotor
abnormalities in infancy (including asymmetries).
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Vol. 25 No. 1 JANUARY 2024 e11
 ARTICLE

Nutritional Needs of the Infant with

Bronchopulmonary Dysplasia
Audrey N. Miller, MD,* Jennifer Curtiss, MS, RD, LD,† Matthew J. Kielt, MD*
*Comprehensive Center for Bronchopulmonary Dysplasia, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College
of Medicine, Columbus, OH
†
Department of Clinical Nutrition and Lactation, Nationwide Children’s Hospital, Columbus, OH

PRACTICE GAP
Infants with bronchopulmonary dysplasia (BPD) often experience postnatal
growth failure, which can affect neurodevelopment and short- and long-
term respiratory outcomes. High-quality evidence on how best to optimize
nutrition in the setting of BPD remains limited. However, recent reviews
and clinical guidance based on growth outcomes can help clinicians
improve growth in this vulnerable population.

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

1. Describe reasons for growth failure in infants with bronchopulmonary

dysplasia (BPD) and how they influence nutritional management.
2. Explain the enteral nutritional needs of infants with BPD throughout
disease progression.
3. Recognize the importance of growth monitoring and how it relates to
the management of BPD.

ABSTRACT
Growth failure is a common problem in infants with established
bronchopulmonary dysplasia (BPD). Suboptimal growth for infants with
BPD is associated with unfavorable respiratory and neurodevelopmental
outcomes; however, high-quality evidence to support best nutritional
AUTHOR DISCLOSURES Drs Miller and practices are limited for this vulnerable patient population. Consequently,
Kielt and Ms Curtiss have disclosed no there exists a wide variation in the provision of nutritional care and
financial relationships relevant to this
article. This commentary does not
monitoring of growth for infants with BPD. Other neonatal populations at
contain a discussion of an unapproved/ risk for growth failure, such as infants with congenital heart disease, have
investigative use of a commercial demonstrated improved growth outcomes with the creation and
product/device.
compliance of clinical protocols to guide nutritional management.
Developing clinical protocols to guide nutritional management for infants
ABBREVIATIONS with BPD may similarly improve long-term outcomes. Given the absence of
BPD bronchopulmonary dysplasia high-quality trials to guide nutritional practice in infants with BPD, the best
BPD-PH bronchopulmonary
available evidence of systematic reviews and clinical recommendations can
dysplasia–associated pulmonary
hypertension be applied to optimize growth and decrease variation in the care of these
MBD metabolic bone disease infants.
PMA postmenstrual age

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 INTRODUCTION
Bronchopulmonary dysplasia (BPD) is the most common
sequelae of preterm birth, with a rising incidence reported
among infants born at or before 28 weeks’ gestation. (1)
Despite notable improvements in the respiratory care of
infants born extremely preterm, rates of BPD are increas-
ing, (2) likely secondary to the improving survival of
infants born extremely preterm, resulting in a growing
population of infants and children with BPD in adult-
hood. BPD is commonly defined in infants born before
32 weeks’ gestation who require ongoing respiratory
support at 36 weeks’ postmenstrual age (PMA), with
the modality of respiratory support defining BPD severity.
(3) Infants with grade 3 BPD require invasive mechanical
ventilation at 36 weeks’ PMA, and are at the highest risk
for late death (before 18–26 months’ corrected age), seri-
ous respiratory morbidity, neurodevelopmental delay, and
suboptimal growth at follow-up. (3)
To date, most nutritional research has centered on in-
fants born preterm who are at risk for BPD with less
emphasis placed on those infants with established dis-
ease. (4) Suboptimal growth early in infancy is a well-
established risk factor for the development of BPD. Preterm
infants who experience intrauterine growth restriction and
are born small for gestational age are more likely to develop
BPD. (5)(6)(7) In addition, infants who develop BPD are at
risk for ongoing growth failure, abnormal growth patterns
such as excess weight gain relative to linear growth, and
delayed growth into adolescence and young adulthood.
(8)(9)(10) Identifying and addressing growth failure early is
critical, as it has been shown to affect both short- and long-
term outcomes.
Owing to a gap in research centered on infants with es-
tablished BPD, the association of suboptimal growth with
adverse outcomes for infants with established BPD is not
well understood. Evidence-based nutritional strategies for
these infants are also not well-defined. Many factors com-
plicate achieving optimal nutrition and growth in infants
with BPD, including limited high-grade evidence to guide
clinical practice. This has led to differences among clini-
cians and centers in the nutritional delivery and monitoring
of infants with BPD. (11) However, even in the absence of ran-
domized controlled trials, there is growing interest in optimiz-
ing multidisciplinary care of infants with BPD. An increasing
body of literature exists, which includes nutritional reviews,
clinical practice guidelines, and published growth outcomes
for this growing population. (4)(5)(12)(13)(14)(15)(16) Our
objective in this review is to summarize the available nu-
tritional information to provide a framework for evidence-
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based nutritional care that improves long-term outcomes
for infants with BPD.
GROWTH AND NUTRITION IN BPD PREVENTION
Suboptimal growth is associated with adverse respiratory
outcomes for infants born preterm. (5)(6) Infants who ex-
perienced intrauterine growth restriction are at risk for de-
layed fetal lung maturation, abnormal pulmonary vascular
angiogenesis, chronic fetal hypoxia, and increased airway
resistance measured at a median postnatal age of 10
months. (17)(18) Infants born at very low birthweight have
minimal energy reserves (body fat and glycogen stores)
and limited stores of essential nutrients (antioxidant vita-
mins A and E, iron, zinc, and long-chain polyunsaturated
fatty acids) involved in lung injury defense and lung re-
pair. (19)(20) Inadequate postnatal nutrition can lead to
delayed somatic growth, delayed alveolar development,
and abnormal lung healing. (19)(20) Nutritional status has
been shown to influence the development of BPD. Under-
nutrition affects the ability of preterm infants to resist hy-
peroxic damage, repair barotrauma-induced cell damage,
fight infection, tolerate prolonged stress, and promote
lung growth in experimental and clinical studies. (20)
Vitamin A deficiency can predispose an infant to the de-
velopment of BPD as it is an important regulator of normal
lung growth and is involved in maintaining the integrity of
epithelial cells of the respiratory tract. (21)(22)(23)(24) Intra-
muscular vitamin A supplementation has been shown to
reduce the incidence of BPD. (21)(25) Vitamin D has anti-
inflammatory properties and is important for lung growth
and repair. (26) Early supplementation of vitamin D (dur-
ing the first month of age) has been shown to reduce the
incidence of BPD. (27) Inositol promotes endothelial cell
growth, acts as an antioxidant, and is involved in surfactant
synthesis. A statistically significant reduction in mortality or
BPD has been reported in infants supplemented with inosi-
tol. (28) Vitamin E, known to neutralize free radicals and
reduce oxidative stress, has been studied in the pathophysi-
ology of BPD with vitamin E deficiency increasing BPD
risk. Vitamin E administration during the acute phase of re-
spiratory distress syndrome has been shown to modify the
development of BPD. (29) Another study reported a correla-
tion between low vitamin E and selenium levels measured
in cord plasma and at days of age and the development of
BPD. (30) A review of vitamin E and its role in preventing
and treating BPD noted that while the findings from stud-
ies of vitamin E supplementation are mixed, results may
have been affected by vitamin E dose, route, and carrier prep-
aration. (31) Several other nutritional factors such as selenium,
Vol. 25 No. 1 JANUARY 2024 e13
 glutamine, human recombinant copper zinc superoxide dis-
mutase, N-acetylcysteine, and zinc have been studied in rela-
tion to BPD but have not been proven to prevent the disease.
(32)(33)
GROWTH AND NUTRITION-RELATED OUTCOMES
IN BPD
The association of suboptimal growth and adverse respira-
tory outcomes continues past infancy. Children with BPD
who demonstrate catch-up growth, or above-average growth
measured by weight gain, have been shown to have greater
longitudinal improvement in pulmonary function testing
compared with children with BPD and average or below-av-
erage weight gain. (34) Linear growth in particular is associ-
ated with improvement in lung function in children with
BPD as noted on pulmonary function testing, even more so
than an increase in weight. (35) Persistent lung hyperinfla-
tion at 4 to 8 years of age has been documented in children
with BPD who had poor nutritional status at 2 years of age,
(36) suggesting that early nutritional interventions may po-
tentially modify severe disease phenotypes.
Early and inadequate nutrition and lack of optimal
growth also contribute to common morbidities observed
in infants with BPD. Infants with BPD are at risk for neu-
rodevelopmental impairment, (3) and although not specifi-
cally studied in BPD, there is a significant correlation
between poor postnatal growth and neurodevelopmental
impairment in infants born preterm. (37)(38)(39)(40) Un-
dernutrition can impair immune system function and pre-
dispose infants to infections. (41) Respiratory infections
and associated inflammation may exacerbate lung injury
in infants with BPD. (7) Preterm infants who experienced
fetal growth restriction and/or are small for gestational
age are at greater risk of developing BPD-associated pul-
monary hypertension (BPD-PH) and are at risk for pulmo-
nary hypertension crises and early mortality. (7) Infants
with BPD-PH who survive often show resolution of pul-
monary hypertension with lung growth. (7)
GROWTH AND NUTRITION CHALLENGES IN
INFANTS WITH ESTABLISHED BPD
Energy Balance
Infants with BPD require more total energy than age-
matched controls without BPD, likely secondary to in-
creased work of breathing and increased metabolic de-
mands. (42)(43)(44) This is especially true during the
acute phase of grade 3 BPD, characterized by high oxygen
needs, high levels of respiratory support, and respiratory
instability. (4)(45) This increased energy need can also be
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seen in the convalescing infant with BPD who is working
to establish full oral feedings. (4) Despite the need for in-
creased energy intake, infants with BPD may receive inad-
equate nutrition during periods of clinical instability or
BPD exacerbation. This can occur secondary to frequent
discontinuation of feedings during periods of acute illness
and chronic fluid restriction affecting nutrient delivery. In-
terestingly, infants with BPD have been noted to have lower
calorie and protein intake after the second week of age
compared with preterm infants without BPD, suggesting
that nutritional deficiencies may indeed be a chronic prob-
lem starting relatively soon after birth. (5)(46) Infants with
chronic illness often have an altered metabolic state, mak-
ing total energy needs difficult to estimate, particularly
when compared to healthy, age-matched controls. Conse-
quently, more research is needed to determine the true en-
ergy needs in infants with established BPD. (47)(48)
Medical Management
Throughout the clinical course of infants with BPD, cer-
tain aspects of medical management may further contrib-
ute to suboptimal growth (Fig 1). For example, systemic
corticosteroids are frequently used in both the prevention
and management of BPD and are known to have a nega-
tive impact on linear growth and cause lower weight gain
velocity, independent of energy expenditure and energy
intake. (5)(49)(50)(51)(52) Systemic corticosteroids affect
growth at the cellular level by increasing protein catabo-
lism, reducing protein accretion, and altering lipid and bone
metabolism. (48)(52)(53)(54) Diuretic therapy is commonly
used in BPD to manage pulmonary edema, yet prolonged
diuretic use can result in chronic electrolyte derangements
that have a negative effect on growth and bone mineraliza-
tion. (16)(55)(56) Infants with BPD are sensitive to rapid
changes and frequent weaning of respiratory support that
may lead to increased levels of stress, work of breathing,
and energy expenditure.
Comorbidities
Infection, a common comorbidity seen in infants with BPD,
can increase energy expenditure, cause protein catabolism,
and reduce fatty acid oxidation. (16) Chronic inflammation
as seen in infants with BPD can suppress insulinlike growth
factors leading to growth suppression. (16) Some infants
with BPD develop significant edema that can lead to changes
in enteral nutrition delivery and increased use of diuretic
therapy. In addition, infants with BPD-PH are at risk for
suboptimal somatic growth compared with infants with BPD
and no pulmonary hypertension. (57)
 Frequent
discontinuation of
enteral feedings
Chronic fluid
restriction
Decreased
Energy Intake
Feeding Linear
Growth
intolerance
Challenges
in BPD
Challenges with
oral feeding
High Energy
Expenditure
Sepsis
Pneumonia Increased work of
breathing
Figure 1. Linear growth challenges seen in infants with bronchopulmonary dysplasia (BPD).
Evolving Nutritional Needs
The nutritional needs of the infant with BPD evolve over
time depending on clinical stability, level of respiratory
support, age, and activity level. (4) Delivering targeted nu-
tritional interventions can therefore be quite challenging
to navigate, especially when infants experience BPD exac-
erbations with subsequent fluctuations in clinical stability.
Four phases of BPD progression have been described with
differing nutritional needs outlined in each phase. (45)
The first, or acute, phase is characterized by physiologic
instability, high oxygen needs, frequent respiratory work
of breathing and desaturations, and poor neuroregulation
(Fig 2). The second, transitional, phase is characterized by
slow weaning of supplemental oxygen, improved work of
breathing, brief periods of quiet alertness, and emerging
tolerance of low-level activities. The third, progrowth,
phase is seen with stable oxygen requirements, comfort-
able work of breathing, and the ability to wean respiratory
support. Changes in growth patterns may also be observed
in the different phases. (Fig 2). As the infant progresses
through these phases, fluid and energy intake, and protein
needs gradually decrease. Recommendations for fluid, en-
ergy, and protein intake (Fig 2) are based on clinical experi-
ence in a 24-bed unit for infants with BPD, where significant
improvement in all growth parameters was documented us-
ing this method. (4)(51)
ENTERAL NUTRITION IN INFANTS WITH
ESTABLISHED BPD
Enteral feeding is preferred over parenteral nutrition and
should be prioritized even in the setting of acute illness,
BPD exacerbations, and periods of sedation and paralysis.
(4) Parenteral nutrition places the infant at risk for central
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Needs vary
depending on:
• Disease severity
• Chronic stress
Evolving Nutritional • Activity level
Needs • Oral feedings
• Age
• Corticosteroids
• Diuretics
Medical • Inadequate
Management respiratory support
• Stressful procedures
• Chronic
inflammation
• Inaccurate length
measurements
line–associated bloodstream infections and parenteral
nutrition–associated cholestasis. (58)(59) Gastric feeding
is physiologic and ideal; 1 study found that transpyloric
feedings were associated with increased hypoxemic events
and a greater proportion of daily hypoxemia in infants with
BPD compared with gastric feedings. (60) Infants with grade
3 BPD requiring tracheostomy will need long-term feeding
access, such as a gastrostomy tube, for ongoing nutritional
support before they are discharged from the hospital. (61)
Fluid and Energy
Fluid restriction in BPD remains a common practice, as
higher fluid intake may contribute to pulmonary intersti-
tial edema and lower lung compliance. (62) Although
there is no evidence to support this practice, (63) many
centers continue to prescribe fluid restriction, especially
during the acute phase of BPD when the presence of ex-
cessive weight due to edema is commonly observed. (64) It
is important to ensure appropriate fluid balance to maintain
normal serum electrolyte concentrations as well as the de-
livery of sufficient calories and protein.
Energy needs vary based on the infant’s age, clinical se-
verity, and activity level. Infants with BPD may require
more than 120 kcal/kg per day, especially in the acute
phase of the disease. (4)(5)(12)(65) The higher energy
needs compared with preterm infants without BPD are
often explained by higher estimated energy expenditures
secondary to increased work of breathing and oxygen re-
quirements. (44)
Protein
Adequate protein intake is essential to support lung develop-
ment, lung repair, linear growth, and long-term improved
Vol. 25 No. 1 JANUARY 2024 e15
 Figure 2. Characteristics, growth observations, and basic nutrition guidelines for infants with severe bronchopulmonary dysplasia based on disease
severity. Reproduced from Miller et al (4) originally published in the Journal of Perinatology.
pulmonary outcomes. Protein needs for infants with estab-
lished BPD are higher than for preterm infants without
BPD. (66)(67) One study found that infants with BPD fed
formula with added protein had improved linear growth,
lean mass accretion, and greater bone mass. (68)
Feeding Selection
Human milk is recommended as the ideal source of nutri-
tion for infants, exclusively until 6 months of age, and
then in combination with complementary food for up to
2 years of age or longer if desired. (69) Maternal milk of-
fers many protective benefits and has been associated with
a lower incidence of developing BPD. (70)(71) A study in in-
fants with established BPD demonstrated that those re-
ceiving long-term maternal milk had fewer systemic
corticosteroid courses, fewer emergency room visits, lower
risk of readmissions, and reduced cough. (72) Preterm in-
fants with BPD require fortification of maternal milk (or
donor milk if being used) to provide essential nutrients
for catch-up growth and bone health. (12)
Nonetheless, owing to prolonged periods of critical ill-
ness during the initial birth hospitalization, provision of
maternal milk may be difficult for infants with established
BPD in the chronic phase of disease when maternal milk
supplies may be low or no longer available. Although in-
fant formulas are readily available, the ideal alternative
to human milk remains unknown as does the ideal age
at which to transition from preterm to term infant
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formulas. If maternal milk is not available, preterm in-
fant formulas are recommended because of their higher
concentration of protein, minerals, and vitamins. (73) As
the infant nears term age, or shortly thereafter, postdi-
scharge formulas can be used, as they contain higher
amounts of energy, protein, minerals, and vitamins com-
pared with term infant formula. (73) If additional calories
are needed above fortification, medium-chain triglycer-
ides or liquid protein may be added, with close monitor-
ing of energy/protein ratio and osmolality. After 1 year
of age, total energy intake may be supplemented with
ready-to-feed pediatric formulas that are available in a
30 kcal/ounce concentration. (74)
ZINC AND ESTABLISHED BPD
There is growing interest in the role of zinc in infants
with BPD. Zinc has several important functions, including
in protein synthesis, enzyme function, tissue repair, cell
division, neurotransmission, immune response, vision,
and growth. (75) Zinc deficiency is well-described in in-
fants born preterm, small for gestational age, and with es-
tablished BPD. (75)(76) This is likely secondary to low
body stores due to reduced placental transfer, minimal
zinc intake after birth, and high zinc needs during rapid
growth. Although the diagnosis of zinc deficiency can be
aided by the presence of dermatitis, diarrhea, infections,
and neurologic disorders, these clinical manifestations are
 not often observed until there is a severe deficiency. (75)
Zinc biomarkers, such as serum alkaline phosphatase lev-
els, have not been useful in determining zinc status. (77)
Knowing that preterm infants with BPD are at high risk
for zinc deficiency and insufficiency, zinc supplementa-
tion should be considered for those demonstrating subop-
timal growth in the setting of appropriate energy and
macronutrient intake. Infants receiving long-term diuretic
therapy should also be considered at risk for zinc defi-
ciency, as diuretics increase urinary zinc excretion. (78)
Zinc supplementation in infants with BPD has been
shown to significantly improve both weight gain velocity
and linear growth. (79) Though zinc supplementation has
not been rigorously studied in infants with established
BPD, observational data suggest that zinc supplementation
is likely benign. No documented side effects of zinc sup-
plementation in infants have been reported. Zinc toxicity
is rare, and ingestion of up to 10 times the recommended
daily intake produces no symptoms. (80) Chronic high
doses of zinc may be associated with copper deficiency,
but this is rare at appropriate doses. (80) Nonetheless, re-
search is needed to determine the most appropriate con-
centration, dose, and duration for zinc use in infants with
established BPD. Our practice is to use compounded oral
zinc acetate, at a strength of 10 mg/mL, often prescribed
at 1 mg twice a day during hospitalization; we discontinue
zinc supplementation when diuretic therapy is stopped
and growth shows consistent improvement.
NUTRITIONAL AND GROWTH MONITORING
Anthropometric Measurements
Routine discussion of overall growth status with the die-
titian and multidisciplinary team is recommended. An-
thropometric data, including weight, length, and head
circumference, should be monitored over time on age-
appropriate growth charts. Monitoring the weight-for-length
ratio is important to identify abnormal growth patterns. In-
creasing weight gain velocity out of proportion to linear
growth velocity may be indicative of edema or a significant
decrease in energy expenditure. (4) Mid-upper arm circum-
ference measurements may help differentiate edema from
“true” weight gain, as the upper arm is less affected by
fluid status. (81) It is also important to consider that opti-
mal weight and linear growth ranges change as the patient
ages (Table).
Accurate length measurements are an essential compo-
nent of the nutrition assessment. Linear growth is a better
marker of nutrition status than weight gain alone. Obtain-
ing length measurements may be seen as challenging in
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intubated infants; however, with routine staff education
and unit protocols in place, obtaining length measure-
ments using length boards should be standard of care. It
is important to consistently obtain reliable length meas-
urements using a pediatric length board. (82)(83) Length
measurements should be performed by 2 trained adults
and is often completed in combination by a nurse, dieti-
tian, and parent. In our experience, parents enjoy helping
with this measurement and being involved in monitoring
their child’s growth.
Laboratory Monitoring
Intermittent laboratory testing may help further assess nu-
tritional status, especially for infants who are prescribed
fluid restriction, diuretics, and select vitamin and mineral
supplements. Electrolyte monitoring is needed for infants
receiving diuretic therapy, and these infants often require
sodium and potassium chloride supplementation. Addi-
tional laboratory testing such as blood urea nitrogen or
prealbumin (transthyretin) measurements can be used to
monitor protein intake. (15)(84) Visceral protein levels,
such as albumin, may reflect the severity of illness versus
nutritional status and can be confounded by postsurgical
stress, liver disease, and kidney injury. (85) If there is con-
cern for iron deficiency, ferritin, hemoglobin, and hemato-
crit can be monitored as well.
Metabolic Bone Disease
Metabolic bone disease (MBD) is common in infants with
BPD, with a reported prevalence of up to 60% at 36
weeks’ PMA. (86) Several factors place infants with BPD
at risk for developing MBD, including preterm birth, post-
natal nutritional management, and exposure to systemic
corticosteroids and long-term loop diuretics. (87)(88) Con-
sequences of MBD include short-term pain and discom-
fort, as well as long-term growth implications such as
reduced bone mass and a higher risk for fracture and oste-
oporosis. (89)(90)(91) Routine screening is recommended
for infants at risk and includes serum concentrations
Table. Age-based Recommendations for Weight Gain
Velocity and Linear Growth (101)
Weight gain Age ( mo) Recommendation ( g/d)
0–3 24–34
3–6 13–21
6–12 8–11
Linear growth Age ( mo) Recommendation ( cm/wk)
0–3 0.8–0.88
3–6 0.46–0.48
6–12 0.29–0.34
Vol. 25 No. 1 JANUARY 2024 e17
 of alkaline phosphatase, calcium, and phosphorus. (92)
Management for MBD consists of enteral feeding adjust-
ments and supplementation with calcium, phosphorus, and
vitamin D. (4)
GROWTH AND RESPIRATORY SUPPORT
Routine growth assessments play a critical role in the re-
spiratory management of infants with BPD. For example,
growth trends help the team determine the timing of extu-
bation or weaning of noninvasive positive pressure. At our
institution, we like to see appropriate or improving growth
assessments prior to a major respiratory support wean,
as linear growth is associated with successful respiratory
weaning. (93) Some infants who have suboptimal growth
on noninvasive positive pressure or nasal cannula second-
ary to persistent increased work of breathing and meta-
bolic demand will likely benefit from an increase in
respiratory support, even if this means a period of me-
chanical ventilation.
FUTURE DIRECTIONS
Many older studies have reported that infants with BPD
require higher caloric intake than preterm infants without
BPD. (42)(43)(44)(94) However, these studies have limita-
tions such as small sample size, varied definitions of BPD,
and imperfect energy measuring techniques such as the
doubly labeled water technique and indirect calorimetry.
Indirect calorimetry testing may be useful for infants un-
dergoing invasive mechanical ventilation but can produce
inaccurate results in the setting of air leaks, high fraction
of inspired oxygen needs above 0.6, and factors that affect
steady state. (94) Further studies are needed to determine
the most accurate method of determining resting energy
expenditure in this population. In addition, future studies
should consider the patient’s age, activity level, respiratory
status, BPD severity, and BPD phenotype when determin-
ing energy needs.
Although the evidence to suggest that infants with BPD
require more protein intake than preterm infants without
BPD is limited, (66)(67)(68) the amount and duration of
the increased protein requirement remains unknown. Pro-
spective randomized controlled trials may help determine
the optimal protein ranges for infants with established
BPD at different age points. There are many studies on
the role of nutrition in BPD prevention, however, future
studies are needed to determine if and how certain nu-
trients play a role in modifying the disease course of estab-
lished BPD, such as vitamins A, D, and E as well as zinc,
and polyunsaturated fatty acids.
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Summary
• Growth failure in infants with BPD has important
short- and long-term implications that necessitate
a long-term multidisciplinary approach to
nutrition delivery and growth improvement. (95)
• Implementation of nutritional clinical guidelines
has led to improvement in growth outcomes in
other neonatal populations at risk for growth
failure, such as infants with congenital heart
disease. (48)(96)(97)(98)(99)(100) As we await
high-quality evidence, clinicians are
encouraged to implement a standardized
approach to feeding infants with BPD using the
available evidence and guidelines.
(4)(5)(12)(13)(14)(16)
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the pathogenesis, pathophysiology, and
pathologic features of bronchopulmonary
dysplasia/chronic lung disease.
• Respiratory/H. Chronic lung disease,
bronchopulmonary dysplasia/2. Know the
prenatal and postnatal risk factors for
bronchopulmonary dysplasia/chronic lung
disease and be aware of various preventive
strategies.
• Recognize the clinical features of
bronchopulmonary dysplasia/chronic lung
disease.
• Recognize the laboratory, radiographic, and
other imaging features of bronchopulmonary
dysplasia/chronic lung disease.
• Know the management of bronchopulmonary
dysplasia/chronic lung disease.
• Know the prognosis, long-term complications,
and permanent sequelae of bronchopulmonary
dysplasia.
• Know the caloric requirements for optimal
postnatal growth of preterm and term infants,
accounting for caloric expenditures needed for

physical activity and maintenance of body
temperature.
• Know the clinical manifestations, diagnosis,
management, and prevention of zinc, copper,
selenium, manganese, and chromium
deficiency.
• Know the immunologic and anti-infective
constituents in human milk and their
physiologic effects.
• Know that human milk needs to be fortified in
order to meet the nutritional needs of preterm
infants.
• Know the medical indications for the use of
non-standard infant formulas to meet the
needs of infants with special health problems.
References
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 NEOREVIEWS QUIZ

NEO
QUIZ
1. Bronchopulmonary dysplasia (BPD) is a common complication of prematurity.
Suboptimal postnatal nutrition has been shown to be a risk factor for the
development of BPD. Very-low-birthweight infants, in particular, have minimal
energy reserves and limited stores of essential nutrients. All of the following
essential nutrients have been shown to be involved in lung defense and lung
repair EXCEPT:
A. Glycogen.
B. Iron.
C. Long-chain polyunsaturated fatty acids.
D. Vitamin A.
E. Zinc.
REQUIREMENTS: Learners can
2. Systemic corticosteroids are commonly used for the medical management of
take NeoReviews quizzes and
infants with BPD and have been shown to result in lower linear growth as claim credit online only at:
well as decreased weight gain velocity. Which of the following statements https://publications.aap.org/
describing the impact of systemic corticosteroids on growth is INCORRECT? neoreviews.

A. Altered lipid metabolism. To successfully complete 2024

B. Altered bone metabolism. NeoReviews articles for AMA PRA
C. Decreased protein accretion. Category 1 Credit™, learners
D. Increased fatty acid oxidation. must demonstrate a minimum
performance level of 60% or
E. Increased protein catabolism. higher on this assessment. If
3. Infections and chronic inflammation are comorbidities of BPD that have you score less than 60% on the
assessment, you will be given
been shown to increase energy expenditure and contribute to suboptimal
additional opportunities to
growth in these patients. Which of the following statements describes an answer questions until an
effect of chronic inflammation that contributes to poor growth in these overall 60% or greater score is
patients? achieved.

A. Increased zinc levels. This journal-based CME activity

B. Decreased insulinlike growth factor. is available through Dec. 31,
C. Decreased sodium reabsorption. 2026, however, credit will be
D. Decreased lipid oxidation. recorded in the year in which
the learner completes the quiz.
E. Reduced fatty acid oxidation.
4. The nutritional needs of infants with BPD vary over time, depending on the
age of the infant and the stage of BPD. In the acute phase of BPD,
characterized by physiologic instability, poor linear growth is observed
alongside variable weight trends. In the transitional phase, weight trend and
linear growth improve while consistent linear growth and improved weight- 2024 NeoReviews is approved
for-length trend are seen once the infant reaches the progrowth phase. for a total of 30 Maintenance of
Certification (MOC) Part 2
Which of the following statements describes a recommended nutritional
credits by the American Board
goal for an infant in the acute phase of BPD? of Pediatrics (ABP) through the
A. Arachidonic acid intake of 5 mg/kg per day. AAP MOC Portfolio Program.
NeoReviews subscribers can
B. Calcium intake of 80 mg/kg per day. claim up to 30 ABP MOC Part 2
C. Energy requirement of 150 mL/kg per day. points upon passing 30 quizzes
D. Protein intake of 3 g/kg per day. (and claiming full credit for
E. Total fluid goal of 110 mL/kg per day. each quiz) per year. Subscribers
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as early as October 2024. To
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go to: https://publications.aap.
org/journals/pages/moc-credit.

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 5. Metabolic bone disease (MBD) is a common complication of prematurity.
Infants with BPD are at particularly high risk because of suboptimal postnatal
nutrition and exposure to systemic corticosteroids and diuretics. What is the
percentage of infants with BPD affected by MBD at 36 weeks’ postmenstrual
age?
A. 40%.
B. 50%.
C. 60%.
D. 70%.
E. 80%.

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 ARTICLE

Optimizing Nutrition in Neonates with

Kidney Dysfunction
Saudamini Nesargi, DNB,* Heidi Steflik, MD, MSCR,† Nivedita Kamath, MD, DNB, DM,‡ David Selewski, MD, MS,§
Katja M. Gist, DO, MSCS,¶ Shina Menon, MDk
*Department of Neonatology, St. Johns Medical College Hospital, Bangalore, India
†
Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC
‡
Department of Pediatric Nephrology, St. Johns Medical College Hospital, Bangalore, India
§
Division of Nephrology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC
¶
Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati
College of Medicine, Cincinnati, OH
k AUTHOR DISCLOSURES Dr Steflik works
Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine,
under a grant from Baxter, has received
Seattle, WA
honoraria for speaking and reviewing at the
Medical University of South Carolina and
MedLink Neurology, respectively, and is an
unpaid board member for the Southern
Society of Pediatric Research. Dr Gist works
PRACTICE GAP under a grant from The Gerber Foundation
and has received consulting fees from
Neonates with kidney disease have complex nutritional requirements Bioporta Diagnostics and Portero Medical.
based on their underlying kidney dysfunction. New clinical guidelines are Dr Menon works under a grant from The
Gerber Foundation and has received
available, but they focus on children of all ages and are not exclusive to consulting fees from Medtronic and Nuwellis.
neonates. Therefore, significant gaps remain, particularly with respect to Dr Selewski works under a grant from and
acute kidney injury and renal replacement therapy in the neonatal has served on an advisory board for
Pharmacosmos. Drs Nesargi and Kamath
population.
disclosed no financial relationships relevant
to this article. This commentary does not
contain a discussion of an unapproved/
OBJECTIVES After completing this article, readers should be able to: investigative use of a commercial product/
device. Drs Nesargi and Steflik contributed
equally to this work.
1. Summarize the pathophysiology of compromised nutrition in neonates
with kidney disease and discuss the key nutritional aspects of acute
ABBREVIATIONS
kidney injury and chronic kidney disease.
AKI acute kidney injury
2. Assess the nutritional needs of neonates with chronic kidney disease ARA arachidonic acid
and apply the Pediatric Renal Nutrition Taskforce clinical practice BMI body mass index
BSA body surface area
recommendations. CKD chronic kidney disease
CRRT continuous renal replacement
3. Recognize the nutritional implications of the use of continuous renal
therapy
replacement therapy for acute kidney injury in neonates. DHA docosahexaenoic acid
EN enteral nutrition
ESPGHAN European Society for Pediatric
ABSTRACT Gastroenterology, Hepatology,
and Nutrition
The nutritional management of neonates with kidney disease is GIR glucose infusion rate
complex. There may be significant differences in nutritional needs based iHD intermittent hemodialysis
IV intravenous
on the duration and cause of kidney dysfunction, including acute kidney KDOQI Kidney Disease Outcomes
injury (AKI) and chronic kidney disease (CKD). Furthermore, the Quality Initiative
treatment modality, including acute (continuous renal replacement PD peritoneal dialysis
PN parenteral nutrition
therapy and peritoneal dialysis [PD]) and chronic (intermittent PRNT Pediatric Renal Nutrition
hemodialysis and PD) approaches may differentially affect nutritional Taskforce
losses and dietary needs. In this review, we discuss the pathophysiology REE resting energy expenditure
RRT renal replacement therapy
of compromised nutrition in neonates with AKI and CKD. We also
SDI suggested dietary intake

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 summarize the existing data and consensus recommendations on the provision of nutrition to neonates with AKI and
CKD. We highlight the paucity of data on micronutrient losses and the need for future prospective studies to enhance
nutritional supplementation to hopefully improve outcomes in these patients.
INTRODUCTION
Nutritional requirements during the neonatal period are
of particular importance as growth rates are higher during
infancy. In critically ill neonates, this is often compounded
by multiple complications related to their underlying path-
ophysiology; therefore, nutrition should be individualized
to optimize the neonates’ nutritional status and growth.
Neonates with kidney dysfunction represent one such
group with unique nutritional needs relative to other criti-
cally ill neonatal populations.
The nutritional considerations in neonates with kidney
dysfunction encompass a broad spectrum related not only
to the acuity or chronicity of kidney dysfunction but also
to the unique aspects of renal replacement therapy (RRT).
Significant differences in nutritional needs in kidney dis-
ease based on the duration and cause of kidney dysfunc-
tion including acute kidney injury (AKI) and chronic
kidney disease (CKD) exist. As the epidemiology and im-
pact of neonatal AKI have become clearer, there has been
a push to optimize the care of these patients, including
nutritional support.
In this review, we will briefly examine nutrition in
healthy neonatal populations, describe the pathophysiology
and nutritional considerations in neonates with AKI and
CKD, and highlight areas for future research.
NUTRITIONAL NEEDS OF HEALTHY NEONATES
The provision of nutrition to neonates depends on numer-
ous factors including gestational age, degree of illness and
comorbidities, postnatal age, and method of feeding. Herein,
we provide a summary that is separated into preterm and
term neonates.
Table 1. Recommended Nutritional Intakes Based on Estimated Nutritional Needs in Healthy Term and Preterm
Infants
Nutritional Components Term Infants
Energy 75–85 kcal/kg per day (maximum: 100 kcal/kg per day)
Enteral: 10–14 g/kg/day
Parenteral (Glucose Infusion Rate): 2.5–10 mg/kg/min
Carbohydrates 2.5–10 mg/kg per minute
Protein and amino acids 1.5–2.5 g/kg per day
Lipids 5–6 g/kg per day
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Preterm Neonates
In preterm infants, postnatal growth should approximate
the growth of a fetus of the same gestational age in utero.
The recommended energy and carbohydrate prescriptions
vary depending on the route of feeding and individual pa-
tient parameters including weight, clinical status, and es-
tablished growth pattern, and thus must be individualized
(Table 1). (1) In all cases, energy intake in preterm infants
must equal the sum of energy expenditure. This includes
energy excreted through losses in stool and urine; energy
expended in basal metabolism, thermoregulation, activity,
and new tissue synthesis; and energy stored as fat, pro-
tein, and glycogen. (1) Significant variations exist in energy
and carbohydrate requirements even in preterm infants.
The 2022 European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition (ESPGHAN) position paper on
enteral nutrition (EN) in preterm infants recommends a
total energy intake of 115 to 140 kcal/kg per day for enter-
ally fed preterm infants who are healthy and growing,
though more than 140 kcal/kg per day may be needed in
some cases. (2) Parenterally supported infants require
fewer kilocalories (as a result of reduced energy costs for nu-
trient absorption and reduced fecal energy losses), whereas
enterally fed neonates require more kilocalories because of
increased diet-induced thermogenesis and increased fecal
energy losses. (2)
Sources of Energy
Glucose is the body’s major energy source and is particu-
larly important for the brain and heart. However, lactose
is the primary carbohydrate found in human milk. Lactose
is incompletely digested in preterm infants, leading to
concerns of increased risk for necrotizing enterocolitis
Preterm Infants
90–130 kcal/kg per day
4–10 mg/kg per minute
Enteral: 11–15 g/kg/day
Parenteral (Glucose Infusion Rate): 4–10 mg/kg/min
2.5–4.5 g/kg per day
4.1–7.4 g/100 kcal
 secondary to carbohydrate malabsorption in this popula-
tion. However, the substitution of lactose with more read-
ily digestible glucose has not been shown to improve
feeding tolerance or weight gain in preterm infants. (2)
Full enteral carbohydrates in preterm neonates should to-
tal 11 to 15 g/kg per day. (2) In parenterally fed preterm
neonates, glucose supplementation should provide appropri-
ate calories for basal glucose metabolism while maintaining
a normal plasma glucose concentration (ie, 54–108 mg/dL).
In term newborns, this typically requires a glucose infusion
rate (GIR) of 6 to 8 mg/kg per minute, but in very-low-birth-
weight preterm infants who are at risk for significant hyper-
glycemia, lower initial rates of 3 to 6 mg/kg per minute may
be more appropriate. (3) GIR can safely be advanced daily by
1 to 2 mg/kg per minute to a goal of 7 to 10 mg/kg per mi-
nute if serum glucose levels remain within normal limits.
Notably, higher GIR (ie, 9–12 mg/kg per minute or higher)
may be needed in very preterm or growth-restricted neonates
with hyperinsulinism-like disorders.
Proteins are vital for adequate growth as they are the
key structural component of all human cells and the main
driver of lean body mass growth. In preterm newborns,
protein supplementation should begin immediately after
birth at 1.5 to 2.5 g/kg per day. After 1 to 2 days, the pro-
tein prescription can be advanced to 3.5 g/kg per day. (4)
In extremely preterm newborns, a combination of EN and
parenteral nutrition (PN) is provided, with slow uptitration
of EN accompanied by downtitration of PN over the first
weeks of age. In transitioning from primarily PN to EN,
first-pass amino acid metabolism must be considered, and
protein content in PN should not be downtitrated before
enteral intake exceeds 75 mL/kg per day and not discontin-
ued until full enteral feedings are achieved. (5) In ex-
tremely preterm neonates receiving full EN, ESPGHAN
recommends 4 g/kg per day of enteral protein for ade-
quate growth, but a higher intake of up to 4.5 g/kg per
day may be needed for optimal weight gain. (2) Typical
preterm formulas contain 2.6 g of protein per 100 mL,
which corresponds to a protein intake of 3.9 to 4.7 g/kg per
day at enteral intakes of 150 to 180 mL/kg per day. Human
milk, particularly donor human milk, is low in protein un-
less provided in volumes greater than 200 mL/kg per day;
thus, multi-nutrient fortification is necessary to achieve the
desired protein concentrations of 4.5 g/kg per day. (2)
Lipids provide preterm infants with most of their en-
ergy requirements, and consequently, a relatively high die-
tary lipid content to supply 36% to 67% of energy intake
is recommended. (6) In preterm infants with a daily en-
ergy intake of 110 kcal/kg, lipid intake is approximately 4.1
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to 7.4 g of fat per 100 kcal, depending on the fat content
of the feedings. There are significant intra- and interindi-
vidual variations in human milk lipid content. In enterally
fed preterm neonates, ESPGHAN recommends a total fat
intake of 4.8 to 8.1 g/kg per day but notes higher intake
may be safe. (2) Long-chain polyunsaturated fatty acids, es-
pecially arachidonic acid (ARA) and docosahexaenoic acid
(DHA) are critical to supplement in preterm neonates, as
active placental transfer of these important fatty acids oc-
curs during the third trimester of pregnancy. These fatty
acids, when supplied in appropriate amounts to preterm
infants (DHA intake of 0.5%–1% of total fatty acids,
!30–65 mg/kg per day; dietary ARA/DHA ratio of 0.5–2),
are associated with improved short-term neurologic out-
comes. (2)(6) In preterm infants requiring PN, lipids are
typically initiated at 1 to 2 g/kg per day of intravenous (IV)
lipid emulsion and can be advanced to 2 to 3 g/kg per day
as tolerated.
Term Neonates
Nutrition prescriptions in term neonates are more straight-
forward than in preterm neonates. EN should be provided
with human milk, and formula should be used if essential.
(7) PN may be needed in term infants such as those with
preexisting congenital anomalies of the gastrointestinal
tract or in those with or at risk for intestinal malperfusion
(ie, some neonates with critical congenital heart disease).
The daily recommended energy requirement for term neo-
nates varies from 75 to 120 kcal/kg per day and 105 to 130
kcal/kg per day depending on the guidelines (Table 1).
(8)(9) There are several factors that may alter this require-
ment, including the use of PN, and the general metabolic
demands of the neonate. In general, if PN is used, the daily
energy requirement is reduced by 10% to 30%. (10)
Sources of Energy
Neonates able to enterally feed with human milk or for-
mula receive 10 to 14 g/kg per day of carbohydrates, which
is usually sufficient for growth. In those requiring PN, a
GIR ranging from 2.5 mg/kg per minute on day 1 to a
maximum of 10 mg/kg per minute is recommended. (11)
Hyperglycemia should be anticipated and managed ac-
cordingly. Neonates who exceed the GIR requirements re-
quire further evaluation.
Protein requirements are lower in term than in preterm
neonates. (8) Human milk and infant formulas provide
sufficient protein (1.5–2.5 g/kg per day) for a term neonate
if consumed in amounts sufficient to meet energy needs.
Human milk is whey predominant, though the ratio of
Vol. 25 No. 1 JANUARY 2024 e27
 whey to casein varies over time, ranging from 90:10 in
the colostrum to 60:40 in mature milk. Whey is more eas-
ily digestible and absorbable and adds a lower solute load
on the kidney. (12) Most commercially available formulas
designed for term infants have a whey-to-casein ratio of
60:40. Proteins when given by PN may be started at 1.5 g/kg
per day. In hospitalized neonates, catabolism is often present,
and protein requirements are often increased up to 3 g/kg
per day. Protein utilization for growth, and not energy, is best
when 30 to 40 kcal/g of protein is provided. (13) Most paren-
teral protein solutions contain essential amino acids.
Approximately 5 g/kg per day of fat is needed in term
neonates. Both human milk and infant formula provide a
sufficient quantity of lipids. In term infants, parenteral
lipid intake should not exceed 4 g/kg per day. (14) Formu-
lations that have essential fatty acids should be used.
ACUTE KIDNEY INJURY
Pathophysiology of Compromised Nutrition
Critical illness is often characterized by a catabolic state,
with muscle protein breakdown and lipolysis, and deterio-
ration in nutritional status is common. (15)(16) This is am-
plified in neonates who have high nutrition requirements
for their rapid rate of growth yet have limited nutrition re-
serves. In addition to protein catabolism, other metabolic
abnormalities seen in AKI include altered amino acid me-
tabolism, peripheral insulin resistance, and induction of a
proinflammatory state that can affect immune function.
(17) Hyperglycemia due to peripheral insulin resistance
and hepatic gluconeogenesis is common. While these fac-
tors lead to a loss of existing protein and energy stores, op-
timal nutrition delivery in neonates and infants with AKI
is also exceptionally challenging. Pathologic positive fluid
balance and fluid overload present in the setting of AKI of-
ten require fluid restriction, which makes it harder to pro-
vide optimal nutrition. As a result, critically ill neonates
(and infants and older children) with AKI are frequently
underfed and more likely to be fasting, thus placing them
at even greater risk for malnutrition. (18) Finally, AKI is
also associated with electrolyte derangements such as hy-
ponatremia, hyperkalemia, hyperphosphatemia, and meta-
bolic acidosis, all of which may necessitate modifications
to EN or PN.
A small subset of patients with severe AKI may require
RRT, either as continuous RRT (CRRT) or peritoneal dial-
ysis (PD). Despite the advances in technology, CRRT pre-
scriptions in neonates, infants, and children have been
largely extrapolated from adults. In adults, the CRRT dose
at initiation of therapy was standardized after the results
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of 2 large randomized controlled trials. (19)(20) An initial
CRRT dose prescription of 25 to 30 mL/kg per hour is rec-
ommended in adults. (21) In pediatric patients, a corre-
sponding dose of 2,000 mL/1.73m2 per hour is used. (22)
While the conversion from a weight-based dose in adults
matches well with a body surface area (BSA)–based dose
in older children, the nonlinear relationship between weight
and BSA results in a disproportionately higher dose in neo-
nates and infants. (23) The impact of this difference in
CRRT dosing on nutritional needs in neonates has not been
well studied.
Malnutrition is extremely common in patients with
AKI receiving CRRT, with a reported incidence of 30% to
55%. (24) One multicenter study of children receiving
CRRT showed that many were receiving insufficient pro-
tein. (25) Additionally, CRRT may result in the depletion
(loss) of important solutes necessary for growth and devel-
opment. This loss of proteins appears to be dependent on
the dialysis dose. (26) A study in adults showed that pa-
tients with severe AKI, even without CRRT, had micronu-
trient concentrations below the reference range that were
not different from those receiving CRRT. (27) These data
suggest that micronutrient absorption and utilization may
be impaired in AKI in general. (27) Zappitelli and col-
leagues evaluated nutritional losses in children receiving
CRRT and reported that 10% of total amino acid intake was
lost during CRRT. (28) Furthermore, patients had a nega-
tive nitrogen balance despite protein provision of approxi-
mately 2 g/kg per day. (28) The authors also identified loss
of folate and selenium during CRRT and suggested that
standard supplementation of these micronutrients may not
be sufficient. A second study from the same center (n515,
median age of 2 years) found that CRRT resulted in a me-
dian loss of 14.6% of prescribed protein. (26) Finally, in a
single-center prospective observational study of 174 children
receiving CRRT (median age of 18 months), 56% had acute
protein-energy wasting, defined as weight greater than the
3rd percentile. (29) Only protein energy wasting was associ-
ated with mortality in this cohort. (29) Unfortunately, most
of these studies include older children. There is limited
data on how these losses affect neonates who are in a criti-
cal stage of growth and development.
Feeding modality may also be a barrier to the provision
of adequate nutrition in neonates with severe AKI, includ-
ing those who require CRRT. A recent single-center study
evaluated 41 patients (median age of 9 years) receiving
CRRT. (30) Approximately 50% of patients received a com-
bination of PN and EN, with 34% receiving exclusively PN
and 12% receiving only EN. The percentage of time meeting
 protein goals by feeding modality was 65% for EN1PN,
34.6% for PN only, and 27.6% for EN only. Interestingly,
when these patients were weaned to EN only from PN1EN,
the average percentage of time protein goals that were met de-
creased to 20%. While this study included older children,
these data highlight that children with AKI are at significantly
increased nutritional risk when they transition from PN to EN.
Estimating Nutritional Needs in AKI
Estimating nutritional needs in critically ill neonates, in-
fants, and children is very challenging. Direct measures of
energy expenditure and indirect calorimetry are not usu-
ally available in clinical practice, and resting energy expen-
diture (REE) may be calculated using the World Health
Organization or the Schofield equations. (24) In critically ill
children, in the acute phase, caloric needs equal REE. (24)
The subsequent recovery phase should incorporate addi-
tional energy requirements for rehabilitation and growth.
Early and repeated nutrition screening and assessment
are recommended to identify children at risk for malnutri-
tion. (24) While there are no screening tools specific to
AKI in neonates, accurate anthropometric measurements
should be obtained early and repeated at least weekly.
These include euvolemic weight, recumbent length, head
circumference, and assessment of muscle and fat distribu-
tion by measuring middle upper arm circumference and
skinfold thickness. Reference values for arm circumfer-
ence and skinfold thickness from the World Health Orga-
nization are only available after 3 months of age, but there
are other smaller studies that have looked at these meas-
urements in neonates. (31)(32) Fluid balance may interfere
with the use of weight as a marker of nutritional status in
those with AKI. Other measures such as net fluid balance,
bioimpedance electrical analysis, or point-of-care ultraso-
nography may help delineate volume status. Bioimpe-
dance analysis can estimate body composition (particularly
total body water and lean mass) by measuring opposition
to electrical flow through tissues with the current and de-
tection electrodes placed on the infant’s wrist and ankle.
(32) However, the prediction equations using this method
are less accurate for neonates as compared to older chil-
dren. (32) Point-of-care ultrasonography may be used for
Table 2. Modifications to the Suggested Dietary Intake of Calories and Proteins in Healthy Term Neonates and
Those on Chronic Dialysis
Energy
Term neonate 93–107 kcal/kg per day
Peritoneal dialysis Deduct 7–9 kcal/kg per day
Hemodialysis Deduct !3 kcal/kg per day
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the assessment of intravascular volume as well as extravas-
cular fluid (such as free intra-abdominal fluid and pleural
effusion). (33)
Nutrition Prescription in Neonates with AKI
The diagnosis of AKI has several potential implications for
nutrition assessment and provision in neonates. The goal
is to provide appropriate nutrition while achieving fluid
homeostasis and avoiding dehydration or progressive volume
overload. This goal can be difficult to achieve, especially if
fluid restriction is necessary in the setting of oliguria or an-
uria. (34) The inability to provide nutrition secondary to fluid
restriction in AKI is an indication of RRT.
Energy expenditure in neonates with AKI may depend
more on the underlying disease, the preexisting nutritional
status, and the coexistence of acute and chronic comorbid-
ities. Based on the phase of AKI, the caloric prescription
must account for rehabilitation and growth. It may also
need to be modified to account for RRT-related net gain or
loss of energy. Both CRRT and PD provide other sources
of calories for nutrition. For CRRT, this includes citrate
(3 kcal/g) from the anticoagulant used, and lactate (3.62 kcal/g)
and glucose from the dialysis fluid. PD provides calories from
the glucose in the dialysis fluid (7–9 kcal/kg per day), which
should be a part of the prescription. (35) Critically ill neonates
with AKI may require higher protein intake to limit negative
protein balance. Protein restriction to lower blood urea ni-
trogen levels or delay RRT initiation is not recommended.
(21)(35) Protein losses may occur during PD, on the order
of approximately 0.1 to 0.28 g/kg per day, and additional
protein intake of at least 0.1 g/kg per day should be pro-
vided to infants on PD. (35) Table 2 summarizes the sug-
gested dietary intake (SDI) in healthy term neonates and
those treated with RRT.
It is also important to appropriately supplement micro-
nutrients (vitamins, trace elements, and carnitine). Sup-
plemental vitamin A should be avoided in all neonates
with AKI because impaired kidney function is associated
with reduced excretion of vitamin A, as well as elevated lev-
els of retinol, both of which may result in hypercalcemia and
hypervitaminosis A. (24) Those requiring RRT may need
supplemental water-soluble vitamins, trace elements (copper,
Protein
1.5–2.5 g/kg per day
Add 0.15–0.3 g/kg per day
Add 0.1 g/kg per day
Vol. 25 No. 1 JANUARY 2024 e29
 zinc, selenium), and carnitine. There are no data to recom-
mend routine measurement of serum concentrations of mi-
cronutrients unless a deficiency or toxicity is suspected based
on clinical signs.
Additional electrolyte abnormalities seen in AKI may
require modification of the nutrition prescription. Normal
values of plasma potassium in neonates are higher com-
pared to levels in older infants, children, and adults, and
appropriate interpretation requires the use of age-based
normative values. (36) For infants with AKI and hyperkale-
mia, human milk, which is naturally low in potassium
compared to standard infant formulas, may be used. Alter-
native approaches include decanting milk with potassium-
binding resins, use of low-potassium infant formulas, or a
brief period of discontinuing EN and supplementing with
IV fluids or PN without potassium. If the patient is already
receiving nutrition exclusively via IV fluids or PN, potassium
should be removed from these fluids until hyperkalemia is
corrected. The enteral or rectal use of sorbitol-based resins
such as sodium polystyrene should be avoided in neonates
because of the risk of intestinal perforation and obstruction.
(36) Hyperphosphatemia may require phosphate restriction
and transition to a low-phosphorous renal infant formula or
treatment with a calcium-based phosphate binder. Hypophos-
phatemia is common during CRRT, and phosphorus supple-
mentation is often needed to avoid complications such as
respiratory muscle weakness, myocardial dysfunction, and en-
cephalopathy. Phosphate is commonly provided as an additive
to CRRT solutions, though in recent years, commercially
available phosphate-containing CRRT solutions have become
available. Patients often need additional supplementation ei-
ther orally or in the PN. Table 3 summarizes the electrolyte
requirements in healthy neonates and those with AKI.
CHRONIC KIDNEY DISEASE
Pathophysiology of Compromised Nutrition
The altered metabolic milieu found in patients with AKI is
also seen in those with CKD. Additional changes include
anorexia secondary to abnormalities in the hormonal and
Table 3. Electrolyte Requirements in Healthy Term Neonates and Typical Changes seen in Patients with Acute
Kidney Injury Compared to Normal
Healthy Term Neonates
No RRT
Sodium (mEq/kg/day) 2-5 May decrease
Potassium (mEq/kg/day) 2-4 Lower
Calcium (mMol/kg/d) 0.25-2 Higher
Phosphorus (mMol/kg/d) 0.5-2 Lower
Magnesium (mMol/kg/d) 0.15-0.25 Unchanged
Acetate/bicarbonate As needed Higher
RRT, renal replacement therapy; iHD, intermittent hemodialysis; PD, peritoneal dialysis; CRRT, chronic RRT
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hypothalamic neuronal circuits that control appetite. (37)
There are also higher circulating concentrations of cyto-
kines, such as leptin, tumor necrosis factor a, and inter-
leukins 1 and 6, which further lead to cachexia. (37)
Estimating Nutritional Needs in CKD
Regular assessment by a pediatric dietitian experienced in
caring for neonates with CKD is imperative, and the Kidney
Disease Outcomes Quality Initiative (KDOQI) clinical prac-
tice guideline includes specific recommendations for regular
evaluations of growth and nutritional status in these neo-
nates. These recommendations include a review of dietary
intake and assessments of length for age, estimated euvole-
mic or “dry” weight and weight for age, body mass index
(BMI) for height/length for age, and head circumference.
(38) This is echoed by the more recent Pediatric Renal Nutri-
tion Taskforce (PRNT) (39) guidelines that recommended as-
sessment of these parameters at least twice as frequently as
they would be performed in a healthy neonate, although
more frequent assessments may be needed in neonates with
severe disease or complications (polyuria, growth delay, de-
creasing/low BMI, comorbid pathologies impacting growth
or nutrient intake, and recent acute medical status changes).
(38) For preterm infants born between 32 and 37 weeks’ ges-
tation, PRNT recommends plotting anthropometric measure-
ments for both gestational and chronologic age for the first
year after birth, and for those born before 32 weeks’ gesta-
tion, these measurements should be obtained through 2 years
of age. (39) Consideration of the underlying pathology of
CKD is also important when nutritional prescriptions are de-
termined; infants with congenital nephrotic syndrome, for ex-
ample, experience excessive protein losses and may require
additional protein/amino acid supplementation beyond that of
infants with CKD secondary to other causes. Careful assess-
ment of body weight and fluid balance is of paramount im-
portance given that the prescription of nutrition is often based
on body weight and both volume overload and that depletion
can occur in neonates with CKD. Dry weight should be fre-
quently reassessed by evaluating body weight along with the
Term infants With Acute Kidney Injury
iHD PD CRRT
May decrease May decrease May decrease
Unchanged /lower Unchanged /lower Higher
Higher Higher Higher
Unchanged /lower Unchanged /lower Higher
Unchanged Unchanged Higher
Unchanged Unchanged Lower
 presence or absence of edema, blood pressure, laboratory val-
ues, and dietary intake. (38) Individualized counseling and in-
terventions, as well as frequent reevaluations and potential
modifications to nutrition plans of care, may be needed. This
requires the coordinated efforts of a dietitian with expertise in
pediatric and renal nutrition, as well as a multidisciplin-
ary team including the child, caregivers, and the pediatric
nephrology team.
Nutrition Prescription in Neonates with CKD
KDOQI recommends centering nutritional care to achieve
the following goals:
1. “maintenance of an optimal nutritional status (ie,
achievement of normal pattern of growth and body com-
position by intake of appropriate amounts and types of
nutrients),
2. avoidance of uremic toxicity, metabolic abnormalities,
and malnutrition, and
3. reduction of the risk of chronic morbidities and mortal-
ity in adulthood.”(38)
More recently Shaw and colleagues from PRNT pro-
vided an update on energy and protein requirements for
children with CKD stages 2 to 5 and on dialysis. (35) Given
the varying national and international terms and defini-
tions for energy and protein requirements, PRNT intro-
duced the term “suggested dietary intake” (SDI) for their
recommendations. In CKD stages 2 to 5, initial prescrip-
tions for nutrition should approximate that of healthy chil-
dren of the same chronologic age, and when weight gain
is suboptimal, the prescription should be adjusted toward
the higher end of the SDI. In infants at risk for obesity,
the nutrition should be adjusted to achieve appropriate
weight gain without compromising the delivery of protein,
fat, carbohydrates, and macro- and micronutrients. In neo-
nates, human milk is preferred, with appropriate fortifica-
tion, when necessary, in the setting of fluid restriction, or
when additional calories are required without increasing
total volume. A whey-dominant formula is recommended
when supplemental feedings are required. Methods of
fortification of human milk with whey-based formulas
have been described elsewhere. (40) A feeding volume of
150 mL/kg per day may be sufficient to meet the nutri-
tional needs of an infant with CKD. However, an infant
with polyuria with a higher-than-normal fluid require-
ment may need additional fluid given either as free water
in between feedings or mixed in to prepare dilute formula.
(40)
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Neonates with CKD requiring RRT warrant special con-
sideration regarding their nutritional needs. Some of these
needs are similar to those discussed for AKI. Adequacy of
nutrition provision is of particular importance during PD
catheter placement because malnutrition with subsequent
abdominal muscle wasting can lead to poor stability of the
catheter, potential leakage, and impaired wound healing.
(41) In children receiving PD, the energy intake from
the dialysate should be considered to range from 7 to
9 kcal/kg per day depending on the dextrose concentra-
tion of the dialysate, the time on dialysis, number of
cycles, dwell times, and the peritoneal membrane trans-
porter status. If there is excessive weight gain in these
children, this energy source needs to be taken into con-
sideration. Dialysate protein loss should be accounted
for, and the recommended protein intake is higher than the
SDI for neonates managed conservatively, with an addi-
tional 0.15 to 0.3 g/kg per day recommended on PD and
0.1 g/kg per day on intermittent hemodialysis (Table 3).
(40) Neonates on PD frequently experience vomiting, poor
appetite and oral intake, and delayed gastric emptying,
which can exacerbate nutritional deficiencies and losses.
(41) Adequate growth and even catch-up growth can be
achieved with appropriate nutrition provision in neonates
with CKD with or without RRT.
The intake of calcium should be maintained between
100% and 200% of SDI. The calcium intake from medica-
tion and dialysate should be considered. The dietary phos-
phate intake should be within the SDI. Human milk and
whey-dominant formula are low in phosphate. (42) Potas-
sium intake should be based on renal function and serum
potassium levels. Human milk has a low potassium con-
tent. In neonates with hyperkalemia, human milk may be
substituted with a low-potassium formula. In formula-fed
infants, the potassium-binding resin can be added to the
formula and decanted. (43)
While the preferred route for the provision of nutrition is
oral, enteral tube feeding via a nasogastric tube or gastrostomy
device may be occasionally needed. PRNT recommends sup-
plemental or exclusive enteral tube feeding in children with
CKD who are unable to meet their nutritional requirements
orally. (35) Despite these recommendations, various studies
have shown limited use of enteral tube feeding outside North
America and some European countries. (44)(45)(46) For short-
term enteral feeding needs, a nasogastric tube is preferred,
whereas a gastrostomy device is preferred for long-term use.
(47) PRNT provides additional clinical practice recommenda-
tions for the optimal delivery of nutrition via enteral tube feed-
ing to children with CKD stages 2 to 5 and on dialysis. (47)
Vol. 25 No. 1 JANUARY 2024 e31
 CONCLUSION
Neonates with kidney dysfunction, be it AKI or CKD, have
unique nutrition needs. It is important to be aware of
their nutritional requirements, know how to assess them
and be able to provide appropriate nutrition, especially as
outlined by PRNT. Based on the type of kidney dysfunction
(acute or chronic) and the need for RRT (CRRT, intermit-
tent hemodialysis, or PD), the needs and losses of macro-
and micronutrients and trace minerals may vary, necessitat-
ing periodic laboratory monitoring and adjustment.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the differences in the nutritional
composition of human milk and infant formula.
• Know the importance of protein and nonprotein
nutrients in achieving optimal utilization of energy
and nitrogen.
• Know the etiology of electrolyte abnormalities in
the neonate.
• Know the impact of renal dysfunction on water
requirements.
• Know how to manage electrolyte abnormalities in
the neonate.
• Know the management of renal failure in the
neonate, including indications for and
complications of the use of hemofiltration,
peritoneal dialysis, and hemodialysis.
• Know the potential adverse effects of
pharmacologic use of fat-soluble vitamins.
• Know the medical indications for the use of
nonstandard infant formulas to meet the needs of
infants with special health problems.
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29. Castillo A, Santiago MJ, L"
opez-Herce J, et al. Nutritional status and
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30. Wong Vega M, Juarez Calderon M, Tufan Pekkucuksen N, Srivaths
P, Akcan Arikan A. Feeding modality is a barrier to adequate protein
provision in children receiving continuous renal replacement
therapy (CRRT). Pediatr Nephrol. 2019;34(6):1147–1150
31. Pereira-da-Silva L, Virella D, Fusch C. Nutritional assessment in
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infant. Am J Hum Biol. 2014;26(3):291–304
33. Singh Y, Tissot C, Fraga MV, et al. International evidence-based
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36. Bonilla-F"elix M. Potassium regulation in the neonate. Pediatr
Nephrol. 2017;32(11):2037–2049
37. Mak RH, Cheung W, Cone RD, Marks DL. Orexigenic and
anorexigenic mechanisms in the control of nutrition in chronic
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38. KDOQI Work Group. 2008 update. Executive summary. Am J
Kidney Dis. 2009;53(3 suppl 2):S11–S104
39. Nelms CL, Shaw V, Greenbaum LA, et al. Assessment of nutritional
status in children with kidney diseases-clinical practice
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Pediatr Nephrol. 2021;36(4):995–1010
40. Shaw V, Anderson C, Desloovere A, et al. Nutritional management
of the infant with chronic kidney disease stages 2-5 and on dialysis.
Pediatr Nephrol. 2023;38(1):87–103
41. Spector BL, Misurac JM. Renal replacement therapy in neonates.
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42. McAlister L, Pugh P, Greenbaum L, et al. The dietary
management of calcium and phosphate in children with CKD
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from the Pediatric Renal Nutrition Taskforce. Pediatr Nephrol.
2020;35(3):501–518
43. Desloovere A, Renken-Terhaerdt J, Tuokkola J, et al. The dietary
management of potassium in children with CKD stages 2-5 and
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Renal Nutrition Taskforce. Pediatr Nephrol. 2021;36(6):
1331–1346
44. Rees L, Azocar M, Borzych D, et al; International Pediatric
Peritoneal Dialysis Network (IPPN) registry. Growth in very young
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2011;22(12):2303–2312
45. Schaefer F, Benner L, Borzych-Du_załka D, et al; International
Pediatric Peritoneal Dialysis Network (IPPN) Registry. Global
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Peritoneal Dialysis Network. Sci Rep. 2019;9(1):4886
46. Sharma S, Sinha A, Malik R, Bagga A. Gastrostomy tube feeding in
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47. Rees L, Shaw V, Qizalbash L, et al; Pediatric Renal Nutrition
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36(1):187–204
Vol. 25 No. 1 JANUARY 2024 e33
 NEOREVIEWS QUIZ

NEO
QUIZ

1. A preterm infant of 31 week’s gestation is starting enteral feeds. The NICU

team is working on calculating the caloric density of feeds to ensure
adequate growth. Which of the following statements describes an
appropriate daily total energy intake for this preterm infant?
A. 60 kcal/kg per day.
B. 75 kcal/kg per day.
C. 90 kcal/kg per day.
D. 120 kcal/kg per day
E. 150 kcal/kg per day.
REQUIREMENTS: Learners can
2. You are caring for an infant born at 25 week’s gestation who is advancing take NeoReviews quizzes and
enteral feeds. Previous studies have demonstrated that proteins are key claim credit online only at:
structural components of all human cells, vital for adequate growth, and a https://publications.aap.org/
main driver of lean body mass growth. What is the recommended amount of neoreviews.
enteral protein intake for adequate growth in an extremely preterm infant?
To successfully complete 2024
A. 11.5 g/kg per day NeoReviews articles for AMA PRA
B. 2 to 2.5 g/kg per day. Category 1 Credit™, learners
must demonstrate a minimum
C. 3 to 3.5 g/kg per day.
performance level of 60% or
D. 4 to 4.5 g/kg per day. higher on this assessment. If
E. 5 to 5.5 g/kg per day. you score less than 60% on the
assessment, you will be given
3. You are taking care of a critically ill term neonate with acute kidney injury additional opportunities to
(AKI). Infants with this condition are often in a catabolic state with muscle answer questions until an
protein breakdown and lipolysis. In addition to increased protein catabolism, overall 60% or greater score is
other metabolic abnormalities can occur in infants with AKI. All of the achieved.
following metabolic derangements can be observed in these patients except:
This journal-based CME activity
A. Altered amino acid metabolism. is available through Dec. 31,
B. Hypoglycemia. 2026, however, credit will be
recorded in the year in which
C. Impaired immune function.
the learner completes the quiz.
D. Peripheral insulin resistance.
E. Proinflammatory state.
4. AKI is a common complication in neonates with critical illness and can be
challenging to manage. Pathologic fluid balance and fluid overload often
require fluid restriction, making it difficult to provide optimal nutrition. In
addition to fluid overload AKI can contribute to each of the following 2024 NeoReviews is approved
for a total of 30 Maintenance of
electrolyte derangements EXCEPT:
Certification (MOC) Part 2
A. Hypercalcemia. credits by the American Board
B. Hyperkalemia. of Pediatrics (ABP) through the
AAP MOC Portfolio Program.
C. Hyponatremia.
NeoReviews subscribers can
D. Hyperphosphatemia. claim up to 30 ABP MOC Part 2
E. Metabolic acidosis. points upon passing 30 quizzes
(and claiming full credit for
each quiz) per year. Subscribers
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as early as October 2024. To
learn how to claim MOC points,
go to: https://publications.aap.
org/journals/pages/moc-credit.

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 5. An infant of 37 week’s gestation with AKI is requiring continuous renal
replacement therapy (CRRT). A common complication of CRRT is the removal
of important solutes necessary for growth and development. Of the patients
receiving CRRT, what percentage experience malnutrition and poor growth?
A. 10%
B. 25%.
C. 45%.
D. 60%.
E. 75%.

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 ARTICLE

Common Clinical Scenarios of Systemic

Hypertension in the NICU
Sheema Gaffar, MD, MS,*† Rangasamy Ramanathan, MD,* Molly Crimmins Easterlin, MD, MS†
*Division of Neonatology, Department of Pediatrics, Los Angeles General Medical Center, Keck School of Medicine, University of Southern California, Los
Angeles, CA
†
Division of Neonatology, Fetal and Neonatal Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los
Angeles, CA

PRACTICE GAPS

The diagnostic criteria and treatment of neonatal hypertension are

inconsistent. Due to an insufficient number of published studies and a lack
of evidence on the long-term effects of hypertension and on the safety and
efficacy of antihypertensive medications, guidelines for the treatment of
hypertension in neonates and infants are lacking. Long-term effects of
neonatal hypertension are also underrecognized, resulting in variable
practices for monitoring and follow-up.

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

1. Identify hypertension in a neonate of any gestational age, initiate diagnostic

evaluation, and establish follow-up and long-term monitoring plan.
2. Recognize common clinical scenarios in which neonatal hypertension
can present in the NICU.
3. Describe antihypertensive therapeutic options in neonates.

ABSTRACT
AUTHOR DISCLOSURES Drs Easterlin,
Ramanathan, and Gaffar have disclosed Hypertension affects !1% to 3% of newborns in the NICU. However, the
no financial relationships relevant to this identification and management of hypertension can be challenging
article. This commentary does not because of the lack of data-driven diagnostic criteria and management
contain a discussion of an unapproved/
investigative use of a commercial
guidelines. In this review, we summarize the most recent approaches to
product/device. diagnosis, evaluation, and treatment of hypertension in neonates and
infants. We also identify common clinical conditions in neonates in whom
ABBREVIATIONS hypertension occurs, such as renal vascular and parenchymal disease,
bronchopulmonary dysplasia, and cardiac conditions, and address specific
ACE angiotensin-converting enzyme
AKI acute kidney injury considerations for the evaluation and treatment of hypertension in those
BPD bronchopulmonary dysplasia conditions. Finally, we discuss the importance of ongoing monitoring and
CoA coarctation of the aorta
long-term follow-up of infants diagnosed with hypertension.
ECMO extracorporeal membrane
oxygenation
IV intravenous
PDA patent ductus arteriosus INTRODUCTION
PMA postmenstrual age
SGA small for gestational age
Hypertension is relatively common in neonates in the NICU. Optimal management of
UAC umbilical arterial catheter neonatal hypertension is guided by the etiology of hypertension, determining when

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 pharmacologic intervention is needed, which antihypertensive
medication to use, and treating the underlying cause. However,
identification and management of neonates with hypertension
can be challenging because of a lack of data-driven diagnostic
criteria, limited studies on the long-term effects of hyperten-
sion, and insufficient randomized controlled trials evaluating
the safety and efficacy of antihypertensive medications.
In this review, we summarize the most recent approaches
to the diagnosis, evaluation, and treatment of hypertension
in neonates and infants. We also identify common clinical
conditions in the NICU in which hypertension occurs, in-
cluding renal vascular and parenchymal disease, bronchopul-
monary dysplasia (BPD), coarctation of the aorta (CoA),
postoperative pain and fluid shifts, and prematurity or growth
restriction. We discuss specific management approaches for
each cause of hypertension. Finally, we review the importance
of ongoing monitoring and long-term follow-up of infants di-
agnosed with hypertension.
DEFINITION OF NEONATAL HYPERTENSION
In neonates, blood pressure is variable in the first few days
after birth because of transitional physiology. Generally, in
term infants, blood pressure rises by 1 to 2 mm Hg per day
for the first 3 to 4 days after birth and then levels off. (1) In
preterm infants, blood pressure is more labile and rises rap-
idly in the first few weeks of age, depending on the infant’s
postmenstrual age (PMA), birthweight, and antenatal expo-
sure to medical conditions of pregnancy. (2)(3) In extremely
preterm infants, blood pressure may initially decrease for
the first few hours after birth before increasing (Table 1).
(4)(5)
Due to this expected variability in blood pressure, it
can be difficult to strictly define normal blood pressure
and high blood pressure in the first weeks after birth. In
practice, for a preterm infant, the lowest acceptable mean
arterial blood pressure in the first few days after birth is
approximately equivalent to the gestational age in weeks,
as long as there is clinical evidence of good systemic per-
fusion. (6)(7)(8) Once a neonate is 2 weeks old, the defini-
tion of normal blood pressure is more standardized because
some normative data exist. (9) The American Academy of
Pediatrics recommends using these blood pressure percen-
tiles to define normal blood pressure ranges for infants who
are older than 2 weeks’ chronologic age and 26 to 44 weeks’
PMA (Table 2). (2)(9)(10)(11) Hypertension is typically defined

Table 1 . BP Values Obtained on the Newborn Day, 3 Days after Birth, and 5 Days after Birth
Newborn Day BP Day 3 BP Day 5 BP
Birthweight
(g) Average 1 0 th Pc 5 0 th Pc 9 0 th Pc Average 1 0 th Pc 5 0 th Pc 9 0 th Pc Average 1 0 th Pc 5 0 th Pc 9 0 th Pc
#1,000 SBP 56 40 55 72 60 46 59 77 62 49 62 77
DBP 35 21 36 48 40 27 38 56 39 29 38 51
MBP 43 27 41 56 48 35 46 64 47 36 47 59
1,001–1,500 SBP 56 43 55 71 65 53 65 78 67 54 68 79
DBP 35 24 36 45 42 32 42 53 43 33 43 54
MBP 43 31 43 56 51 40 51 61 52 41 52 62
1,501–2,000 SBP 59 48 58 70 65 54 65 77 68 57 68 81
DBP 35 26 35 44 42 33 41 52 42 32 42 53
MBP 44 34 44 54 51 42 51 60 52 42 52 64
2,001–2,500 SBP 60 50 59 72 68 58 68 79 73 60 73 86
DBP 37 27 36 46 44 35 44 53 45 35 44 57
MBP 46 36 45 55 53 44 53 62 56 45 55 69
2,501–3,000 SBP 67 54 64 82 71 59 71 84 73 63 74 83
DBP 43 30 41 58 45 34 44 56 43 35 42 54
MBP 52 40 50 68 55 44 54 67 55 45 54 66
3,001–3,500 SBP 69 56 69 82 74 62 73 87 75 63 75 88
DBP 42 32 42 52 47 37 46 58 46 37 45 56
MBP 52 42 52 63 58 46 57 70 57 48 57 68
3,501–4,000 SBP 70 59 70 81 75 62 74 86 80 69 80 91
DBP 42 32 41 52 48 37 47 59 48 39 48 59
MBP 53 43 52 64 58 46 58 70 60 50 60 71
4,001–4,500 SBP 71 58 70 88 75 62 75 88 77 61 78 90
DBP 43 35 42 54 47 36 45 59 46 36 44 58
MBP 53 43 52 66 58 45 58 71 58 45 58 69
Values are based on birthweight for preterm and term infants, based on a retrospective review of 629 infants in Hungarian NICUs. (4) Before
this study, the 1995 study by Zubrow et al (5) on 608 infants in Philadelphia NICUs was used for blood pressure norms in the first few days
after birth. BP5blood pressure, DBP5diastolic blood pressure, MBP5mean blood pressure, Pc5percentile, SBP5systolic blood pressure.
Reprinted with permission from Kiss et al. (4).

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 Table 2 . Blood Pressure Normative Values Obtained for Infants Older than 2 Weeks
Postconceptional Age 5 0 th Percentile 9 5 th Percentile 9 9 th Percentile
44 wk
SBP 88 105 110
DBP 50 68 73
MAP 63 80 85
42 wk
SBP 85 98 102
DBP 50 65 70
MAP 62 76 81
40 wk
SBP 80 95 100
DBP 50 65 70
MAP 60 75 80
38 wk
SBP 77 92 97
DBP 50 65 70
MAP 59 74 79
36 wk
SBP 72 87 92
DBP 50 65 70
MAP 57 72 71
34 wk
SBP 70 85 90
DBP 40 55 60
MAP 50 65 70
32 wk
SBP 68 83 88
DBP 40 55 60
MAP 48 62 69
30 wks
SBP 65 80 85
DBP 40 55 60
MAP 48 65 68
28 wks
SBP 60 75 80
DBP 38 50 54
MAP 45 58 63
26 wks
SBP 55 72 77
DBP 30 50 56
MAP 38 57 63

Infants are at 26 to 44 weeks’ PMA. These values, first published in 2012 by Dionne et al, (9) remain in use presently. DBP5diastolic blood
pressure, MAP5mean arterial pressure, SBP5systolic blood pressure.
Reprinted with permission from Kiss et al. (4).

as persistently elevated systolic, diastolic, or mean blood pres-
sure, greater than the 95th percentile, or any elevated
blood pressure associated with signs or symptoms of or-
gan damage. (6)(10) In the ambulatory setting, persistent
hypertension is defined as hypertension present in more
than 3 office visits. (10) In the intensive care unit, how-
ever, persistent hypertension is vague and often deferred to
the clinician’s judgment.
The technique used in measuring blood pressure is im-
portant as most oscillometric devices are not manufac-
tured specifically for the neonatal population. (12) The
American Academy of Pediatrics, American Heart Associ-
ation, and National Institutes of Health have published
best practice recommendations for blood pressure mea-
surement in infants with an oscillometric device or with
auscultation (manual). (10)(12) Cuff size is selected in re-
lation to the size of the extremity used for measurement;
the right upper arm is typically used for brachial artery
blood pressure measurement, as the left upper arm can
be erroneous in cases of CoA. (10) Although the thigh
can be used for popliteal artery blood pressure measurement
in neonates, the values are not easily compared with pub-
lished reference tables, which use the arm. (10) The length
and width of the cuff should be 80% to 100% and 45% to
70% of the arm circumference, respectively. (10) Measure-
ments should be taken while the infant is calm, laying in the

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 supine position, 1.5 hours after the last feeding, and after the
cuff has been in place for 15 minutes. A repeat blood pres-
sure assessment can be done if the first one is elevated, and
the values can be averaged. (1)(2)(6)(10)(13) An umbilical ar-
terial catheter (UAC) provides direct, continuous intra-arterial
blood pressure measurements that are more accurate than
cuff measurements but also more invasive.
EPIDEMIOLOGY
While the incidence of hypertension varies slightly based
on the definition of hypertension used, it occurs in !1%
to 3% of infants hospitalized in the NICU. (2)(6) It is
more common in the NICU population than in healthy
term newborns where the incidence is !0.2%. (9)(14) Ap-
proximately half (52.8%–57.7%) of neonates diagnosed
with hypertension in the NICU receive pharmacologic treat-
ment with at least 1 antihypertensive medication. (13)(15)
Risk factors for neonatal hypertension include antenatal
factors such as exposure to hypertension of pregnancy, ex-
posure to substance use disorder during pregnancy such as
methamphetamine, and perinatal factors such as exposure
to corticosteroids, as well as preterm birth, low birthweight,
and intrauterine growth restriction. (6) Postnatally, neonates
with increased severity of illness may undergo procedures
such as UAC insertions and extracorporeal membrane oxy-
genation (ECMO), which further increase the risk for hyper-
tension. (10)(11) Additional infant risk factors for hypertension
include renal artery stenosis, renal parenchymal disease, BPD,
CoA, endocrine abnormalities, prematurity, and growth re-
striction. (1)(2)(14)
ETIOLOGY
The most common cause of neonatal hypertension is renal
vascular disease or UAC-associated thrombosis (12)(14)(16)
followed by congenital or acquired renal parenchymal con-
ditions. (1)(10)(12)(15)(17)(18) BPD is the most common
nonrenal cause of hypertension in infants. The most com-
mon cardiac cause of hypertension in neonates is CoA.
Postoperative hypertension can occur in infants with in-
creased thoracoabdominal pressure after abdominal wall
closure or ECMO. Broad neonatal conditions associated with
hypertension include neurologic causes, such as seizures
or intracranial masses, and endocrine diagnoses, such
as hyperthyroidism, mineralocorticoid excess, congenital
adrenal hyperplasia, or genetic etiologies. (12) Despite this
vast number of etiologies, half of neonatal hypertension is
idiopathic. (19)
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PATHOGENESIS
The pathogenesis of hypertension is unique to each clini-
cal condition.
UAC-associated Renovascular Hypertension
UAC-associated thrombosis can result in a partially or
completely occlusive aortic thrombus, from which a large
thrombus or smaller thrombi can embolize into the renal
parenchyma, causing hypertension. (12) Disruption of the
vascular endothelium during placement of the catheter it-
self may also lead to the formation of microemboli, which
may deposit in the renal artery, decreasing perfusion to
the kidney, stimulating renin and aldosterone production,
and causing hypertension secondary to increased sodium
reabsorption and water retention. (20) These microemboli
may be too small to detect on ultrasonography. (12)(14)(16)
Other renovascular abnormalities such as renal artery
stenosis, renal vein thrombosis, and fibromuscular dyspla-
sia are rare but possible causes of neonatal hypertension,
especially in the setting of other common risk factors for
thromboembolic disease such as pregnancies complicated
by diabetes mellitus. (12)(14)
Congenital and Acquired Renal Parenchymal Disease
Congenital anomalies of the kidney and urinary tract can
cause neonatal hypertension by obstructing the urinary
tract. Large cystic kidneys can compress the urinary tract
from the outside, causing obstruction at any level, whereas
obstructions at the ureteropelvic junction and the urethra
are more common from valves or malformations within
the urinary tract itself. (14)(20) Polycystic kidney disease,
multicystic dysplastic kidney disease, and congenital renal
hypoplasia/dysplasia likely cause hypertension because of
the associated abnormal renal parenchyma. (12)(20)(21)
Postnatal renal ultrasonography can confirm these struc-
tural abnormalities, though ideally, these conditions are
known or suspected antenatally. (10)
Acute kidney injury (AKI) is a common yet underdiag-
nosed entity in the NICU that results in acquired renal
parenchymal diseases such as acute tubular necrosis, in-
terstitial nephritis, or cortical necrosis, and subsequent
hypertension from excessive renin release. (12)(14)(20)
Bronchopulmonary Dysplasia-related Hypertension
BPD is the most common nonrenal cause of hypertension
in infants. Hypertension in BPD may be from a combination
of underlying disease and its treatments. Neonates with BPD
are more likely to have vasomotor dysfunction and increased
stiffness of the systemic arteries leading to hypertension.
Vol. 25 No. 1 JANUARY 2024 e39
 (14)(20) This systemic hypertension is likely how neonates
with BPD maintain pulmonary blood supply in the setting of
concurrent pulmonary hypertension and chronic hypoxemia.
In addition, a vast majority of infants with BPD-associ-
ated hypertension were found to have low renin levels,
suggesting that volume excess is a possible contributor to
their hypertension and lung disease. (12)(14)(22)(23)
Treatments for BPD, including corticosteroids and neph-
rocalcinosis-inducing diuretics, may further exacerbate
hypertension. (12)(20)
Coarctation of the Aorta
The most common cardiac cause of hypertension in neo-
nates is CoA. (10) Development of CoA antenatally has
been attributed to decreased blood flow through the aortic
valve and aortic arch causing decreased growth (24) and
postnatally has been attributed to overgrowth of ductal tis-
sue into the aorta causing constriction at those sites. (25)
Normally, blood pressure is 10% to 20% higher in the
legs than in the arms. (10) However, in infants with CoA,
increased pressure is required in the aorta proximal to the
area of coarctation to get blood past the narrowed segment
and to perfuse the lower body. (25) This increased after-
load typically manifests as upper extremity hypertension
relative to the lower extremities. Left ventricular hypertro-
phy and the development of collateral vessels are addi-
tional adaptive mechanisms that develop over time in
response to obstruction in CoA physiology. (24)(25)
Postoperative Hypertension (Pain, Withdrawal, Fluid
Shifts, Compression, Indirect Endocrine Effects)
Agitation due to undertreated pain or sedation withdrawal
may cause hypertension. Postprocedural fluid shifts in the
thoracoabdominal cavity during prolonged surgical proce-
dures can also cause hypertension, (26) particularly after
staged repair of giant omphalocele (27) and ECMO. (28)(29)
An additional mechanism of postoperative hypertension
is endocrine. After abdominal wall closure, increased intra-
abdominal pressure causes renal and adrenal compression, re-
sulting in catecholamine release and subsequent hypertension.
(26)(27) Similar postoperative catecholamine release is com-
mon after surgical repair of CoA as well, termed “paradoxical
hypertension.” (26)(30)(31) The endocrine component of post-
ECMO hypertension is more variable, as some fluid overload
appears to be secondary to impaired water and sodium regula-
tion without evidence of abnormal renin levels, (26) whereas
others have increased renin and endothelin levels along with
oliguria. (28)(29)
Endocrine-related Hypertension
Hyperthyroidism and congenital adrenal hyperplasia are
common endocrine etiologies for hypertension, especially
in the context of abnormal physical examination findings
(Table 3) or elevated thyroid hormone or serum androgen
levels. (10)(32)(33) Endogenous cortisol surges or stress-
dose steroids for adrenally insufficient neonates likely con-
tribute to episodic hypertension as well. Similar surges of
catecholamines and other vasoactive hormones can occur

Table 3 . Pertinent Physical Examination Findings

System Finding Possible Etiology
Vital signs Tachycardia Hyperthyroidism
Irregular respiratory rate Intracranial hypertension
Height, weight Poor growth with low percentiles Chronic renal failure
HEENT Elfin facies Williams syndrome
Webbed neck Turner syndrome
Moon facies Cushing syndrome
Proptosis, thyromegaly, goiter Hyperthyroidism
Chest Murmur, thrill, apical heave Structural heart disease, left ventricular hypertrophy
Widely spaced nipples Turner syndrome
Abdomen Abdominal mass Wilms tumor, Neuroblastoma
Palpable kidneys Hydronephrosis
Genitourinary Ambiguous or virilized genitalia Congenital adrenal hyperplasia
Neurologic Anterior fontanelle pulsation Severe intracranial hypertension, Vein of Galen
Skin Pallor, flushing, diaphoresis Pheochromocytoma
Caf!e-au-lait spots Neurofibromatosis
Adenoma sebaceum Tuberous sclerosis
Malar rash Neonatal lupus erythematosus

These findings suggest an etiology beyond the common hypertensive phenotypes in the NICU. (10) HEENT5head, ears, eyes, nose, and
throat examination.
Adapted from Flynn JT, Kaelber DC, Baker-Smith CM, et al; Subcommittee on Screening and Management of High Blood Pressure in Chil-
dren. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;
140(3):e20171904. (10)

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 as a result of compression from intra-abdominal masses,
tumors (ie, neuroblastoma, Wilms tumor), and operations,
as noted above. (26)
Prematurity or Growth Restriction
Preterm and/or growth-restricted small for gestational age
(SGA) neonates are at an increased risk for hypertension
because of renal immaturity and vascular maldevelopment.
When an infant is born early, in utero renal development is
interrupted, resulting in reduced numbers of nephrons and
glomeruli, making these neonates particularly vulnerable
to postnatal injuries from hypoxia, hypotension, or nephro-
toxins. (14) Preterm birth also interrupts normal vasculo-
genesis, causing decreased elastin production. (16)(34)(35)
Similarly, a fetus with growth restriction secondary to preg-
nancy complications, such as malnutrition or hypertension,
may require increased circulatory pressure to maintain per-
fusion in the setting of high in-utero afterload. (14)(17)
Persistence of this hypertensive state after birth, despite res-
olution of the antenatal environment, highlights the de-
creased arterial compliance that develops with growth
restriction. When these infants undergo subsequent ac-
celerated catch-up growth, increased fluid and sodium
demands worsen their hypertension. (14)(18) Decreased
serum insulinlike growth factor 1 levels in SGA infants
have been shown to affect central aortic elastic proper-
ties and structure, resulting in decreased compliance
and hypertension. (36)
Low-birthweight infants are prone to develop hyperten-
sion after exposure to steroids because of increased gluco-
corticoid sensitivity, a mechanism that may be mediated
by placental 11b-hydroxysteroid dehydrogenase or endothe-
lial nitric oxide synthase. (6)(17) Antenatal glucocorticoid
exposure, particularly within 7 days of birth, results in
decreased glomerular filtration and increased levels of
angiotensin-converting enzyme (ACE) and angiotensin-II,
whereas postnatal exposure manifests as myocardial dys-
function and systemic hypertension from renin-angiotensin-
aldosterone system dysregulation. (17)(35)
There can be a few iatrogenic reasons for neonatal hyper-
tension in the setting of prematurity. Preterm infants often
require parenteral nutrition, placing them at risk of receiving
excessive water, sodium, calcium, and vitamin A/D. (14)(18)
Medications such as caffeine and phenylephrine or atropine
mydriatic ophthalmic drops further increase the risk of hy-
pertension in this cohort. (37) Environmental phthalate
exposure from noninvasive respiratory support equip-
ment, (22)(38) parenteral nutrition storage bags, (18) and
intravenous (IV) line tubing (18)(22) has recently been
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identified as a potential contributor to neonatal hyperten-
sion through increased activation of the mineralocorti-
coid receptors, although more research is needed to further
define this purported effect. (19)(39)(40)
PRESENTATION
Hypertension in neonates is generally asymptomatic and
is usually an incidental observation on routine monitoring.
However, there are specific clinical scenarios that have addi-
tional elements to the presentation of neonatal hypertension.
These common conditions can often be identified by patient
examination and history review.
UAC/Vascular and Renal Parenchymal Factors
Presentation of renal-related hypertension in the NICU
can occur at any time. When occurring in the first 2 weeks
after birth, in situ UAC (20)(41) and severe bilateral con-
genital renal parenchymal diseases such as autosomal re-
cessive polycystic kidney disease (21) are the most likely
suspects. Unilateral renal conditions and thromboembo-
lism may be seen in neonates after this period, because
symptoms take time to manifest. (21) Severe refractory hy-
pertension in a neonate that requires multiple antihyperten-
sive agents suggests congenital conditions such as polycystic
kidney disease or hormone-producing tumors if hyperten-
sion occurs with concurrent hypercalcemia. Physical exami-
nation finding of the abdominal bruit is specific for renal
artery stenosis, whereas the rare but specific triad of gross
hematuria, thrombocytopenia, and palpable flank mass sug-
gests renal vein thrombosis.
BPD-associated Hypertension
BPD-associated hypertension typically presents later dur-
ing the NICU hospitalization, ranging from 40 weeks’
PMA to a median of 4 months’ postnatal age. (14)(23)
While there is a known association between BPD and risk
of hypertension, (42) presentation can be as subtle as a
5 mm Hg increase in blood pressure compared to age-
matched infants, (43) without any correlation between
the severity of BPD and severity of hypertension. In addi-
tion, hypertension resolves independently of the lung dis-
ease, with resolution by 12 months’ postnatal age in most
cases. (14)(23)
Coarctation of the Aorta
Typically, neonatal coarctation presents with upper ex-
tremity blood pressures 10 to 20 mm Hg higher than
lower extremity blood pressures, with larger gradients con-
cerning for longer segments of narrowing. (10)(24) The
Vol. 25 No. 1 JANUARY 2024 e41
 decreased amount of blood perfusing the lower extremities
can also present as a brachial-femoral pulse delay. (25)
However, depending on the location of coarctation,
neonates with CoA can also present with no blood pres-
sure gradient if they have a patent ductus arteriosus
(PDA) and no obstruction at the time of blood pressure
measurement (Table 4). This scenario results in normal
pulse oximetry values and a passed critical congenital heart
disease screen in the nursery or during short NICU stays.
(10)(24)(25) In these patients, symptoms may develop after
hospital discharge or may remain undetected at home as
the ductus arteriosus constricts and closes, creating critical
CoA. (44) Because the left ventricle does not have time to
adapt to the increased afterload by hypertrophying and gen-
erating collateral circulation, these neonates may present in
shock, with florid signs of heart failure including hepato-
megaly, oliguria, lethargy, pulmonary edema, hypotension,
and cardiovascular collapse. (14)(25) If a CoA has been sur-
gically repaired and the infant develops new or worsening
upper extremity hypertension, re-coarctation should be sus-
pected. (10)(44)
DIAGNOSTIC EVALUATION
Once hypertension has been identified, diagnostic evalua-
tion includes the following (10)(12)(20)(22)(25)(37):
• Pertinent antepartum history and neonatal history, in-
cluding a history of postnatal invasive procedures
• Four-extremity blood pressure, with the infant in a calm
state
• Complete physical examination with attention to find-
ings that suggest an uncommon etiology (Table 3) or
end-organ damage to the kidneys, heart, eyes, and
central nervous system (ie, brachial-femoral pulse de-
lay, AKI, left ventricular hypertrophy, hypertensive ret-
inopathy, encephalopathy, altered mental status, or
seizures)
• Evaluation of medications (corticosteroids, anticholinergic
eye drops, vasoactive infusions, parenteral nutrition con-
tents, opioid wean) and relative infant state (comfortable,
Table 4 . Instances When CoA Does Not Present with Blood Pressure Differential. (10)(24)(25)
Four-Extremity Blood Pressures
No gradient
No gradient between the right arm and the right leg (10) or
higher blood pressure in the left arm than the right arm (25)
No gradient between the right arm and the right leg (10)
No gradient between the left arm and the left leg (10)
CoA5coarctation of the aorta, PDA5patent ductus arteriosus.
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calm, sleeping versus agitated because of pain or hunger
versus discomfort because of opioid withdrawal symptoms,
edema, work of breathing)
• Laboratory studies:
8 Serum laboratories: Electrolyte panel, including
calcium, urea, and creatinine to evaluate for kid-
ney disease
8 Urine studies: Urinalysis for hematuria or proteinuria;
urine calcium and creatinine measurement; and urine
culture if there are anatomic risk factors or a history
of urinary tract infection
• Imaging:
8 Echocardiography to evaluate for structural heart dis-
ease, CoA, left ventricular hypertrophy, left ventricle
systolic dysfunction, and left atrium dilation
8 Renal ultrasonography to evaluate for parenchymal or
structural abnormalities with Doppler of renal arteries
and renal veins; ultrasonography of abdominal aorta if
there is a history of UAC
Consultations to consider are as follows:
• Pediatric nephrology
• Pediatric cardiology for the evaluation of cardiac struc-
ture and function
• Pediatric interventionalist or pediatric cardiac surgeon if
concern for CoA or renovascular thromboembolism, al-
though the degree of intervention may be limited by
size
• Pediatric ophthalmology if concerns for hypertensive ret-
inopathy
Other studies to consider are as follows:
• Cranial ultrasonography to evaluate for intracranial hem-
orrhage, mass, and cerebral edema
• Thyroid function tests
• Cortisol level
• Renin and aldosterone levels
• Adrenal steroid hormone levels to determine specific en-
zyme deficiency (particularly 17-hydroxyprogesterone if
there is high suspicion for congenital adrenal hyperpla-
sia secondary to 21-hydroxylase deficiency)
Likely Anatomy
Left or right aortic arch with PDA and CoA (10)(24)
Left aortic arch and aberrant origin of the right subclavian artery
distal to the CoA (10)(25)
Right aortic arch with stenosis in the transverse arch proximal to
the right subclavian artery (10)
Left subclavian artery is hypoplastic or stenotic or arises distal to
the CoA (10)(25)
 • Karyotype to determine genetic sex
• Results of the newborn metabolic screen, specifically for
thyroid level, as well as acylcarnitine, free carnitine, and
ornithine, which are metabolites that are associated with
maternal diabetes mellitus and hypertensive disorders that
affect the neonate (45)
• Urinary catecholamines if suspicion for pheochromocy-
toma or neuroblastoma
• Urinary phthalate levels
GENERAL MANAGEMENT APPROACH
Due to small-scale studies and a lack of evidence on the
long-term effects of hypertension and on the safety and ef-
ficacy of antihypertensive medications, guidelines for the
treatment of hypertension in neonates and infants are
lacking. (36) As such, the treatment of neonatal hypertension
relies on expert consensus and research pertaining to the
treatment of childhood, adolescent, and adult hypertension,
which does not always translate well to neonates. (12)
Nonpharmacologic treatment begins by assessing modifi-
able factors such as fluids, medications, and pain. Volume-
overload states may be treated by decreasing IV fluids, and
high-afterload states may be treated by decreasing the doses of
inotropes, vasopressors, and calcium infusions. Other states of
discomfort that contribute to elevated blood pressure such as
opioid withdrawal or inadequately controlled pain can be
treated with analgesic medications. (1)(2)(16)
Given the lack of clear guidelines regarding pharmaco-
logic treatment, experts suggest the definitions and treat-
ment thresholds shown in Table 5. (9)(12) Generally, the
decision to initiate antihypertensive treatment focuses on
the following 3 factors: blood pressure percentile for PMA,
clinical status, and evidence of end-organ damage. (2)(12)
Experts recommend that an asymptomatic neonate with a
systolic pressure consistently between the 95th and 99th
percentiles (Table 1 if <2 weeks old; Table 2 if >2 weeks
old) and with no end-organ involvement may be observed
and does not require treatment because of expected resolution
over time in most cases. (1)(12)(46) However, if blood pres-
sure continues to remain above the 99th percentile despite
addressing correctable causes (2)(6)(12)(14) or if there is evi-
dence of end-organ damage at any blood pressure percentile,
experts advocate antihypertensive treatment to prevent adverse
effects. (1)(9)
The optimal time course over which blood pressure
should be reduced is also not well-established for neonates
because of limited data on the treatment of severe hyper-
tension in neonates. Extrapolating from pediatric guide-
lines intended for the ambulatory setting suggests blood
pressure should be treated until it is below the 90th per-
centile to minimize end-organ damage. (12) However, the
approach from a recent pediatric case series (January 2023)
(46) may be more applicable to infants in intensive care
units, although it has not been studied in neonates. This
case series on previously normotensive patients (age 1
month to 18 years) with hypertensive emergency admitted
to the pediatric intensive care unit suggested a controlled
reduction of blood pressure to the 95th percentile over the
course of 2 days to account for a delayed return of cerebral
autoregulation. (46) The rationale behind this approach is
applicable to preterm neonates who are at risk of intracra-
nial hemorrhage because of fragile periventricular vessels
and was successfully executed in 28 preterm and term infants,
as described in the case series. (12)(37)(46)(47) Additional

Table 5 . Clinical Definitions and Treatment Thresholds

BP Percentile for End-Organ
Stage PMA Clinical Status Involvementa Treatment Type of Treatment
Normal <95th percentile – – No –
Mild hypertension 95th–99th percentile Healthy No No, observe –
Hospitalized or CKD No Consider treatment Oral or IV
Moderate 95th–99th percentile Healthy Yes Treat Oral
hypertension Hospitalized or CKD Yes Treat Oral or IV
Severe >99th percentile Healthy No Treat Oral
hypertension Healthy, hospitalized, Yes Treat IV
or CKD
Hypertensive SBP >120 or DBP Healthy, hospitalized, – Treat IV infusion
emergency >90 (term) or or CKD
hypertension DBP >80
(preterm)

The definitions and treatment thresholds were proposed in 2019 by Harer and Kent (12) based on data from the Dionne et al (9) study on
infants older than 2 weeks.
BP5blood pressure, CKD5chronic kidney disease, DBP5diastolic blood pressure, IV5intravenous, PMA5postmenstrual age, SBP5systolic
blood pressure.
a
End-organ involvement: left ventricular hypertrophy, altered mental status, and acute kidney injury.
Reprinted with permission from Kiss et al. (4).

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 considerations for neonates include the relative immaturity of
neonatal kidneys and AKI, warranting more caution when us-
ing antihypertensives that are cleared by the kidneys. (14)(16)
Consultation with a pediatric nephrologist with experience in
this population may be helpful in this situation. (12)
ANTIHYPERTENSIVE AGENTS
Common pharmacotherapeutic interventions include thia-
zide and loop diuretics, ACE inhibitors, calcium channel
blockers, b-blockers, and vasodilators. (37) Generally, IV
agents should be used if there are signs of end-organ dam-
age, and continuous infusions are recommended for the
ability to quickly titrate dosing and closely control blood
pressure swings. (28) When initiating and titrating IV an-
tihypertensive therapy, care should be taken to reduce
blood pressure slowly to avoid cerebral ischemia and hem-
orrhage. (48) If the infant is able to tolerate enteral medi-
cations in the absence of severe hypertension, oral/enteral
antihypertensive agents can be considered. Agents with a
long half-life and slower onset of action are most appropri-
ate for hemodynamically stable neonates. (12)(16)
Diuretics
• Diuretic therapy helps treat hypertension and improves
pulmonary function in infants with BPD. (14)
• Thiazide diuretics (such as chlorothiazide and hydrochloro-
thiazide) are commonly used in the NICU because of ease
of administration and less frequent electrolyte disturbances
(37) as compared to loop diuretics (ie, furosemide) that can
lead to an increased risk of electrolyte derangements (ie,
hyponatremia, hypochloremia, metabolic alkalosis, hypocal-
cemia, hypomagnesemia) and nephrocalcinosis because of
hypercalciuria. (12)
• The aldosterone receptor antagonist spironolactone may
have an adjunct role in the treatment of BPD-associated
hypertension because of its potassium-sparing mecha-
nism; however, it has a weak diuretic activity. (14)(19)(23)
b-Blockers
• Propranolol is a nonselective b-1 and b-2 blocker that
may be given orally for the treatment of hypertension; a
rare adverse effect of propranolol is bradycardia.
• Labetalol is a combined b and a-1 blocker with a rapid
onset of action. It is given intravenously and can be
used to treat acute hypertension in a patient who cannot
have enteral medications. It is useful because it does not
cause tachycardia. (12)
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• Esmolol is a very short-acting IV cardioselective b-blocker
that is ideal for the treatment of hypertensive infants with
CoA. (26)
• b-blockers should generally be avoided in infants with
BPD because of the risk of bronchoconstriction. (14)
Calcium Channel Blockers
• Amlodipine and isradipine are enteral calcium channel
blockers. Both medications are easy to administer to in-
fants in compounded solution form and do not require
intensive electrolyte monitoring. (14)
• Due to its shorter duration of action, isradipine can be
initiated for BPD-associated hypertension, with a transi-
tion to amlodipine once blood pressure is controlled. (14)
• Nicardipine has a short half-life and causes peripheral
vasodilation. It is given as a continuous IV infusion and
is particularly useful for infants on ECMO with severe
hypertension. (28)
• Of note, in situations with acutely depressed myocardial
contractility, caution is advised with calcium channel
blockers because calcium influx is a key component of
the cellular action potential.
Vasodilators
• Hydralazine is a vasodilator that can be used for inter-
mittent IV treatment of a patient who cannot tolerate en-
teral medications; however, it may lead to an abrupt
decrease in blood pressure. (12)
• Sodium nitroprusside is also an IV infusion that can be use-
ful for infants on ECMO with severe hypertension refractory
to nicardipine, although there is a risk of toxic metabolite
accumulation (cyanide, thiocyanate, and methemoglobin)
(47), especially in cases of decreased kidney or liver func-
tion. (48)
ACE Inhibitors/Angiotensin Receptor Blockers
• This class of antihypertensives is contraindicated in pa-
tients with bilateral renovascular disease or with solitary
kidney and is generally not recommended for infants
less than 44 weeks’ PMA because of potential adverse
effects on renal development. (11)(20)(48)
• ACE inhibitors and angiotensin receptor blockers can
cause hyperkalemia, AKI, and hypotension; these agents
should be used with extreme caution. When using ACE
inhibitors in preterm infants, consultation with pediatric ne-
phrology is recommended for assistance in determining the
starting dose because of known exaggerated/prolonged hy-
potensive response. (12)(26)
 • In specific situations of older infants with systemic hy-
pertension and concurrent impaired left ventricular dia-
stolic function, enalapril may have a role in improving
ventricular dysfunction, as shown in a small observa-
tional case series of 11 infants who had resolution of hy-
pertension to the 95th percentile and improved left
ventricular diastolic dysfunction on serial echocardio-
grams after 2 weeks of enalapril treatment. (35)
• Captopril has been studied in neonates, with a starting
dose one-tenth of the normal pediatric starting dose,
and close monitoring for hyperkalemia and AKI. (48)
PROGNOSIS, FOLLOW-UP, AND LONG-TERM
MONITORING
Although more than 50% of neonates in the NICU with
hypertension require antihypertensive medications, (13)(15)
most neonatal hypertension resolves by 1 to 2 years of age.
(1)(16)(20) Treatment duration most commonly ranges
from 10 days to 8 to 12 months, (12)(14)(15) with almost all
patients normotensive and off pharmacologic therapy by
24 months’ postnatal age. (20)
Long-term outcomes of neonatal hypertension are not
fully known. (12) The American Academy of Pediatrics rec-
ommends routine blood pressure monitoring in all children
after NICU discharge because of increased risk of develop-
ing hypertension, cardiovascular complications, and chronic
kidney disease in childhood and beyond. (2)(10)(34)(35) For
affected neonates without an etiology for neonatal hyperten-
sion, it is unclear how long the hypertension will persist.
(12) What is clear, however, is the need for follow-up and
ongoing blood pressure monitoring of these patients, as 1%
to 5% of all neonates are hypertensive on follow-up after
NICU discharge, with up to 7.3% remaining hypertensive
at 3 years of age. (10)(14)(49)
In addition, neonates with UAC/vascular thrombosis,
renal parenchymal disease, BPD, CoA, and prematurity or
SGA, are at risk for hypertension later in life, even if their
neonatal hypertension resolves. (16) As such, they require
ongoing general pediatric follow-up to monitor for the re-
currence of hypertension. (11) Some may require further
subspecialty care to evaluate for complications of their
neonatal hypertension, such as retinopathy or congestive
heart failure. (37)(50)
UAC/Renovascular and Renal Parenchymal Disease
Hypertension from vascular thrombosis or AKI eventually
resolves once the inciting agent is removed and the throm-
bus has resolved. (1) However, despite the resolution of hy-
pertension in the NICU, preterm infants with AKI are
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more likely to develop hypertension after NICU discharge,
at 22 to 26 months of age, (14)(51) and may be at increased
risk of developing chronic kidney disease. (52) This under-
scores the importance of diagnosing hypertension in the
NICU so that appropriate follow-up screening and care can
be provided.
Nephrology follow-up, in particular, is recommended for
infants with congenital renal parenchymal disease, obvious
renal anomalies, and some forms of renovascular hyperten-
sion such as renal artery stenosis and renal vein thrombosis
because of the likelihood of persistent hypertension requir-
ing potentially prolonged treatment with antihypertensives
or interventions such as stenting. (2)(10)(12)
BPD-related Hypertension
Most BPD-associated hypertension resolves by 2 years of age,
and antihypertensives can be discontinued by 8 to 12 months
of age. (2)(12) A small number may have persistent hyperten-
sion, increasing risk of chronic kidney disease later in life.
(14)(23) In addition, up to half of infants with BPD-associated
hypertension may first present with elevated blood pressure
after NICU discharge, highlighting the importance of on-
going blood pressure monitoring in infants with BPD.
(9)
Coarctation of the Aorta
Infants with hypertension related to congenital heart dis-
ease and abnormal cardiac anatomy are at increased risk
of developing hypertension that persists into childhood,
(2) even after repair of the heart disease. (53) This risk
is even higher in those with a history of preterm birth
and CoA specifically, despite neonatal surgical repair.
(10)(44)(54) The risks of persistent hypertension and re-co-
arctation are why follow-up is recommended by the American
Academy of Pediatrics and the American Heart Association.
(6)(10)(24) If any suspicion for CoA exists in a newborn after
discharge, follow-up with a pediatric provider who will evalu-
ate pulses, measure 4-extremity blood pressures, and have a
low threshold for echocardiographic evaluation is imperative.
(24)(25)
Postoperative Hypertension
Most cases of postoperative hypertension resolve, but in rare
cases, neonates with repaired giant omphaloceles may need
antihypertensive therapy after NICU discharge, requiring
outpatient follow-up with a provider able to manage and
wean those medications. (27)(37)
Vol. 25 No. 1 JANUARY 2024 e45
 Table 6 . Management Considerations for Common Clinical Conditions of Hypertension in the NICU.
Recommended
Follow-up for
Surveillance and
Clinical Context Timing of Specific Aspects of Pharmacologic Management Management of
of Hypertension Presentation Presentation Treatment Considerations Hypertension
UAC or First 2 wks after birth: Abdominal bruit, ACE inhibitors If associated with renal Nephrology for
renovascular UAC gross hematuria, contraindicated artery stenosis or renovascular
2 wks after birth: thrombocytopenia, with renovascular aortic thrombosis, abnormalities
thromboembolism flank mass disease the duration of
Heparin or papaverine therapy is weeks to
(reduces the risk of months
UAC thrombosis) Once normotensive for
(20)(34) 4–8 wks and
thrombus is
resolved,
antihypertensive
medication can be
weaned (1)
Renal First 2 wks after May be known ACE inhibitors Postnatal renal Nephrology
parenchymal, birth: severe antenatally contraindicated ultrasonography
congenital, or bilateral Palpable kidneys with solitary kidney (10)
acquired conditions AKI or history of AKI and until at least Avoid nephrotoxins
2 wks after birth: 44 wks’ PMA Some congenital renal
unilateral conditions may
conditions require multiple
antihypertensive
medications (2)(20)
BPD-associated Later during NICU None or a subtle β-blockers Glucocorticoid-induced Pediatrician
hypertension hospitalization, 40 elevation (as little contraindicated hypertension Pulmonology
wks to 4 months’ as 5 mm Hg Diuretics: thiazide (ie, resolves once
PMA above normal), chlorothiazide) treatment is
Mostly resolves by concurrent BPD, or preferred over loop stopped; consider
12 months’ PMA chronic lung diuretic discontinuing
disease Calcium channel or reducing the
blockers dose (1)
Spironolactone Fluid overload and
(emerging role) hypoxemia can
(11)(19)(23) contribute (11)
Aortic coarctation Any time during the Arch obstruction: Prostaglandin infusion Specific situations Pediatrician
newborn period, " Upper extremity (ductal patency) (Table 5) require Cardiology
whether in- hypertension β-blockers close monitoring Cardiothoracic
hospital or at (10–20 mm Hg until PDA is closed surgery
home gradient) (24)
May not be detected " Brachial-femoral Surgery is definitive
by pulse oximetry pulse delay treatment (10)
screening for " Heart failure (ie, Re-coarctation is
critical congenital pulmonary edema, possible, even after
heart disease hepatomegaly, surgical repair
oliguria, lethargy)
and eventual shock
No obstruction:
no gradient in
extremity blood
pressures, may
have murmur of
PDA
Postoperative After procedures for Episodic, may have Adequate sedation Address pain and Pediatrician if
hypertension abdominal wall signs of fluid and analgesia fluid/volume requiring
closure, overload (ie, (11)(29) overload (29) antihypertensive
omphalocele edema), oliguria, Vasodilators: nicardipine Discontinue or reduce medications (27)
repair, or ECMO or agitation/ (preferred) (28) or the dose of
distress nitroprusside (47)(49) inotropes and
for continuous steroids, if possible
infusions; hydralazine
(13) for intermittent
IV doses
Consider labetalol (13)
Continued

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 Table 6 . (Continued)
Recommended
Follow-up for
Surveillance and
Clinical Context Timing of Specific Aspects of Pharmacologic Management Management of
of Hypertension Presentation Presentation Treatment Considerations Hypertension
Endocrine Any time Clitoromegaly in If strong suspicion of Endocrinology Depends on the
female infants, and endocrinopathy, consultation etiology
signs of consider initiating Consider special Endocrinology
hyperthyroidism or treatment while studies (see the
catecholamine results are pending Diagnostic
excess Evaluation section)
Obtain newborn
screen results
Prematurity or Any time May be known ACE inhibitors Evaluate medications Pediatrician
growth antenatally contraindicated and consider Nephrology
restriction Low birthweight until at least discontinuing or
May suggest 44 wks’ PMA reducing doses of
suboptimal in caffeine,
utero environment phenylephrine, or
(ie, obesity, atropine mydriatic
hypertension, ophthalmic drops
malnutrition) (17) (37)
Avoid nephrotoxins
If receiving parenteral
nutrition, evaluate
constituents (free
water, sodium,
calcium, vitamin A,
vitamin D) (11)(18)
If concurrent
myocardial
dysfunction, may
require multiple
antihypertensive
medications (13)

Medication contraindications are in bold. ACE5angiotensin-converting enzyme, AKI5acute kidney injury, BPD5bronchopulmonary dysplasia,
ECMO5extracorporeal membrane oxygenation, PDA5patent ductus arteriosus, PMA5postmenstrual age, UAC5umbilical artery catheter.

CONCLUSION
Overall, more information is needed on the causes and con-
sequences of neonatal hypertension to improve recognition
of the condition. More robust data are needed on long-term
outcomes of neonatal hypertension to provide optimal treat-
ment, monitoring, and follow-up of this chronic condition.
(1)(12)(37)(55) Based on limited data, we can use blood pres-
sure reference ranges to diagnose hypertension and expert
guidelines to help with treatment decisions for hyperten-
sion that are common in the NICU (Table 6). Understand-
ing hypertension in the clinical context of the underlying
disease or procedures may help management decisions.
the normal range of pressures and pressure
patterns.
• Know the pathophysiology of common scenarios
in the NICU in which a neonate presents with
systemic hypertension.
• Formulate a differential diagnosis for neonatal
hypertension.
• Know the clinical and diagnostic features of an
infant with systemic hypertension, including
laboratory and imaging studies.
• Know the management of an infant with systemic
hypertension, including adverse effects.

American Board of Pediatrics

Neonatal-Perinatal Content
Specifications
• Know the factors that regulate systemic blood
pressure in term and preterm infants and know
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 INDEX OF SUSPICION IN THE NURSERY
A Term Neonate with Encephalopathy
Shruthi Kumar Bharadwaj, MD, DM,* Smriti Bhargava, MD,† Sheila Samanta Mathai, MD, DM,*
Jayashree Purkaystha, MD†
Departments of *Neonatology and †Pediatrics, Kasturba Medical College and Hospital, Manipal Academy of Higher Education, Manipal, Karnataka, India
AUTHOR DISCLOSURES Drs Bharadwaj,
Bhargava, Mathai, and Purkaystha have
disclosed no financial relationships
relevant to this article. This commentary
does not contain a discussion of an
unapproved/investigative use of a
commercial product/device.
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PRESENTATION
A male infant is born of a nonconsanguineous marriage at 38 weeks of gestation
to a primigravida via normal vaginal delivery at a level 1 hospital. The infant’s
antenatal history is unremarkable, with normal first- and second-trimester scans.
At 30 weeks, a growth scan shows pelvicalyceal system dilation (6 mm) with an
amniotic fluid index of 30. The mother perceives decreased fetal movements the
week before the delivery, but the biophysical profile is normal. Labor is sponta-
neous, and she delivers vaginally after a normal duration of labor. The infant
does not cry at birth and needs resuscitation for 20 minutes without requiring
cardiac compressions. The Apgar score is 5 at 10 minutes after birth, and cord
blood gas is unavailable. He is referred to us (level 3 referral hospital) on nasal
flow oxygen at 3 hours after birth for further management.
On admission, his weight is 2,500 g, and vital signs are stable; however, he has
shallow respiratory efforts. The sensorium is obtunded with reduced spontaneous ac-
tivity, hypotonia, weak cry, poor suck, incomplete Moro reflex, absent gag reflex, and
equal and reactive pupils. He does not have clinical seizures or external dysmorphic
features. Arterial blood gas shows a pH of 7.02, PCO2 of 56 mm Hg (7.45 kPa), bicar-
bonate of 12.2 mEq/L (12.2 mmol/L), base deficit of !14.8 mEq/L (!14.8 mmol/L),
and lactate of 126.7 mg/dL (14.06 mmol/L). A diagnosis of moderate encephalopathy
secondary to perinatal causes is made, and he is started on therapeutic whole body
cooling. Conventional electroencephalogram (EEG), amplitude-integrated EEG, and
neurosonogram are normal. He has evidence of end-organ dysfunction with raised
creatine kinase of 1,887.0 U/L (31.51 mkat/L), troponin T of 0.092 ng/mL (0.09 mg/L),
lactate dehydrogenase of 761 U/L (12.71 mkat/L), aspartate aminotransferase of 67 U/L
(1.12 mkat/L), and activated partial thromboplastin time of 46.1 seconds. Serum creati-
nine is 0.44 mg/dL (38.90 mmol/L), sepsis screen and blood culture are negative, and
the chest radiograph is normal. He remains hemodynamically stable but is electively
placed on mechanical ventilation because of poor sensorium, inadequate breathing ef-
forts, and carbon dioxide retention. Whole body cooling is performed for 72 hours, and
rewarming is completed over 12 hours.
DISCUSSION
Progression
The infant’s sensorium improved over the next 3 days, with spontaneous opening
and normal eye movements, but he remained hypotonic with minimal spontaneous
 infant’s sensorium improved, the hypotonia persisted de-
spite a normal brain scan and sepsis screen, and the dif-
ferentials were revised, as shown in the Table. (1)(2)(3)

Actual Diagnosis
Whole exome sequencing reveals Centronuclear Myopathy
Type 1 (Autosomal Dominant AD) with Pathogenic strain
for DNM2 (1), VARIANT - c.1102G>A, located at EXON 8.

Video. Neonate with improved sensorium and normal eye movements
with minimal limb movements and hypotonia.
limb movements (Video). Although blood gases were normal,
he failed attempts at extubation twice because of persistent
pooling of secretions and the absence of a gag reflex. Given
normal EEG with persistent hypotonia despite improving sen-
sorium, the possibility of a neuromuscular genetic condition
was considered, and whole exome sequencing was ordered.
Differential Diagnosis
Given the need for prolonged resuscitation with encepha-
lopathy, initial differential diagnoses included hypoxic-is-
chemic encephalopathy (HIE), intracranial hemorrhage,
early-onset sepsis, and neuromuscular disease. As the
The Condition
Centronuclear myopathy (CNM) is an inherited congenital
myopathy (CM), which results in muscle weakness, hypoto-
nia, and myopathic features on muscle biopsy. (4) Congenital
myopathies are categorized based on the predominant patho-
logic features as core myopathies (most common), CNM, and
nemaline myopathy. (5)(6) The X-linked form of CNM has a
severe presentation at birth with marked weakness, respira-
tory failure, ophthalmoplegia with hypotonia, and coexisting
birth asphyxia. Autosomal dominant forms present late and
are milder, whereas autosomal recessive forms have an in-be-
tween presentation. (7) Core and nemaline myopathies have
a slow progression. The presence of prominent facial weak-
ness with feeding problems with or without ptosis, general-
ized hypotonia with hyporeflexia, respiratory and bulbar
muscle weakness, and the absence of tongue fasciculations
hint at CNM from other causes in hypotonic infants. (8)
Many of these neonates may succumb in the neonatal period.
The infant in our case presented with generalized hypotonia,
severe respiratory muscle involvement, and evidence of birth
asphyxia. A family history of neonatal deaths or miscarriages
is often present. (9) Polyhydramnios and reduced fetal move-
ments are frequent during pregnancy, as in this case. (10)
MANAGEMENT
Electron microscopy of muscle biopsy and genetic testing
aid in diagnosis, prognostication, and counseling. Current

Table. Causes and Presentation of a Hypotonic Infant

Site of Involvement Presentation Example
Central Central hypotonia (truncal hypotonia > peripheral), Hypoxic ischemic encephalopathy, Chromosomal
preserved neonatal reflexes with or without disorders, an inborn error of metabolism,
encephalopathy, seizures structural malformations of the brain
Anterior horn cell Generalized weakness and absent DTRs, preserved Spinomuscular atrophy
sensorium, fasciculations
Nerve Distal muscle weakness and wasting, along with Peripheral neuropathy
decreased DTRs
Neuromuscular junction Involvement of facial muscles with or without Congenital myasthenia gravis, transient
generalized weakness, feeding difficulties myasthenia gravis, botulism
Muscle Generalized weakness, decreased DTRs, respiratory Congenital muscular or myotonic dystrophy,
weakness, preserved sensorium, joint contractures Congenital or metabolic myopathy

DTR5deep tendon reflex.

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 management is supportive and offers multidisciplinary
team care. Some parents opt for early palliative care in se-
vere cases. Infants who survive beyond the neonatal period
without significant ventilatory requirements need close re-
spiratory function monitoring and sleep studies. Carrier
screening enables parents to make informed decisions re-
garding subsequent pregnancies.
PATIENT COURSE
The infant remained on a ventilator along with enteral tube
feeds for 22 days. His parents opted for palliative care with
the de-escalation of intensive care. Single-gene sequencing
of both parents was negative, suggesting a de novo or spo-
References
radic mutation, which is known to have a severe presenta-
tion. The parents were counseled and offered follow-up
services from the departments of neonatology and medical
genetics. However, the infant died soon after.
Lessons for the Clinician
• HIE often masks an underlying neuromuscular condi-
tion; hence, a deeper understanding and strong index of
suspicion are required for timely diagnosis.
• In diagnostic dilemmas, the most commonly occurring
conditions should be considered first and treated until a
definitive diagnosis is established. In this case, treatment
for HIE was given.
• With affordable and accessible genetic testing, such chal-
lenging cases should be considered for further genetic
evaluation as it is less intrusive.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the basis for (including genetic), clinical
10. Beecroft SJ, Lombard M, Mowat D, et al. Genetics of
and laboratory features (including associated
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abnormalities), differential diagnosis, evalua-
tion, management, and outcomes of neonatal
hypotonia/neuromuscular weakness.
• Know the causes, clinical features, evaluation,
and management of hypoxic-ischemic
encephalopathy.
• Recognize the controversies associated with
the introduction of new genetic tests for rare
and common diseases that present in the neo-
natal period.
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 INDEX OF SUSPICION IN THE NURSERY

A Newborn with Inspiratory Stridor

Ishica B. Zaman,* Dana Mazuru-Witten, MD,† Akshaya J. Vachharajani, MD‡
*University of Missouri School of Medicine, Columbia, MO
†
Departmentof Diagnostic Radiology and Pediatrics, University of Missouri, Columbia, MO
‡
Department of Neonatal-Perinatal Medicine and Pediatrics, University of Missouri, Columbia, MO

PRESENTATION
A newborn male infant is born via cesarean delivery at 31 weeks and 2 days’ ges-
tation to a 21-year-old now gravida 1, para 1 woman. Prenatal laboratory results
show that the woman is positive for Rhesus factor, negative for Coombs sign,
negative for human immunodeficiency virus, negative for hepatitis B surface
antigen, negative for syphilis antibody, nonreactive to the rapid plasma reagin,
Rubella immune, and negative for group B Streptococcus. The pregnancy was
complicated by marginal cord insertion, breech presentation, and a family his-
tory of maple syrup urine disease. The neonate undergoes routine resuscita-
tion, and his Apgar scores are 4 and 8 at 1 and 5 minutes, respectively. The
patient is admitted to NICU for prematurity and respiratory distress. The in-
fant is treated with noninvasive positive pressure ventilation (NIPPV) for respi-
ratory distress with a fraction of inspired oxygen (FiO2) of 0.21. At 5 days of
age, he is switched from NIPPV to continuous positive airway pressure with
an FiO2 requirement of 0.21 to 0.23. He continues to require a 4 L/min high-
flow nasal cannula at a postmenstrual age of 36 weeks, establishing the diagnosis of
grade 2 bronchopulmonary dysplasia. He is observed to have inspiratory stridor at a
corrected gestational age of 37 weeks and continues to need respiratory support.
A flexible fiberoptic laryngoscopy is performed by pediatric otolaryngologists,
which reveals a midline cystic structure present at the base of the tongue (Fig 1).
Further evaluation with magnetic resonance imaging shows a 1-cm cystic lesion
arising from the midline base of the tongue (Fig 2).

DIFFERENTIAL DIAGNOSIS
Inspiratory stridor in neonates is most often due to laryngomalacia, but the pres-
ence of a cyst at the base of the tongue expands the differential diagnosis:

• Laryngomalacia
• Thyroglossal duct cyst
AUTHOR DISCLOSURES Drs Zaman,
• Vallecular cyst
Mazuru-Witten, and Vachharajani have
disclosed no financial relationships
PROGRESSION relevant to this article. This commentary
does not contain a discussion of an
Ultrasonography reveals a thyroid gland normal in appearance and anatomic lo- unapproved/investigative use of a
cation and confirms the presence of a cyst. Endoscopic marsupialization of the commercial product/device.

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 Figure 1. Vallecular cyst on flexible fiberoptic laryngoscopy.
cyst is performed under general anesthesia, which reveals
a vallecular cyst. The patient receives a 7-day course of
amoxicillin and clavulanic acid. No complications develop
in the postoperative period, and the patient’s stridor re-
solves. He is weaned off the respiratory support and is dis-
charged from the hospital after he tolerates oral feeding.
DISCUSSION
Newborns can often present with stridor within a few days
after birth, typically because of an acquired or congenital
anomaly of the airway at the laryngeal or tracheobronchial
levels. (1) The different causes of stridor can be distin-
guished by the varying timing of the stridor. Pathologies
such as laryngomalacia, vocal cord palsy, and postextuba-
tion laryngeal edema are common causes of inspiratory
stridor. The expiratory stridor is more often caused by tra-
cheal conditions, and biphasic stridor is secondary to glot-
tic or subglottic pathologies. (1)
Laryngomalacia is the most common cause of inspira-
tory stridor. (1) The exact etiology is unknown. Diagnosis
is made via laryngoscopy, which reveals collapse of supra-
glottic tissues. Vocal cord paralysis is another potential
cause of inspiratory stridor in a neonate. Potential etiolo-
gies include birth-related trauma, iatrogenic injuries,
central nervous system disorders, and idiopathic causes.
Vocal cord paralysis is often associated with dysphagia and
hoarseness, which may help distinguish it from other
causes of inspiratory stridor. Diagnosis is made by directly
visualizing the vocal cords via laryngoscopy. (2) Neonates
who are intubated can develop laryngeal edema, and two-
thirds of these patients will present with postextubation stri-
dor. The endotracheal tube can cause superficial mucosal
inflammation and vocal cord dysfunction, even if only in
place for a short period. Half of the patients who present
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Figure 2. Cystic structure at the base of the tongue on magnetic reso-
nance imaging.
with postextubation stridor will get reintubated; therefore,
there are several tests to ensure airway patency before extu-
bation, such as ultrasonography, video laryngoscopy, and
the cuff leak test (deflating the cuff of the endotracheal
tube and covering the proximal opening to listen for any
audible air leaking around the cuff as the patient spontane-
ously breathes; hearing an air leak would be a positive test
and indicates that there is no laryngeal edema and that it is
safe to extubate the patient).
The vallecula is a small depression in the epiglottic mu-
cosa located at the base of the tongue between the medial
and lateral glossoepiglottic folds. It can be found at the
transition point between the pharynx and the larynx. Sac-
like pockets of tissue containing fluid or air, also known
as cysts, can form in the vallecula. These cysts are often
the result of an obstructed mucosal duct or can form be-
cause of malformations of the third branchial arch. Vallec-
ular cysts are a very atypical cause of inspiratory stridor in
a newborn. Only 10.5% to 20.1% of all congenital laryn-
geal cysts are represented by vallecular cysts, making
them quite rare. (3) The overall incidence of vallecular
cysts is !3.49 to 5.3 cases per 100,000 newborns. (3)
Findings on physical examination can include inspiratory
stridor, respiratory distress, poor feeding, failure to thrive,
snoring, choking, chronic cough, hoarse cry, cyanosis, and
croup. (4) Larger lesions may lead to life-threatening air-
way obstructions.
Imaging is important in determining the diagnosis. Flexible
laryngoscopy is often the initial step in screening infants with
upper airway obstruction. The laryngoscope is able to deter-
mine the size and location of the cyst. When the wall of the
cyst is thick, it is more difficult to identify whether the lesion
is solid or cystic in nature via laryngoscopy. Ultrasonography is
 the preferred imaging modality over computed tomography be-
cause of the risks of radiation with the latter. Ultrasonography
is able to determine the location and size of the lesion, as well
as the echo and the blood flow to determine whether it is cys-
tic or solid. Ultrasonography is also useful in observing the
thyroid anatomy. If the thyroid is absent and the lesion is solid,
a diagnosis of ectopic thyroid can be considered and a vallecu-
lar cyst can be ruled down. (5) A combination of laryngoscopy
and ultrasonography are used as the main diagnostic tools in
the identification of a vallecular cyst. (6)
Needle aspiration of vallecular cysts is no longer ac-
cepted as adequate treatment because of the high incidence
of recurrence. Surgical excision is now the gold standard
for treatment. The 2 main procedures for vallecular cyst re-
moval are endoscopic complete excision and endoscopic
marsupialization. (5) Marsupialization is typically the treat-
ment of choice as it has a low recurrence rate and its safety
and effectiveness are well balanced. (6) Marsupialization
can be performed using electrocautery, microdissection,
carbon dioxide laser, potassium-titanyl-phosphate laser, or
controlled ablation. (5)
Lessons for the Clinician
• Vallecular cysts are a very atypical cause of inspiratory
stridor in a newborn. (3)
• Findings of physical examination can include inspiratory
stridor, respiratory distress, poor feeding, failure to thrive,
snoring, choking, chronic cough, hoarse cry, cyanosis,
and croup. (4)
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• A combination of laryngoscopy and ultrasonography is
used as the main diagnostic tool in the identification of
a vallecular cyst. (6)
• The treatment of choice for vallecular cysts is removal
via endoscopic marsupialization. (5)
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the clinical manifestations and ap-
proaches to therapy of neck masses in the
newborn infant.
• Know the various causes of stridor in the new-
born and how to assess severity.
References
1. Bhatt J, Prager JD. Neonatal stridor: diagnosis and management. Clin
Perinatol. 2018;45(4):817–831
2. Ryan MA, Upchurch PA, Senekki-Florent P. Neonatal vocal fold
paralysis. NeoReviews. 2020;21(5):e308–e322
3. Alnaimi A, Abushahin A. Vallecular cyst: reminder of a rare cause of
stridor and failure to thrive in infants. Cureus. 2021;13(11):e19692
4. Al-Mahboob AJ, Hajr EA, Alammar A. Tongue cyst in a neonate:
unusual presentation. Cureus. 2020;12(7):e9252
5. Wang GX, Zhang FZ, Zhao J, et al. Minimally invasive procedure for
diagnosis and treatment of vallecular cysts in children: review of 156
cases. Eur Arch Otorhinolaryngol. 2020;277(12):3407–3414
6. Aubin A, Lescanne E, Pondaven S, Merieau-Bakhos E, Bakhos D.
Stridor and lingual thyroglossal duct cyst in a newborn. Eur Ann
Otorhinolaryngol Head Neck Dis. 2011;128(6):321–323
Vol. 25, No. 1 JANUARY 2024 e55
 INDEX OF SUSPICION IN THE NURSERY
Tachycardia in a Premature Neonate
Megan Carney, MD,* Tamara Kalhan, MD,† Ellis Rochelson, MD*
*Department of Pediatrics, Children’s Hospital at Montefiore, Bronx, NY
†
Department of Pediatrics, Division of Neonatology, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
AUTHOR DISCLOSURES Drs Carney,
Kalhan, and Rochelson have disclosed no
financial relationships relevant to this
article. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial
product/device.
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A male infant is delivered at 31 weeks’ gestational age to a 32-year-old woman
with a history of type 1 diabetes mellitus, superimposed preeclampsia, and
smoking history, via urgent C-section indicated for preterm premature rupture
of membranes and concern for placental abruption. In the delivery room, the in-
fant is given continuous positive airway pressure for respiratory distress and
transported to the NICU for prematurity. Laboratory findings on admission are
within normal limits.
In the NICU, the infant is started on total parenteral nutrition, a lipid
injectable emulsion, and human donor milk. Feeds are advanced according
to institutional protocol and fortified with human milk fortifier. On day 6
after birth, the infant is remarkably irritable, and unrelieved by feeding or
pacifying. Physical examination reveals abdominal distention and bloody
stool. Vital signs are notable for sustained tachycardia with a heart rate of
190 to 205 beats/min. Abdominal radiography demonstrates dilation of the
stomach and small bowel loops with pneumatosis intestinalis suggestive of
necrotizing entercolitis. Cardiology is consulted for new-onset persistent
tachycardia.
DISCUSSION
Differential Diagnosis
Tachyarrhythmias can be characterized by narrow or wide QRS complexes.
Wide QRS complexes are generated by slow or uncoordinated ventricular depo-
larization, and can be caused by ventricular tachycardia (VT), supraventricular
tachycardia (SVT) with aberrancy, SVT in an antidromic tachycardia circuit, or
long QT syndrome. (1)(2)(3)(4)(5) This is in contrast to the narrow QRS usually
seen in sinus rhythm that is generated by antegrade conduction through a
healthy His-Purkinje system. Wide complex tachycardia should generally be con-
sidered VT until proven otherwise, though providers must also consider the di-
agnosis of SVT with aberrancy.
Actual Diagnosis
The electrocardiogram was notable for wide complex tachycardia with retro-
grade conducted P-waves, which are P waves that come after the QRS complex
(Fig 1). A second electrocardiogram obtained after the administration of adeno-
sine (0.1 mg/kg) was notable for loss of retrograde P-wave conduction (Fig 2).
 Figure 1. Original electrocardiogram with arrows pointing to retrograde P waves.

The persistence of the tachyarrhythmia in the absence of The Condition

retrograde P-waves excluded a reentrant SVT, and the di- VT is a wide-complex arrhythmia originating below the
agnosis of VT was made. Echocardiography demonstrated bundle of His. Identifiable causes of VT in neonates include
normal ventricular anatomy and systolic function. myocarditis, cardiac tumor, hereditary cardiomyopathy, and

Figure 2. Rhythm strip during adenosine administration with black arrows showing retrograde P waves, red arrows showing loss of retrograde P wave
conduction, and blue arrows showing AV dissociation.

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 electrolyte abnormalities. The most common cause, idio-
pathic VT, is defined as VT without an identified underlying
cause and often occurs in a child with a structurally normal
heart. (1)(4) However, VT is rarely described in this setting.
Several features on ECG are suggestive of VT, as op-
posed to SVT with aberrancy. In VT, there may be ventri-
culoatrial dissociation with a QRS:P ratio greater than 1.
However, due to healthy retrograde AV node conduction
in most infants, there may be a one-to-one QRS:P ratio,
which mimics SVT. (3)(6)(7) Other features suggestive of
VT include the presence of fusion beats, in which there is
an intermediate QRS morphology resembling a mix of si-
nus rhythm and the tachyarrhythmia, and sinus capture
beats, where a narrow-complex sinus beat is seen during
tachycardia due to capture of antegrade conduction down
the AV node. (8) Ventriculoatrial dissociation and/or fu-
sion beats during tachycardia help differentiate VT from
the other types of wide QRS tachycardias. (7)
Cases of preterm infants with recurrent SVT having
necrotizing enterocolitis (NEC) have been reported, in
which the condition may be due to localized hypoxia in
the intestine. (9)(10) VT decreases cardiac output due to
atrioventricular desynchrony, impaired filling time, and
decreased stroke volume. (2) In the patient described in
this case, it is possible that VT led to decreased intestinal
perfusion and subsequent NEC. However, since both pa-
thologies were discovered concurrently, the causality can-
not be determined; in fact, the inflammatory state of NEC
may have been the instigating factor that led to the tachy-
arrhythmia. (11)
TREATMENT/MANAGEMENT
In an infant with VT who is hemodynamically unstable,
which may be suggested by severe hypotension, low mus-
cle tone, and decreased alertness, defibrillation is indi-
cated. In a hemodynamically stable infant with wide
complex tachycardia, adenosine may be considered to help
differentiate between VT and SVT with aberrancy. If the
adenosine is given during VT, there will be a loss of retro-
grade P-waves with no interruption in the tachycardia, as
occurred in this patient. If the rhythm is SVT, and if aden-
osine was given appropriately via rapid intravenous (IV)
push, the tachycardia will usually terminate. (6) Once the
diagnosis of neonatal VT has been established, if the patient
remains hemodynamically stable, medical management can
be considered. First-line options include IV lidocaine, IV es-
molol, or oral propranolol. (2)(4)(12) Once the infant is in
sinus rhythm, a b-blocker is started. Ultimately, neonatal
idiopathic ventricular tachycardia has an excellent prognosis
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and tends to self-resolve within the first few months of age.
(12)(13)(14)
PATIENT COURSE
The patient was treated with a lidocaine bolus (1 mg/kg)
and converted to sinus rhythm (Fig 2). He was started on
an esmolol drip, which was transitioned to propranolol
when he was able to tolerate feeds. For treatment of NEC,
he continued to receive nothing by mouth and received
piperacillin-tazobactam for 10 days. Serial abdominal radi-
ography was performed until there was a normal bowel
gas pattern with no pneumatosis. He was then restarted
on enteral feeds of donor human milk which he tolerated
well. The infant did not have any additional episodes of
VT while he was admitted. Propranolol was later discon-
tinued at a follow-up cardiology appointment when the pa-
tient was 5 months old.
Lessons for the Clinician
• When evaluating a neonate with a suspected arrhythmia,
clinicians must first assess hemodynamic stability.
• Wide QRS complex tachycardia is assumed to be VT in
neonates until proven otherwise.
• If the neonate is hemodynamically stable and if the diag-
nosis remains unclear, clinicians can give adenosine first
to block the atrioventricular node. This can help differenti-
ate between VT and SVT with aberrancy before switching
to another class of medications to treat tachyarrhythmia.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know appropriate management of common
arrhythmias in the fetus and newborn infant,
and understand the potential complications or
adverse effects of approaches and drugs used.
• Know the physiologic consequences of an ar-
rhythmia in a fetus or newborn infant.
• Differentiate normal from common abnormal
electrocardiographic patterns and rhythms in
the fetus and newborn infant.
• Recognize the clinical manifestations, diagno-
sis, and management of infants with perfora-
tions of the gastrointestinal tract (including
gastric and intestinal).
• Know the clinical and diagnostic features, eval-
uation, management, and complications of
NEC.
 References
1. Escudero CA, Tan RBM, Beath CM, Dalal AS, LaPage MJ, Hill AC.
Approach to wide complex tachycardia in pediatric patients. CJC Pediatr
Congen Heart Dis. 2022;1(2):60–73 doi: 10.1016/j.cjcpc.2022.02.003
2. Villain E, Butera G, Bonnet D, Acar P, Aggoun Y, Kachaner J.
Neonatal ventricular tachycardia [article in French]. Arch Mal Coeur
Vaiss. 1998;91(5):623–629
3. Brady WJ, Mattu A, Tabas J, Ferguson JD. The differential diagnosis
of wide QRS complex tachycardia. Am J Emerg Med.
2017;35(10):1525–1529
€
4. Jaeggi E, Ohman A. Fetal and neonatal arrhythmias. Clin Perinatol.
2016;43(1):99–112
5. Ban, J-E. Neonatal arrhythmias: diagnosis, treatment, and clinical
outcome. Korean J Pediatr. 2017;60(11):344–352 doi: 10.3345/
kjp.2017.60.11.344
6. Kothari DS, Skinner JR. Neonatal tachycardias: an update. Arch Dis
Child Fetal Neonatal Ed. 2006;91(2):F136–F144 doi: 10.1136/
adc.2004.049049
7. Katritsis, DG, Brugada J. Differential diagnosis of wide QRS
tachycardias. Arrhythm Electrophysiol Rev. 2020;9(3):155–160
doi: 10.15420/aer.2020.20
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8. Edhouse J, Morris F. Broad complex tachycardia–part I. BMJ.
2002;324(7339):719–722
9. Mecarini F, Comitini F, Bardanzellu F, Neroni P, Fanos V.
Neonatal supraventricular tachycardia and necrotizing
enterocolitis: case report and literature review. Ital J Pediatr.
2020;46(1):117
10. Saini J, Moore A, Hodgson K. Necrotising enterocolitis after
supraventricular tachycardia: an unusual precursor to a common
problem. BMJ Case Rep. 2017;2017:bcr-2017
11. De Plaen IG. Inflammatory signaling in necrotizing enterocolitis.
Clin Perinatol. 2013;40(1):109–124
12. Crosson JE, Callans DJ, Bradley DJ, et al. PACES/HRS expert
consensus statement on the evaluation and management of
ventricular arrhythmias in the child with a structurally normal heart.
Heart Rhythm. 2014;11(9):e55–e78
13. De Rosa G, Butera G, Chessa M, et al. Outcome of newborns with
asymptomatic monomorphic ventricular arrhythmia. Arch Dis Child
Fetal Neonatal Ed. 2006;91(6):F419–F422
14. Levin MD, Stephens P, Tanel RE, Vetter VL, Rhodes LA. Ventricular
tachycardia in infants with structurally normal heart: a benign
disorder. Cardiol Young. 2010;20(6):641–647
Vol. 25, No. 1 JANUARY 2024 e59
 MATERNAL-FETAL CASE STUDIES
Fetal Injury from Maternal Penetrating
Abdominal Trauma in Pregnancy
Emily Barron, BSPH,* Alison Jeffries, BS,* Sarah Pelton, BS,* Katherine Vogel, BS,* Bobbi J. Byrne, MD†
*Indiana University School of Medicine, Indianapolis, IN
†
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Indiana University, Indianapolis, IN
AUTHOR DISCLOSURES Dr Byrne has
attended meetings, with her co-chair,
with the support of the American
Academy of Pediatrics Neonatal
Resuscitation Program Steering
Committee and the PLACES Project
Advisory Committee. Mss Barron, Jeffries,
Pelton, and Vogel have disclosed no
financial relationships relevant to this
article. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial
product/device.
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CASE PRESENTATION
A 33-year-old gravida 2, para 1-0-0-1 woman at 36 weeks and 4 days’ gestation
was brought to the emergency department by ambulance with multiple stab
wounds to her back and abdomen after having been assaulted at home with a
knife by her teenage son. Upon arrival at the level I trauma center, her Glasgow
Coma Scale score was 15 (fully conscious).
On the primary evaluation by the trauma surgeons, the patient was hemody-
namically stable with an intact airway. A secondary evaluation revealed 2 stab
wounds on her left posterolateral chest and a third wound on her epigastric area
near the fundus (Fig 1). Her blood pressure was 158/102 mm Hg, oxygen satura-
tion on a nonrebreather mask was 93%, and hematocrit was 27%. Maternal
chest radiograph revealed a large left-sided pneumothorax and possible pneumo-
mediastinum, with the heart and mediastinum shifted to the right, as well as
tracks of gas along the maternal left lateral chest wall and neck (Fig 2). Obstet-
rics and neonatology were both urgently consulted. Although a urine drug
screen was positive for benzodiazepines and opiates, it is unclear which medica-
tions were given during transport to the hospital. A confirmatory blood test was
not ordered.
The fetal heart rate tracing on arrival was reassuring without decelerations
and with moderate variability. Obstetric history revealed appropriate prenatal
care with an unremarkable prenatal visit 8 days before presentation to the hospi-
tal. The patient denied any history of domestic violence, intimate partner vio-
lence, or physical abuse.
CASE PROGRESSION
The trauma surgeons recommended an exploratory laparotomy via a vertical in-
cision to assess for intra-abdominal injury. There was preparation for a possible
cesarean delivery by the obstetrical team. After general endotracheal intubation,
a chest tube was placed into the left chest for decompression of her pneumotho-
rax. After anesthesia induction, an assessment of the fetal heart rate demon-
strated bradycardia at 70 beats/min; therefore, the interdisciplinary team
decided to urgently perform a cesarean delivery. The neonatology team was pre-
sent with resuscitation equipment and a portable warmer.
 Figure 1. Location of stab injuries documented during the primary survey. EMS 5 emergency medical services. Originally published in Drexler KA, Quist-
Nelson J, Weil AB. Intimate partner violence and trauma-informed care in pregnancy. Reprinted with permission from Drexler et al. (8).

NEONATAL OUTCOME
The male infant was delivered emergently at 36 weeks
and 4 days’ gestation via cesarean delivery and immedi-
ately evaluated by the neonatology team. Apgar scores
were 7 and 8 at 1 and 5 minutes, respectively, and the
birthweight was 3,040 g (76th percentile). The initial
physical examination findings were significant for a 1.5 cm
laceration over his left buttock, 2 cm from the anus that
was penetrating 1 to 2 cm into the subcutaneous tissue.
Direct pressure was applied for hemostasis, and adhesive
strips were applied for initial primary closure. The infant
was administered morphine and acetaminophen for pain.
He was then transferred to the children’s hospital for
surgical evaluation. The wound was inspected, irrigated
with normal saline, and reapproximated with sutures. A
barium enema study demonstrated no evidence of rectal
perforation (Fig 3), and brain magnetic resonance imag-
ing was normal without evidence of head trauma. He began
enteral feedings without difficulty and was transferred back
to the birth hospital, reuniting with his mother, on day 2. He

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 Figure 2. Chest radiograph showing the left pneumothorax and possible left pneumomediastinum.
has remained well at subsequent routine pediatric surveil-
lance visits through 19 months of age.
MATERNAL OUTCOME
During the cesarean delivery, the placenta was delivered in-
tact without evidence of the knife’s penetration. A laceration
in the uterine fundus from the stab wound was noted and
repaired. Exploratory laparotomy during trauma surgery re-
vealed that the patient had an intact bladder, ovaries, and
fallopian tubes, with no additional visceral injuries. The ma-
ternal patient required 2 units of packed red blood cells,
fresh frozen plasma, and 4 L of fluid intraoperatively, with
an estimated blood loss of 1.5 L of hemoperitoneum.
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The maternal patient was transferred to the ICU where
she received comprehensive care from multiple specialty
teams for 5 days. She received medical care for a residual
pneumothorax post chest tube removal, postoperative il-
eus, and a urinary tract infection.
The patient was noted to have multiple psychosocial stres-
sors in addition to her operative and postoperative course, in-
cluding separation from her newborn son and the police
investigation of the assault by her teenage son. She expressed
sadness that she had yet to meet and name her newborn dur-
ing this critical period of bonding. The initial separation from
her infant son and her own recovery contributed to delays in
producing an adequate breast milk supply.
 Figure 3. Barium enema without evidence of rectal perforation. In the image on the left, the small stab wound into the left perineum, adjacent to the in-
fant’s anus, is indicated by the instrument.
The patient experienced flashbacks, anxiety, and nightmares
related to the assault. The psychiatry team diagnosed acute
stress disorder; however, the patient declined psychotropic
medications out of concern for transfer to breast milk. She in-
stead opted for outpatient mental health services. Although
her teenage son had initially been excited about the preg-
nancy, psychiatric symptoms including hallucinations, gran-
diose thinking, and paranoia for 2 months leading up to the
assault tragically affected the family dynamics. The woman
reported seeking care at 2 local inpatient psychiatric institu-
tions, both of which discharged her teenage son despite her
concern that he required further evaluation and interven-
tion. During her hospital stay, she worked with law enforce-
ment to ensure charges were not pressed against her son
and that he received appropriate psychiatric care. Psychiatry
and social work teams provided resources and ensured that
she was discharged to a safe environment. At her follow-up
obstetric and general surgery appointments, she was noted
to be physically recovering without issue.
DISCUSSION
The most common nonobstetric cause of mortality during
pregnancy is trauma. Penetrating abdominal trauma, as
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demonstrated in this case, is less common than blunt trauma,
but it is associated with higher rates of fetal injury and mortal-
ity. In cases of penetrating abdominal trauma, maternal mor-
tality is less likely compared with blunt trauma because of
abdominal visceral displacement and protection by the gravid
uterus; however, fetal mortality ranges from 40% to 70% be-
cause of the high risk associated with preterm delivery or
from direct fetal injury by the penetrating object. (1)(2)
The physiologic changes that pregnant patients experi-
ence during pregnancy are important for clinicians to un-
derstand when caring for a gravid trauma patient. Pregnant
patients experience a 45% increase in plasma volume and
only an 18% to 30% increase in red cell volume, which re-
sults in dilutional anemia. Pregnant individuals may lose
!35% of their blood volume before clinical signs of shock
are detected. (3) Furthermore, 25% of maternal cardiac out-
put is directed toward the placenta; therefore, penetrating
abdominal trauma, particularly if the uterus is penetrated,
can quickly lead to hypovolemic shock. (3) Because fetal he-
moglobin binds oxygen with greater affinity than maternal
hemoglobin, supplemental oxygen should be given to all
pregnant trauma patients to minimize fetal hypoxia. (2)(4)
If a penetrating injury is present, awareness of expected
Vol. 25 No. 1 JANUARY 2024 e63
 fundal height based on gestational age is important to as-
sess if the injury potentially lacerated the uterus. Lastly,
inferior vena cava compression from the gravid uterus
can reduce blood return to the heart by 30%; therefore,
positioning a pregnant patient in the left lateral decubitus
position can help improve circulation. (2)
The assessment of any trauma patient is standardized to
efficiently identify life-threatening injuries and initiate critical
treatments, and this framework is specialized when the
trauma patient is pregnant. Although this patient’s preg-
nancy was visibly identifiable because of her gestational age,
the Society of Obstetricians and Gynecologists of Canada rec-
ommends treating every injured female of childbearing age
as pregnant until proven otherwise because trauma victims
may be unable to answer questions or may be unaware of their
pregnancy status. (2) In addition to the ABCDE (airway, breath-
ing and ventilation, circulation, disability, exposure and environ-
ment) pattern conducted in the primary survey, trauma teams
should determine the gestational age and viability of the fetus
in pregnant patients. (1) In clinical scenarios involving trauma
to a pregnant patient, treatment including surgical evaluation,
imaging, and initial medical stabilization should never be de-
layed or withheld because of the gravid status. (5)
During the secondary survey, fetal heart monitoring
should be initiated, and evidence of placental abruption,
ruptured membranes, labor, and potential fetal injury
should be assessed. (1) Urgent involvement of the obstetri-
cal and neonatal teams for multidisciplinary care is criti-
cal. Delivery, even before viability, may be indicated in
select circumstances to optimize cardiovascular circulation
in a trauma patient in cardiogenic shock.
Multiple factors influence the management approach, in-
cluding the hemodynamic stability of the pregnant patient,
the extent of the trauma, the gestational age, and the impli-
cations of fetal viability. When treating a pregnant trauma
patient, it is important to maintain maternal hemodynamic
stability as it directly correlates to fetal stability. An obstetrical
and trauma team must be prepared for the possible need for
Table. Screening Tools Recommended for Detecting Intimate Partner Violence
Tool Sensitivity Specificity
Humiliation, Afraid, Rape, Kick
Instrument (HARK) 81% 95%
Hurt/Insult/Threaten/Scream
(HITS) 86%–96% 91%–99%
Partner Violence Screen (PVS)
49%–71% 90%–94%
Slapped, Things, and Threaten
(STaT) 96%–64% 100%–75%
Woman Abuse Screening Tool
(WAST) 89%–96% 55%
Adapted with permission from Drexler et al (8).
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intraoperative cesarean delivery at the time of exploratory lap-
arotomy depending on the clinical situation, gestational age,
and injury to the uterus. (4) After delivery, a thorough evalu-
ation of the infant is imperative to identify and treat any non-
obvious traumatic injuries. Ultimately, beyond the primary
survey, the complexity of trauma in pregnancy requires effi-
cient medical management and expertise of an interdisciplin-
ary team including obstetricians, anesthesiologists, surgeons,
and pediatricians.
Healthcare providers should aim to provide universal
screening for interpersonal violence during pregnancy and
facilitate access to resources and interventions if indicated.
Pregnant women are particularly vulnerable to physical,
emotional, and psychiatric abuse. In pregnancy, more
women die from complications of domestic violence than
the combination of the 3 leading obstetric complications
related to maternal mortality. (6)(7) Prevention of violence
against pregnant women should be advocated for and as-
sessed like any other pregnancy comorbidity. (8) The US
Preventive Services Task Force recommends the use of
validated screening tools for detecting intimate partner vi-
olence (Table). A large study of pregnant trauma patients
found that victims of interpersonal trauma were more
likely to have multiple injuries rather than more severe in-
juries compared with victims of accidental trauma. (3) The
study also found that head injuries; contusions of the face,
neck, or scalp; and abrasions/friction burns are risk fac-
tors for interpersonal violence. (3) Beyond detection, ob-
stetric and pediatric clinicians should offer and advocate
for violence prevention education to minimize exposure to
physical conflict where possible. If previous interpersonal
violence is identified, clinicians should make efforts to ob-
jectively document patient responses and examinations in
a portion of the electronic medical record system reserved
for sensitive information that will not prepopulate in pa-
tient-accessible portals. By doing this, pregnant individuals
may be aided in seeking legal protection by providing this
documentation as corroboration of physical harm. (8)
Description
A 4-item self-report survey based on the Abuse
Assessment Screen
A 4-item survey, either self-report or staff-administered,
excluding sexual violence
A 3-item staff-administered survey assesses violence and
current safety, excluding sexual abuse
A 3-item staff-administered survey assesses violence and
threats
An 8-item self-report survey including emotional and
sexual abuse
 This case illustrates the importance of multidisciplinary
care for a near full-term pregnant patient with a penetrating
uterine injury requiring immediate cesarean delivery. Trauma
during pregnancy is not only a leading cause of nonobstetric
maternal mortality, but when directed toward the abdomen, it
can also jeopardize fetal health. Therefore, an understanding
of the use of multidisciplinary evaluation of a trauma patient
in pregnancy is imperative to properly treat life-threatening in-
juries and reduce maternal and fetal mortality. Detection and
education of pregnant women who are at risk of interpersonal
violence should be a priority of health care providers so that
trauma in pregnancy can be mitigated.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the significance, interpretation, and
management of abnormalities or changes in fetal
heart rate patterns during labor including
reassuring and nonreassuring and indeterminate
patterns.
• Know the effects on the fetus and/or newborn
infant of analgesics and anesthetics administered
to the mother during labor.
• Know the issues in the organization of perinatal
care (e.g., regionalization, transport, practice
ANSWER KEY FOR JANUARY 2024 NEOREVIEWS
Nutritional Needs of the Infant with Bronchopulmonary Dysplasia:
1. A; 2. D; 3.B; 4. C; 5. C
Optimizing Nutrition in Neonates with Kidney Dysfunction:
1. D; 2. D; 3. B; 4. A; 5. C
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guidelines, benchmarking data, quality
improvement).
References
1. LA Rosa M, Loaiza S, Zambrano MA, Escobar MF. Trauma in
pregnancy. Clin Obstet Gynecol. 2020;63(2):447–454
2. Jain V, Chari R, Maslovitz S, et al; Maternal Fetal Medicine
Committee. Guidelines for the management of a pregnant trauma
patient. J Obstet Gynaecol Can. 2015;37(6):553–574
3. Albini PT, Zakhary B, Edwards SB, Coimbra R, Brenner ML.
Intimate partner violence and pregnancy: nationwide analysis of
injury patterns and risk factors. J Am Coll Surg. 2023;236(1):
198–207
4. Leshikar DE, Salcedo E. S. Cocanour C. Trauma in Pregnancy. In:
Moore EE, Feliciano DV, Mattox KL, eds. Trauma. 8th ed. New York,
NY: McGraw-Hill Education; 2017
5. American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No 211. Critical care in pregnancy. Obstet Gynecol. 2019;
133:e303–e319
6. El Kady D, Gilbert WM, Xing G, Smith LH. Maternal and neonatal
outcomes of assaults during pregnancy. Obstet Gynecol. 2005;
105(2):357–363
7. Lawn RB, Koenen KC. Homicide is a leading cause of death for
pregnant women in US. BMJ. 2022;379:o2499
8. Drexler KA, Quist-Nelson J, Weil AB. Intimate partner violence and
trauma-informed care in pregnancy. Am J Obstet Gynecol MFM.
2022;4(2):100542
Vol. 25 No. 1 JANUARY 2024 e65
 VISUAL DIAGNOSIS
Umbilical Cord Abnormality in a
Monochorionic-Monoamniotic Twin
Pregnancy
Byron S. Maltez, MD,* Maryam Tarsa, MD,† Sandra L. Leibel, MD, MS‡
*School of Medicine, University of California, San Diego, San Diego, CA
†
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Diego, San Diego, CA
‡
Department of Pediatrics, University of California, San Diego, San Diego, CA
AUTHOR DISCLOSURES Drs Maltez,
Tarsa, and Leibel have disclosed no
financial relationships relevant to this
article. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial
product/device.
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THE CASE
This was a monochorionic-monoamniotic (MoMo) twin gestation with abnormal
color Doppler prenatal ultrasound findings at 26 weeks’ gestation.
Prenatal and Birth Histories
• 33-year-old gravida 1, para 0 woman with benign prenatal screening results.
• Spontaneous twin gestation suspected to be MoMo based on lack of visualiza-
tion of the dividing membrane and the spatial relationship between twins A
and B at 12 1/7 weeks’ gestation (Fig 1).
• Fetal survey at 18 weeks’ gestation (anatomy scan): No abnormalities, the placental
cord insertions for twins A and B were in close relationship to each other (Fig. 2).
• Patient was seen beyond 18 weeks’ gestation with outpatient ultrasonography
every 2 weeks to evaluate fetal growth and monitor for twin-to-twin transfu-
sion syndrome.
Presentation (In Utero at 26 weeks’ Gestation)
At 26 weeks’ gestation, a cord abnormality in both twins was detected on routine
Doppler ultrasonography (Fig 3). As a result of this finding, outpatient management in-
creased with twice-weekly antepartum testing and fetal ultrasonography every 2 weeks.
The patient received a course of betamethasone at 28 weeks’ gestation. Fetal growth
and the amniotic fluid volume were normal until 30 weeks’ gestation when twin A
was noted to have growth restriction with an estimated fetal weight at the third percen-
tile. Twin B also demonstrated decreased growth velocity. The woman was admitted to
the hospital for closer monitoring. Over the next week, twin A developed resistive um-
bilical artery Doppler indices with intermittent fetal decelerations. The decision was
made to proceed with delivery via cesarean section at 32 1 2 weeks’ gestation.
DIFFERENTIAL DIAGNOSIS
• Spontaneous antepartum septostomy
• Umbilical cord entanglement
• Umbilical cord knot
 Figure 1. First trimester transvaginal image at 1 2 1 /7 weeks’ gestation.
This image shows that there is no intertwin membrane. AA indicates twin
A. BB indicates twin B.
ACTUAL DIAGNOSIS
Umbilical cord entanglement.
PROGRESSION
Both twins emerged vigorous with a spontaneous cry.
Twin A had an Apgar score of 7 and 8 and twin B had an
Apgar score of 8 and 9 at 1 and 5 minutes of age, respec-
tively. Entanglement of the umbilical cords was visible af-
ter birth (Figs 4 and 5). Both infants were transported to
the NICU receiving continuous positive airway pressure
(CPAP) at 6 cm H2O with a fraction of inspired oxygen
(FIO2) of 0.21.
Figure 2. First trimester ultrasound scan at 1 8 weeks’ gestation showing
close proximity of the placental cord insertion for twin A and twin B.
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Figure 3. Second trimester ultrasound scan with color Doppler at 2 6
weeks’ gestation showing an umbilical cord anomaly.
Physical Examination (Newborn Day)
Twin A.
• Vital signs stable, temperature 98.8! F (37.1! C)
• Birthweight 1,400 g (18th percentile), head circumference
29 cm (47th percentile), length 42.5 cm (62th percentile).
• Head: Normocephalic and atraumatic; anterior fonta-
nelle open, soft, and flat
• Oral cavity: Intact palate
• Lungs: Clear, equal breath sounds; no respiratory distress
• Cardiovascular: Normal S1 and S2; regular rate and
rhythm; no murmurs
• Abdomen: Soft, nondistended, no masses or organome-
galy; 3-vessel cord
• Genitourinary: Normal preterm female genitalia; patent
anus
Figure 4. Picture of monochorionic-monoamniotic twins soon after delivery
by caesarean section at 3 2 2 /7 weeks’ gestation with umbilical cords intact.
Vol. 25 No. 1 JANUARY 2024 e67

Figure 5. Close-up image of the umbilical cord entanglement after
delivery.
• Skin: No icterus, birthmarks, petechiae, or other rashes
• Neurologic: Normal tone and posture for gestational age
Twin B.
• Vital signs stable, temperature 98.1! F (36.7! C)
• Birthweight 1,545 g (30th percentile), head circumference
28 cm (23th percentile), length 42 cm (55th percentile).
• Head: Normocephalic and atraumatic; anterior fonta-
nelle open, soft, and flat
• Oral cavity: Intact palate
• Lungs: Clear, equal breath sounds; no respiratory distress
• Cardiovascular: Normal S1 and S2; regular rate and
rhythm; no murmurs
• Abdomen: Soft, nondistended, no masses or organome-
galy; 3-vessel cord
• Genitourinary: Normal preterm female genitalia; patent
anus
• Skin: No icterus, birthmarks, petechiae, or other rashes
• Neurologic: Normal tone and posture for gestational
age
Laboratory Studies on Admission
Twin A.
• White blood cell count: 8,100/mL (8.1 × 109/L) with 61%
neutrophils and 0% bands
• Hemoglobin and hematocrit: 15.4 g/dL (154 g/L) and
46% (0.46), respectively
• Platelet count: 187 × 103/mL (187 × 109/L)
• Blood glucose: 23 mg/dL (1.3 mmol/L)
• Venous blood gas: pH 7.31, PCO2 49 mm Hg (6.5 kPa),
bicarbonate 24.7 mg/dL (24.7 mmol/L), base deficit 1.6
mEq/L (1.6 mmol/L) on CPAP 6, FIO2 0.21
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Twin B.
• White blood cell count: 14,200/mL (14.2 × 109/L) with
66% neutrophils and 5% bands
• Hemoglobin and hematocrit: 19.3 g/dL (193 g/L) and
55% (0.55), respectively
• Platelet count: 158 × 103/mL (158 × 109/L)
• Blood glucose: 29 mg/dL (1.6 mmol/L)
• Venous blood gas: pH 7.22, PCO2 60 mm Hg (8 kPa), bi-
carbonate 24.6 mg/dL (24.6 mmol/L), base deficit 3.1
mEq/L (3/1 mmol/L) on CPAP 6, FIO2 21%
Progression
In the NICU, both infants were given intravenous fluid
through an umbilical venous catheter. Both infants also
were treated with caffeine. Twin A was weaned from
CPAP to 2 L high-flow nasal cannula (HFNC) at 4 days of
age while twin B was weaned from CPAP to 2 L HFNC at
6 days of age. They both subsequently weaned to room air
8 days after birth. Twin A underwent head ultrasonogra-
phy at 3 days of age, which demonstrated a 2.6-mm left
choroid plexus cyst that was noted to have resolved on the
head ultrasound scan obtained at 30 days of age. Twin B
did not have any abnormalities noted on ultrasonography
on either day 3 or 30 days of age. Ophthalmologic screen-
ing for retinopathy and hearing screens showed normal
findings.
The placental pathology showed a hypermature MoMo
twin placenta (618 g, with A:B ratio of 50%:50%; with in-
creased syncytial knots on both sides of the placenta). Foci
of villous agglutination were observed on twin A’s placen-
tal side and normoblastemia was observed on twin B’s
portion of the placenta.
What the Experts Say
Fetal ultrasonography at 18 weeks’ gestation (Fig 2) showed
2 umbilical cords with normal color flow; there was no in-
tertwin membrane and the proximity of the cords suggested
a monoamniotic twin gestation. However, the ultrasound
scan obtained at 26 weeks’ gestation (Fig. 3) was most con-
sistent with cord entanglement. This was because of the
chainlike complicated wrapped appearance of the 2 cords.
This finding prompted closer monitoring of the pregnancy.
Umbilical cord entanglement is believed to be a fairly
common, if not ubiquitous feature of monoamniotic twin
pregnancies. (1) Loose cord entanglement without signifi-
cant impingement on blood flow perhaps is not as detri-
mental to perinatal outcome as tight cord entanglement,
which eventually may lead to fetal death. Given such
unique yet common characteristics of monoamniotic twin
 pregnancies and the risk of fetal loss, inpatient and close
fetal monitoring is a common practice in this scenario. Fe-
tal loss due to cord entanglement has been thought to be
a gradual rather than a sudden event. (2) Hence, the fre-
quency of fetal monitoring should be tailored based on
gestational age and interpretation of non-stress testing,
which will help determine the date of delivery.
Rossi et al found that cord entanglement could be con-
sidered a minor complication of MoMo twin pregnancies,
citing an 84% survival rate of both twins and a 90% sur-
vival rate of at least 1 twin. (3) The mere presence of cord
entanglement does not in and of itself contribute to neo-
natal morbidity and mortality. Umbilical cord entanglement
was historically believed to be the cause of intrauterine fetal
death in monoamniotic pregnancies, however, given the
ubiquitous nature of this finding, other mechanisms are
likely at play. (4) Despite the high incidence of cord entan-
glement in MoMo twins, Chitrit et al found that neonatal
outcomes were largely good for affected infants. (5) A retro-
spective study in England demonstrated that 74% of MoMo
twins required NICU admission with respiratory distress
syndrome as the most common diagnosis as a result of pre-
term birth. Eighty-six percent of MoMo twins had a defini-
tive diagnosis of cord entanglement postpartum. (6)
The lack of a dividing membrane between twins A and
B had been confirmed on multiple ultrasound scans in the
early first trimester, which makes spontaneous antepar-
tum septostomy very unlikely. Umbilical cord knots can
be seen in singleton fetuses while cord entanglement re-
quires the presence of 2 or more cords in utero. Hence,
the ultrasound cord finding was mostly consistent with
the existence of cord entanglement.
Summary
• Cord entanglement is a common occurrence in
MoMo twin gestations.
• Routine prenatal monitoring is required for de-
tecting changes in fetal growth and to decrease
the risk of fetal death; monitoring should be tai-
lored based on gestational age.
• Postnatal management of MoMo twin newborns
with cord entanglement should follow routine
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guidelines for resuscitation and outcomes are
dependent on the gestational age and birth-
weight at delivery.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the general principles, applications, and
limitations of ultrasonography, including Doppler
blood flow measurements, in assessment of fetal
conditions and well-being.
• Know the rationale, interpretation, and limitations
of maternal detection of fetal movement, of the
biophysical profile, the non-stress test, and the
contraction stress test as means of assessing fetal
well-being.
• Know the potential fetal complications of multiple
gestation such as cord problems, twin-twin
transfusion, “stuck twin,” conjoined twins, etc.
• Know how to evaluate fetal growth rate and fetal
growth restriction and the management of fetal
growth restriction.
References
1. Dias T, Mahsud-Dornan S, Bhide A, Papageorghiou AT, Thilaganathan
B. Cord entanglement and perinatal outcome in monoamniotic twin
pregnancies. Ultrasound Obstet Gynecol. 2010;35(2):201–204
2. Post A, Heyborne K. Managing monoamniotic twin pregnancies. Clin
Obstet Gynecol. 2015;58(3):643–653
3. Rossi AC, Prefumo F. Impact of cord entanglement on perinatal
outcome of monoamniotic twins: a systematic review of the literature.
Ultrasound Obstet Gynecol. 2013;41(2):131–135
4. Lewi L. Cord entanglement in monoamniotic twins: does it really
matter? Ultrasound Obstet Gynecol. 2010;35(2):139–141
5. Chitrit Y, Korb D, Morin C, Schmitz T, Oury J-F, Sibony O. Perinatal
mortality and morbidity, timing and route of delivery in
monoamniotic twin pregnancies: a retrospective cohort study. Arch
Gynecol Obstet. 2021;303(3):685–693
6. Glinianaia SV, Rankin J, Khalil A, et al. Prevalence, antenatal
management and perinatal outcome of monochorionic monoamniotic
twin pregnancy: a collaborative multicenter study in England, 2000-
2013. Ultrasound Obstet Gynecol. 2019;53(2):184–192
Vol. 25 No. 1 JANUARY 2024 e69