t.

me/neonatology

t.me/neonatology
 NeoReviews
PERSPECTIVE Editor-in-Chief: Dara Brodsky, Boston, MA
Associate Editor, IOS Cases: Elizabeth Schulz, Bethesda, MD
e71 Potential Neurologic Manifestations of COVID-19 Infection Associate Editor, IOS Cases: Jayasree Nair, New York, NY
Associate Editor, CME: Santina A. Zanelli, Charlottesville, VA
in Neonates Associate Editor, NeoQuest: Rita Dadiz, Rochester, NY
Deepika Rustogi, Garima Saxena, Saurabh S. Chopra, Amuchou Soraisham Associate Editor, Perspectives: Mamta Fuloria, Bronx, NY
Associate Editor, Maternal-Fetal Medicine: Brett Young, Boston, MA
Associate Editor, Video Corner: Akshaya Vachharajani, Columbia, MO
Assistant Editor, CME: Theodore De Beritto, Los Angeles, CA
ARTICLES Associate Editor, Complex Fetal Care: •••
•• •
Carl Backes, Columbus, OH •

•
•
e78 Congenital Anomalies of the Kidneys and Urinary Tract
Jeanette Fong, Theodore De Beritto
EDITORIAL BOARD
Anisha Bhatia, Canton, OH MOC

•
•
• •
Colby Day, Jacksonville, FL
••
•••

Jennifer Hanford, Columbia, MO

e88 Nephrocalcinosis in Neonates Alison Chu, Los Angeles, CA
Gia J. Oh, Lavjay Butani Corinne L. Leach, Buffalo, NY
Krithika Lingappan, Houston, TX
Sai Mukthapuram, Cincinnati, OH
e99 Renal Tubular Acidosis in the Neonate Zeynep Salih, Carmel, IN
Brian R. Lee Thomas E. Wiswell, Honolulu, HI
Clyde Wright, Aurora, CO
Manager, Journal Publishing: Josh Sinason
Medical Copy Editor: Beena Rao
INDEX OF SUSPICION IN THE NURSERY
Publisher: American Academy of Pediatrics
e107 Lactic Acidosis in a Neonate with Ventriculomegaly and President: Benjamin D. Hoffman
Chief Executive Officer/Executive Vice President:
Hypoplasia of the Corpus Callosum Mark Del Monte
Chief Product and Services Officer/SVP Membership, Marketing,
Abdullah Bin Shoaib, Christa Rose Tabacaru and Publishing:
Mary Lou White
e110 A Preterm Infant with Pneumoperitoneum Vice President, Publishing: Mark Grimes
Director, Journal Publishing: Joseph Puskarz
Jubara Alallah, Abdelfatah I. Abuzaid, Abdulaziz Alkhotani, Edward Riachy
NeoReviews™

t.me/neonatology
e114 One Bone in Two Pieces: Does It Have to Be a Fracture? (ISSN 1526-9906) is owned and controlled by the American Academy of Pediatrics. It is
published monthly by the American Academy of Pediatrics, 345 Park Blvd., Itasca, IL 60143.
Kathleen Forcier, Meghan Imrie Statements and opinions expressed in NeoReviews™ are those of the authors and not
necessarily those of the American Academy of Pediatrics or its Committees. Recommendations
included in this publication do not indicate an exclusive course of treatment or serve as a
standard of medical care. Subscription price for NeoReviews™ for 2024: AAP/CPS Member, $160;
AAP In-Training/National A_liate Member, $145; Nonmember, $199; Nonmember In-Training /
MATERNAL-FETAL CASE STUDIES Allied Health, $125; AAP Perinatal Section Member, $145.
Institutions call for pricing (866-843-2271).
e117 Elevation of Maternal Serum a-Fetoprotein: Implications for © AMERICAN ACADEMY OF PEDIATRICS, 2024. All rights reserved. Printed in USA. No part
the Neonate may be duplicated or reproduced without permission of the American Academy of
Pediatrics.
Jessica Celine Morgan, Linda M. Ernst, Ian Grable POSTMASTER: Send address changes to NEOREVIEWS™, American Academy
of Pediatrics, Member and Customer Care, 345 Park Blvd., Itasca, IL 60143.
CME/MOC Information:
The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council
VISUAL DIAGNOSIS for Continuing Medical Education (ACCME) to provide continuing medical education for
physicians.
e122 A 3-day-old Neonate with Generalized Edema and a The AAP designates this journal-based CME activity for a maximum of 24.0 AMA PRA
Category 1 Credit(s)™. Physicians should claim only the credit commensurate with
Bullous Rash the extent of their participation in the activity.
Dhanya Jayaraj, Vidya Ramdas, Abeer Ateeq Al-Balushi, Salima Al Asiry, In order to earn CME credits and/or ABP MOC Part 2 points, you must participate in
this activity online at www.neoreviews.org, where you will view additional information,
Mohammed Al Yahmadi, Manoj N. Malviya complete your CME quizzes, and claim credit online.
NeoReviews™ and NeoReviewsPlus™ are supported, in part, through an educational grant
from Abbott Nutrition, a proud supporter of the American Academy of Pediatrics.
The American Academy of Pediatrics is committed to principles of equity, diversity,
and inclusion in its publishing program.

facebook.com/neoreviews

twitter.com/AAPJournals

T.ME/NEONATOLOGY

Answer Key appears on page e126.

t.me/neonatology
 PERSPECTIVE

Potential Neurologic Manifestations of

COVID-19 Infection in Neonates
Deepika Rustogi, MD,* Garima Saxena, MD,* Saurabh S. Chopra, MD,*† Amuchou Soraisham, MBBS, MD‡
*Department of Neonatology and Pediatrics, Yashoda Superspeciality Hospital, Kaushambi, Ghaziabad, UP, India
†
Department of Pediatric Neurology, Max Super Speciality Hospitals, Delhi-NCR, India
‡
Department of Pediatrics and Neonatology, Foothills Medical Centre, Cumming School of Medicine, University of Calgary, Alberta, Canada

EDUCATION GAPS

Potentially devastating neurologic complications of acute COVID-19 infection

in the adult population have been reported extensively in the literature.
However, data on the neurologic impact of COVID-19 on neonates are limited.

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

t.me/neonatology
1. Describe the spectrum of acute neurologic manifestations that have
been reported in neonates with COVID-19, along with the suggested
pathophysiologic mechanisms.
2. Summarize the laboratory, imaging, and electroencephalographic findings
in neonates with neurologic symptoms in the setting of COVID-19 infection.
3. Describe the potential effect of COVID-19 infection on long-term
neurodevelopmental outcomes.

AUTHOR DISCLOSURES Dr Soraisham is

ABSTRACT the cochair of the Canadian Pediatric
Society’s NRP Committee. Dr Chopra has
In contrast to adults, neonates and infants with coronavirus disease 2019 attended meetings with the support of
(COVID-19) infection have milder symptoms and are less likely to require Kepler Pharma. Drs Rustogi and Saxena
hospitalization. However, some neonates with COVID-19 can present with have disclosed no financial relationships
relevant to this article. This commentary
significant symptoms. Recent evidence suggests that neurologic does not contain a discussion of an
manifestations of neonatal COVID-19 infection may be higher than initially unapproved/investigative use of a
thought. In this comprehensive review of the current literature, we summarize commercial product/device.

the clinical, laboratory, and radiologic findings, as well as potential

management strategies for COVID-19–related neurologic illness in neonates. ABBREVIATIONS
Although the growing brain may be affected by neurologic disease associated CNS central nervous system
with COVID-19 infection, the few published studies on the long-term COVID-19 coronavirus disease 2019
CSF cerebrospinal fluid
outcomes after COVID-19 infection in neonates and infants provide conflicting
EEG electroencephalography
results. Larger collaborative clinical studies are needed to determine whether MIS-C multisystem inflammatory
COVID-19 infection in neonates has long-term neurodevelopmental outcomes. syndrome in children
MRI magnetic resonance imaging
RT-PCR reverse transcriptase
polymerase chain reaction
BACKGROUND SARS-
CoV-2 severe acute respiratory
Our lives have not been the same since the world was impacted by the deadly severe syndrome–coronavirus 2
acute respiratory syndrome–coronavirus 2 infection (SARS-CoV-2, also referred to as infection

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e71

t.me/neonatology
 coronavirus disease 2019 [COVID-19]) with postpartum infec-
tion being the most common mode of neonatal acquisition.
(1) Affected neonates are either asymptomatic or present with
a mild illness, with the most common reported symptoms in-
cluding fever, vomiting, diarrhea, cough, respiratory distress,
and lethargy. (2)(3)(4) Our understanding of the disease in the
neonatal period is evolving. Rare reports of neonates with
COVID-19 infection leading to multisystem involvement with
neurologic symptoms have been published (Table 1). The aim
of this review is to describe the reported findings of neuro-
logic complications associated with SARS-CoV-2 among
neonates and advocate for further large-scale collaborative
research to study the potential long-term impact of this in-
fection on neurodevelopmental outcomes.
NEUROLOGIC PRESENTATION IN NEONATAL
COVID-19 INFECTION
Central nervous system (CNS) complications of acute
COVID-19 are well-described in the adult population. (5)
Children have not been spared from these symptoms, and
the risk is unpredictable, ranging from 5% to 57% across
various reports. (6)(7) Neonatal data on neurologic mani-
festations associated with COVID-19 are extremely limited,
with most reported evidence coming from isolated case re-
ports that have limited inferential value. Globally, there
are knowledge gaps in the epidemiology, neurologic mani-
festations, and long-term outcomes of SARS-CoV-2 infec-
tion among neonates.
Although there are many systematic reviews on COVID-19
infection in younger children and adolescents, only a few focus
on neonates. (1)(4)(8) Neonates typically acquire COVID-19
infection postnatally from infected care providers. Vertical
transmission can occur in neonates born to COVID-19–positive
pregnant persons, though the risk is small. (9)(10) In some
cases, it is difficult to determine whether vertical or hori-
zontal transmission has occurred. Transplacentally acquired
COVID-19 infection is considered more severe because of
the in utero fetal inflammatory process, (3)(8) and thus, af-
fected neonates are more likely to present with more severe
systemic symptoms, and potentially be at increased risk for
long-term neurologic sequelae similar to other intrauterine
viral infections. However, these long-term potential effects
remain speculative as they have not been scientifically
proven. (9)
Recent evidence suggests that neurologic manifestations
from neonatal COVID-19 infections may be more significant
than previously thought. (1)(7)(8)(11)(12)(13)(14)(15) A system-
atic review by Raschetti et al reported neurologic manifesta-
tions in 18.6% of symptomatic neonates with SARS-CoV-2
e72 NeoReviews
t.me/neonatology
(n518/97). (8) A literature review by de Moraes from Brazil
noted neurologic features in 26.4% of affected neonates. (16)
Further data are needed to clarify the neurologic impact of
COVID-19 infections in neonates.
PATHOPHYSIOLOGY OF NEUROLOGIC
INVOLVEMENT IN NEONATES WITH COVID-19
There are several mechanisms by which CNS involvement
may occur in association with COVID-19 infection in neo-
nates. The postulated mechanisms of brain injury (Figure)
include coronavirus-related neuronal damage (ie, neuroin-
vasive), direct neurotoxic effects causing endothelial injury,
resulting in apoptosis and necrosis, postinfectious autoanti-
body-mediated (including antineuronal and antiglial anti-
bodies), and parainfectious brain injury as a result of
cytokine storm. (3)(7)(17)(18)(19) Pulmonary involvement
also affects the neurologic system indirectly through the hy-
pothesized concept of brain-lung cross talk via ventilation-
perfusion mismatch, hypoxia, hypercarbia, oxidative stress,
the Bohr effect, and lung inflammation. (18)(19) Both direct
t.me/neonatology
invasion of the CNS as well as hyperinflammation can
cause vascular endothelial damage, leading to vasculitis and
stroke. It is likely that there is an overlap of various patho-
physiologic neurologic mechanisms of neonatal COVID-19
infection.
NEUROLOGIC MANIFESTATIONS IN NEONATES
WITH COVID-19
Table 1 provides a summary of published clinical, laboratory,
and radiologic findings of reported cases of neonates with
COVID-19 infection and neurologic involvement. Among
newborns with COVID-19 infection who exhibit neurologic
manifestations, clinical findings can be quite varied, poten-
tially involving the entire neuraxis. (20)(21)(22)(23) The most
common neurologic symptom reported in neonates with
COVID-19 infection is lethargy. (16) However, lethargy and
tone abnormalities can be found in the setting of various
nonencephalitic, infectious, and metabolic processes in neo-
nates, even in the absence of specific CNS findings and do
not address the localization of the disease process or its
mechanism. Neurologic symptoms can be divided into non-
specific and specific symptoms as described in Table 2. Neo-
nates can have neurologic manifestations similar to the
multisystem inflammatory syndrome in children (MIS-C),
which is reported in less than 5% of affected neonates. (3)
There are a few reports of a perinatally acquired COVID-19
infection giving rise to neonatal stroke as a result of ische-
mia and cerebral venous sinus thrombosis. (24)(25)(26)
However, there is no substantial evidence to support the
T.ME/NEONATOLOGY
 Table 1. Summary of Clinical, Laboratory, and Radiographic Findings of Reported Cases of Neonates with COVID-19 and Neurologic Manifestations
Authors, Country
of Origin Source Population Neonatal Clinical Presentation Laboratory Results Neuroimaging
Fragoso et al, (11) Case report Term male tested positive Clonic seizures, lethargy, hypotonia, Lymphopenia, thrombocytopenia Brain MRI at 15 days of age–bilateral
Brazil for COVID-19 at 3 days brisk tendon reflexes, no primitive CSF analysis normal white matter abnormalities, restricted
of age reflexes at 5 days of age, required EEG–persistent electrographic diffusion in corpus callosum
intubation seizures Follow-up MRI at 31 days of age–cystic
cavitations
Kumar et al, (12) Case report Late preterm with Persistent pneumonia, difficulty in Thrombocytosis, lymphocytic MRI brain at 42 days of age- subcortical
India perinatal COVID weaning from ventilator leukocytosis volume loss, cystic changes, tiny
infection Encephalopathy with seizure at 42 EEG normal hemorrhages, loss of myelination at
days of age the posterior limb of the internal
Symptoms improved over 8 weeks capsule
Lorenz et al, (15) Letter to the Term female with COVID- Lethargy and fever 24 hours after CSF negative for SARS-CoV-2 Head ultrasound scan without
Germany editor positive mother birth, progressed to encephalitis at abnormalities
NP and rectal swabs 3 days of age
positive for SARS-CoV-2 Double-peaked course of respiratory
symptoms (distress followed by
hypopnea)
Alvarado-Socarras Case report Term male neonate Hyperthermia and transient neurologic Leukopenia Head ultrasound scan without
et al, (14) symptoms at 21 days of age EEG normal abnormalities
Colombia (drowsiness, poor feeding,
hypotonia)
Tetsuhara et al, (21) Case report Term male Recurrent apnea at 29 days of age due Normal cell counts and MRI brain–T2 hyperintensity, FLAIR
Japan NP and rectal swabs to nonconvulsive status epilepticus inflammatory markers sequence hypointensity in the deep
positive for SARS-CoV-2 requiring mechanical ventilation CSF normal and negative for SARS- and subcortical white matter,
CoV-2 diffusion restriction in the corpus
EEG–rhythmic spike and wave callosum
complex of 1.5–2 Hz in the left Follow-up MRI on day 45–multiple cystic

t.me/neonatology
hemisphere cavitations
on-Aguilar
Chac
Scientific 26-day-old male infant 2 paroxysmal episodes associated with Leukopenia Cranial ultrasound scan normal
et al, (13) letter NP swab for SARS-CoV-2 altered tone and posture, fever of Increased CPK and LDH
Spain was positive 12 hours, with nasal discharge, CRP and metabolic panel normal
vomiting, irritability, watery stools Blood, urine, CSF, and stool cultures
negative
EEG normal
Brum et al, (22) Case report 17-day-old term male Fever, seizures, and lethargy Neutropenia, mildly elevated CRP, MRI–2 small focal lesions in left frontal
Argentina newborn consumption coagulopathy white matter with diffusion restriction
Acquired postnatally CSF normal with negative RT-PCR suggestive of ischemic lesions
Raschetti et al, (8) Systematic 176 published cases 18% neurologic symptoms Elevated inflammatory markers (CRP, Abnormal lung imaging–64%
France review 70% postnatal acquisition procalcitonin) 15.5% MRI brain–gliosis of periventricular and
30% vertical transmission subcortical white matter
Dhir et al, (1) Systematic 58 neonates with 50% respiratory symptoms Not analyzed Not mentioned
India review SARS-CoV-2 38% ICU admission
Mother tested positive in 15.5% fever
91% of these neonates 5.2% lethargy & poor feeding
17% ventilated
Continued

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4
e73
t.me/neonatology
 causation except for circumstantial evidence, with COVID-19

Authors concluded that the occurrence

No abnormalities detected on cranial being the only temporal association found.

CRP5C-reactive protein, CPK5creatine phosphokinase, CSF5cerebrospinal fluid; EEG5electroencephalogram; ICU5intensive care unit, LDH5lactate dehydrogenase, MRI5magnetic resonance
of long-term neuropsychiatric
LABORATORY AND RADIOLOGIC FINDINGS IN
Neuroimaging

COVID-19–INFECTED NEONATES WITH

sequelae is unknown
NEUROLOGIC MANIFESTATIONS
Various laboratory abnormalities have been published in
ultrasound

clinical cases of neonates with COVID-19 infection includ-

ing abnormal cell count, increased inflammatory markers,
increased liver function tests, and abnormal electrolytes.
imaging; NP5nasopharyngeal, RT-PCR5reverse transcriptase polymerase chain reaction, SARS-COVID-195severe acute respiratory syndrome–coronavirus 19. The most reported abnormalities have been leukopenia,
neutropenia, and thrombocytopenia. (3)(11)(12)(22) Con-
55% increased lactate (>2 mmol/L)

trary to what would be expected, inflammatory markers

29% elevated CRP (>5 mg/L)

were mostly reported as normal. (8)(12)(13) In a systematic

Laboratory Results

review, inflammatory markers were increased in only 15%

of neonates with COVID-19. (8) Elevated C-reactive pro-
tein and procalcitonin levels were found in a few cases.
9% leukopenia

Not analyzed

(8)(11) Measurement of cytokine levels (such as interleukin

6) and proinflammatory markers (like ferritin, D-dimer,
lactate dehydrogenase, and pro–brain natriuretic peptide)

t.me/neonatology
and qualitative antibody detection tests could not be done
in most cases due to logistical constraints.
3 premature neonates with respiratory
Neonatal Clinical Presentation

Most clinical studies in neonates with COVID-19 infec-

Most common symptoms: Fever,

tion have reported unremarkable cerebrospinal fluid (CSF)

poor feeding, or vomiting

findings. Even in those with severe neurologic symptoms,

26% neurologic features
46% respiratory distress

CSF studies, including cytology, biochemistry, and culture,

were normal. COVID-19 virus could not be identified with
23% asymptomatic

distress died

reverse transcriptase polymerase chain reaction (RT-PCR)

in any of the case reports in neonates, supporting the
symptom profile to be vascular or inflammatory in origin.
Although the sensitivity as well as the validity of CSF test-
ing for COVID-19 RT-PCR is unknown, all CSF studies
Average age at diagnosis

that have been reported in neonates, infants, and children

positive RT-PCR test

were negative. (7)(14)(15) Antineuronal and antiglial auto-

87 newborns with a
Population
66 neonates with

antibodies seen with immune-mediated postinfectious dis-

SARS-CoV-2

52% postnatal
26% perinatal

eases have not been tested in CSF specimens of neonates

9 days

with COVID-19 with neurologic symptoms. Appropriate

CSF studies seem to be lacking to establish the diagnosis of
COVID-19–related neurologic disorders, and neurologic in-
volvement from COVID-19 should be considered even in the
review (45

and case
Prospective
national

reports)
Source

articles
Literature
cohort

absence of CSF pleocytosis or other CSF abnormalities.

study

Neonates with profound neurologic presentations would be

Table 1. (Continued)

anticipated to develop alterations in electroencephalography

(EEG) findings and neuroimaging. EEG studies have been re-
de Moraes et al, (16)
United Kingdom
Authors, Country

ported in only a few neonates with COVID-19–related neuro-

Gale et al, (23)

logic manifestations, with findings including normal studies,

of Origin

abnormal background, ictal spikes, nonconvulsive electro-

Brazil

graphic status epilepticus, and asymmetric rhythmic spike-

wave patterns (Table 1).

e74 NeoReviews
T.ME/NEONATOLOGY

t.me/neonatology

Neuroinvasion
(Viral neurotropism)
- Vasculis
- Stroke
- Encephalis
Brain-Lung Cross Talk
Figure. Potential pathophysiology of neurological manifestations in neonates with perinatally and postnatally acquired COVID infection.
Magnetic resonance imaging (MRI) with MR spectros-
copy (MRS) of the brain is the most studied neuroimag-
ing parameter in COVID-19–infected neonates with
neurologic illness. There is no specific pattern of brain
injury in neonates with neurologic manifestations associ-
ated with COVID-19 infections. Normal CNS imaging
has been reported by many, (14)(15) whereas a few stud-
ies found pronounced abnormalities including white
matter injury, demyelination, multiple foci of restricted
diffusion, ischemic stroke, and cavitation. (11)(12)(21)(22)
(24)
MANAGEMENT STRATEGIES FOR COVID-19–INFECTED
NEONATES WITH NEUROLOGIC FINDINGS
There are no standard treatment guidelines for the manage-
ment of neonatal COVID-19–related neurologic manifesta-
tions. Clinicians have used antibiotics, inhaled steroids,
systemic steroids, and antiviral agents as well as intrave-
nous immunoglobulin. There is no role for antiviral medi-
cations such as lopinavir, ritonavir, remdesivir, or specific
medications like chloroquine or hydroxychloroquine in the
management of neonatal COVID-19 infection, irrespective
of the mode of transmission or symptom profile. (27)(28)
Table 2. Spectrum of Neurologic Symptoms in Neonatal COVID-19
Nonspecific Symptoms
Lethargy
Irritability, high-pitched cry
Hypotonia
Apnea
t.me/neonatology
Neurotoxic
(Hyperinflammaon &
Hypercoagulaon)
- Encephalopathy syndrome Post-Infecous
(Autoanbody-mediated)
- Stroke
- Acute disseminated
encephalomyelis
- Acute necrozing encephalis
Para-infecous Brain Injury
(Cytokine-mediated)
In a population-based cohort study from the United Kingdom,
3% of neonates received antiviral agents, 3% received corti-
t.me/neonatology
costeroids, and 2% received pooled immunoglobulin. (23)
However, the overall number of patients was very small
(n566) and no improvement in outcome was docu-
mented. (23) Nebulized steroids, along with a course of
azithromycin, have been used in cases with postinfectious
viral pneumonia as an immunomodulator. (12)(13) How-
ever, their role in neonates remains unclear. The use of
intravenous immunoglobulin for the treatment of severe
COVID-19–associated neurologic disease has been extrapo-
lated from adult trials and is based on the assumption of
neurologic symptoms being a part of a MIS-C (9)(29); al-
though there is no evidence to support or refute the use of
intravenous immunoglobulin in neonates. Neonates and
children have been treated with various steroid regimens
(high-dose methylprednisolone, low-dose prednisolone,
dexamethasone) in isolated case reports, based on the hy-
pothesis that acute COVID-19 infection leads to multisys-
tem inflammation and dysfunction of the immune system.
We could not find any scientific evidence to suggest routine
use of steroids in COVID-19–associated neurologic dis-
ease, especially when the long-term implications remain
questionable.
Specific Symptoms
Febrile seizure, nonfebrile seizure, nonconvulsive status epilepticus
Altered sensorium, encephalopathy, encephalitis
Meningitis
Stroke
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e75
 IMPACT OF ACUTE NEONATAL COVID-19
INFECTION WITH NEUROLOGIC SYMPTOMS ON
LONG-TERM NEURODEVELOPMENT
Early life, especially the first 1,000 days, is a critically impor-
tant and vulnerable period for long-term neurodevelopment,
as it is characterized by rapid neuronal growth and matura-
tion, which lays the foundation for lifelong brain architec-
ture. (30)(31) There are only a few published studies (with a
few more ongoing) that have examined the neurodevelop-
mental outcomes of neonates with COVID-19 and neuro-
logic symptoms. Rapidly accumulating evidence suggests
that neonates with early transient neurologic symptoms
make a complete recovery, though the impact of the COVID-19
pandemic on the growing brain is not completely known. Ayed
et al from Kuwait enrolled 58 neonates diagnosed with SARS-
CoV-2 infection prospectively using their national registry
and assessed their 18-month neurodevelopmental outcomes
using Bayley Scales of Infant and Toddler Development, 3rd
Edition. (32) Although they reported no difference in the
neurodevelopmental outcomes compared with controls, the
authors acknowledged the need for longer follow-up.
(32) Aldrete-Cortez et al from Mexico concluded that in-
fants prenatally exposed to SARS-CoV-2 (n556) had ab-
sence of fidgety movements between 3 to 5 months of
age and were at higher risk for serious neurologic disor-
ders. (33) A multicenter observational study conducted in
China on neonates born to women with COVID-19 in-
fections reported abnormal brain MRI findings in 3 of 5
infected neonates; these findings included delayed mye-
lination, brain dysplasia, and abnormal signal in the
periventricular white matter but normal physical
growth at 44 weeks’ postmenstrual age. (34) Hessami
et al conducted a systematic review of infants delivered
during the COVID-19 pandemic and found that their
neurodevelopment in the first year of age was not al-
tered by perinatal exposure to SARS-CoV-2. (35) How-
ever, the infants in this study had significant risks of
communication delay, regardless of maternal infection.
(35) Shuffrey and colleagues reported that infants born
during the pandemic (independent of maternal COVID
infection) had differences in neurodevelopment at age
6 months with significantly lower scores in gross mo-
tor, fine motor, and personal social subdomains, which
was assessed using the Ages and Stages Questionnaire,
3rd edition. (36) These preliminary conflicting results
should not make researchers and clinicians complacent;
good-quality data are still insufficient to draw unbiased
conclusions.
e76 NeoReviews
t.me/neonatology
CONCLUSION
It is evident from scientific publications that neonates
with COVID-19 infection can present with primary neuro-
logic manifestations, though the mechanism is uncertain.
Pediatric specialists, neonatologists, and pediatric neurolo-
gists should be aware of possible neurologic involvement
associated with novel coronavirus in neonates and infants
and its possible potential to cause long-term neurodevelop-
mental consequences. Larger collaborative clinical studies
are needed to understand the long-term neurodevelop-
mental implications of COVID-19 infection in neonates.
TAKE HOME MESSAGE
• The spectrum of neurologic manifestations in neonates
with COVID-19 is variable, with lethargy being the most
commonly reported symptom.
• The postulated mechanisms of brain injury in acute
neonatal COVID infection include neuroinvasion, direct
neurotoxicity, brain-lung cross talk, and immune-mediated
t.me/neonatology
neurotoxicity.
• There is no scientific evidence to support the routine
use of antivirals, steroids, or any other specific medica-
tion in the neonatal age group to treat COVID-19 infec-
tions (including those with neurologic manifestations)
and thus, management should be symptomatic and
supportive.
• Potential long-term neurodevelopmental impact of neo-
natal COVID-19 infection on the growing brain cannot
be disregarded.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Know the normal CSF counts and chemistries in pre-
term and term neonates and changes with infection.
References
1. Dhir SK, Kumar J, Meena J, Kumar P. Clinical features and
outcome of SARS-CoV-2 infection in neonates: a systematic review.
J Trop Pediatr. 2021;67(3):fmaa059
2. Rawat M, Chandrasekharan P, Hicar MD, Lakshminrusimha S.
COVID-19 in newborns and infants-low risk of severe disease: silver
lining or dark cloud? Am J Perinatol. 2020;37(8):845–849
T.ME/NEONATOLOGY
3. Sankaran D, Nakra N, Cheema R, Blumberg D, Lakshminrusimha
S. Perinatal SARS-CoV-2 infection and neonatal COVID-19: A 2021
Update. NeoReviews. 2021;22(5):e284–e295
4. Trevisanuto D, Cavallin F, Cavicchiolo ME, Borellini M, Calgaro S,
Baraldi E. Coronavirus infection in neonates: a systematic review.
Arch Dis Child Fetal Neonatal Ed. 2021;106(3):330–335
5. Mao L, Jin H, Wang M, et al. Neurologic manifestations of
hospitalized patients with coronavirus disease 2019 in Wuhan,
China. JAMA Neurol. 2020;77(6):683–690
6. LaRovere KL, Riggs BJ, Poussaint TY, et al; Overcoming COVID-19
Investigators. Neurologic involvement in children and adolescents
hospitalized in the United States for COVID-19 or multisystem
inflammatory syndrome. JAMA Neurol. 2021;78(5):536–547
7. Stafstrom CE, Jantzie LL. COVID-19: Neurological considerations in
neonates and children. Children (Basel). 2020;7(9):133
8. Raschetti R, Vivanti AJ, Vauloup-Fellous C, Loi B, Benachi A, De
Luca D. Synthesis and systematic review of reported neonatal SARS-
CoV-2 infections. Nat Commun. 2020;11(1):5164
9. Kumar P, Fadila, Prasad A, et al. Vertical transmission and clinical
outcome of the neonates born to SARS-CoV-2-positive mothers: a
tertiary care hospital-based observational study. BMJ Paediatr Open.
2021;5(1):e001193
10. Vayalumkal JV, Soraisham AS, Abou Mehrem A, et al. Congenital
SARS-CoV-2 infection in two neonates with confirmation by viral
culture of the placenta in one case. Viruses. 2023;15(6):1310
11. Fragoso DC, Marx C, Dutra BG, et al. COVID-19 as a cause of acute
neonatal encephalitis and cerebral cytotoxic edema. Pediatr Infect Dis
J. 2021;40(7):e270–e271
12. Kumar VH, Natarajan C, Siddharth M, et al. Post covid pneumonia
pulmonary fibrosis and encephalitis in a term neonate with prenatal
exposure to SARS CoV-2: A case report. IDCases. 2022;27:e01414
13. Chac
on-Aguilar R, Osorio-C
amara JM, Sanjurjo-Jimenez I,
Gonz
alez-Gonz
alez C, L
opez-Carnero J, P
erez-Moneo B. COVID-19:
Fever syndrome and neurological symptoms in a neonate. An
Pediatr (Engl Ed). 2020;92(6):373-374
14. Alvarado-Socarras JL, Theurel-Martin D, Cruz-Hernandez M,
Rodriguez-Morales AJ. Community-acquired neonatal SARS-CoV-2
infection associated with neurological symptoms in Colombia. J Trop
Pediatr. 2021;67(1):fmab022
15. Lorenz N, Treptow A, Schmidt S, et al. Neonatal early-onset
infection with SARS-CoV-2 in a newborn presenting with
encephalitic symptoms. Pediatr Infect Dis J. 2020;39(8):e212
16. de Moraes FM, de Souza JWPS, Alves LP, et al. SARS-CoV-2
infection and possible neonatal neurological outcomes: a literature
review. Viruses. 2022;14(5):1037
17. Leven Y, B€
osel J. Neurological manifestations of COVID-19 - an
approach to categories of pathology. Neurol Res Pract. 2021;3(1):39
18. Battaglini D, Brunetti I, Anania P, et al. Neurological manifestations
of severe SARS-CoV-2 infection: potential mechanisms and
implications of individualized mechanical ventilation settings. Front
Neurol. 2020;11:845
19. Pezzini A, Padovani A. Lifting the mask on neurological
manifestations of COVID-19. Nat Rev Neurol. 2020;16(11):636–644
20. Stafstrom CE. Neurological effects of COVID-19 in infants and
children. Dev Med Child Neurol. 2022;64(7):818–829
21. Tetsuhara K, Akamine S, Matsubara Y, et al. Severe encephalopathy
associated with SARS-CoV-2 Omicron BA.1 variant infection in a
neonate. Brain Dev. 2022;44(10):743–747
t.me/neonatology
22. Brum AC, Glasman MP, De Luca MC, et al. Ischemic lesions in the
brain of a neonate with SARS-CoV-2 infection. Pediatr Infect Dis J.
2021;40(9):e340–e343
23. Gale C, Quigley MA, Placzek A, et al. Characteristics and outcomes
of neonatal SARS-CoV-2 infection in the UK: a prospective national
cohort study using active surveillance. Lancet Child Adolesc Health.
2021;5(2):113–121
24. Vasilescu DI, Rosoga AM, Vasilescu S, et al. SARS-CoV-2 Infection
during pregnancy followed by thalamic neonatal stroke—case report.
Children (Basel). 2023;10(6):958
25. Campi F, Longo D, Bersani I, et al. Neonatal cerebral venous
thrombosis following maternal SARS-CoV-2 infection in pregnancy.
Neonatology. 2022;119(2):268–272
26. Brogna C, Brogna B, De Biase M, et al. Perinatal cerebral ischemic
lesion and SARS-CoV-2 infection during pregnancy: a case report
and a review of the literature. J Clin Med. 2022;11(22):6827
27. Chawla D, Chirla D, Dalwai S, et al; Federation of Obstetric and
Gynaecological Societies of India (FOGSI), National Neonatology
Forum of India (NNF) and Indian Academy of Pediatrics (IAP).
Perinatal-Neonatal Management of COVID-19 Infection - Guidelines
of the Federation of Obstetric and Gynaecological Societies of India
(FOGSI), National Neonatology Forum of India (NNF), and Indian
Academy of Pediatrics (IAP). Indian Pediatr. 2020;57(6):536–548
28. Nayak M, Panda S, Pradhan JB, Mohakud NK. Coronavirus disease
t.me/neonatology
2019 in neonates - what is known and what needs to be known.
Cureus. 2020;12(8):e10171
29. Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi SR,
Hajizadeh R. The use of intravenous immunoglobulin gamma for
the treatment of severe coronavirus disease 2019: a randomized
placebo-controlled double-blind clinical trial. [published correction
appears in BMC Infect Dis. 2020;20(1):895] BMC Infect Dis.
2020;20(1):786
30. UNICEF. 2017. First 1000 Days: the critical window to ensure that
children survive and thrive. https://www.unicef.org/southafrica/
media/551/file/ZAF-First-1000-days-brief-2017.pdf Accessed Novem-
ber 12, 2023
31. Schwarzenberg SJ, Georgieff MK; Committee on Nutrition.
Advocacy for improving nutrition in the first 1000 days to support
childhood development and adult health. Pediatrics. 2018;141(2):
e20173716
32. Ayed M, Alsaffar Z, Bahzad Z, et al. coronavirus infection in
neonates: neurodevelopmental outcomes at 18 months of age. Can
J Infect Dis Med Microbiol. 2023;2023:6140085
33. Aldrete-Cortez V, Bobadilla L, Tafoya SA, et al. Infants prenatally
exposed to SARS-CoV-2 show the absence of fidgety movements and
are at higher risk for neurological disorders: A comparative study.
PLoS One. 2022;17(5):e0267575
34. Zeng LK, Zhu HP, Xiao TT, et al. Short-term developmental
outcomes in neonates born to mothers with COVID-19 from
Wuhan, China. World J Pediatr. 2021;17(3):253–262
35. Hessami K, Norooznezhad AH, Monteiro S, et al. COVID-19
pandemic and infant neurodevelopmental impairment: a
systematic review and meta-analysis. JAMA Netw Open.
2022;5(10):e2238941
36. Shuffrey LC, Firestein MR, Kyle MH, et al. Association of birth
during the COVID-19 pandemic with neurodevelopmental status at
6 months in infants with and without in utero exposure to maternal
SARS-CoV-2 infection. JAMA Pediatr. 2022;176(6):e215563
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e77
 ARTICLE

Congenital Anomalies of the Kidneys

and Urinary Tract
Jeanette Fong, MD,* Theodore De Beritto, MD, MS*
*Division of Neonatology, Department of Pediatrics, Mattel Children’s Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los
Angeles, CA

EDUCATION GAPS

Familiarity with the development of the renal system will help neonatal
clinicians have a better understanding of congenital anomalies of the
kidneys and urinary tract. After diagnosis, clinicians need to support infants
with these anomalies, with the goal of preserving kidney function to delay
need for transplantation.

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

t.me/neonatology
1. Describe the developmental biology of the bladder, ureters, and kidneys.
2. List the different mechanisms that can lead to congenital anomalies of
the kidneys and urinary tract (CAKUT).
AUTHOR DISCLOSURES Drs Fong and 3. Explain the different options for prenatal and postnatal diagnosis and
De Beritto have disclosed no financial
management of CAKUT.
relationships relevant to this article. This
commentary does not contain a
discussion of an unapproved/
investigative use of a commercial ABSTRACT
product/device.
Congenital anomalies of the kidneys and urinary tract encompass the
spectrum of disorders that include the kidneys, ureters, bladder, and urethra.
ABBREVIATIONS
These abnormalities often lead to altered renal size and location, dysplastic
AKI acute kidney injury changes in the kidney parenchyma, and anomalies in the collecting system.
CAKUT congenital anomalies of the
Though the etiology of each of these conditions can be variable, it is known
kidneys and urinary tract
CHARGE coloboma, congenital heart that the collection of these defects represent 40% to 50% of all pediatric end-
disease, choanal atresia, mental stage renal disease worldwide. The multifaceted management of these
and growth retardation, genital
conditions is aimed at preserving kidney function and ultimately delaying the
anomalies, and ear
malformations and hearing loss need for transplantation. With the advancement of prenatal ultrasonographic
CKD chronic kidney disease techniques, these conditions are more likely to be diagnosed before birth,
CT computed tomography which often leads to rapid postnatal intervention and better outcomes.
MCDK multicystic dysplastic kidney
PUV posterior urethral valve
UPJ ureteropelvic junction
UTI urinary tract infection
VACTERL vertebral defects-anal atresia-
EPIDEMIOLOGY
cardiovascular anomalies-
tracheoesophageal fistula with Congenital anomalies of the kidneys and urinary tract (CAKUT) is a term that
esophageal atresia-radial and encompasses a variety of anomalies involving dysplastic changes within the pa-
renal dysplasia-limb defects
VCUG voiding cystourethrogram renchyma of the kidney, changes in location and size of the kidney, and anoma-
VUR vesicoureteral reflux lies of the collecting system including the urethra, bladder, and ureters. (1) It is

e78 NeoReviews

t.me/neonatology
T.ME/NEONATOLOGY
the most frequent malformation at birth and represents
40% to 50% of pediatric end-stage renal disease worldwide.
(2) The prevalence of CAKUT is estimated to be about 4 to
100 per 10,000 individuals. (1) Though the etiology is not
completely understood, 10% to 25% of CAKUT cases are at-
tributable to genetic disorders. (1) These genetic disorders
are frequently associated with extrarenal comorbidities in-
cluding developmental delays, congenital heart disease, endo-
crine disruption, and immunodeficiencies. Thus, a diagnosis
of CAKUT should prompt clinicians to consider a genetic
evaluation to aid in risk stratification and clinical decision-
making. Patients with CAKUT are more likely to be born
preterm and have increased morbidity and mortality. (1)
DEVELOPMENTAL BIOLOGY OF THE KIDNEYS,
URETER, AND BLADDER
Development of the Kidney
Kidney development involves the formation of the follow-
ing 3 unique organs: the pronephros, mesonephros, and
metanephros. (3) The pronephros is a vestigial structure of
7 to 10 nephrotomes that develops in the cervical region
and regresses by the end of the fourth week of gestation.
As the pronephros regresses, it is replaced by the meso-
nephros. (4) The mesonephros has excretory tubules in an
S-shaped loop that includes a glomerulus and Bowman cap-
sule at the proximal end. (4) During the second month of
gestation, most of the mesonephros involutes. Its remnants
remain proximal to the testis and ovaries and eventually de-
velop into the vas deferens in males and vestigial tissue in
females. (4) At the fifth week of gestation, the metaneph-
ros, or definitive kidney, begins developing from the inter-
mediate mesoderm. This occurs when the wolffian duct
swells to form the uretic bud and invades into the nearby
metanephric mesenchyme. The cell signaling between the
metanephric mesenchyme and the uretic bud results in pat-
terned and branching divisions, which eventually form the
collecting ducts of the kidney as well as major and minor
calyces of the renal pelvis. (4)
When the metanephrogenic blastema and branching
uretic bud become adjacent, they form comma-shaped bodies,
which then transition to S-shaped bodies. (4) The caudal
pole of the S-shaped body forms the glomeruli, and the ce-
phalic portion forms the tubular elements of the nephron.
(4) The metanephric kidney then ascends from the pelvis to
the thoracolumbar region. (4) During this ascent, pelvic
vasculature from the aorta is replaced with more cephalad
vasculature from the aorta. (4) During the second half of
gestation, the metanephric kidney becomes functional and
t.me/neonatology
nephrogenesis is complete at 34 weeks’ gestation. Each kidney
contains 800,000 to 1.2 million nephrons. (4)
Development of the Bladder and Urethra
In the second and third months of gestation, the bladder
and urethra are formed. Between the fourth and seventh
weeks of development, the cloaca, which will develop into
the urethra and urinary bladder, is separated into the
primitive urogenital sinus (ventral portion) and anorectal
canal (dorsal portion). (4) The primitive urogenital sinus
develops into the bladder, prostatic and membranous ure-
thra, and the penile urethra in males. In females, it develops
into the bladder, urethra, and vaginal vestibule. Subsequently,
the ureteral orifices migrate cephalad, and the mesonephric
ducts enter the prostatic urethra to form the trigone of the
bladder. (4)
COMMON TYPES OF CAKUT BY CLASS OF
t.me/neonatology
DISORDER
Hydronephrosis
Vesicoureteral Reflux. Vesicoureteral reflux (VUR) is de-
fined as the retrograde flow of urine from the bladder to
the upper urinary tract. (3) It is caused by aberrant inser-
tion of the ureter into the bladder wall and is often associ-
ated with genetic mutations (Table 1). (4) The incidence of
VUR is estimated to be between 0.4% and 1.8%, with a
clinical presentation that is variable, ranging from asymp-
tomatic to severe nephropathy. (5) Approximately 30% to
40% of infants who present with a urinary tract infection
(UTI) are diagnosed with VUR. (6)
VUR is classified as grades 1 to 5, with grade 1 being
the mildest form and grade 5 being the most severe form.
Grading of VUR is based on height of the reflux and de-
gree of dilation of the ureters. (7) The grades are described
as follows:
Grade 1: Reflux only into the nondilated ureter
Grade 2: Reflux into the ureter and the renal pelvis without
dilatation
Grade 3: Reflux with mildly dilated ureter and pyelocalyceal
system
Grade 4: Reflux with the tortuous and moderately dilated
ureter with blunting of the renal fornices, with
the papillary impression being preserved
Grade 5: Reflux with the tortuous and severely dilated ureter,
dilatation of pyelocalyces with loss of fornices, and
papillary impression
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e79
 Table 1. CAKUT and Associated Genes in Humans
Type of
Malformation Renal Phenotype
Vesicoureteral reflux Urine refluxes to various degrees
from bladder up into the
collecting system
Renal agenesis Absent kidney and ureter
Renal hypoplasia Decreased number of ureteric
bud branches and nephrons
Small kidney size
Often associated with renal
dysplasia
Renal dysplasia Decreased number of ureteric
bud branches and nephrons
Undifferentiated stromal and
mesenchymal cells
Cysts or cartilage
Multicystic dysplastic Absent glomeruli and tubules
kidney
Horseshoe kidney Kidneys lower in location and are
fused at inferior lobes
Duplication of the Duplex ureters and kidneys or
collecting system duplex ureters and the
collecting system
Genes
TRAP1, PAX2, SOX17, TNXB, ROBO2,
SIX1, SIX5, CHD1L
RET, FGF20, GDNF, FRAS1, FREM2
BMP4, SIX2, PAX2, SALL1, UMOD,
HNF1B
HNF1B, UMOD, NPHP1, BMP4, PAX2,
SIX2, XPNPEP2
CYP4A11, HNF1B, ELN, FRG1, FRG2,
UPIIIA, PEX26, ALG12
HNF1B
BMP4, FOXC1, FOXC2, ROBO2
Cause
Abnormal insertion of the ureter
into the bladder wall
No interaction between the
ureteral bud and metanephric
mesenchyme
Irregular interaction between the
ureteric bud and metanephric
mesenchyme
Same as renal hypoplasia
Same as renal hypoplasia
Abnormality in the renal capsule
Supernumerary ureteric bud
emerging from the
mesonephric duct

t.me/neonatology
CAKUT5congenital anomalies of the kidneys and urinary tract
Adapted from Vogt and Springel. (4)

Importantly, most grade 1 and 2 cases of VUR will re-
solve spontaneously, whereas 50% of grade 3 cases and a
smaller percentage of grade 4 and 5 cases will resolve
without intervention. (3)
VUR can be further classified into primary and second-
ary. Primary VUR derives from a short intravesical length
of the ureter, which results in incomplete or improper clo-
sure of the ureteral orifice; primary VUR may improve as
the child grows. Secondary VUR occurs as a result of blad-
der outlet obstruction and often leads to bilateral reflux.
Voiding cystourethrogram (VCUG) delineates the anatomy
of the urinary system and is the gold standard for diagno-
sis of VUR. (6)
Medical management of VUR depends on the grade,
the presence or absence of a febrile UTI, age and sex of
the patient, and the presence of bladder or bowel dysfunc-
tion. While spontaneous resolution of VUR can occur be-
fore 5 years of age for grades 1 to 3, patients may require
antibiotic prophylaxis to prevent UTI and renal damage.
Moreover, antibiotics are recommended for patients with
febrile UTIs. The relationship between bladder or bowel
dysfunction and VUR is being studied, and, therefore,
management is consequently being assessed as well. (8)
Surgical treatment is indicated for severe cases including
recurrent UTIs despite antibiotic prophylaxis, high-grade
reflux, renal damage, and low probability of spontaneous
resolution.
Ureteropelvic Junction Obstruction. Ureteropelvic junction
(UPJ) obstruction is 1 of the most common causes of
hydronephrosis in children. It has an incidence of 1 in 1,000
to 1 in 1,500. (9) It is characterized by impaired urine flow
from the renal pelvis into the ureter and is most commonly
secondary to congenital obstruction. A common congenital
etiology is ureteral hypoplasia. Because of an abnormal con-
figuration of the smooth muscle layer, an aperistaltic seg-
ment of the ureter is formed, which impedes urine drainage
from the renal pelvis into the ureter. (9) This often leads to
a functional obstruction rather than a mechanical one. (9)
Congenital UPJ obstruction is diagnosed using antenatal
ultrasonography during the second trimester. (9) Common
symptoms in older children include periodic abdominal or
groin pain, vomiting, recurrent pyelonephritis, and fever. If
antenatally diagnosed, renal ultrasonography should be re-
peated within 48 hours after birth if there is evidence of se-
vere hydronephrosis or after 48 hours if the hydronephrosis
is mild or moderate.
Evaluation can include a VCUG to rule out VUR or intra-
venous pyelography to determine the degree of dilation of
the affected renal pelvis as compared to the contralateral side.
Diuretic renography remains the gold standard for evaluation
of the severity of the UPJ obstruction. It determines the split
function (the relative contribution of each of the kidneys to to-
tal renal function) of each kidney and identifies any renal ob-
struction via radiotracers. The most common radiotracer is

e80 NeoReviews

t.me/neonatology
 technetium 99m-mercaptoacetyltriglycine (99m Tc-MAG3),
which is secreted by the proximal renal tubules and filtered by
the renal glomeruli. (9) The half-life of 99m Tc-Mag3 corre-
lates with a split function in either kidney. If the split func-
tion is less than 40%, the kidney is considered significantly
damaged. (9)
Consultation with urology is advised to aid in the man-
agement of UPJ obstruction. If the patient is younger than
18 months, UPJ may be transient and improve spontane-
ously after a few months. In children older than 18 months
and with a split renal function of more than 40%, renal
scans are often repeated at 3-, 6-, and 12-month intervals. If
there is less than 40% of differential function, a pyeloplasty
is often recommended to limit further damage. In short, this
procedure involves resection of the obstructed segment of
the ureter, replacement with a normal caliber portion of ure-
ter, and finally reattachment to the renal pelvis. (9) This can
be performed as an open, laparoscopic, or robotic-assisted
procedure.
Posterior Urethral Valve. Posterior urethral valve (PUV) is
among the most common causes of urinary tract obstruction
in neonates and is the most common cause of lower urinary
tract obstruction. In the United States, the incidence of PUV
is estimated to be 1 in 5,000 to 1 in 8,000 births. (10) PUV
is defined as an obstructing membranous flap or fold in the
lumen of the posterior part of the urethra in males. It can re-
sult in various complications including urinary retention,
chronic kidney disease (CKD), and in utero pulmonary hypo-
plasia secondary to low amniotic fluid levels. PUV may be di-
agnosed antenatally or postnatally. Antenatal ultrasonographic
findings include bilateral hydronephrosis, dilated prostatic
urethra, and distended bladder with thickened wall greater
than 3 mm with poor emptying over 30 minutes. Historically,
the ultrasonographic “keyhole sign” with dilated proximal
urethra and thick-walled distended bladder was thought to
be diagnostic of PUVs, but a recent study suggests that this
sign may not reliably predict PUV. (11) Postnatally, the pre-
sentation of PUV can vary, ranging from lethargy, poor
feeding, delayed voiding, and palpable bladder, to urosepsis
in the most severe scenario.
Antenatal diagnosis includes serial ultrasonography to
monitor amniotic fluid levels and assess for renal dyspla-
sia. Fetal urinary electrolytes and b-2 microglobulin can
be measured to assess fetal renal function. (3) Postnatally,
if the diagnosis of PUV is of concern, blood tests, imag-
ing, and urodynamic studies can be obtained. These can
include renal and bladder ultrasonography, VCUG, and re-
nal scintigraphy.
T.ME/NEONATOLOGY
t.me/neonatology
Antenatal management is typically deferred because of
high morbidity and mortality. Postnatal management in-
cludes initial correction of electrolytes and management of
possible respiratory distress or urosepsis. Additionally, uri-
nary catheterization (often placed by the urology team)
may be necessary if the patient has urinary retention.
Prognosis depends on the severity of the obstruction
and any in utero sequelae. Many infants develop CKD and
bladder dysfunction. In a study of 75 patients with PUV,
21% developed end-stage renal failure by the end of the
mean follow-up period, which was 64 months of age. (12)
The study found several factors that were prognostic for
kidney function, such as renal volume below the third per-
centile, more than 3 UTIs with fever, decreased eGFR at
1 year of age, elevated renal echogenicity, and pathological
corticomedullary differentiation. (12) Infants require close
observation and monitoring by both urology and nephrology
teams to monitor kidney function and for the management
of CKD. Nephrotoxic medications such as nonsteroidal anti-
inflammatory drugs and aminoglycosides should be avoided,
t.me/neonatology
if possible. (3)(10)
Renal Parenchymal Malformations
Renal Agenesis (Unilateral and Bilateral). Unilateral renal
agenesis occurs in 1 in 2,000 infants. (13) It can be associated
with VACTERL (vertebral defects–anal atresia–cardiovascular
anomalies–tracheoesophageal fistula with esophageal atresia–
radial and renal dysplasia–limb defects) association, a single
umbilical artery, or contralateral VUR. Renal agenesis has an
autosomal dominant pattern of inheritance and can be associ-
ated with several gene mutations. (14) Diabetes mellitus dur-
ing pregnancy or the use of specific drugs during pregnancy
may also cause renal agenesis. (14) Bilateral renal agenesis is
estimated to occur in 1 in 8,500 infants and is typically in-
compatible with life. (14) This agenesis occurs secondary to
developmental failure of the uretic bud and the metanephric
mesenchyme. In unilateral renal agenesis, long-term renal
function is retained because of a normal contralateral kidney;
however, it requires annual monitoring because of compen-
satory contralateral renal hypertrophy.
Symptoms of bilateral renal agenesis include flattened fa-
cies and defects of the lower extremities and genital tract.
Pulmonary hypoplasia and respiratory failure may also be
observed. (15) Patients with unilateral renal agenesis are of-
ten asymptomatic, but they can develop elevated blood pres-
sure, high protein levels in the urine, and VUR. (13)
In infants antenatally suspected to have unilateral renal
agenesis, ultrasonography of the kidney and urinary tract
is suggested. In addition, urology and nephrology should
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e81
 be consulted to assist in multidisciplinary management.
Renal agenesis has a high incidence of VUR. If renal
ultrasonography demonstrates high-grade VUR or if UTIs
occur, a VCUG can be obtained as a second-line investiga-
tion technique to help determine if antibiotic prophylaxis
or surgical correction is required. (16) In female infants,
pelvic ultrasonography should be performed to look for
m€ ullerian duct anomalies. Upon discharge, infants require
regular follow-up to monitor kidney function and blood
pressure. (16)
Renal Dysplasia. Renal dysplasia is an abnormality in renal
development in which renal parenchyma is replaced either
partially or completely by cartilaginous tissue or disorga-
nized epithelial structures. (4) It is the most common
cause of CKD and renal failure in neonates. (17) Several
genes have been attributed to renal dysplasia; however, the
actual underlying mechanisms are complex and remain
poorly understood. Renal dysplasia occurs frequently in in-
fants with obstructive uropathy and various congenital dis-
orders such as VACTERL association, CHARGE (coloboma,
congenital heart disease, choanal atresia, mental and
growth retardation, genital anomalies, and ear malformations
and hearing loss) syndrome, brachio-oto-renal syndrome,
Jeune syndrome, or trisomies 13, 18, and 21. (4) The func-
tion of dysplastic kidneys is variable. Infants with bilateral
dysplasia may exhibit signs in the first few days after birth
and often develop progressive renal insufficiency during
childhood and adolescence. Concentration and acidification
defects may also be present. There is no specific treatment
available for renal dysplasia, and management includes
monitoring blood pressure and kidney function at regular
intervals.
Multicystic Dysplastic Kidney. Multicystic dysplastic kidney
(MCDK) is a severe form of renal dysplasia that results
in a nonfunctioning kidney. Normal renal architecture is
absent and, instead, replaced by multiple large cysts that
resemble a cluster of grapes. (4) It is seen in 1 in 1,000 to
1 in 4,300 live births and affects predominantly males and
the left kidney. (18) The failure of the uretic bud to merge
and branch properly into the metanephros is a possible
contributor to the pathogenesis of MCDK. (4)
Most affected patients have unilateral involvement with
50% of cases associated with extrarenal anomalies. If MCDK
is bilateral, it is usually fatal. Most patients with MCDK
undergo partial or complete involution over time. (19)
Postnatal management is conservative, and patients are mon-
itored with serial ultrasonography to ensure involution and
appropriate compensatory growth of the contralateral kidney.
e82 NeoReviews
t.me/neonatology
Surgical removal is reserved for children in whom the
MCDK grows too large over time. In unilateral MCDK, hy-
pertension and malignancy do not appear to occur at in-
creased rates in comparison to the general population. (20)
Disordered Renal Migration and Collecting System
Formation
Ectopic Kidney. During the first 8 weeks of development,
the kidney normally ascends, rotates 90 degrees, and con-
cludes with a medial rotation toward the renal hilum. In
renal ectopy, the kidney is abnormally located and does
not cross the midline. (21) This occurs in 1 in 1,000 indi-
viduals. (3) The most common presentation of renal ec-
topy is a pelvic kidney. (21) In crossed renal ectopy, 1
kidney crosses the midline and usually lies inferior to the
contralateral kidney.
An ectopic kidney may be diagnosed during routine ante-
natal ultrasonography. Diagnosis may also be made postna-
tally by palpation of a pelvic mass on physical examination.
Renal ectopia can be associated with other urologic abnor-
t.me/neonatology
malities such as VUR, contralateral renal dysplasia, cryptor-
chidism, and hypospadias in males and agenesis of the
uterus and vagina or unicornuate uterus in females.
Once identified, management should include evalua-
tion for other anomalies, serial serum creatinine levels
to monitor kidney function, and VCUG. (21) A 99mTc-
dimercaptosuccinic acid scan is also recommended to as-
sess renal function.
Horseshoe Kidney. A horseshoe kidney occurs in 1 in
500 infants and has a male predominance. (22) This ab-
normality consists of kidneys that are fused at the inferior
lobes and located lower in the abdomen than usual. The
connection between the 2 kidneys can be in a midline or
lateral position, with the lateral producing an asymmetric
horseshoe kidney. (22) This isthmus consists primarily of
renal parenchyma with a minority composed of fibrous
bands. Further ascent of the kidney is often prevented by
the inferior mesenteric artery at L3. (3) While the HNF1B
gene has been associated with horseshoe kidneys, no spe-
cific etiology has been identified. (4) This condition has
been associated with Edward and Turner syndromes. (22)
Because infants are often asymptomatic, this condition
is typically identified incidentally on ultrasonography or
computed tomography (CT). CT and magnetic resonance
imaging can provide additional information including the
evaluation of renal anatomy and vascularization. A VCUG
can be used to identify VUR as the incidence is higher in
patients with horseshoe kidney compared to the general
population. There is also a higher incidence of nephrolithiasis
as well as an increased risk of some renal cancers including
transitional cell cancer and Wilms tumor. (22)
Duplication of the Collecting System. The most common
congenital kidney abnormality is duplication of the collect-
ing system. (23) There is a female predominance, and in
8% of fetuses with this condition ultrasonography shows
abnormal urinary tract findings after 28 weeks’ gestation.
(3) There is often incomplete duplication of the collecting
system that can be associated with VUR and ureteroceles,
which increase the risk of UTIs. Postnatal diagnostic im-
aging to confirm duplication can include intravenous ur-
ography, renal ultrasonography, or CT. For patients with a
duplication of the collecting system, management can
range from observation to surgical intervention and de-
pends on the segment affected and its native function. (3)
DIAGNOSIS AND MANAGEMENT
Physical Examination
In infants with suspected renal disease, it is critical to
evaluate blood pressure and volume status. Hypertension
may be observed in infants with polycystic kidney disease,
acute kidney injury (AKI), thrombosis, or obstructive urop-
athy. (4) Hypotension may be seen in infants with sepsis,
hemorrhage, or volume depletion. Hydrops fetalis, AKI, or
congenital nephrotic syndromes can be present as edema.
Lastly, congenital nephrotic syndromes, as well as urinary
tract obstruction or volume overload, can present as ascites.
When examining an infant with a suspected CAKUT,
special attention should be paid to the abdomen. The
most common cause of a renal abdominal mass is hydro-
nephrosis, and of all neonatal abdominal masses, two-
thirds are genitourinary in origin. (4) When examining
the abdomen, the absence of or laxity in the abdominal
muscles should be observed; this may suggest Eagle-Barrett
(prune belly) syndrome. The bladder should be examined as
well, and if it is distended, it may suggest a lower urinary
tract obstruction or spinal cord lesion. There are several
anomalies that can alert clinicians to possible renal defects;
these include limb deformities, atypical external ears, isolated
microcephaly without known etiology, hemihypertrophy,
aniridia, imperforate anus, cryptorchidism, abnormality
of the external genitalia, cloacal or bladder exstrophy, or
persistent urachus. (4)
The oligohydramnios (Potter) sequence is a constella-
tion of physical findings that may be seen in infants with
severe neonatal kidney disease, including bilateral renal
dysplasia, bilateral urinary tract obstruction, or autosomal
recessive polycystic kidney disease. This occurs because of
t.me/neonatology
the marked reduction of fetal kidney function, oligohy-
dramnios, and resultant fetal deformation via compression
of the fetus against the uterine wall. Findings include a
small, compressed chest wall, clubfoot, hip dislocation,
and arthrogryposis. Distinguishing facial features include
posteriorly low-set ears, wide-set eyes, beaked nose, de-
pressed nasal bridge, and receding chin. (4) These patients
usually have respiratory failure caused by pulmonary hy-
poplasia. (4)
Laboratory Evaluation
Urinalysis. If urinalysis is indicated, freshly voided urine is
preferred to accurately characterize the renal function.
Testing can include urine creatinine and protein levels,
the presence of bacteria, and white blood cell count to as-
sess for infection. If a urine culture is required, it is best
to obtain it via a catheterized sample. Cloudiness of urine
may suggest the presence of crystals or a UTI. It should
be noted that the specific gravity is usually very low in neo-
nates (<1.004), but may rise secondary to high-molecular-
t.me/neonatology
weight solutes such as glucose, contrast agents, or other
reducing substances. (4)
Serum Creatinine. Immediately after birth, the serum creati-
nine concentration reflects the creatinine concentration of
the pregnant person. In term infants, the serum creatinine
level gradually decreases from a range of 0.6 to 1 mg/dL
(53.04–88.40 mmol/L) to a mean value of 0.4 mg/dL
(35.36 mmol/L) within the first 2 weeks after birth. In pre-
term infants, the decline in serum creatinine is slower
and may not reach a nadir for 1 to 2 months. If the serum
creatinine level remains elevated or increases, there is
likely an impairment of renal function. (4)
Radiologic Evaluation. Ultrasonography is the most common
radiologic tool for diagnosis. It is indicated for infants with a
history of an abnormal antenatal ultrasonography, abdominal
mass on physical examination, AKI, hypertension, hematu-
ria, congenital malformation, or genetic syndrome with in-
creased risk of urinary tract anomalies. Nonurgent postnatal
ultrasonography should be performed at least 48 hours after
birth to ensure that there is adequate urine output in the ne-
onate for accurate assessment of hydronephrosis. A Doppler
flow study of the renal vessels and aorta may be helpful in
the evaluation of infants with suspected renovascular hyper-
tension, arterial or venous thrombosis, or AKI. (4)
VCUG should be considered in infants with significant
hydronephrosis, hydroureter, or documented UTIs. VCUG
involves the instillation of a radiopaque contrast into the
bladder by urinary catheter.
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e83
 Radioisotope renal scans can be helpful in locating
anomalous kidneys and identifying obstruction or renal
scarring. This imaging is also able to determine the contri-
bution of each kidney to overall renal function. Interpreta-
tion may be difficult in the first few weeks of age because
of the relatively low glomerular filtration rate of newborns. (4)
Consultations
In infants with suspected CAKUT, it is beneficial to con-
sult both nephrology and urology for further evaluation
and management guidance. Depending on the condition,
it may be beneficial to include pediatric surgery and endo-
crinology. Genetics consultation should also be considered
if additional congenital anomalies are found. (4)
Management
Because of the recent advances in early diagnosis of fetal
CAKUT, fetal surgical interventions have seen an increase.
While fetal intervention may decrease mortality, it has re-
sulted in more children born with renal dysfunction. To
accommodate this early diagnosis, it has become neces-
sary to multidisciplinary treatment plans that start soon
after birth. (24)(25)(26) Early postnatal management goals
include surgical interventions to create adequate urine flow,
respiratory support for potential pulmonary hypoplasia, and
support of metabolic and electrolyte functions, with the ulti-
mate goal of decreasing the need for dialysis. (27) In a recent
study, a cohort of 42 subjects with severe CAKUT were
followed from birth to 6 ± 2.8 years, and their outcomes
were observed prospectively. (27) The focus of their medical
management was to prevent UTIs and preserve and promote
maximum residual renal function. Management included
nutritional support with formula (often whey protein based
with individualized adaptations to maintain electrolyte and
nutritional balance), early introduction of growth hormone,
and strict management of any associated mineral bone disorder.
During this initial assessment of the cohort, the authors deter-
mined that nadir serum creatinine predicted progression to
CKD with high sensitivity and specificity, whereas cystatin C
predicted progression to end-stage renal disease. (27) The over-
arching goal was to avoid dialysis for as long as possible with
the goal of preemptive transplantation. Ultimately, the study re-
ported that infant survival was dependent on the severity of the
kidney disease (CKD stages 1–5 vs end-stage renal disease) with
worsening disease associated with lower survival. (27)
PROGNOSIS AND OUTCOMES
CAKUT is a major cause of morbidity in children. Given
the variety of pathologies, the prognosis and outcomes of
e84 NeoReviews
t.me/neonatology
Table 2. Prognostic Criteria Using Fetal Urine Analysis
Fetal Urine Favorable Prognostic Factor
Osmolality <210 mOsm/L (<210 mmol/L)
Sodium <100 mEq/L (<100 mmol/L)
Chloride <90 mEq/L (<90 mmol/L)
Calcium <8 mg/dL (<2 mmol/L)
b2 microglobulin <2 mg/L
Note: These prognostic factors of fetal urine can be applied if fetal
ultrasonography demonstrates kidneys without cortical cysts or
hyperechogenicity. Adapted from Poudel et al. (3)
CAKUT are variable. The development of prognostic criteria
using fetal urine has been established (Table 2). A 2009 study
assessed the risk of progression of CAKUT to end-stage renal
disease in 312 patients who were preselected based on anoma-
lies in kidney number or size. (28) By age 30 years, 58 patients
had required dialysis, with a yearly incidence of 0.023 over a
combined 2,474 patient risk years. (28) Patients with a solitary
kidney or renal hypodysplasia associated with PUVs were at
significantly higher risk for dialysis. (28) Studies investigating
markers for predicting early progression to advanced stages of
t.me/neonatology
CKD in the CAKUT population are under way. (27) Future in-
vestigations are needed to fully assess the long-term prognosis
of these patients.
CONCLUSION
CAKUT includes a wide range of defects that are multifacto-
rial in nature but commonly due to abnormal development
during organogenesis. The multifaceted management of
these conditions is aimed at preserving kidney function and
ultimately delaying the need for transplantation. With the ad-
vancement of ultrasonographic techniques, these conditions
are more likely to be identified and diagnosed prenatally,
which often leads to early intervention and the best outcomes.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Recognize the clinical manifestations of anatomic ab-
normalities of the kidneys and urinary tract in infants.
• Know how to diagnose specific anatomic abnormali-
ties of the kidneys and urinary tract in infants.
• Know the recommended supportive and corrective
treatment of anatomic abnormalities of the kidneys
and urinary tract in infants.
• Know how prenatal diagnosis of renal abnormalities
affects postnatal management.
T.ME/NEONATOLOGY

References
1. Hays T, Thompson MV, Bateman DA, et al. The prevalence and
clinical significance of congenital anomalies of the kidney and
urinary tract in preterm infants. JAMA Netw Open.
2022;5(9):e2231626
2. Capone VP, Morello W, Taroni F, Montini G. Genetics of congenital
anomalies of the kidney and urinary tract: the current state of play.
Int J Mol Sci. 2017;18(4):796
3. Poudel A, Afshan S, Dixit M. Congenital anomalies of the kidney
and urinary tract. NeoReviews. 2016;17(1):e18–e27
4. Vogt BA, Springel T. The kidney and urinary tract of the neonate.
In: Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff and Martin’s
Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant.
Philadelphia, PA: Elsevier; 2020
5. Sargent MA. What is the normal prevalence of vesicoureteral reflux?
Pediatr Radiol. 2000;30(9):587–593
6. Banker H, Aeddula NR. Vesicoureteral reflux. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2023 https://
www.ncbi.nlm.nih.gov/books/NBK563262/ Accessed November 11,
2023
7. Medical versus surgical treatment of primary vesicoureteral reflux:
report of the International Reflux Study Committee. Pediatrics.
1981;67(3):392–400
8. Lee H, Lee YS, Im YJ, Han SW. Vesicoureteral reflux and bladder
dysfunction. Transl Androl Urol. 2012;1(3):153–159
9. Al Aaraj MS, Badreldin AM. Ureteropelvic junction obstruction. In:
StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2023
https://www.ncbi.nlm.nih.gov/books/NBK560740/ Accessed
November 11, 2023
10. Bingham G, Rentea RM. Posterior urethral valve. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2023 https://
www.ncbi.nlm.nih.gov/books/NBK560881/ Accessed November 11,
2023
11. Bernardes LS, Aksnes G, Saada J, et al. Keyhole sign: how specific is
it for the diagnosis of posterior urethral valves? Ultrasound Obstet
Gynecol. 2009;34(4):419–423
12. Pohl M, Mentzel HJ, Vogt S, Walther M, R€ onnefarth G, John U.
Risk factors for renal insufficiency in children with urethral valves.
Pediatr Nephrol. 2012;27(3):443–450
13. Cleveland Clinic. Renal agenesis. https://my.clevelandclinic.org/
health/diseases/24161-renal-agenesis. Accessed November 10, 2023
14. Orphanet. Renal agenesis. https://www.orpha.net/consor/cgi-bin/
OC_Exp.php?lng=EN&Expert=411709 Accessed November 10, 2023
15. Bhandari J, Thada PK, Sergent SR. Potter syndrome. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2023. https://
t.me/neonatology
www.ncbi.nlm.nih.gov/books/NBK560858/ Accessed November 11,
2023
16. Groen In ’t Woud S, Westland R, Feitz WFJ, et al. Clinical
management of children with a congenital solitary functioning
kidney: overview and recommendations. Eur Urol Open Sci.
2021;25:11–20
17. Phua YL, Ho J. Renal dysplasia in the neonate. Curr Opin Pediatr.
2016;28(2):209–215
18. National Institute of Diabetes and Digestive and Kidney Diseases.
Multicystic Dysplastic Kidney. https://www.niddk.nih.gov/health-
information/kidney-disease/children/multicystic-dysplastic-kidney.
Accessed November 10, 2023
19. Alamir A, Al Rasheed SA, Al Qahtani AT, et al. The outcome of
multicystic dysplastic kidney disease patients at King Abdulaziz
Medical City in Riyadh. Cureus. 2023;15(4):e37994
20. Chang A, Sivananthan D, Nataraja RM, Johnstone L, Webb N,
Lopez PJ. Evidence-based treatment of multicystic dysplastic kidney:
a systematic review. J Pediatr Urol. 2018;14(6):510–519
21. Rosenblum ND. Kidney development. In: Gilbert SJ, Weiner DE,
eds. National Kidney Foundation Primer on Kidney Diseases (Sixth
Edition). Philadelphia, PA: WB Saunders; 2014:19–25. 10.1016/
B978-1-4557-4617-0.00002-9.
22. Kirkpatrick JJ, Leslie SW. Horseshoe kidney. In: StatPearls [Internet].
Treasure Island, FL: StatPearls Publishing; 2023. https://www.ncbi.
t.me/neonatology
nlm.nih.gov/books/NBK431105/ Accessed November 11, 2023
23. Visuri S, Jahnukainen T, Taskinen S. Prenatal complicated duplex
collecting system and ureterocele-important risk factors for urinary
tract infection. J Pediatr Surg. 2018;53(4):813–817
24. Zurowska AM, Fischbach M, Watson AR, Edefonti A, Stefanidis CJ;
European Paediatric Dialysis Working Group. Clinical practice
recommendations for the care of infants with stage 5 chronic kidney
disease (CKD5). Pediatr Nephrol. 2013;28(9):1739–1748
25. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD
Update Work Group. KDIGO 2017 Clinical practice guideline
update for the diagnosis, evaluation, prevention, and treatment of
chronic kidney disease-mineral and bone disorder (CKD-MBD).
Kidney Int Suppl (2011). 2017;7(1):1–59
26. KDOQI Work Group. KDOQI Clinical practice guideline for
nutrition in children with CKD: 2008 update. Executive summary.
Am J Kidney Dis. 2009;53(3 Suppl 2):S11–S104
27. Katsoufis CP, DeFreitas MJ, Infante JC, et al. Risk assessment of
severe congenital anomalies of the kidney and urinary tract
(CAKUT): a birth cohort. Front Pediatr. 2019;7:182
28. Sanna-Cherchi S, Ravani P, Corbani V, et al. Renal outcome in
patients with congenital anomalies of the kidney and urinary tract.
Kidney Int. 2009;76(5):528–533
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e85
 NEOREVIEWS QUIZ

NEO
QUIZ

1. Congenital anomalies of the kidneys and urinary tract (CAKUT) represent the
most common congenital malformation at birth, with a prevalence of 4 to
100 per 10,000 individuals. Furthermore, these congenital anomalies account
for 40% to 50% of pediatric end-stage renal disease worldwide. What
proportion of CAKUT can be attributed to genetic disorders?
A. 5%.
B. 25%.
C. 45%.
D. 65%.
E. 85%.
REQUIREMENTS: Learners can
2. Kidney development progresses in 3 phases: the pronephros, the mesonephros, take NeoReviews quizzes and
and the metanephros (or definitive kidney). The metanephros begins developing claim credit online only at:
during the fifth week of gestation. During this stage, the metanephrogenic https://publications.aap.org/
blastema and branching uretic bud become adjacent, forming S-shaped bodies neoreviews.

that will develop into the glomeruli for the caudal pole and the renal tubule for
To successfully complete 2024
the cephalic pole. At what gestation is nephrogenesis complete? NeoReviews articles for AMA PRA
Category 1 Credit™, learners
A. 30 weeks.

t.me/neonatology
must demonstrate a minimum
B. 32 weeks. performance level of 60% or
C. 34 weeks. higher on this assessment. If
D. 36 weeks. you score less than 60% on the
E. 38 weeks. assessment, you will be given
additional opportunities to
3. Vesicoureteral reflux (VUR) occurs in 0.4% to 1.8% of children. VUR is caused answer questions until an
by abnormal insertion of the ureter into the bladder, resulting in retrograde overall 60% or greater score is
flow of urine from the bladder to the upper urinary tract. How many infants achieved.

presenting with a urinary tract infection are diagnosed with VUR?

This journal-based CME activity
A. 10%. is available through Dec. 31,
2026, however, credit will be
B. 30%.
recorded in the year in which
C. 50%. the learner completes the quiz.
D. 70%.
E. 90%.
4. Posterior urethral valve (PUV) represents the most common cause of lower
urinary tract obstruction, with an incidence of 1 in 5,000 to 1 in 8,000 births
in the United States. PUV can lead to severe complications including
pulmonary hypoplasia because of low amniotic fluid levels, urinary retention, and 2024 NeoReviews is approved
for a total of 30 Maintenance of
chronic kidney disease. Which of the following prenatal ultrasonographic findings
Certification (MOC) Part 2
is not consistent with a diagnosis of PUV? credits by the American Board
A. Bilateral hydronephrosis. of Pediatrics (ABP) through the
AAP MOC Portfolio Program.
B. Dilated prostatic urethra. NeoReviews subscribers can
C. Poor bladder emptying over 30 minutes. claim up to 30 ABP MOC Part 2
D. Small bladder. points upon passing 30 quizzes
E. Presence of a “keyhole sign.” (and claiming full credit for
each quiz) per year. Subscribers
can start claiming MOC credits
as early as October 2024. To
learn how to claim MOC points,
go to: https://publications.aap.
org/journals/pages/moc-credit.

e86 NeoReviews T.ME/NEONATOLOGY

t.me/neonatology
5. Multicystic kidney disease (MCKD) is a form of renal dysplasia in which the
normal renal architecture is replaced by multiple large cysts, resulting in a
nonfunctional kidney. MCKD is the most common type of renal cystic
disease, occurring in 1 in 1,000 to 1 in 4,300 live births. Which of the
following statements regarding MCKD is correct?
A. MCKD affects predominantly females.
B. The right kidney is more commonly affected.
C. Extrarenal anomalies occur in 30% of patients with MCKD.
D. MCKD is associated with an increased risk of hypertension and malignancy
later in life.
E. Most patients with MCKD experience partial or complete involution
overtime.

t.me/neonatology

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e87

t.me/neonatology
 ARTICLE

Nephrocalcinosis in Neonates
Gia J. Oh, MD,* Lavjay Butani, MD*
†
Department of Pediatrics, Division of Pediatric Nephrology, University of California, Davis, Children’s Hospital, Sacramento, CA

EDUCATION GAPS

Nephrocalcinosis is a common finding in preterm neonates. The causes

and contributors of nephrocalcinosis are varied and range from benign
metabolic factors to potentially life-threatening conditions. Neonates with
nephrocalcinosis should undergo an evaluation to elucidate contributing
factors and initiate therapy as appropriate.

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

t.me/neonatology
1. Define nephrocalcinosis and the types that occur in the neonatal
population.
2. Describe how to categorize and evaluate the causes of nephrocalcinosis
in neonates.
3. Explain the natural history of nephrocalcinosis of prematurity and its
management.

ABSTRACT
Nephrocalcinosis occurs in as many as 40% of preterm neonates. Many
causes and contributors predispose neonates to develop nephrocalcinosis,
including metabolic, genetic, and iatrogenic factors. Because nephrocalcinosis
can be a manifestation of an underlying genetic disorder, neonates with
nephrocalcinosis must undergo an evaluation to identify and address
contributors, to prevent further renal calcium deposition that can potentially
AUTHOR DISCLOSURES Drs Oh and lead to renal dysfunction. In this article, we review the epidemiology,
Butani have disclosed no financial pathogenesis, diagnosis, and evaluation of nephrocalcinosis in neonates. We
relationships relevant to this article. This
commentary does not contain a also summarize the natural history of nephrocalcinosis of prematurity as well
discussion of an unapproved/ as the management of this condition.
investigative use of a commercial
product/device.

ABBREVIATIONS INTRODUCTION
CaSR calcium-sensing receptor Nephrocalcinosis (NC) refers to the deposition of calcium precipitates, calcium
dRTA distal renal tubular acidosis
GFR glomerular filtration rate oxalate, and calcium phosphate in the renal parenchyma. (1) Neonates, especially
NC nephrocalcinosis preterm neonates, have unique physiology and metabolic requirements, includ-
NKCC2 sodium-potassium-chloride ing immature renal tubular function and higher dietary calcium intake, which
cotransporter
ROMK renal outer medullary increase their predisposition to developing NC. NC has been reported to have a
potassium channel wide prevalence, ranging from 7% to 41% of preterm neonates. (2) The wide

e88 NeoReviews T.ME/NEONATOLOGY

t.me/neonatology
range in prevalence rate stems from the heterogeneity of
study settings and the interobserver and intraobserver vari-
ability in ultrasonographic detection of NC.
Calcium deposition can occur in the renal cortex (cortical
NC) or in the medulla (medullary NC). Cortical NC is rare
and occurs primarily in the setting of severely destructive dis-
eases of the cortex, such as cortical necrosis, chronic pyelone-
phritis, or primary and secondary oxalosis. (1)(3) Medullary
NC is the most common form of NC, comprising 97% of
reported cases of NC in the literature. (1) NC can further be
classified as microscopic, diagnosed by identifying calcium
precipitates on light microscopic examination of renal tis-
sue, and macroscopic, diagnosed with radiographic studies.
(1) Most of this review is focused on macroscopic medul-
lary NC.
NC and nephrolithiasis are related but distinct conditions.
(4) In contrast to NC, in which calcium deposition is diffuse
within the renal tubular epithelium and the interstitium,
nephrolithiasis refers to discrete stones of different types
(some of which contain calcium) that are located within the
urinary collecting system. NC may lead to calcium nephroli-
thiasis in particular conditions and calcium nephrolithiasis is
often present without diffuse medullary NC. (4)
PATHOGENESIS
Calcium oxalate and calcium phosphate deposits in the renal
interstitium and tubules are a result of a complex interaction
between crystallization-promoting factors (hypercalciuria,
hyperoxaluria, hyperphosphaturia), crystallization-inhibiting
factors (urine volume, urinary citrate, urinary magnesium),
and genetic variations in renal calcium handling. (2)
In the renal tubules, non–crystal-binding epithelia and
crystal inhibitors, such as citrate, allow the crystals to pass
through the nephron and collecting system without crystal
retention. (4) The high calcium concentration in the tubular
fluid activates calcium-sensing receptors (CaSR) in the col-
lecting duct, which in turn decreases the effect of antidiuretic
hormone, leading to more dilute urine. (4) Tubular calcium
crystal retention, followed by tubular NC, can occur if these
defense mechanisms fail. Tubular epithelia undergoing re-
generation after an injury express multiple crystal-binding
molecules, such as osteopontin and hyaluronan—that are
not present in intact and healthy epithelia. (4) Notably, osteo-
pontin and hyaluronan are important in nephrogenesis and
expressed prominently in fetal and preterm kidneys, render-
ing preterm neonates susceptible to NC. (5) Interstitial NC is
hypothesized to occur when intratubular crystals are internal-
ized by vesicles on the apical membrane, translocated through
the epithelial cell to the basolateral membrane, and then
t.me/neonatology
released into the interstitium. (4) De novo calcification in the
interstitium can also occur, but the mechanisms remain un-
known. (1)(4)
Genetic mutations in renal tubular transporters, chan-
nels, and receptors that result in hypercalciuria may lead
to NC (Table). In the thick ascending loop of Henle, the
bulk of calcium reabsorption occurs through the paracellu-
lar pathway. This passive transport through the epithelial
tight junction is driven by an electrochemical gradient. (6)
The apical sodium-potassium-chloride cotransporter (NKCC2)
and the renal outer medullary potassium (ROMK) channel
generate the needed electrochemical gradient for calcium to
passively diffuse through the epithelial membrane. (6)
Calcium-sensing receptors are also present in the thick as-
cending limb and they regulate calcium reabsorption by alter-
ing the permeability of calcium in the paracellular pathway
by changing claudin expression in the tight junction. (6)
RADIOGRAPHIC DIAGNOSIS OF
NEPHROCALCINOSIS
t.me/neonatology
NC is an asymptomatic condition that is often identified
incidentally or during screening of at-risk neonates. NC
can be detected with plain abdominal radiography, ultraso-
nography, and computed tomography (CT). Ultrasonogra-
phy is more sensitive than plain radiography and CT is
more specific than ultrasonography in the diagnosis of
NC. The intraobserver agreement in detecting NC with ul-
trasonography is high (k coefficient 0.8–0.84) whereas the
interobserver agreement is more variable (k coefficient
0.46–0.76). (7)(8) Because CT involves high radiation ex-
posure, ultrasonography is the preferred method to diag-
nosse and monitor NC in infants and children. Because
calcium deposits occur most commonly in the medulla of
neonates with NC, ultrasonography typically demonstrates
increased echogenicity of the renal medulla (Fig 1). In ad-
dition to NC, the differential diagnosis for the ultrasono-
graphic finding of medullary hyperechogenicity in neonates
includes acute kidney injury, autosomal recessive polycystic
kidney disease, and normal transient echogenicity in the
newborn (ie, Tamm-Horsfall nephropathy). (9)(10)(11)
CAUSES OF NEPHROCALCINOSIS IN NEONATES
NC in neonates develops due to a number of causes in-
cluding inherited and acquired processes (Table). These
can be associated with disruptions in calcium homeosta-
sis, as in Williams syndrome and primary hyperparathy-
roidism, or can be associated with normocalcemia, as in
inherited tubulopathies. In the section below, we describe
a few select conditions that cause NC in neonates.
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e89
 Table. Acquired and Inherited Causes of Nephrocalcinosis in Neonates (1)(3)
Disorder
Normocalcemia
Acquired
Nephrocalcinosis of prematurity
Loop diuretics
Glucocorticoids
Inherited: Tubulopathies
Dent disease
Lowe syndrome (Oculocerebrorenal
syndrome)
Fanconi-Bickel syndromea (44)
Bartter syndrome
Familial hypomagnesemia with
hypercalciuria and
nephrocalcinosis
Distal renal tubular acidosis
Inherited: Extrarenal disease
Primary hyperoxaluria, type 1
Hereditary hypophosphatemic
rickets with hypercalciuria
Hypercalcemia
Acquired
Calcium supplementation
Hypervitaminosis D
Subcutaneous fat necrosis (48)
Inherited: Extrarenal disease
Williams syndrome
Neonatal severe primary
hyperparathyroidism (49)
Idiopathic infantile hypercalcemia
(50)(51)(52)
Hypophosphatasia, perinatal and
infantile types (53)
e90 NeoReviews
Inheritance Mode/ Gene/ Protein (when applicable); Clinical Features
 Risk factors consistently observed in studies are low gestational age at birth, low birthweight,
and loop diuretic use. Less consistent risk factors include longer duration of mechanical
ventilation, exposure to dexamethasone, and parenteral nutrition (16)(20)(43)
 Known to induce hypercalciuria
 Known to induce hypercalciuria
 X-linked recessive/ CLCN5/ chloride transporter CIC-5
 Diffuse proximal tubular dysfunction (Fanconi syndrome), hypercalciuria, nephrocalcinosis,
nephrolithiasis. Many progress to end stage kidney disease.
 X-linked recessive/ OCRL1/ enzyme phosphatidylinositol (4)(5) bisphosphate 5 phosphatase
 Fanconi syndrome, hypercalciuria, nephrocalcinosis, nephrolithiasis. Many progress to end
stage kidney disease.
 Congenital cataract, cognitive disability
 Autosomal recessive/ SLC2A2/ glucose transporter GLUT2
 Renal Fanconi syndrome, hypercalciuria, nephrocalcinosis
 Glycogen storage disease, impaired galactose tolerance, hepatomegaly, rickets
 Autosomal recessive/ several genes/ transporter proteins in the loop of Henle
 Polyuria, hypochloremia, hypokalemic metabolic alkalosis, elevated renin, elevated aldosterone,
normotension, hypercalciuria, nephrocalcinosis
 Autosomal recessive/ CLDN16 and CLDN19/ tight junction proteins claudine-16 and claudine-19,
respectively
 Urinary loss of magnesium and calcium, nephrocalcinosis; homozygotes progress to end stage
kidney disease
t.me/neonatology
 Congenital ocular abnormalities (myopia magna, nystagmus, macular colobomata) are present with
CLDN19 pathogenic variant.
 Autosomal recessive, autosomal dominant/ several genes / proteins in acid-secretory intercalated
cells in the distal nephron
 Hyperchloremic non-anion gap metabolic acidosis
 Variable extrarenal manifestations depending on the involved gene: sensorineural hearing loss, tooth
enamel abnormalities, spherocytosis
 Autosomal recessive/ AGXT/ peroxisomal enzyme alanine glyoxylate aminotransferase
 Nephrocalcinosis, nephrolithiasis, hyperoxaluria, end stage kidney disease
 Systemic oxalosis including heart conduction disturbances, oxalate osteodystrophy, peripheral
neuropathy
 Autosomal recessive/ SLC34A3/ sodium-dependent phosphate cotransporter
 Renal phosphate wasting, hypophosphatemia, rickets, hypercalciuria, nephrocalcinosis,
nephrolithiasis
 Calcium intake higher in preterm infants with nephrocalcinosis than those without
nephrocalcinosis (20)(43)(45)
 Cases reported in infants given inadvertent overdose (46) and given pharmacologic doses of
vitamin D (47)
 Rare form of panniculitis (erythematous, firm plaques and nodules over extremities, back, buttocks),
mostly in term and post-term infants associated with perinatal trauma; self-limited
 Autosomal dominant/deletion of genes in chromosome 7q
 Characteristic facial features (broad forehead, periorbital fullness, flat nasal bridge, long
philtrum, small chin), supravalvular aortic stenosis, endocrine, genitourinary abnormalities;
hypercalcemia and hypercalciuria in infants and toddlers, nephrocalcinosis in >5-10% of
patients
 Autosomal dominant/ inactivating mutation in CASR/ calcium-sensing receptor CaSR
 Hypercalcemia, polyuria, failure to thrive, respiratory distress, bone deformity, fractures,
nephrocalcinosis
 Autosomal recessive/ CYP24A1 and SLC34A1/ 25-hydroxyvitamin D 24-hydroxylase and sodium-
phosphate cotransporter 2A, respectively
 Hypercalcemia following vitamin D administration, increased vitamin D sensitivity
 Autosomal recessive/ ALPL/ tissue nonspecific alkaline phosphatase
 Low serum alkaline phosphatase
 Skeletal hypomineralization, pulmonary hypoplasia, tracheomalacia, craniosynostosis,
intracranial hypertension, hypercalcemia, hypercalciuria, nephrocalcinosis
Continued
T.ME/NEONATOLOGY
t.me/neonatology
Table. (Continued)
Disorder Inheritance Mode/ Gene/ Protein (when applicable); Clinical Features
Hypocalcemia
Inherited
Autosomal dominant hypocalcemia  Activating mutation in CASR/ calcium-sensing receptor CaSR
with Bartter syndrome  Bartter syndrome with hypocalcemia, inappropriately low parathyroid hormone
Autosomal dominant hypocalcemia  Activating mutations in CASR/ calcium-sensing receptor CaSR
with hypercalciuria (54)  Hypocalcemia, inappropriately low parathyroid hormone, hypercalciuria, nephrocalcinosis
a
Not to be confused with renal Fanconi syndrome which is diffuse proximal tubular dysfunction

Nephrocalcinosis in Preterm Infants
NC of prematurity is the most common form of NC in
neonates. Multiple factors lead to NC in neonates, includ-
ing hypercalciuric medications and electrolyte imbalances,
in addition to prematurity.
To understand why NC is common in preterm infants,
knowledge of renal embryology is needed. Nephrogenesis
begins between 9 and 10 weeks of gestation and new neph-
rons form at an exponential rate between 20 and 28 weeks
of gestation. (12) Nephrogenesis is completed by 36 weeks of
gestation in most fetuses, though some studies have re-
weeks (12%). (15) Preterm infants with NC were found to
have significantly lower birthweight than those without
NC. (17)(18)(19) In a study of neonates with birthweights
between 500 and 1,659 g, the odds of developing NC in-
creased 1.65 times for every 100-g decrease in birthweight,
independent of other risk factors. (17)
Medications with a hypercalciuric effect also increase the
risk of NC in premature infants. Furosemide, dexamethasone,
vitamin D, and caffeine are commonly used medications in
NICUs and have been associated with the development of
NC. (2) Furosemide, in particular, has been identified as a sig-

ported a wider range of 32 to 37 weeks of gestation. (13) Neo-
nates born before the completion of nephrogenesis have
immature renal epithelia, which are more susceptible to crys-
tal binding as previously discussed. In addition, premature
kidneys have a relatively well-developed loop of Henle, lead-
ing to a low urine flow rate and consequently, an increased
risk of calcium crystal aggregation. (2)
NC is observed in 16% to 27% of neonates born before
32 weeks’ gestation (14)(15)(16)(17) and occurs at a rate
twice as high in infants born before 28 gestational weeks
(26%) compared with infants born at 28 to 32 gestational
t.me/neonatology
nificant risk factor in multiple studies. (15)(17)(18)(19) The use
of cumulative furosemide doses greater than 10 mg/kg during
the NICU admission was found to be the strongest risk factor
for NC in an observation study of 55 neonates born before 32
weeks of gestation. (17) Furosemide inhibits the NKCC2 co-
transporter in the thick ascending loop of Henle, which leads
to a decrease in the electrochemical gradient across the epi-
thelial membrane, resulting in decreased paracellular trans-
port and lower reabsorption of calcium.
Metabolic risk factors associated with NC in preterm in-
fants include high intake of calcium, phosphorus, and

Figure 1. Ultrasound images of medullary nephrocalcinosis. Calcium depositions appear hyperechoic (white) on ultrasonography. Medullary nephrocalcinosis
can be mild with punctate and scattered echogenic foci in the renal pyramids (A), or it can be severe with extensive and diffuse hyperechogenicity of the renal
pyramids (B).

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e91

t.me/neonatology
 ascorbic acid; (20) administration of parenteral nutrition;
(14) metabolic acidosis; (21) hypercalciuria; (17) hyperoxa-
luria; (14) and hypocitraturia. (22)
Bartter Syndrome
Bartter syndrome is a rare salt-losing tubulopathy charac-
terized by polyuria, hypokalemia, and hypochloremic met-
abolic alkalosis. (23) Pathogenic mutations in several
genes encoding transport proteins in the loop of Henle,
including the NKCC2 cotransporter and the ROMK chan-
nel, result in decreased sodium, potassium, and chloride
reabsorption. (3) The electrochemical gradient that drives
calcium reabsorption is also decreased, similar to the ef-
fect of furosemide therapy, leading to hypercalciuria and
subsequent NC.
Four of the 5 types of Bartter syndrome present prenatally
with polyhydramnios, due to fetal polyuria, and premature
birth (median age at birth 29–33 weeks of gestation). (23)
Neonates present with polyuria, rapid weight loss, dehy-
dration, and failure to thrive. Impaired salt reabsorption
leads to a chronic hypovolemic state, which activates the
renin-angiotensin-aldosterone system. Increased aldoste-
rone activity leads to excessive potassium and proton se-
cretion in the distal tubule, resulting in hypokalemia and
metabolic alkalosis.
Distal Renal Tubular Acidosis
Distal renal tubular acidosis (dRTA) is characterized by a
normal anion gap hyperchloremic metabolic acidosis and
inappropriately high urinary pH due to impaired renal
ammonium excretion. Metabolic acidosis is buffered by
the skeletal system and the ensuing calcium release from
bone leads to hypercalciuria. Metabolic acidosis also in-
creases proximal tubular reabsorption of urinary citrate
leading to hypocitraturia. In dRTA, the combination of hy-
percalciuria and hypocitraturia results in NC. (24) Patho-
genic mutations encoding the acid-base regulatory proteins
in the distal tubule cause the primary (inherited) forms of
dRTA. Infants may present with failure to thrive, vomiting,
polyuria, and dehydration. (24) Primary dRTA can be asso-
ciated with extrarenal features depending on the affected
gene: sensorineural hearing loss (ATP6V1B1, FOXI1), tooth
enamel abnormalities (WDR72), and hereditary spherocytosis
(SLC4A1). (25)
Primary Hyperoxaluria
Primary hyperoxaluria is a rare autosomal recessive disor-
der caused by defects in glyoxylate metabolism, resulting
in hepatic overproduction of oxalate and accumulation of
e92 NeoReviews
t.me/neonatology
oxalate in various organs, including the kidneys. Primary
hyperoxaluria type 1, caused by a pathogenic variant in the
AGXT gene, is the most common and the most severe
form, with about 10% of patients presenting in infancy or
early childhood. (26) Symptoms include NC, recurrent
kidney stones, recurrent urinary tract infections, and kid-
ney failure even on initial presentation in as many as 73%
of patients. (27) The NC found in patients with primary
hyperoxaluria is extensive and often involves the renal cor-
tex in addition to the medulla. (28)
EVALUATION OF NEPHROCALCINOSIS
Diagnostic evaluation is needed to determine the underly-
ing cause of NC. A history of prematurity, low birth-
weight, and bronchopulmonary dysplasia requiring loop
diuretic therapy should raise the suspicion for NC of pre-
maturity. The presence of skeletal anomalies may indicate
inherited rickets, hypophosphatasia, or neonatal severe pri-
mary hyperparathyroidism. Family history of consanguin-
ity may raise concerns for autosomal recessive disorders
t.me/neonatology
including many of the tubulopathies discussed previously
or primary hyperoxaluria. Physical examination should fo-
cus on the neonate’s growth, fluid status, and features
suggestive of underlying genetic conditions such as Wil-
liams syndrome. Erythematous nodules and plaques in a
term infant with NC may indicate subcutaneous fat necro-
sis, another cause of NC found in neonates who have un-
dergone therapeutic hypothermia (see Table).
Serum electrolytes, including calcium, phosphorous,
and magnesium, need to be evaluated in all neonates with
NC (Fig 2). Conditions that cause NC can be divided ac-
cording to the presence of normocalcemia, hypercalcemia,
and hypocalcemia (Table). Concomitant electrolyte abnor-
malities can also help to determine the underlying cause.
Hypochloremic hypokalemic metabolic alkalosis may indi-
cate Bartter syndrome, hyperchloremic hypokalemic meta-
bolic acidosis may point to dRTA, hypophosphatemia may
suggest proximal tubular dysfunction as seen in Dent dis-
ease and Lowe syndrome, and hypomagnesemia may indi-
cate familial hypomagnesemia with hypercalciuria and
NC. Serum parathyroid hormone and vitamin D levels are
indicated if serum calcium is abnormal. Low serum alka-
line phosphatase can suggest hypophosphatasia.
The initial evaluation of NC includes urinalysis and a spot
urine calcium-to-creatinine ratio. A urine calcium-to-creatinine
ratio greater than 0.8 mg/mg (2.2 mol/mol) is considered el-
evated in infants. (29) An elevated urine oxalate-to-creatinine
ratio greater than 0.26 mg/mg (360 mol/mol) in infants
younger than 6 months warrants further evaluation for
T.ME/NEONATOLOGY
 Medullary Nephrocalcinosis
Check serum electrolytes (including Ca, Mg, PO43), serum creanine, urinalysis, spot urine calcium-to-creanine rao
Serum Calcium Result
High
Check parathyroid hormone, Concomitant electrolyte
vitamin D, alkaline phosphatase abnormalies
• Calcium supplementaon Renal tubular acidosis
• Hypervitaminosis D • Renal Fanconi syndrome
• Subcutaneous fat necrosis • Distal renal tubular acidosis
• Williams syndrome Metabolic alkalosis
• Neonatal severe primary • Barer syndrome
hyperparathyroidism Hypomagnesemia
• Idiopathic infanle hypercalcemia • Familial hypomagnesemia
• Hypophosphatasia, perinatal and with hypercalciuria and
infanle types nephrocalcinosis
Figure 2. Suggested initial evaluation for neonates with medullary nephrocalcinosis.
possible primary hyperoxaluria. (29) Low urinary specific
gravity may indicate a concentrating defect, whereas glucosu-
ria in the setting of euglycemia is consistent with proximal
tubular dysfunction. Urine pH greater than 5.5 in the setting
of metabolic acidosis suggests dRTA.
If there is a strong suspicion for an underlying genetic eti-
ology for NC, genetic testing should be considered, because
management and prognosis differ widely between the various
hereditary conditions. In one study, 43% of patients with the
onset of NC before 5 years of age had a causative pathogenic
variant as identified on whole-exome sequencing. (30)
MANAGEMENT
A comprehensive discussion on the management and prog-
nosis of NC caused by various inherited diseases is available,
(29)(31) and is beyond the scope of this review. The following
sections will focus on NC in preterm infants.
Initial management of preterm infants with NC includes
assessment of risk factors associated with NC and modifying
them, when possible. Though not specifically studied in pre-
term infants with NC, thiazide diuretics have been shown to
decrease urinary calcium excretion and halt NC in small ob-
servational studies in children. (32)(33) Therefore, it is recom-
mended to change from loop diuretics to thiazide diuretics
in the setting of NC whenever possible.
Citrate supplementation is used commonly in pediatric
and adult patients with nephrolithiasis and concurrent hy-
pocitraturia. Citrate is converted to bicarbonate by the
liver, resulting in higher urinary pH, which leads to de-
creased citrate reabsorption by the proximal tubules. (29)
Citrate binds calcium to form a soluble complex, decreas-
ing free calcium available to form other, less soluble
t.me/neonatology
Normal Low
Normal electrolytes Check parathyroid hormone,
vitamin D
• Autosomal dominant
Prematurity, low Extensive hypocalcemia with
birthweight, loop nephrocalcinosis, elevated Barer syndrome
diurec therapy serum creanine, • Autosomal dominant
• Nephrocalcinosis consanguinity, elevated hypocalcemia with
of prematurity urine oxalate-to-creanine hypercalciuria
rao, genec test
• Primary hyperoxaluria
type 1
precipitates. In a randomized controlled trial of 74 pre-
term (<32 weeks’ gestation) neonates, those receiving so-
dium citrate supplementation had lower urine calcium-
t.me/neonatology
to-citrate and higher citrate-to-creatinine ratios than those
not receiving therapy. (34) The occurrence of NC tended to
be lower in the sodium citrate group (34%) compared to the
group that received no treatment (44%), but this difference
was not statistically significant. (34) Citrate supplementation
may be considered in preterm infants with NC or at a high
risk of developing NC if concurrent hypocitraturia is present.
Hypocitraturia is defined as urine citrate-to-creatinine ratio less
than 0.2 to 0.42 mg/mg (0.12–0.25 mol/mol). (29) It is impor-
tant to note, however, that alkaline urine increases the risk of
calcium phosphate precipitation, and it is recommended to
stop citrate supplementation in patients with high urinary pH.
Furthermore, citrate must be administered with caution in pa-
tients with dRTA, as they have primarily alkaline urine.
Higher water intake and ensuing dilute urine decreases
the supersaturation of calcium crystals; thus, the neonate’s
fluid intake should be increased as tolerated. In addition,
calcium and phosphorus intake should be evaluated to en-
sure that the amount is within the recommended dietary
allowance and appropriate for the patient.
LONG-TERM FOLLOW-UP
Preterm infants with persistent NC should have renal health
monitoring after discharge from the NICU. NC-related
monitoring includes renal ultrasonography, serum creati-
nine measurement, and blood pressure measurement
within a few weeks to a few months of hospital discharge
depending on the severity the NC. The frequency of these
monitoring studies may vary from every few months to
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e93
 annually for the first few years after birth depending on the
results of the studies. Long-term monitoring may be con-
ducted by the patient’s primary care provider or by a pediatric
nephrologist, depending on the severity of the NC as well as
the comfort level and resources of the primary provider. The
patient with NC should be referred to a pediatric nephrologist
for persistent NC beyond the first 2 to 3 years of age, abnor-
mal electrolytes, or elevated serum creatinine value for the pa-
tient's age and size, or for elevated blood pressure readings.
PROGNOSIS
NC in preterm infants resolves spontaneously in 66% by
15 months of age, 85% by 30 months of age, and 90% by
7.5 years of age. (35)(36) Despite the self-resolution of NC,
there remain concerns for possible long-term renal consequen-
ces. Long-term effects on kidney function, kidney growth, tubu-
lar function, and systemic blood pressure have been studied.
Kidney Function
In observational studies involving 160 preterm infants
with NC, patient follow-up at 4 to 7 years demonstrated
that the estimated glomerular filtration rate (GFR) by serum
creatinine measurement was found to be within the normal
range at 92 to 132 mL/min per 1.73 m2. (35)(37)(38) How-
ever, in additional case-control studies with follow-up at 2 to
7.5 years, 14% to 15% of children had an estimated GFR
lower than 85 mL/min per 1.73 m2. (36)(39) Notably, in both
studies, the proportion of cases with estimated GFR lower
than 85 mL/min per 1.73 m2 was not statistically different
than that in control groups of children with a history of pre-
maturity without NC (6%–9%). These findings highlight the
now well-established risk factor of extreme prematurity itself
on the development of chronic kidney disease. (40) Indeed,
Rakow et al showed that the mean cystatin C–based esti-
mated GFR was similar between the groups with a history of
prematurity with (25.5 weeks of gestation) and without NC
(25.9 weeks of gestation), but these estimated GFR values
were lower than that of the full-term control group (39.7 weeks
of gestation). (38) Important factors to consider when extract-
ing neonatal and pediatric estimated GFR data from older
studies include changes in the serum creatinine measuring
method, changes in the Schwartz GFR calculator, and the
tendency for serum creatinine to overestimate GFR in in-
fants and children with low muscle mass. (41)
Kidney Growth
Kidney growth, measured in length or volume, is impaired
in children with a history of prematurity and NC compared
with healthy children without a history of prematurity (37) or
e94 NeoReviews
t.me/neonatology
at short-term follow-up. (39) At 7-year follow-up, when kid-
ney growth is compared to gestational age– and birthweight-
matched control group, no significant differences were found
between the preterm infants with and without NC. (36)(38)
The kidney growth of preterm infants with and without NC,
however, was significantly lower compared with healthy chil-
dren. (36)(38) Current evidence suggests that NC itself does
not independently impair kidney growth.
Tubular Function
Tubular functions were evaluated at follow-up of premature
infants with a history of NC using various methods. Most
commonly, tubular reabsorption of phosphate, glucosuria,
and low-molecular-weight proteinuria for proximal tubular
function and early morning urine osmolarity and acid-base bal-
ance were measured for distal tubular function. (35)(36)(37)(39)
Tubular reabsorption of phosphate was found to be lower in
the NC group, but plasma phosphate level was within nor-
mal range in all children, questioning the clinical signifi-
cance of this finding. (36) Glucosuria was uniformly absent.
t.me/neonatology
In general, proximal tubular function was intact compared to
that in matched control groups and healthy children.
Urine concentration capacity was intact in preterm in-
fants with a history of NC as assessed by early morning
urine osmolality, (36)(37) but reported to be decreased in
14% of patients after desmopressin administration. (35)
However, studies did not examine the patients’ urine vol-
ume to assess for polyuria. Serum bicarbonate level was
low (<21 mEq/L [21 mmol/L]) in 7 (17.5%) of 40 children
with history of neonatal NC at 2-year follow-up, but a pre-
maturity-matched control group was not studied. (35) At
7.5-year follow-up, median plasma serum bicarbonate level
was found to be significantly lower in the NC group com-
pared to the matched control group, but with uncertain
clinical significance (23 vs 24 mEq/L [23 vs 24 mmol/L];
P5.006). (36) These studies demonstrated that distal tubu-
lar function may be abnormal on laboratory tests in some
children, but its clinical significance remains debatable.
Systemic Blood Pressure
In a case series of 50 children with a history of prematu-
rity and NC, systolic and diastolic blood pressures were
noted to be in the hypertensive range in 30% and 34%, re-
spectively, at 2-year follow-up. (35) At a longer follow-up
period of 7.5 years, systolic blood pressure was in the hy-
pertensive range in 7% of 42 children with a history of
prematurity and NC, which was similar to a prematurity-
matched control group (6%). (36) Likewise, Fayard et al
showed that 90 children with a history of prematurity and

NC had similar blood pressure measurements compared to
175 children born preterm without NC in their prospective ob-
servational study. (15) Comparable blood pressure readings in
these 2 populations were confirmed by ambulatory blood pres-
sure monitoring. (38) Although none of the former preterm
children, with and without NC, had hypertension on ambula-
tory blood pressure monitoring, 50% of these children lacked
the day-to-night physiologic decrease in blood pressure, which
is a well-established risk factor for cardiovascular disease. (42)
As with kidney function that was discussed previously, NC
does not appear to be an independent risk factor for hyperten-
sion but may be one contributing factor.
CONCLUSION
NC can develop in neonates due to prematurity and iatro-
genic contributors, or it can be a manifestation of an under-
lying genetic disease. A systemic evaluation of the neonate
with NC includes a thorough history and physical examina-
tion, serum electrolytes, and urine laboratory studies to dif-
ferentiate between self-limited NC of prematurity and a
genetic disease that requires specific therapy. While the prog-
nosis of NC due to a heritable disease includes end-stage kid-
ney disease, NC of prematurity often resolves over time.
Summary
• NC is a common complication observed in neonates,
especially preterm neonates.
• The etiology of NC is multifactorial and includes
metabolic, nutritional, and iatrogenic (such as
medications) contributors.
• NC may be the manifestation of an underlying
genetic disease process that is amenable to
intervention, and therefore, warrants systematic
evaluation based on history, physical examination,
and screening laboratory tests.
• NC of prematurity often resolves over time with
some residual sequelae that are of questionable
clinical significance.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the etiology of electrolyte abnormalities in
the neonate.
t.me/neonatology
T.ME/NEONATOLOGY
• Recognize the clinical and laboratory manifestations
of electrolyte abnormalities in the neonate.
• Know how to interpret various renal function
tests (eg, urinalysis, creatinine clearance).
• Know the mechanism of action of commonly used
diuretic drugs in infants.
References
1. Shavit L, Jaeger P, Unwin RJ. What is nephrocalcinosis? Kidney Int.
2015;88(1):35–43
2. Schell-Feith EA, Kist-van Holthe JE, van der Heijden AJ. Nephrocalcinosis
in preterm neonates. Pediatr Nephrol. 2010;25(2):221–230
3. Oliveira B, Kleta R, Bockenhauer D, Walsh SB. Genetic,
pathophysiological, and clinical aspects of nephrocalcinosis. Am J
Physiol Renal Physiol. 2016;311(6):F1243–F1252
4. Vervaet BA, Verhulst A, D’Haese PC, De Broe ME. Nephrocalcinosis:
new insights into mechanisms and consequences. Nephrol Dial
Transplant. 2009;24(7):2030–2035
5. Verhulst A, Asselman M, De Naeyer S, et al. Preconditioning of
the distal tubular epithelium of the human kidney precedes
t.me/neonatology
nephrocalcinosis. Kidney Int. 2005;68(4):1643–1647
6. Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and
magnesium homeostasis. Clin J Am Soc Nephrol. 2015;10(7):1257–1272
7. Schell-Feith EA, Holscher HC, Zonderland HM, et al. Ultrasonographic
features of nephrocalcinosis in preterm neonates. Br J Radiol.
2000;73(875):1185–1191
8. Dick PT, Shuckett BM, Tang B, Daneman A, Kooh SW. Observer
reliability in grading nephrocalcinosis on ultrasound examinations
in children. Pediatr Radiol. 1999;29(1):68–72
9. Hemachandar R, Boopathy V. Transient renal medullary
hyperechogenicity in a term neonate. BMJ Case Rep. 2015;2015
doi:10.1136/bcr-2015-211285
10. Robalo B, Stone R, Saldanha J, Lobo L, Almeida M. An unusual case
of renal medullary hyperechogenicity and hypertension: autosomal
recessive polycystic kidney disease (ARPKD). Pediatr Nephrol.
2009;24(8):1473–1476
11. Makhoul IR, Soudack M, Smolkin T, et al. Neonatal transient renal
failure with renal medullary hyperechogenicity: clinical and laboratory
features. Pediatr Nephrol. 2005;20(7):904–909
12. Rosenblum S, Pal A, Reidy K. Renal development in the fetus and
premature infant. Semin Fetal Neonatal Med. 2017;22(2):58–66
13. Ryan D, Sutherland MR, Flores TJ, et al. Development of the
human fetal kidney from mid to late gestation in male and female
infants. EBioMedicine. 2018;27:275–283
14. Narendra A, White MP, Rolton HA, et al. Nephrocalcinosis in preterm
babies. Arch Dis Child Fetal Neonatal Ed. 2001;85(3):F207–F213
15. Fayard J, Pradat P, Lorthois S, Bacchetta J, Picaud J-C. Nephrocalcinosis
in very low birth weight infants: incidence, associated factors, and
natural course. Pediatr Nephrol. 2022;37(12):3093–3104
16. Nasseri F, Azhir A, Rahmanian S, Iranpour R, Adibi A.
Nephrocalcinosis in very low birth weight infants. Saudi J Kidney
Dis Transpl. 2010;21(2):284–289
17. Gimpel C, Krause A, Franck P, Krueger M, von Schnakenburg C.
Exposure to furosemide as the strongest risk factor for
nephrocalcinosis in preterm infants. Pediatr Int. 2010;52(1):51–56
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e95

18. Malone Jenkins S, Chan G, Weaver-Lewis K, Bardsley T, Felix J,
Grinsell M. Vitamin D, bone density, and nephrocalcinosis in preterm
infants: a prospective study. Pediatr Nephrol. 2022;37(6):1325–1332
19. Chang H-Y, Hsu C-H, Tsai J-D, et al. Renal calcification in very low
birth weight infants. Pediatr Neonatol. 2011;52(3):145–149
20. Schell-Feith EA, Kist-van Holthe JE, Conneman N, et al. Etiology of
nephrocalcinosis in preterm neonates: association of nutritional
intake and urinary parameters. Kidney Int. 2000;58(5):2102–2110
21. Hein G, Richter D, Manz F, Weitzel D, Kalhoff H. Development of
nephrocalcinosis in very low birth weight infants. Pediatr Nephrol.
2004;19(6):616–620
22. Sikora P, Roth B, Kribs A, Michalk DV, Hesse A, Hoppe B.
Hypocitraturia is one of the major risk factors for nephrocalcinosis in
very low birth weight (VLBW) infants. Kidney Int. 2003;63(6):
2194–2199
23. Konrad M, Nijenhuis T, Ariceta G, et al. Diagnosis and management
of Bartter syndrome: executive summary of the consensus and
recommendations from the European Rare Kidney Disease
Reference Network Working Group for Tubular Disorders. Kidney
Int. 2021;99(2):324–335
24. Giglio S, Montini G, Trepiccione F, Gambaro G, Emma F. Distal
renal tubular acidosis: a systematic approach from diagnosis to
treatment. J Nephrol. 2021;34(6):2073–2083
25. Wagner CA, Unwin R, Lopez-Garcia SC, Kleta R, Bockenhauer D,
Walsh S. The pathophysiology of distal renal tubular acidosis. Nat
Rev Nephrol. 2023;19(6):384–400
26. Milliner DS, Harris PC, Cogal AG, Lieske JC. Primary hyperoxaluria
type 1. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews.
Seattle, WA: University of Washington; 1993
27. Wannous H. Primary hyperoxaluria type 1 in children: clinical and
laboratory manifestations and outcome. Pediatr Nephrol. 2023;38(8):
2643–2648
28. Strauss SB, Waltuch T, Bivin W, Kaskel F, Levin TL. Primary
hyperoxaluria: spectrum of clinical and imaging findings. Pediatr
Radiol. 2017;47(1):96–103
29. Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in
children. Kidney Int. 2011;80(12):1278–1291
30. Daga A, Majmundar AJ, Braun DA, et al. Whole exome sequencing
frequently detects a monogenic cause in early onset nephrolithiasis
and nephrocalcinosis. Kidney Int. 2018;93(1):204–213
31. Singh P, Harris PC, Sas DJ, Lieske JC. The genetics of kidney stone
disease and nephrocalcinosis. Nat Rev Nephrol. 2022;18(4):224–240
32. Reusz GS, Dobos M, Tulassay T, Milt
enyi M. Hydrochlorothiazide
treatment of children with hypercalciuria: effects and side effects.
Pediatr Nephrol. 1993;7(6):699–702
33. Auron A, Alon US. Resolution of medullary nephrocalcinosis in children
with metabolic bone disorders. Pediatr Nephrol. 2005;20(8):1143–1145
34. Schell-Feith EA, Moerdijk A, van Zwieten PHT, et al. Does citrate
prevent nephrocalcinosis in preterm neonates? Pediatr Nephrol.
2006;21(12):1830–1836
35. Schell-Feith EA, Kist-van Holthe JE, van Zwieten PHT, et al.
Preterm neonates with nephrocalcinosis: natural course and renal
function. Pediatr Nephrol. 2003;18(11):1102–1108
36. Kist-van Holthe JE, van Zwieten PHT, Schell-Feith EA, et al. Is
nephrocalcinosis in preterm neonates harmful for long-term blood
pressure and renal function? Pediatrics. 2007;119(3):468–475
e96 NeoReviews
t.me/neonatology
T.ME/NEONATOLOGY
37. Porter E, McKie A, Beattie TJ, et al. Neonatal nephrocalcinosis: long
term follow up. Arch Dis Child Fetal Neonatal Ed. 2006;91(5):
F333–F336
38. Rakow A, Laestadius Å, Liliemark U, et al. Kidney volume, kidney
function, and ambulatory blood pressure in children born extremely
preterm with and without nephrocalcinosis. Pediatr Nephrol.
2019;34(10):1765–1776
39. Giapros V, Tsoni C, Challa A, et al. Renal function and kidney
length in preterm infants with nephrocalcinosis: a longitudinal
study. Pediatr Nephrol. 2011;26(10):1873–1880
40. Hingorani S, Schmicker R, Ahmad KA, et al; PENUT Trial
Consortium; PENUT Primary Investigators and coauthors. Prevalence
and risk factors for kidney disease and elevated bp in 2-year-old
children born extremely premature. Clin J Am Soc Nephrol.
2022;17(8):1129–1138
41. Starr MC, Charlton JR, Guillet R, et al; Neonatal Kidney Collaborative
Board. Advances in neonatal acute kidney injury. Pediatrics. 2021;148(5):
e2021051220
42. Ingelsson E, Bj€
orklund-Bodegård K, Lind L, Arnl€ov J, Sundstr€om J.
Diurnal blood pressure pattern and risk of congestive heart failure.
JAMA. 2006;295(24):2859–2866
43. Mohamed GB, Ibrahiem MA, Abdel Hameed WM. Nephrocalcinosis
in pre-term neonates: a study of incidence and risk factors. Saudi J
Kidney Dis Transpl. 2014;25(2):326–332
t.me/neonatology
44. Govindarajan S, Khandelwal P, Sharma S, et al. Clinical features and
genetic sequencing of children with Fanconi-Bickel syndrome.
Indian J Pediatr. 2023;90(2):178–180
45. Jacinto JS, Modanlou HD, Crade M, Strauss AA, Bosu SK. Renal
calcification incidence in very low birth weight infants. Pediatrics.
1988;81(1):31–35
46. Ketha H, Wadams H, Lteif A, Singh RJ. Iatrogenic vitamin D
toxicity in an infant–a case report and review of literature. J Steroid
Biochem Mol Biol. 2015;148:14–18
47. Vanstone MB, Oberfield SE, Shader L, Ardeshirpour L, Carpenter
TO. Hypercalcemia in children receiving pharmacologic doses of
vitamin D. Pediatrics. 2012;129(4):e1060–e1063
48. Mitra S, Dove J, Somisetty SK. Subcutaneous fat necrosis in
newborn-an unusual case and review of literature. Eur J Pediatr.
2011;170(9):1107–1110
49. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use
of bisphosphonate and calcimimetic in neonatal severe primary
hyperparathyroidism. Pediatrics. 2012;129(3):e812–e816
50. Schlingmann KP, Kaufmann M, Weber S, et al. Mutations in
CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med.
2011;365(5):410–421
51. Lenherr-Taube N, Young EJ, Furman M, et al. Mild idiopathic
infantile hypercalcemia-part 1: biochemical and genetic findings.
J Clin Endocrinol Metab. 2021;106(10):2915–2937
52. Figueres M-L, Linglart A, Bienaime F, et al. Kidney function and
influence of sunlight exposure in patients with impaired 24-hydroxylation
of vitamin D due to CYP24A1 mutations. Am J Kidney Dis. 2015;65(1):
122–126
53. Tournis S, Yavropoulou MP, Polyzos SA, Doulgeraki A.
Hypophosphatasia. J Clin Med. 2021;10(23):5676
54. Roszko KL, Stapleton Smith LM, Sridhar AV, et al. Autosomal
dominant hypocalcemia type 1: A systematic review. J Bone Miner
Res. 2022;37(10):1926–1935
 NEOREVIEWS QUIZ

NEO
QUIZ

1. You suspect nephrocalcinosis in a 32-week gestation infant under your care.

Preterm neonates have unique physiology and metabolic requirements
which increases their risk of developing nephrocalcinosis. Which of the
following is NOT a predisposing factor for nephrocalcinosis in preterm
neonates?
A. Decreased effect of antidiuretic hormone.
B. Higher dietary calcium intake.
C. Immature renal tubular function.
D. Increased calcium concentration in tubular fluid.
E. Expression of osteopontin and hyaluronan in the tubular epithelium.
REQUIREMENTS: Learners can
2. In the neonatal kidney, the bulk of calcium reabsorption occurs through the take NeoReviews quizzes and
paracellular pathway. An electrochemical gradient is generated by the apical claim credit online only at:
Na1-K1-2Cl- cotransporter and renal outer medullary potassium channels. In https://publications.aap.org/
which portion of the nephron does this process occur? neoreviews.

A. Bowman capsule. To successfully complete 2024

B. Collecting duct. NeoReviews articles for AMA PRA
C. Distal convoluted tubule. Category 1 Credit™, learners

t.me/neonatology
must demonstrate a minimum
D. Proximal convoluted tubule.
performance level of 60% or
E. Thick ascending loop of Henle. higher on this assessment. If
3. A 28-week gestation infant is admitted to the NICU for management of you score less than 60% on the
assessment, you will be given
hydrops and prematurity. You discuss the hypercalciuric effects of
additional opportunities to
medications that may be needed in their care as well as the associated answer questions until an
increased risk of nephrocalcinosis development. Which of the following overall 60% or greater score is
medications is associated with the highest risk of nephrocalcinosis achieved.
development?
This journal-based CME activity
A. Caffeine. is available through Dec. 31,
B. Calcium gluconate. 2026, however, credit will be
recorded in the year in which
C. Dexamethasone.
the learner completes the quiz.
D. Furosemide.
E. Hydrochlorothiazide.
4. A 38-week gestation infant is admitted to the NICU for evaluation of multiple
dysmorphic features and genetic testing. Subsequent laboratory studies
demonstrate an elevated urine calcium-to-creatinine ratio, leading to the
diagnosis of nephrocalcinosis. What percentage of patients with 2024 NeoReviews is approved
for a total of 30 Maintenance of
nephrocalcinosis have a causative pathogenic variant on whole-exome
Certification (MOC) Part 2
sequencing? credits by the American Board
A. 10%. of Pediatrics (ABP) through the
AAP MOC Portfolio Program.
B. 20%.
NeoReviews subscribers can
C. 40%. claim up to 30 ABP MOC Part 2
D. 60%. points upon passing 30 quizzes
E. 80%. (and claiming full credit for
each quiz) per year. Subscribers
can start claiming MOC credits
as early as October 2024. To
learn how to claim MOC points,
go to: https://publications.aap.
org/journals/pages/moc-credit.

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e97

t.me/neonatology
 5. Nephrocalcinosis is diagnosed in a 34-week gestation infant via laboratory
evaluation and ultrasonography. The long-term consequences of
nephrocalcinosis include kidney and tubular dysfunction, poor kidney
T.ME/NEONATOLOGY
growth, and elevated systolic blood pressure. The parents of this patient ask
about the long-term outcomes of nephrocalcinosis. What percentage of
nephrocalcinosis cases will have resolved by 30 months of age?
A. 15%.
B. 25%.
C. 45%.
D. 60%.
E. 85%.

t.me/neonatology

e98 NeoReviews

t.me/neonatology
 ARTICLE

Renal Tubular Acidosis in the Neonate

Brian R. Lee, MD*
*Department of Neonatology, Southern California Permanente Medical Group, Pasadena, CA

EDUCATION GAPS

Metabolic acidosis is a significant metabolic derangement that negatively

impacts neonates. Clinicians who care for neonates should be able to
recognize and understand the pathophysiology of renal tubular acidosis, a
cause of metabolic acidosis.
T.ME/NEONATOLOGY

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

1. Describe acid-base homeostasis by the kidney.

2. Differentiate between the 3 major types of renal tubular acidosis (RTA).

t.me/neonatology
3. Explain how to diagnose and treat RTA.

ABSTRACT
Metabolic acidosis can manifest in the neonatal period and cause significant
morbidity and mortality in neonates. Preterm infants are at an even higher risk
of developing metabolic acidosis. If the acidosis results from a dysfunction of
acid-base homeostasis by the renal system, the disorder is known as renal
tubular acidosis (RTA). In this review, we will describe renal development and
normal acid-base homeostasis by the renal system. We will also discuss the
pathophysiology of the different types of RTA, laboratory findings to aid in
diagnosis, and treatment considerations. Understanding RTA will help AUTHOR DISCLOSURES Dr Lee has
neonatal clinicians recognize and diagnose an infant affected by RTA and disclosed no financial relationships
relevant to this article. This commentary
initiate treatment in a timely manner. does not contain a discussion of an
unapproved/investigative use of a
commercial product/device.

INTRODUCTION
ABBREVIATIONS
Metabolic acidosis is a common laboratory finding encountered in the neonatal
period, especially in preterm infants. If the acidosis occurs as a result of a dys- ATPase adenosine triphosphatase
CO2 carbon dioxide
function of acid-base homeostasis by the renal system, the disorder is known as dRTA distal renal tubular acidosis
renal tubular acidosis (RTA). In this review, we will describe renal development GFR glomerular filtration rate
and normal acid-base homeostasis by the renal system. We will also discuss the H1-ATPase hydrogen-ATPase
H2CO3 carbonic acid
pathophysiology of the different types of RTA, laboratory findings to aid in diag- H2 O water
nosis, and treatment considerations. HCO3
bicarbonate ion
Na-H sodium hydrogen
Na-HCO3
sodium bicarbonate
ACID-BASE HOMEOSTASIS PHA pseudohypoaldosteronism
pRTA proximal renal tubular
A normal pH in arterial blood is 7.35 to 7.45. Maintenance of this systemic pH acidosis
is important for metabolic functions and is therefore tightly regulated by RTA renal tubular acidosis

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e99

t.me/neonatology
 multiple buffers within the body. The main buffering sys-
tem, known as the bicarbonate buffer system, functions
through the regulation of bicarbonate ions (HCO3
) and
carbon dioxide (CO2). (1) The relationship between HCO3

and CO2 is explained by the following chemical equation:
CO2 1 H2O $ H2CO3 $ H1 1 HCO3

where H2O is water, H2CO3 is carbonic acid, and H1 is
hydrogen ions.
The pH of this buffer system is defined by the Henderson-
Hasselbach equation as follows:
½ HOC3

pH 5 6:1 1 log 0:03 x pCO2
(6.1 represents the acid-dissociation constant of carbonic acid,
0.03 represents a solubility constant of CO2 in the blood)
Changes in PCO2 are mainly dependent on alveolar mi-
nute ventilation.
Bicarbonate Reabsorption in the Kidney
The kidneys play a major role in the regulation of HCO3

concentration in the blood, and they accomplish this by
means of the following 2 major functions: reabsorption of
filtered HCO3
and production of new HCO3
. (2)
In the kidney, HCO3
is freely filtered at the glomeru-
lus, and, thus, the concentration of HCO3
in plasma and
Figure 1. Bicarbonate reabsorption in the proximal tubule cell. Figure created with the aid of BioRender. ATPase5adenosine triphosphatase,
CA II5carbonic anhydrase 2, CA IV5carbonic anhydrase 4, CO25carbon dioxide, H15hydrogen ion, H2CO35carbonic acid, HCO3
5bicarbonate ion,
K15potassium ion, Na15sodium ion, NBCe1-A5sodium bicarbonate cotransporter, NHE35sodium-hydrogen exchanger.
e100 NeoReviews
t.me/neonatology
the ultrafiltrate is the same. In the proximal tubule, 80% of
the filtered HCO3
is reabsorbed. This occurs via the actions
of the sodium-hydrogen (Na-H) exchangers (NHE3) at the
apical membrane of the renal epithelial cells in the proximal
tubule and the sodium-bicarbonate (Na-HCO3
) cotransporter
(NBCe1-A cotransporter) on the basolateral membrane of the
same cells (Fig 1). (3) Na-H exchangers actively secrete H1
into the lumen of the proximal tubule, which combine with
filtered HCO3
to form H2CO3 and ultimately H2O and CO2.
CO2 diffuses across the apical membrane into the cell and
combines with H2O by the action of intracellular carbonic an-
hydrases to form H2CO3, which, in turn, then forms H1 and
HCO3
ions. Following this, HCO3
is transported into the
interstitial space along with sodium via the Na-HCO3
co-
transporter. Sodium-potassium pumps on the basolateral
membrane keep the concentration of sodium within the prox-
imal tubule cell low for these processes to function.
In the distal convoluted tubule and collecting ducts,
HCO3
is also reabsorbed, however, in limited capacity, as
compared to the proximal tubule. Approximately 10% of
t.me/neonatology
filtered HCO3
that is not reabsorbed in the proximal tu-
bule is reabsorbed in the distal nephron. (4) Hydrogen
ions that are transported into the lumen of the distal tu-
bules also drive the generation of HCO3
, similar to the
production of HCO3
seen in the proximal tubules via the
Figure 2. Ammoniagenesis. The majority of ammoniagenesis occurs in the mitochondrial space, in which glutamine is converted to glutamate and then to
a-ketoglutarate, via the PDG and GDH enzymes, respectively. Further formation of ammonia occurs in the cytoplasm via PNC. Asterisk (*) refers to a simplification
showing the byproduct of GDH and succinate, which undergoes multiple conversions before entering the PNC as aspartate. Figure created with the aid of BioRender.
GDH5glutamate dehydrogenase, HCO3
5bicarbonate ion, NH415ammonium ion; PDG5phosphate-dependent glutaminase, PNC5purine nucleotide cycle.

action of intracellular carbonic anhydrase. The HCO3
hydrogen-potassium exchangers also transport H1 into
generated is then transported into the bloodstream via the the lumen of the distal convoluted tubule. (4) These hy-

t.me/neonatology
chloride-bicarbonate exchanger AE1 and the Na-HCO3
drogen ions then combine with ammonia and other titrat-
cotransporter NBCe1-A. (5) able acids and are excreted in the urine.

Excretion of Hydrogen RENAL DEVELOPMENT OF THE FETUS AND

In addition to HCO3
reabsorption in acid-base homeosta-
sis, the kidney also plays a role in the excretion of H1.
The predominant mechanism of H1 excretion is via the
excretion of ammonium, which is not completely under-
stood. (6) H1 is buffered by ammonia in the urine, as
well as in smaller amounts as other titratable acids such
as phosphoric acid. (7) The majority of ammonia in the
urine is generated rather than filtered via the glomerulus,
in a process known as ammoniagenesis (Fig 2), in the re-
nal epithelial cells. (8) While all segments of the nephron
have the ability to form ammonia, most of this occurs in
the proximal tubule. The main mechanism of ammoniagen-
esis involves the enzymes phosphate-dependent glutaminase
and glutamate dehydrogenase. In the mitochondria, phosphate-
dependent glutaminase converts glutamine into glutamate,
which produces ammonium. Glutamate is then further me-
tabolized into ammonium and a-ketoglutarate by glutamate
dehydrogenase. This process also generates HCO3
, which
is reabsorbed into the bloodstream. Another minor pathway
that generates ammonia involves the metabolism of aspartate
in the purine nucleotide cycle.
H1 is also secreted in the distal tubules of the nephron
and the collecting duct (Fig 3). On the luminal membrane
of a-intercalated cells, hydrogen pumps actively transport
H1 into the lumen of the distal convoluted tubule, and
FUNCTION IN THE NEWBORN
Fetal development of the kidneys, or nephrogenesis, begins
with the formation of the ureteric bud, which is the precursor
to the genitourinary system. (9) This occurs at 5 weeks’ ges-
tation. The ureteric bud eventually divides into the structures
that form the major and minor calyxes and the collecting
ducts. Adjacent mesenchymal cells, known as the metanephric
blastema, are invaded by the dividing ureteric bud and form
the structures of the nephron, including the glomeruli and re-
nal tubules. (9) Formation of nephrons continues until 35 to
37 weeks’ gestation and is generally complete at 38 weeks’ ges-
tation. Many factors influence the number of nephrons that
are formed at birth, including fetal growth restriction, cho-
rioamnionitis, genetics, and prematurity. (10) While the
healthy adult kidney can contain a wide number of nephrons,
ranging from 250,000 to more than 2 million nephrons, (10)
the healthy term neonatal kidney contains 1 million neph-
rons. (11) In neonates, there is a positive correlation between
the weight and development of the neonatal kidney and the
gestational age of the neonate (i.e., the older the gestational
age of an infant, the greater the number of nephrons).
At birth, a full-term neonate has a glomerular filtration rate
(GFR) approximately one-fifth or one-sixth of that of an adult,
representative of the functional immaturity of the neonatal
kidney. (11) Preterm infants have an even further decrease in

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e101

t.me/neonatology
 T.ME/NEONATOLOGY

t.me/neonatology
Figure 3. Hydrogen excretion. H1 excretion in the a-intercalated cell of the collecting duct. H1 is generated via intracellular CA II, and is secreted into
the lumen of the collecting duct via hydrogen ATPases and hydrogen-potassium exchangers. The HCO3
generated by CA II is transported into the
bloodstream via the chloride-bicarbonate exchanger AE1. Figure created with the aid of BioRender. AE15anion exchanger 1, ATPase5adenosine tri-
phosphatase, CA II5carbonic anhydrase II, CO25carbon dioxide, H15hydrogen ion, HCO3
5bicarbonate ion, H2O5water.

renal function. The GFR of a preterm infant at 32 to 34
weeks’ gestation is 14 mL/min per 1.73 m2, compared to
a term infant who has a GFR of 21 mL/min per 1.73 m2.
(9) This is a result of many potential factors. Preterm in-
fants have immature kidneys as a result of incomplete
nephrogenesis at birth, as well as immaturity of the renal
vascular system, which leads to a lower renal perfusion
pressure. (9) Preterm infants often have other medication
complications including hypoxia, hypercapnia, acidosis, and
hypotension, which may negatively impact renal function.
RENAL TUBULAR ACIDOSIS
RTA is the impaired ability of the renal system to main-
tain a normal acid-base status, (7) either through an
impairment in HCO3
reabsorption or excretion of H1, or
both. Patients with all forms of RTA have hyperchloremic
metabolic acidosis, with a normal anion gap. The patho-
physiology and clinical signs and symptoms of the 4 types
of RTA are discussed below (Tables 1 and 2).
RTA Type I
RTA type I, or distal RTA (dRTA), is caused by a defect in
acid excretion in the distal nephron, either because of im-
paired H1 secretion or an increased permeability of the lu-
minal membrane to H1.
RTA type I can be caused by mutations in the gene
SLC4A1 that encodes the chloride-bicarbonate exchanger AE1,
which is found on the basolateral membrane of cells in the

Table 1. Renal Tubular Acidosis (RTA)

RTA Type Primary Defect Serum Bicarbonate Serum Potassium Urine pH Urine Anion Gap
I (distal) Defect in acid Elevated (>5.5)
secretion Low Low or normal Positive
II (proximal) Defect in Usually <5.5, but
bicarbonate variable depending
reabsorption Low Low or normal on serum Negative
bicarbonate.
IV (hyperkalemic) Mineralocorticoid <5.5
deficiency or
tubular aldosterone Normal Elevated Positive
resistance

e102 NeoReviews

t.me/neonatology
Table 2. Common Causes of Renal Tubular Acidosis
(RTA) in the Neonatal Period
RTA Type Causes
I (distal) Primary
 AE1 mutations (SLC4A1)
 Hydrogen-ATPase mutations (ATP6V1B1,
ATP6V0A4)
Secondary
 Systemic lupus erythematosus
 Sjogren syndrome
 Amphotericin B
II (proximal) Primary
 NBCe1-A (sodium-bicarbonate
cotransporter) mutations
 Carbonic anhydrase mutations
 NHE3 (sodium-hydrogen exchanger)
mutations
 Glycogen storage disease type I
 Hereditary fructose intolerance
 Galactosemia
 Tyrosinemia
 Dent’s disease
 Lowe syndrome
 Renal immaturity
Secondary
 Carbonic anhydrase inhibitors
IV (hyperkalemic) Aldosterone deficiency
 Congenital adrenal hyperplasia
o 21-hydroxylase deficiency
o 3-beta-hydroxysteroid dehydrogenase
deficiency
o lipoid adrenal hyperplasia
 Congenital adrenal hypoplasia
 Aldosterone synthase deficiency
 Pseudohypoaldosteronism type II
Aldosterone resistance
 Psuedohypoaldosteronism type I
 Spironolactone
collecting duct, (12) or mutations genes, which encode subu-
nits of the hydrogen-ATPase (H1-ATPase) ATP6V1B1 and
ATP6V0A4. (13) A mutation in AE1 causes an increase in in-
tracellular HCO3
in the distal tubule cells, which inhibits
H1 formation. Mutations in the H1-ATPase prevent proper
H1 secretion into the lumen. A form of AE1 is also present
on red blood cell membranes, and a defect in the encoding
genes may also cause dRTA with hereditary spherocytosis or
ovalocytosis. (12)(14) The ATP6V1B1 and ATP6V0A4 genes
are also expressed in the cochlea and may lead to sensorineu-
ral hearing loss. (13)
Secondary causes of RTA type I include autoimmune
disorders such as systemic lupus erythematosus and Sjog-
ren syndrome, but these diagnoses are rare in neonates.
Amphotericin B may cause dRTA as it increases the per-
meability of the luminal membrane to H1.
dRTA may manifest clinically with nonspecific signs
such as failure to thrive, poor feeding, hypotonia, and irri-
tability. Biochemical analysis may show a nonanion gap
metabolic acidosis, a low serum HCO3
level, and elevated
t.me/neonatology
serum chloride. Urine pH may be abnormally elevated as
well, typically with a pH of more than 5.5, with a decrease
in urine ammonium and titratable acids. (15) A positive
urine anion gap may also suggest a defect in ammonium
excretion. (9) Hypercalciuria may result initially from met-
abolic acidosis, and nephrolithiasis may occur because of
the precipitation of calcium phosphate in the urine.
RTA Type II
RTA type II, or proximal RTA (pRTA), is caused by a de-
fect in the maximum HCO3
reabsorption by the proximal
tubules. (9)(16) As a result, filtered HCO3
above the low-
ered reabsorptive capacity is wasted via urine, at usually a
serum HCO3
level of 15 mEq/L. (9) Of note, the proxi-
mal tubule has many functions, including the transport of
phosphate, magnesium, amino acids, and glucose, and pa-
tients with pRTA may also have disorders relating to these
separate functions.
The immaturity of the renal system seen in both term
and preterm neonates may lead to a transient pRTA because
t.me/neonatology
of the inability to maximally reabsorb filtered HCO3
. (17)
Term neonates have a reabsorptive capacity of 20 to 24
mEq/L HCO3
, whereas preterm neonates have a reabsorp-
tive capacity of 15 to 24 mEq/L HCO3
. (9) Preterm new-
borns are at a higher risk of excessive solute wasting in the
urine, including minerals, amino acids, and glucose. In
addition, the preterm kidney is unable to concentrate urine
maximally. (15)
pRTA can manifest as a result of a general dysfunction
of the proximal tubule, which is known as renal Fanconi
syndrome. This may be the result of various genetic
causes or acquired causes, including inborn errors of me-
tabolism such as glycogen storage disease type I, heredi-
tary fructose intolerance, galactosemia, and tyrosinemia,
in which pathologic accumulation of metabolites cause im-
pairment in proximal tubule function. (18) Two X-linked
recessive disorders that may cause pRTA are Dent disease
and Lowe syndrome. Dent disease, because of a mutation
in the CLCN5 gene, affects proximal tubule hydrogen-
chloride exchangers and the function of the H1-ATPase,
and patients may also have other electrolyte derange-
ments, rickets, hypotonia, cataracts, and intellectual im-
pairment. (19) Lowe syndrome, because of a mutation
of the OCRL1 gene, is an X-linked recessive disorder
causing pRTA, and affected patients may also present
with hypotonia, rickets, glaucoma, and neurodevelop-
mental delay. (20)
Other genetic causes of isolated pRTA include mutations
in the NBCe1-A or in the carbonic anhydrase enzyme, (16)(21)
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e103
 and mutations in the Na-H exchanger, NHE3. (22) These
isolated defects in HCO3
reabsorption are rare. A second-
ary cause of pRTA in the neonatal period is the use of
carbonic anhydrase inhibitors such as acetazolamide,
which can be used in infants with bronchopulmonary
dysplasia.
Similar to dRTA, pRTA may manifest clinically as
failure to thrive, poor feeding, hypotonia, and irritabil-
ity. As pRTA is a defect in HCO3
reabsorption, HCO3

will be reabsorbed until it reaches the capacity of the
neonate’s proximal tubules. Affected patients have hy-
perchloremic, nonanion gap metabolic acidosis. (15) The
urine pH may be normal if the proximal tubules have
not reached their reabsorptive capacity of HCO3
; for
example, if the tubular reabsorptive capacity is patholog-
ically lowered to 15 mEq/L HCO3
, the urine will be ap-
propriately acidified to a pH of 5.5 or less with a serum
HCO3
level of 14 mEq/L. Nephrolithiasis does not usu-
ally occur in patients with pRTA if the urine is appropri-
ately acidified, which prevents the precipitation of calcium
phosphate and promotes the formation of water-soluble
calcium oxalate.
RTA Type III
RTA type III is rare and appears in patients with muta-
tions in carbonic anhydrase. (23) Patients have impair-
ments in proximal tubule HCO3
reabsorption, as well as
a distal tubule inability to excrete acid. Because of its rar-
ity, there is a paucity of information on this subtype, and
it is poorly defined and rarely discussed in the context of
neonates.
RTA Type IV
The main defect in RTA type IV is a mineralocorticoid
deficiency or a tubular aldosterone resistance. Normally,
aldosterone activates mineralocorticoid receptors to in-
crease the activity of the Na-H exchanger, NHE3, and the
H1-ATPase in the proximal tubules. It also increases the
activity of sodium-potassium ATPases, sodium channels,
and aquaporins in the distal nephron. The overall effect
of aldosterone is to increase sodium reabsorption and po-
tassium excretion. (24)(25)
After birth, neonates have a physiologic aldosterone re-
sistance, which is manifested clinically as hyponatremia,
hyperkalemia, and elevated levels of plasma aldosterone
and renin. This aldosterone resistance is increased in pre-
term infants. (25) As a result, injuries to the renal system
(ie, urinary tract infection) in the neonatal period have
been associated with the development of transient type IV
e104 NeoReviews
t.me/neonatology
RTA, which is worsened in the presence of an underlying
genetic disorder. (26)(27)
Neonates may have a mineralocorticoid deficiency as a
result of congenital adrenal hyperplasia, as found in 21-hy-
droxylase deficiency, 3-beta-hydroxysteroid dehydrogenase
deficiency, and lipoid adrenal hyperplasia. (28) In addition,
preterm infants may have immaturity of the synthetic path-
way of aldosterone, leading to hypoaldosteronism, which, in
the absence of other disorders, improves by the third day af-
ter birth. (29) Genetic causes of mineralocorticoid deficiency
include defects in the synthetic pathway of aldosterone,
such as aldosterone synthase deficiency, (30) or develop-
mental disorders, such as congenital adrenal hypoplasia.
Pseudohypoaldosteronism (PHA) type 2, also called Gordon
syndrome, is due to mutations in the WNK1, WNK4, KLHL3,
and CUL3 genes. (31)
PHA has an autosomal dominant or recessive pattern
of inheritance and affected neonates have a resistance to
aldosterone. Renal PHA type 1 is caused by a mutation in
the NR3C2 gene, which encodes for the mineralocorticoid
t.me/neonatology
receptors present in the distal tubules and collecting ducts;
(32) systemic PHA type 1 is due to mutations encoding for
the ENaC subunit genes. (33) Spironolactone may also
cause an aldosterone resistance by competing with aldoste-
rone for the aldosterone receptor.
Patients with type IV RTA may manifest clinically with
failure to thrive, poor feeding, vomiting, dehydration, and
lethargy. In addition, laboratory studies show hyponatremia,
hyperkalemia, and metabolic acidosis. Patients with a miner-
alocorticoid deficiency have a lower plasma aldosterone level
and increased adrenocorticotropic hormone levels, and pa-
tients with aldosterone resistance have increased aldosterone
and cortisol levels and a decreased adrenocorticotropic hor-
mone level.
DIAGNOSIS
If RTA is suspected in an infant, a blood gas analysis needs
to be conducted to confirm if there is metabolic acidosis,
along with the screening of sodium, chloride, and HCO3

levels to calculate the anion gap. As noted previously, neo-
nates with all forms of RTA have hyperchloremic metabolic
acidosis with a normal anion gap. Serum bicarbonate may be
low in some forms of RTA or may be normal. Serum potas-
sium may be low, normal, or elevated. (34) Other electrolytes
that may be affected in RTA are calcium and phosphate.
Urine pH can be measured in patients with RTA and
may be persistently elevated despite metabolic acidosis.
The urine anion gap can be measured to estimate ammo-
nia secretion and is calculated as urine sodium plus urine

potassium minus urine chloride, or urine (Na 1 K – Cl).
Ammonium is excreted along with chloride, and if ammo-
nium excretion is decreased, the urine anion gap will be-
come more positive as less chloride will be secreted. The
urine anion gap is normally positive, but it may be difficult
to interpret in newborns because of a lack of normal values.
MANAGEMENT
In general, patients with RTA should be treated with bicar-
bonate supplementation to correct the metabolic acidosis,
and patients who present with failure to thrive or dehydra-
tion should also be given an adequate daily caloric intake
and have fluid deficits corrected.
Patients with dRTA generally require lower doses of bicar-
bonate than patients with pRTA to maintain normal serum
pH and HCO3
levels. (9) In dRTA, correction of the meta-
bolic acidosis and treatment of hypokalemia can be achieved
with potassium citrate; oral solutions can be given starting at
2 to 3 mEq bicarbonate/kg per day. In pRTA, higher doses of
bicarbonate, potentially reaching 15 mEq/kg per day, may be
required. (35) Depending on the cause of the proximal tubule
dysfunction, potassium, sodium, phosphate, and magnesium
supplementation may also be required. (35) In patients with
hyperkalemic RTA, all sources of potassium should be con-
sidered and discontinued if hyperkalemia is present. As with
the other forms of RTA, patients should be given bicarbonate
supplementation to correct the metabolic acidosis associated
with hyperkalemic RTA. Depending on the cause of the RTA,
mineralocorticoid replacement therapy may be indicated to
correct the underlying cause.
CONCLUSION
Metabolic acidosis is a potentially life-threatening condi-
tion in the neonate and has many causes. Understand-
ing RTA as a cause of metabolic acidosis will allow for
the timely diagnosis and treatment of neonates with this
condition and can prevent serious morbidity or mortal-
ity. In the absence of any genetic disorder that may
cause long-term morbidity, patients with RTA, if diag-
nosed and treated quickly, generally have a good long-
term prognosis.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the causes and differential diagnosis of meta-
bolic acidosis and metabolic alkalosis in infants.
t.me/neonatology
T.ME/NEONATOLOGY
• Recognize the clinical and laboratory manifestations of
metabolic acidosis and metabolic alkalosis in infants.
• Know how to manage metabolic acidosis and meta-
bolic alkalosis in infants.
References
1. Hamm LL, Nakhoul N, Hering-Smith KS. Acid-base homeostasis.
Clin J Am Soc Nephrol. 2015;10(12):2232–2242
2. Iacobelli S, Guignard JP. Renal aspects of metabolic acid-base
disorders in neonates. Pediatr Nephrol. 2020;35(2):221–228
3. Boron WF. Acid-base transport by the renal proximal tubule. J Am
Soc Nephrol. 2006;17(9):2368–2382
4. Pereira PCB, Miranda DM, Oliveira EA, Silva ACSE. Molecular
pathophysiology of renal tubular acidosis. Curr Genomics.
2009;10(1):51–59
5. Laing CM, Toye AM, Capasso G, Unwin RJ. Renal tubular acidosis:
developments in our understanding of the molecular basis. Int J
Biochem Cell Biol. 2005;37(6):1151–1161
6. Handlogten ME, Osis G, Lee HW, Romero MF, Verlander JW,
t.me/neonatology
Weiner ID. NBCe1 expression is required for normal renal ammonia
metabolism. Am J Physiol Renal Physiol. 2015;309(7):F658–F666
7. Palmer BF, Kelepouris E, Clegg DJ. Renal tubular acidosis and
management strategies: a narrative review. Adv Ther. 2021;38(2):
949–968
8. Weiner ID, Verlander JW. Renal ammonia metabolism and
transport. Compr Physiol. 2013;3(1):201–220
9. Martin R, Fanaroff A, Walsh M. Fanaroff and Martin’s Neonatal-
Perinatal Medicine, 11th ed. Philadelphia, PA: Elsevier; 2019
10. Ryan D, Sutherland MR, Flores TJ, et al. Development of the
human fetal kidney from mid to late gestation in male and female
infants. EBioMedicine. 2018;27:275–283 10.1016/j.ebiom.2017.12.016
11. Baum M. Neonatal nephrology. Curr Opin Pediatr. 2016;28(2):
170–172 10.1097/MOP.0000000000000325
12. Walsh S, Borgese F, Gabillat N, Guizouarn H. Southeast Asian AE1
associated renal tubular acidosis: cation leak is a class effect. Biochem
Biophys Res Commun. 2009;382(4):668–672
13. Alexander RT, Law L, Gil-Pe~ na H, Greenbaum L, Santos F.
Hereditary distal renal tubular acidosis. GeneReviews [Internet].
Seattle, WA: University of Washington, Seattle; 2019. https://
www.ncbi.nlm.nih.gov/books/NBK547595/. Accessed November 11,
2023
14. Ribeiro ML, Alloisio N, Almeida H, et al. Severe hereditary
spherocytosis and distal renal tubular acidosis associated with the
total absence of band 3. Blood. 2000;96(4):1602–1604
15. Copelovitch L, Kaplan BS. Glomerulonephropathies and disorders of
tubular function. In: Gleason Christine A, Devaskar SU, eds. Avery’s
Diseases of the Newborn, 9th ed. Philadelphia, PA: WB Saunders;
2012;chap 86:1222–1227
16. Haque SK, Ariceta G, Batlle D. Proximal renal tubular acidosis: a
not so rare disorder of multiple etiologies. Nephrol Dial Transplant.
2012;27(12):4273–4287
17. Ramiro-Tolentino SB, Markarian K, Kleinman LI. Renal bicarbonate
excretion in extremely low birth weight infants. Pediatrics. 1996;98(2
Pt 1):256–261
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e105
 18. Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders.
Indian J Pediatr. 2005;72(9):771–776
19. Devuyst O, Thakker RV. Dent’s disease. Orphanet J Rare Dis.
2010;5(1):28
20. Loi M. Lowe syndrome. Orphanet J Rare Dis. 2006;1(1):16
21. Kurtz I, Zhu Q. Structure, function, and regulation of the SLC4
NBCe1 transporter and its role in causing proximal renal
tubular acidosis. Curr Opin Nephrol Hypertens. 2013;22(5):
572–583
22. Igarashi T, Sekine T, Inatomi J, Seki G. Unraveling the molecular
pathogenesis of isolated proximal renal tubular acidosis. J Am Soc
Nephrol. 2002;13(8):2171–2177
23. Borthwick KJ, Kandemir N, Topaloglu R, et al. A phenocopy of CAII
deficiency: a novel genetic explanation for inherited infantile
osteopetrosis with distal renal tubular acidosis. J Med Genet.
2003;40(2):115–121
24. Salyer SA, Parks J, Barati MT, et al. Aldosterone regulates Na1, K1
ATPase activity in human renal proximal tubule cells through
mineralocorticoid receptor. Biochim Biophys Acta. 2013;1833(10):
2143–2152
25. Martinerie L, Pussard E, Foix-L’Helias L, et al. Physiological partial
aldosterone resistance in human newborns. Pediatr Res.
2009;66(3):323–328
26. Maruyama K, Shinohara M, Hatakeyama S, Onigata K. Distal renal
tubular acidosis associated with hypercalcemia and nephrocalcinosis
in an infant. Pediatr Nephrol. 2002;17(11):977–978
e106 NeoReviews
t.me/neonatology
27. Tseng MH, Huang JL, Huang SM, et al. Clinical features, genetic
background, and outcome in infants with urinary tract infection and
type IV renal tubular acidosis. Pediatr Res. 2020;87(7):1251–1255
28. Padidela R, Hindmarsh PC. Mineralocorticoid deficiency and
treatment in congenital adrenal hyperplasia. Int J Pediatr Endocrinol.
2010;2010:656925
29. Travers S, Martinerie L, Boileau P, Lombes M, Pussard E.
Alterations of adrenal steroidomic profiles in preterm infants at
birth. Arch Dis Child Fetal Neonatal Ed. 2018;103(2):F143–F151
30. Rajkumar V, Waseem M. Hypoaldosteronism. StatPearls [Internet].
Treasure Island, FL: StatPearls Publishing; 2023. https://www.ncbi.
nlm.nih.gov/books/NBK555992/. Accessed November 11, 2023
31. Tsuji S, Yamashita M, Unishi G, et al. A young child with
pseudohypoaldosteronism type II by a mutation of Cullin 3. BMC
Nephrol. 2013;14(1):166
32. Jeong HA, Park YK, Jung YS, et al. Pseudohypoaldosteronism in a
newborn male with functional polymorphisms in the
mineralocorticoid receptor genes. Ann Pediatr Endocrinol Metab.
2015;20(4):230–234
33. Attia NA, Marzouk YI. Pseudohypoaldosteronism in a neonate
presenting as life-threatening hyperkalemia. Case Rep Endocrinol.
2016;2016:6384697 doi:10.1155/2016/6384697
34. Yaxley J, Pirrone C. Review of the diagnostic evaluation of renal
tubular acidosis. Ochsner J. 2016;16(4):525–530
t.me/neonatology
35. Reddy S, Kamath N. Clinical approach to renal tubular acidosis in
children. Karnataka Paediatr J. 2020;35(2):88–94
T.ME/NEONATOLOGY
 INDEX OF SUSPICION IN THE NURSERY

Lactic Acidosis in a Neonate with

Ventriculomegaly and Hypoplasia of the
Corpus Callosum
Abdullah Bin Shoaib, MD,* Christa Rose Tabacaru, MD†‡
*Department of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
†
Department of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
‡
Department of Pediatrics, University of Cincinnati, Cincinnati, OH

PRESENTATION

t.me/neonatology
A female infant weighing 2,920 g is born to a 28-year-old gravida 1, para 1 woman at 39
weeks and 3 days’ gestation. The infant had undergone fetal magnetic resonance imag-
ing (MRI) at 29 weeks because of concerns for ventriculomegaly, which showed micro-
cephaly and severe lateral ventriculomegaly, with evidence of remote germinal matrix
hemorrhage and an abnormal cortical sulcation pattern. Pregnancy complications in-
clude gestational diabetes mellitus and maternal hypothyroidism. Infectious serologies
for TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and
herpes simplex) infections are negative.
The infant is born at a community hospital via cesarean delivery because of failure to
thrive. She is admitted to the special care nursery on continuous positive airway pres-
sure and then transferred to our quaternary care NICU on day 25 for evaluation of poor
feeding. Neurology is consulted shortly after the time of transfer because of abnormali-
ties on fetal MRI, which recommends a postnatal MRI and a genetics consultation for
whole exome sequencing. The postnatal MRI of the brain (Fig 1) demonstrates supra-
tentorial ventriculomegaly, reduced parenchymal volume, and hemorrhagic staining in
bilateral ventricles, as well as the absence/severe hypoplasia of the corpus callosum,
aqueductal stenosis, and delayed myelination of white matter.
At day 32, the infant begins to have bloody stools. An abdominal radiograph con-
firms pneumatosis. The patient is kept nil per os, and antibiotics are started because
of concerns for necrotizing enterocolitis. On day 37, the infant has an acute change
in her mental status, acting lethargic and obtunded. An arterial blood gas analysis is
conducted, which reveals pH of 7.1, PCO2 of 43.8 mm Hg (5.83 kPa), bicarbonate of
8.50 mEq/L (8.5 mmol/L), and base deficit of 24. Ammonia level is elevated to
182.07 mg/dL (130 mmol/L), lactate level is elevated to 139.28 mg/dL (15.46 mmol/L),
and anion gap is elevated to 21 mEq/L (21 mmol/L). The lactate/pyruvate ratio is 15.7. AUTHOR DISCLOSURES Drs Shoaib and
Neurology is consulted again, and although neurologic examination is only notable for Tabacaru have disclosed no financial
microcephaly at the time of transfer, the infant is noted to be obtunded and to have slug- relationships relevant to this article. This
commentary does not contain a
gish pupils with minimal spontaneous movement, no response to noxious stimuli, and
discussion of an unapproved/
decreased appendicular tone. No particular odor is noted on physical examination. Con- investigative use of a commercial
tinuous electroencephalography (EEG) is performed, which shows evidence of extremely product/device.

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e107

t.me/neonatology

Figure 1. Postnatal magnetic resonance imaging of the brain shows
severe, asymmetric lateral ventriculomegaly. The upper range of normal
of this metric would be expected to be roughly 26 mm. (1)
suppressed background activity with a few isolated electro-
graphic seizures. Repeat MRI of the brain revealed extensive cy-
totoxic edema throughout both hemispheres, with evidence of a
very elevated lactate peak on magnetic resonance (MR) spec-
troscopy (Fig 2). Results from whole exome sequencing con-
firm the diagnosis.
DIAGNOSIS
Differential Diagnosis
Given the EEG pattern of a burst-suppression pattern and the
age at presentation, developmental epileptic encephalopathy
Figure 2. Long time of echo magnetic resonance spectroscopy of the patient with significant lactate peak (red arrow).
e108 NeoReviews
t.me/neonatology
was on the differential. Although developmental epileptic en-
cephalopathies often have genetic or structural underpinnings,
given the acute change in the patient’s status, with seizures oc-
curring infrequently on EEG, an alternative diagnosis was felt
to be more likely. The presence of hyperammonemia, encepha-
lopathy, and seizures raised concerns that the infant has an un-
derlying inborn error of metabolism. In light of the profoundly
elevated ammonia, there was concern for an underlying amino
acid disorder, such as an organic aciduria (methylmalonic
aciduria or isovaleric aciduria) or a urea cycle disorder.
Actual Diagnosis
The elevated lactate/pyruvate ratio is consistent with a de-
fect in the metabolism of pyruvate or another mitochondrial
disorder affecting the respiratory transport chain. Whole
exome sequencing reveals a likely pathogenic, de novo mu-
tation in the PDHA1 gene, consistent with pyruvate dehy-
drogenase (PDH) deficiency.
t.me/neonatology
DISCUSSION
The pyruvate dehydrogenase complex (PDHC) is a complex of
three enzymatic subunits that exist within the mitochondria.
This complex consists of PDH (E1), dihydrolipoamide acetyl-
transferase (E2), and dihydrolipoamide dehydrogenase (E3).
(2) This complex catalyzes the conversion of pyruvate into
acetyl-CoA, which then enters the Krebs cycle, thereby allowing
for the production of adenosine triphosphate (ATP). (2)(3) Defi-
ciency in activity of any subunit leads to a decrease in the
amount of acetyl-CoA that can enter the Krebs cycle (Fig 3).
The inability to generate ATP via the Krebs cycle leads to an
Figure 3. Schematic of the role of the pyruvate dehydrogenase complex as a regulating point between glycolytic and oxidative pathways (ie, the Krebs cycle).
increase in anaerobic metabolism, which through the process
of glycolysis converts pyruvate into lactate. (2)(3)
The spectrum of clinical presentations in patients with
PDHC deficiency varies according to the extent of enzyme
dysfunction. (2) In the setting of illness, patients may experi-
ence an acute metabolic decompensation, which, in the neo-
natal period, can present as respiratory distress. (2) Laboratory
study at this time would demonstrate lactic acidosis with an
elevated ratio of lactate to pyruvate in the serum. (2) Neurons
may suffer injury because of a lack of ATP. (2) As a result, dif-
fusion-weighted imaging on MRI may show evidence of cyto-
toxic edema, and MR spectroscopy may reveal an elevated
lactate peak during this acute period. Clinically, this cerebral
injury can manifest as seizures or encephalopathy. (2)(3)(4)(5)
The meta-analysis by Patel et al of patients with PDH defi-
ciency discusses the clinical spectrum of patients with PDHC
deficiency. Their study reports an incidence of developmental
delay or deficits in 57% of patients, abnormal tone (hypertonia
or hypotonia) in 46%, and seizures in 26%. (2) Other com-
mon symptoms include microcephaly, ataxia, and facial dys-
morphisms. (2) Ventriculomegaly and hypoplastic or absent
corpus callosum are also often seen in patients with PDHC
deficiency. (2)(3) Affected children have progressive disease
and a shortened life expectancy, with an earlier age of presen-
tation being associated with lower life expectancy. (2)
Treatment options are limited and include antiseizure
medications or medications to decrease tone in hypertonic
patients. (2)(4) Other treatment options include thiamine
supplementation, dichloroacetate, and ketogenic diet. (4)(5)
Thiamine is a cofactor in PDH, and supplementation is
thought to assist in maximizing PDHC activity. (4) Dosing
guidelines are not elucidated, with a wide range of doses be-
ing reported. (4) Other therapies, such as dichloroacetate, are
thought to inhibit enzymes that inhibit PDH, such as PDH ki-
nase. (4) The use of the ketogenic diet in PDHC deficiency
has been reported in multiple case series and has been shown
to help in reducing seizure burden, but it does not appear to af-
fect further progression of the disease. (4)(5) The ketogenic diet
is thought to help by generating ketone bodies as an alterna-
tive to pyruvate as an energy source for the brain. (5)
t.me/neonatology
Lessons for the Clinician
• Elevated lactate-to-pyruvate ratio in the neonate in the set-
ting of profound lactic acidemia should prompt concern for
pyruvate dehydrogenase complex (PDHC) deficiency.
• Stigmata of PDHC deficiency may include hypogenesis
of the corpus callosum and ventriculomegaly.
• Mainstays of management include seizure control and keto-
genic diet to provide usable fuel in the form of ketone bodies.
American Board of Pediatrics
t.me/neonatology
Neonatal-Perinatal Content
Specifications
• Know how age at presentation (in utero, neonate, in-
fancy or later) affects the differential diagnosis of the
clinical presentation of genetic disorders.
• Know the causes, clinical features, laboratory evalua-
tion, and acute management of metabolic encepha-
lopathies in newborn infants.
• Understand the differential diagnosis and evaluation
of neonatal seizures.
• Know the indications for and limitations of various neuroim-
aging studies and be able to recognize normal and abnormal
structures and changes during development and growth.
References
1. Gravendeel J, Rosendahl K. Cerebral biometry at birth and at 4 and 8
months of age. A prospective study using US. Pediatr Radiol.
2010;40(10):1651–1656 doi: 10.1007/s00247-010-1687-6
2. Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The
spectrum of pyruvate dehydrogenase complex deficiency: clinical,
biochemical and genetic features in 371 patients. Mol Genet Metab.
2012;106(3):385–394 doi: 10.1016/j.ymgme.2012.03.017
3. Prasad C, Rupar T, Prasad AN. Pyruvate dehydrogenase deficiency and
epilepsy. Brain Dev. 2011;33(10):856–865 doi: 10.1016/j.braindev.2011.08.003
4. Bhandary S, Aguan K. Pyruvate dehydrogenase complex deficiency
and its relationship with epilepsy frequency–an overview. Epilepsy Res.
2015;116:40–52 doi: 10.1016/j.eplepsyres.2015.07.002
5. Sofou K, Dahlin M, Hallb€ o€
ok T, Lindefeldt M, Viggedal G, Darin N.
Ketogenic diet in pyruvate dehydrogenase complex deficiency: short-
and long-term outcomes. J Inherit Metab Dis. 2017;40(2):237–245 doi:
10.1007/s10545-016-0011-5
Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e109
 INDEX OF SUSPICION IN THE NURSERY

A Preterm Infant with

Pneumoperitoneum
Jubara Alallah, MD,*†‡ Abdelfatah I. Abuzaid, MD,§ Abdulaziz Alkhotani, MD,§ Edward Riachy, MD¶
*Neonatology Section, Pediatric Department, King Abdulaziz Medical City, Ministry of National Guard, Jeddah, Kingdom of Saudi Arabia
†
Neonatology Section, King Abdullah International Medical Research Centre, Jeddah, Kingdom of Saudi Arabia
‡
Neonatology Section, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia
§
Department of Pediatrics, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
¶
Department of Pediatric Surgery, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia

CASE PRESENTATION

T.ME/NEONATOLOGY
AUTHOR DISCLOSURES Drs Alallah,
Abuzaid, Alkhotani, and Riachy 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.
t.me/neonatology
A male twin infant was born at 33 weeks’ gestation via an emergency cesarean
delivery due to unstoppable preterm labor. The pregnancy was benign, with no
medical illness during the pregnancy, and prenatal laboratory screening tests
were normal. There was no consanguinity and no sepsis concerns. The infant
was delivered at a local hospital and emerged active and well-appearing. His Ap-
gar score was 9 and 9 at 1 and 5 minutes, respectively. He had stable vital signs
with a temperature of 97.7 F (36.5 C), heart rate of 160 beats/min, respiratory
rate of 65 breaths/min, blood pressure of 60/35 mm Hg, and oxygen saturation
of 90%. The infant’s birthweight was 2.3 kg (77th percentile), and the initial
newborn examination revealed no dysmorphic features.
The infant developed respiratory distress soon after birth and was transferred
to the NICU where he was placed on continuous positive airway pressure of 5 cm
H2O with a fraction of inspired oxygen (FiO2) of 0.23. A partial sepsis evaluation
was initiated; the infant was kept nil per os (NPO) with intravenous fluids and
was started on ampicillin and amikacin. A nasogastric tube (NGT) was inserted as
the infant was on CPAP for venting air. His respiratory distress improved 2 days
after birth, and he was transitioned to a high-flow nasal cannula before being
weaned to an oxygen hood.
On the third day after birth, the patient presented with a sudden onset of ab-
dominal distention, emesis, and coffee-ground aspirates from NGT that became
greenish in color. In addition to a distended but soft abdomen, the infant had
intermittent desaturations, hypotonia, and lethargy. The infant’s scrotum also
appeared to be distended. The infant’s blood pressure and heart rate were main-
tained, and a radiograph revealed massive pneumoperitoneum (Fig 1). He was
then transferred to our hospital for further care.
Upon arrival at our hospital, the neonate was stable, had normal vital signs,
and was on low-flow nasal cannula at 2 L/min and a FiO2 of 0.21. The neonate
had respiratory distress, and his abdomen was distended without redness or dis-
coloration of the abdominal wall. Laboratory investigations were all within nor-
mal limits, and the neonate's capillary blood gas showed a pH of 7.34, PCO2 of

e110 NeoReviews

t.me/neonatology

Figure 1. Abdominal radiograph showing intraperitoneal air in the sub-
diaphragmatic area (black arrows) and football sign associated pneumo-
scrotum (blue arrow), which signifies massive pneumoperitoneum on day
3 after birth.
42 mm Hg, PaO2 of 140 mm Hg, HCO3 of 18.7, and base
excess of 7. Abdominal radiography on arrival revealed
intraperitoneal air (ie, the “football sign”), with NGT deep
in the left lower quadrant of the abdomen (Fig 2).
DISCUSSION
Differential Diagnosis
The differential diagnosis for abdominal distention and pneu-
moperitoneum in a preterm newborn includes the following:
• Necrotizing enterocolitis
• Spontaneous intestinal perforation
• Intestinal malrotation with volvulus and perforation
• Sepsis
Actual Diagnosis
Pneumoperitoneum due to gastric perforation
Case Progression
The patient was referred to a higher level of care with spon-
taneous intestinal perforation. Antibiotic treatment was con-
tinued the same as in the referral hospital. The patient was
t.me/neonatology
t.me/neonatology
Figure 2. Abdominal radiograph on day 4 after birth showing massive
pneumoperitoneum with intraperitoneal air in the subdiaphragmatic area
(black arrows) and deep nasogastric tube ending at the left lower quad-
rant (blue arrow), suggesting gastric perforation.
taken to the operating room shortly after admission to the
NICU, where an emergency laparotomy was performed.
Upon exploration, 2 areas of perforation measuring 6 mm
and 3 mm were found on the lesser curvature of the anterior
aspect of the stomach, in an otherwise healthy-looking, non-
ischemic stomach. There was no abnormal fluid in the ab-
dominal cavity. The position of the duodenojejunal junction
and cecum was appropriate. The rest of the abdominal cavity
was free of any other pathology. The perforations were closed
primarily with absorbable sutures. The incision was closed
without drain placement. A new NGT was inserted by the
surgeon in the operating room. After surgery, the patient re-
turned to the NICU on a mechanical ventilator in stable con-
dition. The patient was kept NPO and continued to receive
antibiotics (vancomycin and gentamicin). The neonate was
gradually weaned from the mechanical ventilator and suc-
cessfully extubated to nasal cannula and then to room air
on day 3 after surgery. The neonate was kept NPO for a
total of 7 days and received total parenteral nutrition and
omeprazole.
On the seventh postoperative day, a diatrizoate (Gastrografin)
study was performed, which did not detect extravasation or
leakage of the contrast from the gastric repairs. The stomach
Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e111
 was of normal size and shape, with no mucosal ulceration or
filling defects. Normal emptying time of the stomach was also
observed (Fig 3).
The infant started to gradually receive feedings through
an NGT, which was inserted by the surgeon during sur-
gery with 2 mL of feed every 3 hours, which increased by
2 mL every 6 hours. He was monitored closely for feeding
intolerance and abdominal changes and reached full feed-
ings without any issues. His antibiotics were stopped
7 days postoperatively, and the blood culture showed no
growth.
The infant was discharged from the hospital on postop-
erative day 10 in good condition, in room air, and tolerat-
ing full oral feedings. Follow-up appointments were made
with the outpatient department in general pediatrics and
pediatric surgery clinics.
Neonatal gastric perforation is a very rare, life-threaten-
ing condition, accounting for almost 7% of all gastrointes-
tinal perforations in the neonatal age group. (1)(2) Reports
of gastric perforation in neonates are limited and have
been reported among term and preterm infants.
The etiology of neonatal gastric perforation remains un-
clear. The exact mechanisms of neonatal gastric perfora-
tion are unknown, but possible causes include perinatal
depression, local gastric ischemia, excessive respiratory
support with high pressures, increased intragastric
pressure, high gastric acidity, and congenital defects of
the gastric musculature. Trauma during endotracheal
intubation and feeding tube insertion has been re-
ported to be associated with gastric perforation. The
Figure 3. Water-soluble contrast study on postoperative day 7 showed no detected contrast extravasation or leakage, as well as normal size and shape
of the stomach without mucosal ulceration or filling defects.
e112 NeoReviews
t.me/neonatology
use of corticosteroids in combination with cyclooxygen-
ase inhibitors for the treatment of patent ductus arterio-
sus is another risk factor. (2) Neonatal gastric perforation
can occur in the presence of 1 or a combination of multi-
ple risk factors.
In our case, a traumatic injury is highly likely the cause
of this infant’s gastric perforation because of the deep po-
sition of NGT as seen in the radiograph and the healthy-
looking gastric wall noted during surgery.
The clinical presentation of neonatal gastric perforation
includes abdominal distention, decreased activity, feeding
intolerance, respiratory distress, gastrointestinal bleeding,
abdominal wall erythema, and potentially shock. The most
common location for gastric perforation is the greater cur-
vature, followed by the lesser curvature, anterior wall, and
posterior wall. In a report of 168 cases, the time of perfo-
ration is usually between the second and seventh day after
birth, with a mean of 3.5 days. (3) Treatment should be
started as soon as possible and includes intravenous flu-
ids, cessation of feedings, broad-spectrum antibiotics, total
t.me/neonatology
parenteral nutrition, and prompt surgical intervention.
Surgical management remains the treatment of choice.
Gastrorrhaphy alone (a suture of a perforation of the stom-
ach) or combined with a gastrostomy is the most com-
monly performed procedure for this diagnosis. Outcomes
of gastric perforations are affected by gestational age, with
preterm infants having 4.21 times higher mortality rates
compared with full-term infants. (3) The mortality rate in
the 1980s was 100%, which has significantly decreased to
16.7% in the 2010s. (4) The improvement in survival rates
is likely due to earlier diagnosis and improvements in the
quality of neonatal care. Quality improvement programs to
reduce complications related to NGT tube insertion in-
clude standardized protocols and guidelines for NGT in-
sertion. Comprehensive training and education should be
provided to health care professionals involved in neonatal
care to enhance their knowledge and skills in NGT inser-
tion. Improved monitoring and documentation, including
confirmation of the tube position, are important.
Lessons for the Clinician
• Neonatal gastric perforation is a rare and life-threatening
condition in neonates.
• The etiology remains controversial, but trauma during
feeding tube placement has been reported to be associ-
ated with gastric perforation in infants.
• Early diagnosis of neonatal gastric perforation has favor-
able outcomes, and surgery remains the treatment of
choice.
t.me/neonatology
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Recognize the clinical manifestations, diagnosis, and
management of infants with perforations of the gas-
trointestinal tract (including gastric and intestinal).
References
1. Lin CM, Lee HC, Kao HA, et al. Neonatal gastric perforation: report of
15 cases and review of the literature. Pediatr Neonatol. 2008;49(3):65–70
2. Byun J, Kim HY, Noh SY, et al. Neonatal gastric perforation: a single
center experience. World J Gastrointest Surg. 2014;6(8):151–155
3. Chen TY, Liu HK, Yang MC, et al. Neonatal gastric perforation:
a report of two cases and a systematic review. Medicine (Baltimore).
2018;97(17):e0369
4. Yang T, Huang Y, Li J, et al. Neonatal gastric perforation: case series
and literature review. World J Surg. 2018;42(8):2668–2673
t.me/neonatology
Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e113
 INDEX OF SUSPICION IN THE NURSERY
One Bone in Two Pieces: Does It Have
to Be a Fracture?
Kathleen Forcier, MD,* Meghan Imrie, MD†
*Department of Pediatrics, Palo Alto Medical Foundation, Palo Alto, CA
†
Division of Pediatric Orthopedics, Department of Orthopedic Surgery, Stanford University, Palo Alto, CA
AUTHOR DISCLOSURES Dr Imrie has
served as fellow chair at the Pediatric
Orthopaedic Society of North America.
Dr Forcier has 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.
e114 NeoReviews
T.ME/NEONATOLOGY
CASE PRESENTATION
A female infant is delivered to a 33-year-old gravida 2, para 1 woman via sponta-
neous vaginal delivery at 40 2/7 weeks’ gestation. The pregnant woman received
good prenatal care; her laboratory findings are unremarkable, except for gesta-
t.me/neonatology
tional thrombocytopenia, with a recent platelet count of 110 × 103/mL (110 × 109/L).
An anatomy scan performed at 20 weeks’ gestation was normal.
The delivery is uncomplicated, requiring just 2 pushes before delivery of the
shoulders. The infant is appropriate for gestational age, with a birthweight of 3.1 kg.
The infant’s physical examination at 1.5 hours after birth is normal except for a
right ear pit and nontender bony prominences palpated over the midshaft of the
clavicle bilaterally. No crepitus is noted. There is no evidence of brachial plexus in-
jury: the infant moves both upper extremities equally, the Moro reflex is symmetric,
and the infant’s grasp is strong bilaterally. Capillary refill is 2 seconds in the fin-
gertips. No other bony anomalies are noted. There are no skin findings such as
caf
e-au-lait spots.
To investigate the bony abnormalities noted on clavicular examination, a
chest radiograph is performed at 2 hours after birth (Fig 1). The film is read as
a left clavicular fracture. The radiologic reading is inconsistent with the physical
examination given that there is no crepitus and the lesions are nontender. The
bony prominence is noted bilaterally on examination, but the view of the right
clavicle at the time of the radiography obscured any mid-shaft clavicular finding.
The diagnosis of a fracture is also surprising given the delivery history. The
chest radiograph does not show any other fractures that might suggest osteogen-
esis imperfecta. On review of the radiograph, the bony ends of the infant’s left
clavicle appear rounded and smooth in contrast to a fracture that typically has
jagged ends. Differential diagnosis includes clavicular fracture, pseudoarthrosis
of the clavicle, and cleidocranial dysplasia. The team consulted a pediatric ortho-
pedic surgeon at a nearby children’s hospital, who recommended routine care
with follow-up in their clinic. The infant is then discharged from the hospital on
day of life 2 with follow-up at the orthopedic surgery clinic at 2 weeks of age. At
that time, the infant’s chest radiograph demonstrates bilateral clavicular involve-
ment (Fig 2) and fails to show any callus formation. Based on these findings, the
infant’s diagnosis is consistent with pseudoarthrosis of the clavicles.
t.me/neonatology

Figure 1. Anteroposterior chest radiograph at 2 hours of age. The arrow
shows the left midclavicular gap.
DISCUSSION
Pseudoarthrosis of the clavicle is a rare condition resulting
from the failure of fusion between the ossification centers
of the clavicle. (1)(2)(3)(4) It occurs more often on the right
side than on the left, and bilateral cases, such as our patient,
are extremely uncommon. Left-sided cases can be associated
with dextrocardia, (1)(5) subclavian artery malformations, or
cervical ribs. (1) Pseudoarthrosis of the long bones can be as-
sociated with neurofibromatosis. Patients often present in
Figure 2. Anteroposterior chest radiograph at 13 days after birth.
t.me/neonatology
infancy with a painless mass in the area of the clavicle. Sub-
tle differences between a clavicular fracture and pseudoarth-
rosis can be noted on radiographs. Due to the traumatic
nature of a fracture, the bony ends are often sharp, whereas
in pseudoarthrosis, the ends are bulbous and rounded. (4)(6)
The midclavicular gap is often wider with pseudoarthrosis
than with a fracture. (5) In cases of clavicular fracture due to
birth trauma, callus formation will be present on the radio-
graph within 2 weeks of delivery but will be absent in the
case of pseudoarthrosis. (4)(5)
In the newborn period, pseudoarthrosis of the clavicle
poses no risks; however, as patients grow, the deformity
can become more conspicuous, and some patients develop
pain around the shoulder girdle or have a limited range
of motion. (1)(2) Less frequently, patients can develop thoracic
outlet syndrome or other vascular compromise. (1)(2)(4) Refer-
ral to orthopedic surgery is important to prevent/treat
these symptoms as they arise later in life. Surgical repair
is generally considered the standard of care to optimize
shoulder mobility, minimize upper limb pain, and miti-
t.me/neonatology
gate cosmetic concerns. Repair consists of resection of the
pseudoarthrosis, bone grafting (often from the iliac crest),
and internal fixation (with either plates or Kirschner
wires). Many surgeons advocate for correction between 3
and 6 years of age. In children older than 6 years, the in-
creasing gap size makes autologous bone grafting more
challenging, but there are higher rates of nonunion when
the procedure is performed in children younger than
18 months. (1)(2)
As with our patient, this condition is often confused
with clavicular fracture from birth trauma or child abuse
later in life. Clavicular fractures are the most common
birth fracture, occurring in 0.2% to 3.5% of births. (7)(8)
Risk factors include birthweight greater than 4,000 g, in-
creased head circumference, gestational diabetes mellitus,
shoulder dystocia, and mechanically assisted delivery. (7)(8)
On physical examination, clavicular fractures are associated
with pain and crepitus at the fracture site, rather than a pain-
less mass, and may also be associated with evidence of bra-
chial plexus injury or pseudoparalysis of the upper limb due
to pain.
Another disorder associated with congenital clavicular
anomalies is cleidocranial dysplasia. This autosomal domi-
nant disorder is caused by a mutation in the RUNX2 gene,
and affected infants present with a triad of 1) hypoplasia
or aplasia of the clavicles, 2) deformity of the skull (large
fontanelles, macrocephaly), and 3) dental anomalies (delayed
loss of deciduous teeth and eruption of permanent teeth or
supernumerary teeth). (6)
Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e115
 Lessons for the Clinician
• Pseudoarthrosis of the clavicle presents as a painless
mass in the midclavicular area compared to a clavicular
fracture that presents with pain and crepitus at the site
of the injury.
• Radiographs of patients with pseudoarthrosis of the
clavicle demonstrate bulbous and rounded edges of
the bone sections, whereas the bone fragments of a
clavicular fracture have jagged and sharp ends on
radiograph.
• Callus formation will be evident radiographically as a
clavicular fracture heals, whereas callus formation is
never seen in patients with pseudoarthrosis.
• Repair is recommended in patients with pseudoarthrosis
of the clavicle at 3 to 6 years of age to prevent shoulder
pain and limited range of motion later in life.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Recognize the clinical features and know how to diag-
nose and manage congenital anomalies of the upper
extremities, such as syndactyly, polydactyly, absent
e116 NeoReviews
t.me/neonatology
clavicles, absent radius, Sprengel deformity, and limb
reduction.
References
1. Kim AE, Vuillermin CB, Bae DS, Samora JB, Waters PM, Bauer AS.
Congenital pseudarthrosis of the clavicle: surgical decision making
and outcomes. J Shoulder Elbow Surg. 2020;29(2):302–307
2. Mart
ınez-Aznar C, Parada-Avenda~ no I, G

omez-Palacio VE, Abando-
Ruiz S, Gil-Albarova J. Surgical treatment of congenital pseudoarthrosis
of the clavicle: Our 22-year, single-center experience. Jt Dis Relat Surg.
2021;32(1):224–229
3. Walker BM, Vangipuram SD, Kalra K. Congenital pseudoarthrosis
of the clavicle: a diagnostic challenge. Glob Pediatr Health. 2014;1:
X14563384
4. Alsaeed AA. Surgical management of congenital pseudoarthrosis of
the clavicle: a review of current concepts. Cureus. 2021;13(10):e18482
5. Fontoura-Matias J, Vilan A. Clavicle lump: Not always a fracture - a
case of congenital pseudoarthrosis. Pediatr Int (Roma).
2021;63(12):1544–1545
t.me/neonatology
6. Franceschi R, Stringari G, Soli F, Pedrolli A, Maines E. Newborn with
cleidocranial dysplasia. Skeletal Radiol. 2022;51(12):2351–2352
7. Rehm A, Promod P, Ogilvy-Stuart A. Neonatal birth fractures: a
retrospective tertiary maternity hospital review. J Obstet Gynaecol.
2020;40(4):485–490
8. Erg€
un T, Sarikaya S. Newborn clavicle fractures: does clavicle fracture
morphology affect brachial plexus injury? J Pediatr Orthop. 2022;42(4):
e373–e376
T.ME/NEONATOLOGY
 MATERNAL-FETAL CASE STUDIES

Elevation of Maternal Serum

a-Fetoprotein: Implications for the
Neonate
Jessica Celine Morgan, MD,* Linda M. Ernst, MD, MHS,† Ian Grable, MD*
*Department of Obstetrics and Gynecology, University of Chicago/NorthShore University Health System, Evanston, IL
†
Department of Pathology and Laboratory Medicine, NorthShore University Health System, Evanston, IL

THE CASE
Presentation

t.me/neonatology
A 30-year-old gravida 3, para 2-0-0-2 pregnant woman was seen for a maternal-
fetal medicine consultation because of an elevated maternal serum a-fetoprotein
(msAFP) level at 19 multiples of the median (MoM). Her previous obstetrical
history was significant for 2 full-term vaginal deliveries. One neonate was born
small for gestational age, weighing approximately 2,400 g at 37 weeks’ gestation.
She denied any other known pregnancy complications and has no significant
medical or surgical history.
Her detailed anatomic survey at 22 weeks and 5 days’ gestation revealed
growth that was appropriate for gestational age, with no anatomic explanation
for the elevated msAFP; specifically, views of the ventral wall, posterior fossa,
spine, and placenta appeared normal. The maternal ovaries were visualized bilat-
erally, and there were no masses or concerns for malignancy. The patient was
counseled about the potential risk of adverse pregnancy outcomes with elevated
msAFP, including spontaneous abortion, preterm birth, fetal growth restriction,
fetal demise, and preeclampsia. There were no obvious fetal or maternal ultrasono-
graphic findings to explain the significant elevation of this serum marker. Repeat
ultrasonography was planned in addition to referral to oncology and hepatology for
further evaluation.
T.ME/NEONATOLOGY
Progression
The patient presented at 25 weeks and 2 days’ gestation with preterm premature rup-
ture of membranes (PPROM). She was admitted for maternal and fetal inpatient sur-
veillance. The patient received betamethasone for fetal benefit, latency antibiotics, and
a course of magnesium sulfate for fetal neuroprotection. A neonatologist met with AUTHOR DISCLOSURES Dr Ernst receives
royalties from Elsevier. Drs Morgan and
the family and reviewed neonatal outcomes and the management associated with a Grable have disclosed no financial
preterm birth. The pregnant patient received an expedited evaluation with hepatology relationships relevant to this article. This
and oncology to evaluate for evidence of maternal malignancy that may cause the commentary does not contain a
discussion of an unapproved/
msAFP elevation. The evaluation, including liver function tests, right upper quadrant investigative use of a commercial
ultrasonography, and abdominal magnetic resonance imaging, was normal. product/device.

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e117

t.me/neonatology
 Maternal Outcome
At 28 weeks and 2 days’ gestation, the patient developed
preterm labor and vaginal bleeding. She underwent an un-
complicated classic cesarean delivery for breech malpre-
sentation. Intraoperatively, there was clinical suspicion for
placental abruption with a retroplacental blood clot adher-
ent to the placenta.
Neonatal Outcome
The nonvigorous preterm neonate emerged from the breech
presentation. Cord clamping was delayed for 30 seconds.
The infant’s Apgar score was 3 at 1 minute, 7 at 5 minutes,
and 9 at 10 minutes, and the birthweight was 1,130 g
(52nd percentile). The infant responded to initial resuscitation
and was placed on continuous positive airway pressure for
respiratory support because of respiratory distress.
In the NICU, chest radiography revealed small lung
volumes and moderate-to-severe respiratory distress syn-
drome. The infant underwent intubation and was treated
with antibiotics, caffeine, and intratracheal surfactant. The
infant had bloody output from the nasogastric tube and
had recurrent difficulty tolerating tube feedings. Abdomi-
nal distention was noted during the first week of age, with
multiple radiographs showing diffuse abdominal disten-
tion. The neonatology team consulted with the gastroen-
terology team, who performed an endoscopy and barium
enema for persistent gastroenteric bleeding. Imaging re-
vealed possible Hirschsprung disease, and transfer to a fa-
cility with pediatric surgery was recommended. Apart
from this, there were no congenital anomalies or concern
for underlying malignancy such as an AFP-secreting tu-
mor, and there were no abnormal findings related to the
liver on imaging or laboratory tests.
After transfer, the infant was found to have worsening
kidney function, edema, and proteinuria with concern for
nephrotic syndrome. The evaluation for Hirschsprung dis-
ease was negative. Genetic testing was pursued, with whole
genome sequencing identifying 2 variants in the NPHS1
gene consistent with Finnish type steroid-resistant nephrotic
syndrome. The infant is currently 44 weeks’ postmenstrual
age and continues to be treated in the NICU because of re-
current apneic and bradycardic episodes.
Maternal Postpartum Follow-up
At 6 weeks’ postpartum, the maternal AFP level was
checked and was found to have returned to the normal
range, showing resolution of the elevated AFP level.
Placental pathology demonstrated high-grade acute in-
flammation, low-grade maternal vascular pathology, and
e118 NeoReviews
t.me/neonatology
Table. Commonly Recognized Causes of an Elevated
msAFP Level in Pregnancy
Placental
Maternal Causes Fetal Causes Causes
Malignancy Ventral wall defect Abruption (Fig 1)
 Ovarian  Gastroschisis (Fig 2) Placental
 Hematologic  Omphalocele insufficiency
 Hepatic  Bladder exstrophy Placental tumors
Idiopathic hereditary Neural tube defect (Fig 3) Chorioangioma
elevated AFP  Encephalocele
levels  Myelomeningocele
Congenital nephrotic
syndrome
Multifetal gestation
AFP5a-fetoprotein, msAFP5maternal serum a-fetoprotein
low-grade chronic inflammation, which is associated with
early preterm births and small-for-gestational-age neonates.
There was also a retroplacental hematoma.
DISCUSSION
msAFP levels have been used as a method of prenatal
t.me/neonatology
screening, specifically for fetal open neural tube defects
(ONTDs) since the 1980s. (1) An elevated msAFP level
may result from other fetal anomalies including ventral
wall defect or bladder exstrophy, twin gestation, placental
insufficiency, and rarely maternal malignancy. (2) Causes
of an elevated msAFP level are outlined in the Table. (3)
The timing of msAFP screening is recommended to be
between 15 and 22 weeks’ gestation; therefore, the correct
gestational age is critical as results are reported as an
MoM correlating to gestational age. With advances in ul-
trasonography, the American College of Obstetricians and
Gynecologists (ACOG) recognizes that the primary useful-
ness of msAFP screening in pregnancy has shifted from
being a primary screening technique for ONTDs and other
structural abnormalities to one that may screen for placen-
tal insufficiency. (4)(5)
When interpreting an elevated msAFP level—after en-
suring gestational age is correctly calculated and there are
no other factors that may lead to an erroneously elevated
level—a detailed anatomic ultrasonographic assessment is
performed. (4) Ultrasonography is often targeted toward
specific fetal anatomy, growth, placental appearance, and
maternal ovaries.
If a detailed anatomic survey reveals an obvious source
of the elevated msAFP level, such as an ONTD, gastroschi-
sis, placenta accreta, or significant bleeding, then elevation
of msAFP is attributed to the sonographic etiology. If
there are no findings on ultrasonography, including of the
maternal ovaries, then this is considered an unexplained
 T.ME/NEONATOLOGY

Figure 1. Placenta with abruption. Images of the delivered placenta show macroscopic changes consistent with placental abruption. A. The chorionic
(fetal) surface of the 330 g placenta is demonstrated. A separate 53-g blood clot was delivered with the placenta. B. The maternal surface of the placenta
shows peripheral parenchyma indentation and adherent retroplacental blood (arrow). The separate blood clot is also shown in this image and is of ap-
propriate size to fit within the peripheral indentation.

msAFP elevation, and counseling is focused on the poten- an elevated msAFP level. While assessing for other sour-
tial risk of pregnancy complications. (6) ces of elevated AFP levels, there was no evidence of mater-
It is known that there is an association between adverse nal malignancy or other underlying maternal disease. At

pregnancy outcomes and an unexplained msAFP eleva-
tion. Risks include placental insufficiency resulting in fetal
growth restriction, intrauterine fetal demise, and oligohy-
dramnios, as well as development of hypertensive disor-
ders of pregnancy and preterm delivery (7)(8); these risks are
directly correlated to the degree of msAFP elevation. (9) For
pregnancies with a significantly elevated msAFP level above
2.5 MoM, the pregnancy should be closely monitored with
ultrasonographic surveillance, and frequent blood pressure
surveillance is appropriate because of the risk of hypertensive
disease in pregnancy. (10)(11)(12) A neonatology consultation
can also be considered if preterm delivery is anticipated.
In this case, the pregnant patient experienced a delivery
at an extreme preterm gestational age, with placental
abruption and PPROM, both of which are associated with
t.me/neonatology
the woman’s postpartum visit, she had a normal serum
AFP level, indicating that the previous AFP elevation was as-
sociated with the pregnancy. The neonate was diagnosed
with a rare autosomal recessive form of congenital nephrotic
syndrome. In a case series of an elevated msAFP level in
pregnancy with a diagnosis of fetal congenital nephrotic syn-
drome, pregnancies are often complicated by preterm birth,
enlarged placenta, and proteinuria. (13)(14)(15)(16) The mater-
nal proteinuria, originating from fetal renal disease, causes
excessive levels of msAFP. (13) The fetal proteinuria and
edema from congenital nephrotic syndrome are hypothe-
sized to result in placental edema, leading to decidual injury
and placental abruption, although the occurrence of this rare
disease limits extensive study of associated obstetric outcomes.
This infant’s rare autosomal recessive genetic diagnosis will

Figure 2. Gastroschisis. Ultrasound images demonstrate an example of a ventral wall defect that can result in an elevated maternal serum a-fetoprotein
level. The transverse view (left) of the fetal abdomen shows a free-floating bowel (noted with yellow calipers) in the amniotic fluid. The sagittal view
(right) shows the fetal head on the left side of the image and the fetal abdomen on the right side of the image. The free-floating bowel can be seen on
the ventral wall of the abdomen (arrows).

Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e119

t.me/neonatology
 Figure 3. Open neural tube defect. Ultrasound images demonstrate an example of an open neural tube defect that can result in an elevated maternal
serum a-fetoprotein level. Note the “lemon-shaped” skull (arrow) and the obliteration of the posterior fossa in the image on the left. The sagittal view on
the right shows the lumbar and sacral spine with an open defect (arrow).
affect future pregnancy counseling because additional genetic
screening showed that the infant inherited the disease from
both the mother and father.
American Board of Pediatrics
Neonatal-Perinatal Content
Specifications
• Know the essentials of prenatal care, including risk as-
sessment, perinatal referral, screening, and standard
monitoring.
• Know the effects on the fetus and/or newborn infant of
maternal or placental malignancy and its management.
• Know the effects on the fetus and/or newborn infant
of mild preeclampsia and its management.
• Know the effects on the fetus and/or newborn infant
of severe preeclampsia, including HELLP syndrome,
and its management.
• Know the differential diagnosis and potential risks to
the fetus and/or newborn infant of first, second, and
third trimester vaginal bleeding.
• Know the rationale, methods, and interpretation of re-
sults of first and second trimester screening for aneu-
ploidy (eg, nuchal translucency, choroid plexus cysts)
and neural tube defects.
• Understand 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 how to use obstetric and ultrasonographic data to
determine gestational age, and know their limitations.
• Know the diagnosis and management of maternal/
fetal blood loss such as placenta previa, placenta abrup-
tion, vasa previa, and maternal-fetal hemorrhage.
• Know the significance and obstetrical management of
meconium-stained amniotic fluid.
T.ME/NEONATOLOGY
e120 NeoReviews
t.me/neonatology
References
1. Burton BK. Elevated maternal serum alpha-fetoprotein (MSAFP):
interpretation and follow-up. Clin Obstet Gynecol. 1988;31(2):293–305
2. Milunsky A, Alpert E. Results and benefits of a maternal serum
alpha-fetoprotein screening program. JAMA. 1984;252(11):1438–1442
3. Spaggiari E, Ruas M, Dreux S, et al. Management strategy in
pregnancies with elevated second-trimester maternal serum alpha-
t.me/neonatology
fetoprotein based on a second assay. Am J Obstet Gynecol.
2013;208(4):303.e1–303.e7
4. Neural tube defects. Practice Bulletin No. 187. American College of
Obstetricians and Gynecologists. Obstet Gynecol. 2017;130:e279–e290
5. Indications for outpatient antenatal fetal surveillance. ACOG
Committee Opinion No. 828. American College of Obstetricians
and Gynecologists. Obstet Gynecol. 2021;137:e177–e197
6. Krantz D, Hallahan T, Janik D, Carmichael J. Maternal serum
screening markers and adverse outcome: a new perspective. J Clin
Med. 2014;3(3):693–712
7. Waller DK, Lustig LS, Cunningham GC, Feuchtbaum LB, Hook EB.
The association between maternal serum alpha-fetoprotein and
preterm birth, small for gestational age infants, preeclampsia, and
placental complications. Obstet Gynecol. 1996;88(5):816–822
8. Androutsopoulos G, Gkogkos P, Decavalas G. Mid-trimester
maternal serum HCG and alpha fetal protein levels: clinical
significance and prediction of adverse pregnancy outcome. Int J
Endocrinol Metab. 2013;11(2):102–106
9. Yeaton-Massey A, Baer RJ, Rand L, Jelliffe-Pawlowski LL, Lyell DJ.
Adverse pregnancy outcomes by degree of maternal serum analyte
elevation: a retrospective cohort study. AJP Rep. 2020;10(4):
e369–e379
10. Mariona FG, Hassan MM, Syner FN, Chik LC, Sokol RJ. Maternal
serum alpha-fetoprotein (MSAFP) and fetal growth. J Perinat Med.
1984;12(4):179–183
11. Chandra S, Scott H, Dodds L, Watts C, Blight C, Van Den Hof M.
Unexplained elevated maternal serum alpha-fetoprotein and/or
human chorionic gonadotropin and the risk of adverse outcomes.
Am J Obstet Gynecol. 2003;189(3):775–781
12. Bredaki FE, Matalliotakis M, Wright A, Wright D, Nicolaides KH.
Maternal serum alpha-fetoprotein at 12, 22 and 32 weeks’ gestation in
screening for pre-eclampsia. Ultrasound Obstet Gynecol. 2016;47(4):
466–471
13. Lee BH, Ahn YH, Choi HJ, et al. Two Korean infants with
genetically confirmed congenital nephrotic syndrome of
 Finnish type. J Korean Med Sci. 2009;24(suppl 1):
S210–S214
14. Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol.
2009;24(11):2121–2128
15. Sepp€al€a M, Rapola J, Huttunen NP, Aula P, Karjalainen O,
Ruoslahti E. Congenital nephrotic syndrome: prenatal diagnosis
T.ME/NEONATOLOGY
t.me/neonatology
and genetic counselling by estimation of aminotic-fluid and
maternal serum alpha-fetoprotein. Lancet. 1976;2(7977):
123–125
16. Jain JB, Chauhan S. Congenital nephrotic syndrome. In: StatPearls
[Internet]. Treasure Island, FL: StatPearls Publishing; 2023 https://
www.ncbi.nlm.nih.gov/books/NBK572058/ Accessed November 12, 2023
t.me/neonatology
Vol. 25 No. 2 F E B R U A R Y 2 0 2 4 e121
 VISUAL DIAGNOSIS
A 3-day-old Neonate with Generalized
Edema and a Bullous Rash
Dhanya Jayaraj, MD,* Vidya Ramdas, MD, MRCPCH (UK),* Abeer Ateeq Al-Balushi, MD, OMSB,†
Salima Al Asiry, MD, MRCPCH,* Mohammed Al Yahmadi, MD, MRCPCH,* Manoj N. Malviya, MRCP (UK)*
*Department of Pediatrics, Khoula Hospital, Muscat, Oman
†
Department of Dermatology, Al Nahdha Hospital, Muscat, Oman
AUTHOR DISCLOSURES Drs Jayaraj,
Ramdas, Al-Balushi, Asiry, Yahmadi, and
Malviya 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.
e122 NeoReviews
THE CASE
A 3-day-old male infant presented with generalized edema and bullous rash in-
volving the face, arms, chest, abdomen, and legs.
t.me/neonatology
Prenatal and Birth Histories
• Born to a 34-year-old gravida 3, para 2 woman of Asian origin
• Third-degree consanguineous parents
• Uneventful antenatal period; antenatal scans were normal
• Family history: 2 elder siblings are healthy; suspected Dubin-Johnson syndrome
in a maternal uncle
• Delivery at 38 weeks’ gestation by elective cesarean delivery because of pre-
vious cesarean delivery; no prolonged rupture of membranes or maternal
fever
• Apgar scores were 8 and 9 at 1 and 5 minutes, respectively
• Tachypnea noted soon after birth, which required nasal oxygen and resolved
within 24 hours
• On day 2, he developed jaundice requiring single-light phototherapy for 24 hours.
The mother’s blood group is O positive, and the infant’s blood group is B positive.
The direct Coombs test was positive, but his hematocrit remained stable, and there
was no sign of hemolysis.
Presentation (3 Days after Birth)
Three days after birth, the infant was noted to have generalized edema, bullous
rash on the face, arms, chest, abdomen, and legs (Fig 1A), and brownish red
urine (Fig 1B). He was referred to our hospital for evaluation.
Vital Signs
• Heart rate: 130 beats/min
• Respiratory rate: 40 breaths/min
• Blood pressure: 72/45 mm Hg (mean 52 mm Hg)
• Oxygen saturation 99% in room air
• Temperature: 98.1 F (36.7 C)
t.me/neonatology

Figure 1. A. Bullous rash involving the arms, chest, abdomen, and legs on day 3 after birth. B. Brownish red urine at 5 days of age.
Physical Examination
• Birthweight 3 kg (just below 50th percentile), birth head
circumference 35 cm (just below 90th percentile), birth
length 51 cm (just below 50th percentile)
• Weight at admission on day 3: 3.3 kg
• General: Active, generalized edema
• Head: Size and shape normal, fontanelles normal
• Face: No dysmorphism, ruptured bullous lesion over
cheeks
• Oral cavity: Pink, no cleft palate, no oral ulcers
• Skin: Bullae with brownish pink fluid over the legs and
abdomen, with a few ruptured bullae over the face,
chest, arms, and abdomen; skin appeared sclerematous;
no pallor or jaundice
• Lungs: No respiratory distress, normal breath sounds on
both sides
• Cardiovascular: Normal S1-S2, no murmur
• Abdomen: No organomegaly, anus patent
• Neurologic: Active with normal neonatal reflexes
• Spine: Normal
• Genitourinary: Normal term male genitalia
t.me/neonatology
T.ME/NEONATOLOGY
t.me/neonatology
Laboratory Studies
• White blood cell count 12.8 × 103/mL (12.8 × 109/L), neutro-
phils 6.9 ×103/mL (6.9 × 109/L), lymphocytes 3.5 × 103/mL
(3.5 × 109/L)
• Hemoglobin: 14.4 g/dL (144 g/L)
• Platelet count: 159 × 103/mL (159 × 109/L)
• C-reactive protein: Negative
• Peripheral blood smear: Normal
• Reticulocyte count: 5.5%
• Serum bilirubin: Total 11.2 mg/dL (191.56 mmol/L), con-
jugated bilirubin 2.9 mg/dL (49.60 mmol/L)
• Aspartate aminotransferase 31 U/L (0.52 mkat/L), alanine
aminotransferase 48 U/L (0.80 mkat/L), alkaline phos-
phatase 135 U/L (2.25 mkat/L), g-glutamyltransferase
(GGT) 650 U/L (10.86 mkat/L)
• Prothrombin time 11.8 s, partial thromboplastin time
28.80 s, international normalized ratio 1.03
• Renal function tests: blood urea nitrogen 3.70 mg/dL
(1.32 mmol/L), creatinine 0.43 mg/dL (37.7 mmol/L), so-
dium 138 mEq/L (138 mmol/L), potassium 4.8 mEq/L
(4.8 mmol/L)
Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e123
 • Urinalysis: Normal without red blood cells
• Blood and urine cultures: Sent
Over the next 2 days, fresh bullae continued to erupt
on his face, anterior chest, abdomen, and over extremities,
sparing his entire back. Bullae were flaccid, filled with
pink fluid. Urine continued to be abnormal in color, and a
repeat urinalysis was normal. The infant’s stool color was
normal.

DIFFERENTIAL DIAGNOSIS
• Bullous impetigo
• Congenital erythropoietic porphyria
• Epidermolysis bullosa (EB)
• Phototherapy-induced rash

ACTUAL DIAGNOSIS
Congenital erythropoietic porphyria (CEP), due to homozy-
gous mutation in the uroporphyrinogen III synthase
(UROS) gene, c.791T>C p.(Leu264Pro)
At admission to our hospital, a provisional diagnosis of

the infant’s rash was attributed to bullous impetigo due to
Staphylococcus, and he was started on ampicillin and gen-
tamicin, with pending blood culture results, which were
later noted to be negative. A diagnosis of porphyria was
considered because of the urine color and the bullous
rash over areas of the skin that had been exposed to
phototherapy.
Given the possible diagnosis of porphyria, the team had the
mother nurse the infant in an incubator, protecting him from
ambient light. His urine continued to have a brownish red
color, but no new areas of skin involvement were noted. A
Wood lamp examination of his urine revealed coral red fluo-
rescence (Fig 2). Hence, the urine was sent for porphyrin esti-
mation, which showed a porphyrin level of 42,004.99 nmol/L
(23,336.1 nmol/mol of creatine), with a normal value of less
than 300 nmol/L. Whole exome sequencing was performed.
He continued to have conjugated hyperbilirubinemia with el-
evated GGT levels, which later returned to normal levels
(Table).
He was discharged from the hospital after 10 days with
the recommendation to avoid sunlight exposure and the
use of blackout curtains for windows. His skin at the time
of discharge demonstrated healing rashes with possible
scarring (Fig 3). The results of whole exome sequencing
showed a homozygous mutation in the UROS gene,
c.791T>C p.(Leu264Pro), confirming the diagnosis of
CEP. He is now 8 months old, growing normally, and pro-
tected from direct sunlight, with only hypopigmentation of
the previous skin lesions (Fig 4).
t.me/neonatology
Figure 2. Coral red fluorescence of urine under Wood’s lamp.
WHAT THE EXPERTS SAY
Porphyrias are a group of inherited disorders caused by
various enzyme deficiencies essential for heme synthesis.
Heme is necessary for hemoglobin production in the bone
marrow and cytochrome P450 hemoproteins in the liver.
CEP, also known as Gunther disease, is a rare and se-
vere form of porphyria, with only around 200 reported
cases in the literature. CEP is an autosomal recessive dis-
order caused by a homozygous mutation of the UROS
gene. Rare cases of CEP with X-linked mutations of the
GATA1 gene have been described.
Deficiency in the UROS enzyme results in the accumu-
lation of uroporphyrinogen I, which is further oxidized to
uroporphyrin I and coproporphyrin I; these compounds
then accumulate in erythrocytes and the skin and are re-
sponsible for most of the clinical phenotypes of CEP. The
photo-oxidation of porphyrins in the skin causes free radical
injury, leading to mechanical skin fragility with blistering.
These porphyrins are excreted in the urine, giving a reddish
hue or port-wine color to the urine. The photoactive property

e124 NeoReviews

t.me/neonatology
Table. Infant’s Laboratory Values Showing Conjugated Hyperbilirubinemia with Elevated GGT Levels
Day 3 Day 7 Day of Discharge (Day 10) Follow-up at 3 wk
Hb, g/dL (g/L) 14.4 (144) 14 (140) 14.3 (143) 9.7 (97)
Total bilirubin, mg/dL (µmol/L) 11.2 (192) 9.5 (162) 6.3 (107) 4.5 (77)
Conjugated bilirubin, mg/dL (µmol/L) 2.9 (49) 4.6 (78) 5.9 (101) 3.6 (61)
ALT, U/L (µkat/L) 31 (0.52) 17 (0.28) 27 (0.45) 34 (0.57)
AST, U/L (µkat/L) 48 (0.80) 54 (0.90)
ALP, U /L (µkat/L) 135 (2.25) 154 (2.57) 167 (2.79)
GGT, IU/L (µkat/L) 650 (10.86) 350 (5.84) 508 (8.48) 178 (2.97)

ALP5alkaline phosphatase, ALT5alanine aminotransferase, AST5aspartate aminotransferase, GGT5c-glutamyltransferase, Hb5hemoglobin.

of porphyrin pigments in the urine (and teeth) produces a
bright pink fluorescence under Wood lamp illumination,
which is a significant clue to the diagnosis of CEP and was
found in our patient.
The age of presentation and clinical phenotypes of CEP
are highly variable, with severe disease presenting in utero
as nonimmune hydrops or in newborns ranging from a
severe photosensitive blistering rash and hemolytic ane-
mia to late-onset mild photosensitivity in adulthood. The
first clue to a diagnosis of CEP is often pink or dark red
exposed to light with a wavelength of 400 to 410 nm, similar
to the wavelength used in phototherapy to treat neonatal
jaundice. Recurrent blistering leads to chronic ulcers with
delayed healing and bone resorption, causing destruction of
the end of the digits of fingers and deformities. Although
our patient had cholestasis and elevated GGT levels, there
was no sign of liver disease, and his condition normalized;
the cholestasis and high GGT levels were attributed to possi-
ble short-term toxic effects of the elevated porphyrins.
The reported mean life expectancy of patients with CEP is

urine or staining of the diaper. A typical manifestation of
CEP is blistering photosensitivity of parts exposed to light.
Skin edema precedes blister formation in cutaneous photo-
sensitivity. The photo-oxidation intensifies when a patient is
t.me/neonatology
40 to 60 years. The homozygous c.217T>C (p.Cys73Arg)
mutation, present in one-third of cases, is associated with se-
vere diseases such as hydrops fetalis, transfusion dependency
for recurrent hemolytic anemia, and severe cutaneous photo-
sensitivity. While our patient did not have hemolytic anemia,

Figure 4. Follow-up at 8 months of age showing hypopigmentation of

Figure 3. Healing rash at 13 days of age. the previously involved areas.

Vol. 25, No. 2 F E B R U A R Y 2 0 2 4 e125

t.me/neonatology
 T.ME/NEONATOLOGY

he is being followed as an outpatient to monitor for this
possibility.
Management strategies for patients with CEP are sup-
portive with strict avoidance of sunlight exposure by using
protective clothing and protective films over the windows.
Bone marrow or hematopoietic stem cell transplantation
is the definitive therapy reserved for patients with severe
cutaneous and hematologic involvement. Genetic counsel-
ing and prenatal screening of at-risk family members can
prevent morbidities with early interventions such as avoid-
ing sun exposure and screening for hemolytic anemia.
In our case, the provisional diagnosis at admission was
bullous impetigo caused by Staphylococcus. However, a nor-
mal white blood cell count and differential count, as well as
a sterile blood culture excluded this diagnosis. Another possi-
bility was phototherapy-induced cutaneous rash, which oc-
curs in the setting of transient porphyrinemia because of
hemolytic disease of the newborn. Even in the presence of
neonatal jaundice with an ABO incompatibility and positive
Coombs test result, there was no evidence of hemolysis as
(XLP). PCT is not described in infancy, with onset usually
in the fifth or sixth decade of age. EPP and XLP mostly
present in early childhood with acute painful nonblistering
photosensitivity. Hence, CEP was the most likely diagnosis
because of the age at onset and the classic photosensitive
blistering rash with reddish urine.
In summary, CEP is a rare genetic disorder that should be
suspected in a newborn presenting with a bullous photosensi-
tive rash with pink or brownish red urine. Early diagnosis pre-
vents morbidities associated with light exposure.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Know the etiology and differential diagnosis of bullous
skin lesions.

t.me/neonatology
indicated by normal peripheral smear, stable hemoglobin lev-
els, and declining unconjugated bilirubin levels. A neonate
with EB can present with a recurrent bullous rash, but this
diagnosis in this infant is less likely because bullae in pa- Suggested Reading
tients with EB are filled with clear fluid and are present at  Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: recent
the site of friction; moreover, no new skin lesions erupted af- advances. Mol Genet Metab. 2019;128(3):288–297

ter avoiding light exposure as would be expected in patients
with EB.
Other types of porphyria that can present as a photosensi-
tive rash include porphyria cutanea tarda (PCT), erythro-
poietic protoporphyria (EPP), and X-linked protoporphyria
 Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias
and photosensitivity: pathophysiology for the clinician. Postgrad Med.
2018;130(8):673–686
 Katugampola RP, Anstey AV, Finlay AY, et al. A management
algorithm for congenital erythropoietic porphyria derived from a study
of 29 cases. Br J Dermatol. 2012;167(4):888–900

ANSWER KEY FOR FEBRUARY 2024 NEOREVIEWS

T.ME/NEONATOLOGY
Congenital Anomalies of the Kidneys and Urinary Tract:
1. B; 2. C; 3. B; 4. D; 5. E
Nephrocalcinosis in Neonates:
1. E; 2. E; 3. D; 4. C; 5. E

e126 NeoReviews

t.me/neonatology