contents

NeoReviews Vol. 18 No. 6 June 2017

Editor-in-Chief: Alistair G.S. Philip, Palo Alto, CA
Deputy Editor: Dara Brodsky, MD, Boston, MA
Associate Editor: Josef Neu, Gainesville, FL
Assistant Editor, CME: Henry C. Lee, Palo Alto, CA
ARTICLES Editorial Fellow: Alison Chu, Los Angeles, CA
EDITORIAL BOARD
e345 Congenital Diseases of the Kidneys: Prognosis Rita Dadiz, Rochester, NY
and Treatments Sergio Golombek, Valhalla, NY
Joseph R. Hageman, Evanston, IL
Rich Feldenberg, Anne Beck Ivan Hand, Brooklyn, NY
Martin Keszler, Providence, RI
Karen M. Puopolo, Philadelphia, PA
e357 Neonatal Hypertension Renate D. Savich, Jackson, MS
Kirtida Mistry, Charu Gupta Michael P. Sherman, Columbia, MO
Akshaya J. Vachharajani, St. Louis, MO
Thomas E. Wiswell, Honolulu, HI
e372 Neonatal Urogenital Issues: Evaluation Santina A. Zanelli, Charlottesville, VA
and Management Founding Editor: William W. Hay Jr, Denver, CO
International Advisory Board:
Gino J. Vricella, Douglas E. Coplen Malcolm Battin, Auckland, New Zealand
Matts Blennow, Stockholm, Sweden
INDEX OF SUSPICION IN THE NURSERY Jose Diaz Rossello, Montevideo, Uruguay
Jeanie Cheong, Victoria, Australia
e386 Case 1: The Inconsolable Infant in the NICU Lizhong Du, Hangzhou, Zhejiang, P.R. China
Janusz Gadzinowski, Poznan, Poland
Sravanti Kurada, Tessy Joseph Gorm Greisen, Copenhagen, Denmark
Hercilia Guimares, Maia, Portugal
e389 Case 2: An Infant with Poor Weight Gain and Kazushige Ikeda, Tokyo, Japan
Helen Mactier, Glasgow, Scotland
Persistent Tachycardia Jorge Csar Martinez, Buenos Aires, Argentina
Frank Pohlandt, Ulm, Germany
Amornluck Krasaelap, Nirupama Kannikeswaran Francesco Raimondi, Naples, Italy
Siddarth Ramji, New Delhi, India
e392 Case 3: Respiratory Distress and Tachycardia Eric Shinwell, Jerusalem, Israel
Umberto Simeoni, Marseille, France
in a Preterm Neonate Bo Sun, Shanghai, China
Cleide Trindade, Sao Paolo, Brazil
Andrew W. McCrary, Laura C. Page, Gregory H. Tatum, Maximo Vento, Valencia, Spain
Rachel G. Greenberg, Stephanie Burns Wechsler, Andrew Whitelaw, Bristol, United Kingdom
David Woods, Cape Town, South Africa
Pinar Gumus Balikcioglu Tsu-Fuy Yeh, Taichung, Taiwan
Khalid Yunis, Beirut, Lebanon
e395 Video Corner: Delivery Room Management Liaison, NeoReviewsPlus Self-Assessment
William A. Engle, Indianapolis, IN
of a Neonate with Inspiratory Stridor Liaison, Council on International Neonatal Nurses:
Patrick Sloan, Brittany Blue, Akshaya Vachharajani Carole Kenner, Ewing, NJ
Liaison, National Association for Neonatal Nurses:
e398 Strip of the Month: Placental Abruption Carol Wallman, Denver, CO
Managing Editor: Luann Zanzola
Case Report Editorial Associate: Lawanda Tucker
Karla Daniela Guerrero, Michelle D. Winter, Ann Borders Publisher: American Academy of Pediatrics
Senior Vice President, Education and Publishing: David Jaffe, MD
Department of Publishing Director: Mark Grimes
e408 Visual Diagnosis: Rash in a Newborn Division of Journal Publishing Director: Joseph Puskarz
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Congenital Diseases of the Kidneys: Prognosis and
Treatments
Rich Feldenberg, MD,* Anne Beck, MD
*Department of Pediatrics and Division of Nephrology, St Louis University School of Medicine, St. Louis, MO

Education Gap
To provide optimal counseling and care, clinicians need to understand the
different mechanisms that can lead to congenital anomalies of the kidneys
and urinary tract and the different options for prenatal diagnosis and
treatment.

Abstract
Chronic kidney disease (CKD) is a growing public health problem with a
huge economic burden on society. In children, congenital anomalies of the
kidneys and urinary tract (CAKUT) are the most common cause for CKD.
Normal development of the kidneys and urinary tract progresses through a
complex series of events and requires the expression of key transcription
factors to occur with precision in the fetus. It is now known that many
genetic defects can lead to CAKUT. Most CAKUT can be identied prenatally
with antenatal ultrasonography, and in cases of severe oligohydramnios,
AUTHOR DISCLOSURE Drs Feldenberg and prenatal options such as vesicoamniotic shunting and amnioinfusion can
Beck have disclosed no nancial relationships improve the chances for survival. For infants born with severe renal
relevant to this article. This commentary does
not contain a discussion of an unapproved/
impairment, transfer to a center specializing in infant dialysis should be
investigative use of a commercial product/ considered, because survival of infants receiving dialysis has been shown to
device.
be reasonably good, and survival improves further if kidney transplantation
ABBREVIATIONS can eventually be achieved.
ACE angiotensin-converting enzyme
ANH antenatal hydronephrosis
CAKUT congenital anomalies of the
kidneys and urinary tract Objectives After completing this article, readers should be able to:
CKD chronic kidney disease
ESRD end-stage renal disease 1. Understand the developmental biology of the kidneys, ureter, and
GDNF glial cell linederived neurotrophic bladder.
factor
LUTO lower urinary tract obstruction
2. Understand the different mechanisms that can lead to congenital
MCDK multicystic dysplastic kidney anomalies of the kidneys and urinary tract (CAKUT).
MM metanephric mesenchyme
PUV posterior urethral valves
3. Understand the different options for prenatal diagnosis and treatment of
RAS renin-angiotensin system CAKUT.
RCT randomized, controlled trial
RRT renal replacement therapy
UPJ ureteropelvic junction
VUR vesicoureteral reux

Vol. 18 No. 6 JUNE 2017 e345

 BURDEN OF CONGENITAL DISEASES OF THE KIDNEYS: ureters, bladder, and urethra in fetal life. They are not
HOW BIG IS THE PROBLEM? unied in the sense of having any single genetic etiology
or common pattern of injury but can result from a wide
As with any chronic illness, chronic kidney disease (CKD)
array of genetic and/or environmental factors that make an
adversely affects the lives of those having the condition as
impact on the precise orchestration and timing of organo-
well as those closest to themtheir family and friends. In
genesis of the kidneys and urinary tract.
addition to its personal toll, it also burdens society in the
CAKUT includes structural defects such as antenatal
form of economic, social, and ethical stresses. So how
hydronephrosis (ANH), renal agenesis, renal dysplasia,
prevalent is CKD, and how often and in what ways does it
renal ectopia, ureteropelvic junction (UPJ) obstruction,
affect infants and children? Although CKD may some-
vesicoureteral reux (VUR), duplicated renal collecting
times seem unfairly ignored in the minds of the public, it
systems, and posterior urethral valves (PUV) (Table 1). (4)
has in fact been shown to constitute a growing and major
CAKUT can be seen with single gene mutations, such as
public health problem. As many as 11% of the population of
Alagille syndrome, caused from a mutation in the JAG1
North America suffers from CKD and more than 100,000
gene, and showing defects in the liver, heart, face, and
people initiated treatment for end-stage renal disease
kidneys. The kidney anomalies in Alagille syndrome can
(ESRD) in 2003. It has been shown that ESRD programs
vary in severity but can include renal agenesis, hypoplas-
in North America contributed a remarkable $25.2 billion
tic kidneys, UPJ obstruction, and VUR. (5)
to societys health-care costs. (1)
Other disorders with a CAKUT component will be associ-
CKD occurs less often in children than adults, with an
ated with well-recognized syndromes or nonrandom associa-
incidence of 15 to 74.7 per million children, and children
tions, displaying both renal and extrarenal defects, such as
account for only about 2% of all patients with ESRD. (1)(2)
the VACTERL syndrome (OMIM 192350), which has the
However, the associated problems of impaired growth and
nonrandom pattern of vertebral abnormalities, anal atre-
disordered psychological and social development that CKD
sia, cardiovascular defects, tracheoesophageal stula, renal
inicts on its childhood victims can result in many decades
anomalies, and limb defects. At least 3 of the defects need
worth of potentially lost quality of life; the life expectancy for
to be present for the condition to be classied as VACTERL.
a child receiving dialysis is estimated to be only an average
The renal anomalies in VACTERL can vary in type and
of 20 additional years from the time of initiating dialysis. (1)
severity and may include hydronephrosis, ectopic kid-
This would seem to make childhood CKD a much more se-
neys, renal agenesis, and dysplasia. There are some well-
rious and devastating diagnosis than is generally appreciated.
described single-gene defects that can include features of
The stages of CKD represent a spectrum of disease se-
VACTERL. Holt-Oram and Smith-Lemli-Opitz syndromes
verity, and in children, stages 1 to 4 are about 50 times more
are 2 such conditions, with patients with Holt-Oram syn-
prevalent than stage 5, which is also known as ESRD. (1)(3)
drome having defects in limbs and heart due to mutation in
There is also growing recognition that many of the mild
transcription factor TBX5, and patients with Smith-Lemli-
forms of congenital kidney disease that appear relatively
Opitz syndrome exhibiting facial anomalies, limb defects,
benign during the childhood years may eventually prog-
ress to ESRD later in adult life, and so may still have a more
negative impact on both the patient and society at some TABLE 1. Common Types of CAKUT
future date. (2)
CLASS OF DISORDER CAUSES

Hydronephrosis Vesicoureteral reux, UPJ

obstruction, LUTO
CONGENITAL ANOMALIES OF THE KIDNEYS AND
URINARY TRACT COMPRISE A FULL RANGE OF Renal parenchymal Agenesis, dysplasia, multicystic
malformations dysplastic
STRUCTURAL DEFECTS
Disordered renal migration Ectopic kidneys, horseshoe
In the adult population, many CKDs originate from kidney and collecting system kidneys, duplicated collecting
formation system
injury secondary to chronic diabetes and hypertension,
whereas in children, a large proportion of CKD results Congenital anomalies of the kidneys and urinary tract (CAKUT) are a
from congenital anomalies of the kidneys and urinary tract diverse group of renal developmental disorders. They mostly occur
(CAKUT). CAKUT is not a single disease but merely sporadically but can be seen in association with a number of well-
characterized syndromes. LUTOlower urinary tract obstruction;
descriptive for a large collection of diverse developmental UPJureteropelvic junction
disorders that arise during the formation of the kidneys,

e346 NeoReviews
and developmental delay due to mutation in the DHCR7
gene. VACTERL is also sometimes associated with chromo-
somal anomaly trisomy 18. (5)(6)(7)
Most cases of VACTERL syndrome, however, are not
associated with other syndromes outside of the VACTERL
spectrum. The etiology of most cases of VACTERL syn-
drome is not clear, but several genes have been identied to
be involved with this phenotype, including mutations in
mitochondrial DNA, in the PTEN tumor-suppressor gene,
and in Fanconi anemia genes. (5) This would seem to suggest
that there are multiple potential genetic etiologies leading to
a common constellation of defects and that VACTERL is not
a single disease (Table 2).
Although the disorders listed here highlight the preva-
lence and varied nature of congenital renal defects in many
complex developmental syndromes, most cases of CAKUT
are sporadic. They are nonsyndromic, with the exact etiol-
ogy unclear and the defects isolated exclusively to the renal
and urinary system. CAKUT accounts for 48% to 59% of
cases of CKD in children, (2) and oligohydramnios, low
birthweight, prematurity, and rst pregnancy are risk fac-
tors for death in children with CAKUT. (8)
EMBRYONIC DEVELOPMENT OF THE KIDNEY AND
URINARY TRACT
Because of the complex nature of renal development, there
are multiple opportunities for interference, through muta-
tions in crucial genes or environmental stresses, affecting
TABLE 2. Syndromes That Can Be Associated With VACTERL
MECHANISM SYNDROME GENE
Single-gene Alagile syndrome JAG1 gene
defects
Holt-Oram TBX5 gene
syndrome
Smith-Lemli-Opitz DHCR7 gene inborn error in
syndrome cholesterol synthesis
Chromosomal Trisomy 18 Third copy (complete or partial) Heart defects, GI, microcephaly, cleft Horseshoe kidney, hydronephrosis,
anomalies of chromosome 18
VACTERL syndrome is a nonrandom association that includes vertebral anomalies, anal atresia, cardiovascular defects, tracheoesophageal stula, renal
anomalies, and limb defects. Most cases are sporadic, but the disorder can be seen with some well-characterized syndromes. ASDatrial septal defect;
GIgastrointestinal; TOFtetralogy of Fallot; UPJureteropelvic junction; VSDventriculoseptal defect; VURvesicoureteral reux
various stages in the ontogeny of the kidney, which unfor-
tunately lead to the outcome of a CAKUT disorder. In
humans and other mammals, the kidneys develop through a
multistep process, progressing from an anterior to posterior
track. To produce mature kidneys, 2 transient phases must
be navigated. These are characterized by partial develop-
ment, followed by regression of primitive kidneys, and then
a third and nal phase that results in a pair of functioning
kidneys that serve to lter blood, excrete metabolic waste
products, and regulate plasma electrolyte concentrations and
osmolality.
The process begins with formation of the nephritic duct
(day 22 in humans) in the intermediate mesoderm at an
anterior position. The duct induces nearby intermediate
mesoderm cells to form the primitive tubules of the rst
kidney, known as the pronephros. In humans, the pro-
nephros quickly degenerates, never forming a functioning
renal organ, but continues as a working kidney in sh and
the water-living larvae of amphibians. As the tubules of
the pronephros disappear, the nephritic duct grows caudally,
following parallel to the tract of intermediate mesoderm.
At a location caudal to the pronephros, the signals of the
nephric duct transform the intermediate mesoderm into the
next primitive kidneythe mesonephros. Like the proneph-
ros, the mesonephros forms a series of tubules (day 25
in humans), but degenerates after a short time. (9) However,
in the case of the mesonephros, parts of the tubules remain,
becoming components of the male reproductive tracts (vas
deferens), but do not contribute to the nal kidney (Fig 1).
EXTRA-RENAL FEATURES RENAL DEFECTS
Liver defects (bile duct paucity), Renal defects, agenesis, hypoplasia,
heart defects (TOF, VSD), facial UPJ obstruction, VUR
defects (prominent forehead,
short chin)
Heart defects (ASD, VSD, Ectopic kidneys, horseshoe
arrhythmias), limb defects kidneys, VUR, hypoplasia
(polydactyly, hypoplastic thumb)
Heart defects, limb defects, UPJ obstruction, hydronephrosis,
developmental delay dysplasia
palate, rocker bottom feet, duplicated collecting system
growth delay, developmental
delay
Vol. 18 No. 6 JUNE 2017 e347
 Figure 1. Development of the kidneys and urinary system in mammals proceeds through 3 phases, moving from anterior to posterior in the developing fetus,
beginning with the pronephros, then the mesonephros, and nally the metanephros. The pronephros and mesonephros regress, and it is the metanephros
that eventually becomes the working kidneys. Reciprocal induction by chemical signals between the nephric duct and the intermediate mesenchyme is
necessary for differentiation of cells into renal tissue.

Still further caudal, near the level of the developing hind
limb, is the metanephric mesenchyme (MM), which will
eventually develop into the nal kidneys if the proper
signaling cascade is achieved. The MM cells produce and
secrete glial cell linederived neurotrophic factor (GDNF);
once the nephric duct reaches the level of the MM and is
exposed to the chemical gradient of GDNF, it responds
by producing a diverticula that homes in on, and invades,
the MM tissue. (10) This diverticula coming off the nephric
duct is known as the ureteric bud, and it reciprocates
the chemical communication with the MM by secreting
a number of transcription factors, including Fgf2 and
BMP7, which are necessary to prevent the cells of the
MM from undergoing apoptosis, as occurred with the pro-
nephros and mesonephros. The MM is the only tissue that
can respond to ureteric bud signaling because of expression
in this tissue of WT1. (9)
As the ureteric bud invades the MM, it will begin a series
of branching events inuenced by GDNF. Cells from the
MM that condense onto the tips of the ureteric bud (known
as cap mesenchyme) will eventually form the nephron. The
proper number of branching events by the ureteric bud is
critical to achieve the appropriate number of nephrons in the
nal kidney (with normal variation ranging from 300,000
to 1,000,000). Too few nephrons lead to small hypoplastic
kidneys. Cystic dysplastic kidneys and multicystic dysplastic
kidneys (MCDK) contain undifferentiated mesenchyme
with too few ureteric bud branches. The severity of cystic
dysplastic kidneys can vary from mild to severe, with MCDK
being the most extreme version, essentially containing no
normally differentiated renal epithelium. (11) If the renal
dysplasia is unilateral (as it is in most cases), the prognosis
remains good, because the contralateral kidney can continue
to function normally most of the time. (12)
The branches of the ureteric bud eventually form the
collecting ducts, renal pelvis, and the ureters. The cap
mesenchyme that condensed onto the branches of the
ureteric bud go on to become the glomerulus, proximal tu-
bule, loop of Henle, and distal tubule. (11) The bladder itself
originates from a portion of the cloaca, and the nephric duct
empties into the bladder, under the direction of Hox genes.
All these events need to be precise in both time and space in
order for the kidneys, ureters, and bladder to form properly.
Many genes known to be involved in kidney development
are transcription factors, which activate target genes directly,
whereas other genes important in the developmental

e348 NeoReviews
process affect the epigenetic landscape, affecting how recep-
tive a gene is to being transcribed. PAX2 is 1 key gene in the
developing kidney that, when expressed, has been shown
to produce epigenetic modications to intermediate meso-
derm. It prepares cells for the fate of differentiating into
kidney epithelial cells. Through its interaction with several
other key proteins, PAX2 activation results in methylation
of specic amino acid residues on histone molecules,
thereby modifying chromatin and making the associated
DNA open for transcription. Mutations in PAX2 are known
to cause the autosomal dominant renal coloboma syndrome
(OMIM 120330), characterized by optic nerve coloboma,
hypoplastic kidneys, and vesicoureteral reux. (5)(13)
Similarly, activation of the gene WT1 leads to epigenetic
modication of histones, resulting in a more open and
transcriptionally active chromatin. (14) Patients with a het-
erozygous WT1 mutation are prone to develop Wilms tumor
in the kidney, and mice with homozygous WT1 mutation
have a total lack of kidney development. (5)(15)(16)(17) While
renal coloboma syndrome and Wilms tumor are both rare
diseases, PAX2 and WT1 and their downstream protein tar-
gets may play important roles in some of the much more
common CAKUT conditions.
EPIGENETIC PHENOMENA AND CAKUT
Several well-studied systems have demonstrated changes
to the intrauterine environment leading to changes in the
epigenetic landscape of the developing fetus. There is evi-
dence that exposure of the fetus to factors such as hyper-
glycemia in gestational diabetes or intrauterine growth
restriction, because of maternal malnutrition or placental
insufciency, can alter the DNA and histone methylation
pattern affecting normal development. Hyperglycemia in-
creases methylation lysine 3 of histone H3 of genes pro-
moting brosis of the kidney, and these epigenetic changes
seem to persist. This accounts for the so-called metabolic
memory whereby disease risk for renal brosis remains
high despite the reversal of the underlying etiology, such as
resolution of hyperglycemia. (18)
Epidemiologic studies have suggested that infants of
diabetic mothers have a higher incidence of multiple con-
genital defects, including CAKUT defects. Glucose crosses
the placenta, and high maternal glucose levels can lead to
fetal hyperglycemia. In a case-controlled study performed in
Canada with 945 cases of CAKUT and 4,725 controls, the
authors concluded that maternal diabetes in the rst 20
weeks of pregnancy was associated with infants born with
CAKUT, with an odds ratio of 1.67. (19) Although plausible,
given what we know, whether epigenetic alterations due to
fetal exposure to hyperglycemia directly alter the genetic
programming of the developing kidney and urinary tract is
still unclear.
TERATOGENS AND CAKUT
Teratogenic intrauterine exposures can affect the develop-
mental network of kidney development, making congenital
birth defects of the kidneys more likely. The renin-angioten-
sin system (RAS) is vital for normal renal development. RAS
plays a crucial role in ureteric bud branching, vasculogenesis,
and development of the renal papilla. (20) Exposure to
angiotensin-converting enzyme (ACE) inhibitors and
angiotensin receptor blockers during critical periods
of renal development can result in ACE fetopathy, with
resulting renal hypoplasia, UPJ obstruction, and renal
tubular dysgenesis. (21) The effects are most pronounced
if the exposure occurs during the second half of preg-
nancy. If severe, ACE fetopathy will result in the Potter
sequence and pulmonary hypoplasia. (11)
PRENATAL DIAGNOSIS OF CAKUT
The widespread use and sensitivity of fetal ultrasonography
has resulted in antenatal detection of the majority of renal
malformations. (22) Ultrasonographic screening for fetal
anomalies can detect renal agenesis, MCDKs, hydro-
nephrosis, and abnormally shaped bladders from midway
through gestation.
Fetal urinary production starts at 9weeks gestation;
therefore, the fetal bladder should be visualized from 13
weeks onward. By 20weeks, fetal urine produces 90% of
amniotic uid. Reference curves for renal volume and the
amount of amniotic uid are available. (23) Fetal kidneys can
be visualized at 12 weeks, and by 25 weeks, the renal cortex
and medulla are distinctly demonstrated on ultrasonogra-
phy. Parameters for expected length (appropriate growth)
based on gestational age are also available. (24)
Fetal hydronephrosis is most commonly detected during
routine ultrasonography between 18 and 22 weeks gesta-
tion. Several systems have been developed to diagnose and
grade the severity of hydronephrosis, but there is no con-
sensus on the most appropriate criteria. (25) See Poudel et al
(4) for an overview of the Society for Fetal Urology criteria.
In general, the likelihood of having a signicant renal anom-
aly correlates with the severity of hydronephrosis. Because of
renal immaturity, hydronephrosis detected before 25 weeks
warrants repeat scanning. As expected, studies performed
in the third trimester are the most helpful in predicting the
postnatal outcome of CAKUT. (26)
Vol. 18 No. 6 JUNE 2017 e349
 Thinning of the renal parenchyma and/or cortical cysts
may be seen with hydronephrosis. They indicate injury or
impaired development of the renal cortex. Increased echo-
genicity of the renal cortex may indicate abnormal renal
parenchymal development. These ndings are associated
with poor postnatal renal function when combined with
hydronephrosis (Fig 2). (27)
Normally, the fetal ureters are not seen on ultrasonog-
raphy, so when they are visualized, ureteric or bladder
obstruction or VUR may be indicated. Bilateral involvement
increases the risk of a signicant renal abnormality and of
impaired postnatal renal function. The bladder wall is
normally thin. If the bladder wall is thick, urethral obstruc-
tion such as PUV in a male fetus may be present. If the
bladder is not seen, consider the diagnosis of bladder
exstrophy.
Oligohydramnios at or beyond the 20th week of gesta-
tion is the most reliable predictor of abnormal fetal renal
function. However, its absence does not ensure normal fe-
tal renal function. Because amniotic uid is predominantly
composed of fetal urine, biochemical analysis is useful in
further assessing fetal renal function. Sodium and chloride
concentration greater than 90 mEq/L (90 mmol/L) and urinary
osmolality less than 210 mOsm/kg H2O (210 mmol/kg H2O)
Figure 2. Bilateral vesicoureteral reux seen on voiding cytourethrogram.
e350 NeoReviews
in the amniotic uid are indicative of fetal renal tubular
impairment and poor renal prognosis. (28) Under these
circumstance, more invasive testing such as vesicocentesis
(bladder taps) may be undertaken. Evaluation begins with 2
consecutive vesicocenteses performed 24 to 48 hours apart.
(29)(30) The urine sample is sent for sodium, chloride,
osmolality, calcium, and b2-microglobulin. Prognostic indi-
cators of fetal urine are outlined in Table 3. The electrolyte
analysis is from the second drainage because stagnant
urine may not accurately reect the correct renal function.
PRENATAL SURGICAL INTERVENTIONS TO IMPROVE
SURVIVAL
Some varieties of CAKUT, such as renal ectopia and unilateral
MCDK, may result in less severe short-term morbidity and
mortality; the disorders leading to lower urinary tract obstruc-
tion (LUTO) are more likely to be on the most severe end
of the clinical spectrum. LUTO is thought to occur in about
2.2 in every 10,000 births. (32) First-trimester LUTO tends to
be more severe than LUTO identied at later stages of
the pregnancy. (33) The major cause of LUTO is related to
PUV, but other causes such as urethral atresia and prune
belly syndrome can also produce the similar pheno-
type of megacystis, renal cystic-dysplasia, and oligohy-
dramnios. The most severe cases of LUTO, with severe
oligohydramnios, may result in Potter syndrome with lethal
pulmonary hypoplasia. (33) Several interventions have
aimed at improving the outcome for fetuses with LUTO.
LUTO can often be diagnosed prenatally using antenatal
ultrasonography demonstrating bilateral hydroureter, a
thick distended bladder, and oligohydramnios; all of these
might lead one to conclude that a promising opportunity
exists for interventions that could potentially alter peri-
natal survival. The major options for intervention include
vesicoamniotic shunting, vesicocentesis, and fetal cystos-
copy. The ideal candidates for fetal surgical intervention
are those fetuses diagnosed with LUTO that have normal
genetic karyotyping studies and no serious extrarenal
organ involvement.
Vesicoamniotic shunting is performed by placing a dou-
ble pig-tailed catheter into the fetal bladder. This is done
under ultrasound guidance with local anesthesia adminis-
tered to the mother. The distal end of the catheter is placed
into the fetal bladder and the proximal end remains in the
amniotic space, so that fetal urine may bypass the obstructed
bladder outlet. An amnioinfusion may rst be necessary be-
fore shunt placement if there is signicant oligohydramnios
or anhydramnios. (33)(34) In cases of shunt dislocation
or malfunction, a reintervention shunt placement can be

TABLE 3. Prognostic Criteria Using Fetal Urine
URINARY COMPONENT FAVORABLE
Sodium <100 mEq/L (<100 mmol/L)
Chloride <90 mEq/L (<90 mmol/L)
Osmolality <210 mOsm/L (<210 mmol/kg)
Calcium <8 mg/dL (<2 mmol/L)
b2-microglobulin <2 mg/L
For a fetus to be categorized as having good prognostic indicators, the
values in this table should be within the favorable range (using gestation-
specic cutoffs), and the fetal kidneys should not demonstrate cortical
cysts or hyperechogenicity on ultrasonography. (25) It should be noted
that a systematic review of fetal urine analysis challenged the clinical
accuracy of predicting postnatal renal function. (30)(31)
performed. Complications of vesicoamniotic shunting can
include dislocation of the shunt, premature rupture of
membranes, infection, and spontaneous abortion. (32)
The percutaneous shunting for lower urinary tract
obstruction (PLUTO) study was a prospective randomized
controlled trial (RCT) designed to determine whether vesi-
coamniotic shunting or conservative management im-
proved survival of male fetuses with LUTO. The time
points for study were 28 days after delivery and at 2 years,
and renal function in each group was also examined as an
endpoint. The study had multicenter participation and was
conducted in the British Isles and the Netherlands from
August 2006 to December 2010. Although the study ini-
tially recruited 144 patients, only 31 remained in the RCT
portion of the study. Sixty-eight patients elected to termi-
nate the pregnancy given the diagnosis of LUTO, and 45
opted out of the RCT, preferring instead to decide whether
they would receive the shunt or conservative treatment.
These patients were still studied and became part of a
registry that was followed prospectively alongside the
RCT patients. (35)
Sixteen of the RCT patients were randomized to the
vesicoamniotic shunt group and 15 to the conservative man-
agement group. Twenty-eight days after delivery, 8 infants
survived after receiving the shunt compared with 4 who
received conservative management; at 2 years, 7 children
in the shunt group survived compared with 3 who received
conservative management. The registered (nonrandomized
group) had only 4 infants who survived at 28 days compared
with 24 who received conservative management, and at
2 years follow-up, 2 in the shunt group survived versus 23
in the conservative management group.
The difference in survival in patients in the RCT versus
the registry is likely because of selection bias in the registry
patients based on the treatment they chose. The patients
with the less severe nding on prenatal ultrasonography
tended to choose more conservative management. The
patients in the RCT tended to have more severe LUTO.
While the number of randomized patients was small, the
results indicate that vesicoamniotic shunting improved
survival but did not appear to improve the outcome for
renal function.
An alternative to vesicoamniotic shunting is fetal cystos-
copy, which can be performed without the need for amniotic
infusion, and thus may limit some of the potential risk
related to multiple needle insertion into the amniotic space.
During fetal cystoscopy, a trochar is introduced into the fetal
bladder under ultrasound guidance, and endoscopic visu-
alization of the bladder and posterior urethra is performed.
If PUVs are identied, they can then be disrupted through
various methods, such as laser fulguration or hydroablation.
(36) In a retrospective study from Brazil, 111 fetuses with
high-grade LUTO were enrolled to receive vesicoamniotic
shunt, fetal cystoscopy, or no intervention. The study end-
points were patient survival and kidney function at 6-month
follow-up. The study concluded that survival was improved
by either vesicoamniotic shunt or fetal cystoscopy compared
with no intervention, but that fetal cystoscopy appeared to
have the added advantage over vesicoamniotic shunt of
preserving kidney function. This study lacked the power of
an RCT, but the authors suggested that a more physiologic
drainage achieved by fetal cystoscopy may protect the kid-
neys from damage due to obstruction in a way that vesicoamni-
otic shunting does not. (36) Perhaps an RCT comparing the
2 techniques could more convincingly answer this question.
Oligohydramnios is associated with lack of fetal lung
development and pulmonary hypoplasia, which, when
severe, will be incompatible with life. To minimize the risk
of pulmonary hypoplasia, infusion of uid into the amniotic
space can be accomplished. If fetal urine is not able to leave
the bladder, or the fetal kidneys are so poorly developed that
no urine is produced, then serial amniotic uid infusion
will be necessary to keep the amniotic volume optimal. If
started early, this can improve the chances for adequate lung
development. There is increasing risk to the fetus with
multiple infusions, however, because of puncturing of the
membrane multiple times during the pregnancy. A rela-
tively recent advance in this area is the amniotic port, in
which a catheter can be placed into the amniotic space and
an infusion port placed under the mothers skin. The port
can be accessed as needed without additional punctures to
the amniotic membrane.
Vol. 18 No. 6 JUNE 2017 e351
 POSTNATAL INTERVENTIONS
For infants born with CAKUT, surgical interventions can
sometimes improve the odds of preserving renal function.
For obstructions at varying levels of the urinary tract, various
options exist to protect the kidneys if they are thought to still
have potential for function. If the kidneys demonstrate ade-
quate corticomedullary differentiation and parenchyma, they
may have potential worth protecting if obstructed. UPJ
obstruction accounts for approximately 10% to 30% of
newborn hydronephrosis. (37) A large proportion of con-
genital UPJ obstructions are mild, self-limiting, and do not
require any intervention. In these cases, observation alone
with serial ultrasound monitoring may be sufcient. For
more severe degrees of UPJ obstruction, diverting the urinary
ow through a low-pressure outlet will assist in protecting the
kidney from further injury, and often the serum creatinine will
be seen to decrease after such a diverting procedure. In cases
with UPJ obstruction, a nephrostomy tube can be placed for
this purpose. This is usually considered a temporizing inter-
vention, and once stable, the patient can be taken to the
operating room for a dismembered pyeloplasty to surgically
excise the stricture, with reanastomosis of the renal pelvis and
ureter (Fig 3).
In cases of PUV, with bladder outlet obstruction, place-
ment of a Foley catheter can acutely relieve the high pressure
transmitted to the kidneys from the bladder. Once the PUV
is conrmed on voiding cystourethrography, the patient can
be taken to the operating room for valve ablation surgery
to remove the valve tissue using various methods, such as
laser, cold-knife incision, and electrosurgical ablation. (38)
For situations in which the bladder wall is thick and
hypertrophied and may be at risk for dysfunction, a ves-
icostomy may be performed.
Figure 3. Renal ultrasound image revealing hydronephrosis. Such a nding
may be seen with a congenital urinary tract obstruction.
e352 NeoReviews
RENAL REPLACEMENT THERAPY AND PROGNOSIS IN
THE INFANT
Prenatal interventions, such as vesicoamniotic shunting
for LUTO or amnioinfusions for renal dysplasia/agenesis,
may improve the chance for survival of fetuses with these
serious conditions. But what if these conditions result in
severe kidney failure?
LUTO secondary to PUV shows a biphasic peak inci-
dence for time to progression to ESRD, with the rst peak
being in infancy and the second peak occurring in adoles-
cents. In the most severe cases, the kidneys are so dysplastic
and poorly developed that there is severe oliguric kidney
failure at the time of birth or very soon afterwards. Many of
the seemingly less severe cases still result in highly dys-
plastic kidneys, which display poor growth over time, even-
tually culminating in ESRD.
Infant dialysis is technically challenging and costly;
therefore, it would be helpful to have a clear idea of which
patients would be at highest risk for early renal failure. In
one Australian study, microarray analysis was used to exam-
ine the DNA of 45 children with PUV. A correlation was
found between early-onset renal failure and copy number
variant in genes implicated in the development of the kidneys
and urinary tract (33% with copy number variants in the early
renal failure PUV group vs 9% in a control group). (39) This
suggests that genetic testing might be used to determine which
patients are most at risk for a severe early onset.
Dialysis can be problematic in the newborn and requires
strong nephrologic expertise, which may not be available at all
institutions. However, over the last 20 years, renal replace-
ment therapy (RRT) has improved outcomes in infants and
children, and success has been reported. In one prospective
study, which enrolled patients from 32 countries throughout
Europe, Japan, Australia, and New Zealand, 264 infants who
began RRT in their rst month after birth were followed. Of
these, 64.8% were male and the causes of kidney failure
included CAKUT (54.6%), CKD (13.3%, with 80% of these
being autosomal recessive polycystic kidney disease),
cortical necrosis (11.4%), angiotensin receptor blocking
fetopathy (1.1%), and no specic etiology (8.7%). Re-
nal vascular disease, congenital nephrotic syndrome,
hemolytic-uremic syndrome, and oxalosis comprised the
additional 11% of patients in the study. Within the rst
month after birth, 91.7% of the patients started RRT with
peritoneal dialysis, 8.0% started hemodialysis, and 1
patient (0.4%) received a kidney transplant. (40) In this study,
81.2% of the patients survived for 2 years. One patient
who received the kidney transplant in the rst month after
birth died the following day. The most common causes
of death in the group were infections and cardiac disorders.
Based on the results of the study, the patients gender,
underlying renal disease, and birthweight did not affect
the risk of death, but associated neurologic disease increased
risk for death by 5 times. (40) In this study, 17.0% had kidney
transplantation in the rst 2 years, and 37.5% had received a
kidney transplant by age 5 years.
Another multicenter study examined more than 1,000
infants who started dialysis at a median age of 4.5 months
and median weight of 5.7 kg. The majority (86.3%) were
started on peritoneal dialysis, with the remaining 13.7%
starting hemodialysis. They found that risk of death and
likelihood of receiving a kidney transplant were equal for
patients receiving both peritoneal dialysis and hemodialy-
sis. At 5 years, the overall mortality rate was 16.1%. Most
deaths were caused by infection and cardiac disease, and the
risk for death was highest in those starting dialysis at a youn-
ger age and in those patients with a non-CAKUT etiology
for their kidney failure. (41)
For children with ESRD, dialysis is generally considered
a bridging step until kidney transplantation is possible.
Assessing the odds for successful kidney transplantation,
10 kg is generally agreed to be the smallest size. To support
a newborn with ESRD to the 10-kg mark, intensive nutri-
tional therapy, often with tube feeding, is required. These
infants generally have oral aversions and have failure to
thrive due to frequent vomiting and an increased catabo-
lism. A study in Greece, which evaluated 75 children
who received a kidney transplant from 1990 to 2012,
showed that at 20 years follow-up, patient survival was
93.3% for recipients of a living related donor transplant and
88.7% for deceased donor recipients. Graft survival at 20
years was 69.3% for the living related donor graft and
64.5% for the deceased donor graft. (42) Children diagnosed
with CKD in the newborn period are at increased risk for
impaired growth and development. Kidney transplanta-
tion offers the best chance for more normal growth and
development in those with ESRD.
CONCLUSION
CAKUT includes a wide range of defects that have their origin
during the critical period of organogenesis of the urinary
system. The condition includes a full spectrum and array of
defects and can include minor conditions, such as mild self-
resolving hydronephrosis, all the way to anuric renal failure
due to PUV or bilateral renal agenesis. Its etiologies can
include many of the genes known to be critical in urinary
tract development, as well as environmental factors that
can interfere with development at key stages; however, in
the majority of cases, the etiology remains unknown. Most
cases can be detected and diagnosed prenatally with mod-
ern antenatal ultrasonography. Recent advances, such as
amnioinfusion and vesicoamniotic shunting, have made
survival to delivery possible if detected early enough, by
minimizing Potter sequence and pulmonary hypoplasia.
These interventions still prove inadequate to protect the
kidneys from maldevelopment, and for those infants born
with ESRD, dialysis has been shown to be successful.
Kidney transplantation is still the denitive therapy for
infants with ESRD. Because of technical issues, infants need
to weigh more than 10 kg to be considered ready for trans-
plantation. This often requires 1 to 2 years of RRT and
intensive nutritional support.
American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Recognize the clinical manifestations of anatomic abnormalities
of the kidneys and urinary tract in infants.
Know how to diagnose specic anatomic abnormalities 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.
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NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click Journal CME from Gateways orange main menu or go directly to: http://www.
aappublications.org/content/journal-cme.

1. An infant in the NICU undergoes renal ultrasonography, which shows mild cystic dysplastic NOTE: Learners can take
kidneys. The infant is having normal urine output and the electrolytes are normal. The NeoReviews quizzes and
parents are wondering how this might have occurred and the prognosis. Which of the claim credit online only
following correctly describes the relationship of congenital kidney problems and later at: http://Neoreviews.org.
chronic kidney disease?
A. Chronic kidney disease caused by congenital kidney and urinary tract abnor- To successfully complete
malities far outnumbers the occurrence of chronic kidney disease that begins in 2017 NeoReviews articles
adulthood, such as from diabetes or hypertension. for AMA PRA Category 1
B. The life expectancy of a child who starts dialysis is 5 to 10 years from the initiation of CreditTM, learners must
dialysis. demonstrate a minimum
C. There is growing recognition that many of the mild forms of congenital kidney performance level of 60%
disease that appear relatively benign during the childhood years may eventually or higher on this
progress to end-stage renal disease. assessment, which
D. In children, the most common stage of chronic kidney disease is stage 5 or end- measures achievement of
stage renal disease. the educational purpose
E. A good aspect of having chronic kidney disease as a neonate or child is that it is an and/or objectives of this
isolated problem that can be treated with medications or dialysis and does not activity. If you score less
have an impact on growth, nutrition, psychological issues, or social development. than 60% on the
2. A male infant is admitted to the NICU and noted to have several anomalies, including anal assessment, you will be
atresia and tracheoesophageal stula. Radiographs reveal vertebral anomalies. Renal given additional
ultrasonography has been ordered. Which of the following correctly describes the opportunities to answer
vertebral defectsanal atresiacardiovascular anomaliestracheoesophageal stula with questions until an overall
esophageal atresiaradial and renal dysplasialimb defects (VACTERL) association? 60% or greater score is
A. At least 5 characteristics of VACTERL need to be present and documented for a achieved.
diagnosis of VACTERL to be applied to a patient.
B. The renal anomalies in VACTERL can vary in type and severity and may include This journal-based CME
hydronephrosis, ectopic kidneys, renal agenesis, and dysplasia. activity is available
C. The diagnosis of VACTERL is conrmed by testing for 2 genes (TBX5 and DHCR7) through Dec. 31, 2019,
that encompass 95% of cases of VACTERL. however, credit will be
D. Regardless of the number of characteristics corresponding to each of the letters of recorded in the year in
VACTERL, the association is only considered appropriate to describe a patient if which the learner
there is a severe renal anomaly. completes the quiz.
E. Approximately 25% to 50% of patients with trisomy 21 can be classied as also
having VACTERL and kidney disease.
3. A fetus is diagnosed prenatally with multicystic dysplastic kidney disease (MCDK). Which of
the following statements regarding MCDK is correct?
A. MCDK is a relatively mild form of cystic dysplastic kidney disease.
B. The prognosis does not differ between unilateral and bilateral disease.
C. MCDK describes a condition in which there are too few nephrons and small
kidneys.
D. Normally, there are approximately 1 billion nephrons in a neonatal kidney;
however, in MCDK, the number of nephrons ranges from 100,000 to 200,000.
E. In kidneys affected by MCDK, there is essentially no normally differentiated renal
epithelium.
4. A newborn has multiple congenital anomalies and renal ultrasonography is ordered to
assess for kidney disease that may be associated with a genetic syndrome. Which of the
following genetic or maternal risk factors is correctly paired with a corresponding kidney
disease seen in childhood?

Vol. 18 No. 6 JUNE 2017 e355

 A. PAX2 gene and VACTERL syndrome with hydronephrosis.
B. DHCR7 and Holt-Oram syndrome with hydronephrosis.
C. Trisomy 15 and ureteropelvic junction malformation.
D. WT1 and Wilms tumor.
E. Maternal diabetes and renal coloboma syndrome.
5. A woman who has had a previous child with hydronephrosis and kidney disease is
pregnant and receiving prenatal counseling and ultrasonography at her prenatal visit.
Which of the following statements regarding ultrasonography of the fetal kidneys is
correct?
A. Fetal urinary production starts at 9 weeks gestation, and the fetal bladder should
be visualized from 13 weeks onward.
B. By 20 weeks, fetal urine results in 25% of amniotic uid.
C. Fetal kidneys are usually rst visualized at 18 to 20 weeks of gestation.
D. Fetal hydronephrosis cannot be detected until after 25 weeks gestational age.
E. Studies in the second trimester assessing hydronephrosis are most predictive of a
postnatal outcome of a congenital anomaly of the kidney or urinary tract.

Parent Resources from the AAP at HealthyChildren.org

Children with a Single Kidney: https://www.healthychildren.org/English/health-issues/conditions/genitourinary-tract/Pages/Children-with-
a-Single-Kidney.aspx
Kidney Cysts in Infants, Children & Teens: https://www.healthychildren.org/English/health-issues/conditions/genitourinary-tract/Pages/
Kidney-Cysts-in-Infants-Children-Teens.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

e356 NeoReviews
 Neonatal Hypertension
Kirtida Mistry, MD,* Charu Gupta, MD*
*Division of Nephrology, Childrens National Health System, Washington, DC

Education Gaps
1. Recognition of hypertension in the neonate is challenging due to
changing blood pressure values with age and size and lack of outcomes-
based normative data.
2. Although recommendations exist on when to initiate antihypertensive
therapy, data regarding whether treatment of mild hypertension affects
cardiovascular and other outcomes need to be determined.
3. There is a lack of data and knowledge regarding the use of
antihypertensive medications in preterm and term newborn infants,
including dosing, short-term adverse reactions, and longer-term sequelae.

Abstract
In the past few decades, as neonatal intensive care technology has
advanced, so has identication and awareness of hypertension in this
population. As in older children, the denition of normal blood pressure and
accordingly, hypertension, remains a statistical denition rather than based
on outcomes. Although the overall incidence of hypertension in neonatal
nurseries is low, certain groups of neonates are at higher risk and should be
monitored more closely. This article reviews the parameters dening
normal and elevated blood pressures in neonates using current available
data, etiology and risk factors, approach to investigation, and management
of neonatal hypertension.

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

1. Identify infants at risk for developing hypertension.

AUTHOR DISCLOSURE Drs Mistry and Gupta
have disclosed no nancial relationships
2. Better recognize and diagnose hypertension in neonates.
relevant to this article. This commentary does
3. Understand the evaluation of hypertension in the NICU.
not contain a discussion of an unapproved/
investigative use of a commercial product/ 4. Begin antihypertensive therapy when necessary, choosing the appropriate
device.
agent.
ABBREVIATIONS
5. Understand the importance of proactively alleviating known risk factors,
BP blood pressure
CAKUT congenital anomalies of the kidney
when possible, in at-risk neonates.
and urinary tract
SD standard deviation

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 INTRODUCTION
Hypertension is seen in fewer than 3% of infants in the
NICU. (1)(2)(3) The incidence rises in high-risk neonates
with umbilical arterial catheters, bronchopulmonary dys-
plasia, intraventricular hemorrhage, acute and/or chronic
renal failure, and congenital anomalies of the kidneys and
urinary tract. Data regarding normal and elevated blood
pressure (BP) based on statistical models have become
available, thus facilitating the identication of infants with
BPs higher than expected compared with their peers of the
same sex, size, and postconceptual age. When identied,
appropriate evaluation should be instituted to determine the
etiology of hypertension; in turn, this can be used to inform
appropriate management, and when indicated, pharmaco-
therapy. When choosing antihypertensives, one must con-
sider the effects of medications on the developing and
growing human body. It remains unclear when to initiate
antihypertensive therapy because data pertaining to out-
comes of untreated versus treated hypertension are lacking.
Most neonates require antihypertensives for only a short
period, with only a small minority requiring long-term
therapy. (3)
MEASURING BP IN NEONATES
To discriminate between normal BP and hypertension using
data from clinical studies, it is important to standardize
the method by which BP is measured in young infants.
Although invasive arterial BP monitoring remains the gold
standard, noninvasive methods using oscillometric devices
are commonly used in most modern NICUs; most recent
studies now use this method, making data more clinically
relevant and usable for bedside clinicians. Direct arterial BP
measurement via umbilical or peripheral arterial catheters
is the most reliable method in critically ill neonates.
Noninvasive BP monitoring using conventional sphyg-
momanometry is not recommended in newborns because
Korotkoff sounds are unreliable in this age group. (4)
Another noninvasive method of BP measurement is the
ultrasonic Doppler. This method tends to underestimate
systolic BP compared with simultaneous oscillometric mea-
surements, is cumbersome, and is rarely used in clinical
practice. (5)
Oscillometric devices measure the mean arterial pres-
sure, then project a systolic and diastolic BP value based
on an algorithm. (6) BP monitors from different manu-
facturers use varied algorithms for oscillometric detec-
tion and have variable accuracy, which can lead to
discrepant BP values. (7) Although BP measurements
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using oscillometric devices are generally considered
comparable with invasive intra-arterial measurements,
(8) in ill neonates, these measurements may not be
ideal. This is because oscillometric devices have been
shown to overestimate the systolic and diastolic BP
compared with BP values obtained from invasive meth-
ods in the cohort of sick neonates, hence direct arterial
BP monitoring is preferable in this particular popula-
tion. (9) On the other hand, in small for gestational age
infants, another study demonstrated that oscillometric
devices underestimated systolic BP. (10)
A standardized method for noninvasive BP measure-
ment in infants using an oscillometric device is depicted in
Table 1, based on the study by Nwankwo et al. (11) This
procedure minimizes factors that may articially increase
BP, such as feeding (may increase BP by 20 mm Hg),
crying, head being tilted or kept up, sucking on a pacier,
etc. (5) Conversely, sleeping infants have systolic BP that is
5 mm Hg lower than in infants who are awake. (4)
DEFINITION AND DIAGNOSIS OF HYPERTENSION
The generally accepted denition of hypertension in new-
borns is derived from older children in whom systolic
and/or diastolic BP values persistently greater than or equal
to the 95th percentile for height, age, and sex constitutes
hypertension. A newborn is diagnosed with hypertension
if the systolic and/or diastolic BP readings on 3 separate
occasions are at or above the 95th percentile for postcon-
ceptual age. (12)(13) If BP elevation is more severe, that is,
TABLE 1. Standardized Method for Blood
Pressure (BP) Measurement in
Newborns (11)
Infant position: Prone or supine
Device type: Oscillometric devices
Cuff size: Appropriate for neonatescuff width to arm
circumference ratio 0.450.70
Cuff location: Right upper arm
Timing:
- Infant should be asleep, or if awake, should be quiet
- Ensure that the infant is not disturbed for at least 15 min after the
cuff is placed
- Feed or medical intervention should have been at least 1.5 hours
before the BP measurement
Number of BP readings: At least 3 readings, 2 minutes apart
TABLE 2. Neonatal Blood Pressures and Potential Treatment Parameters
POSTCONCEPTUAL AGE 50th PERCENTILE 95th PERCENTILE 99th PERCENTILE

44 weeks
SBP 88 105 110
DBP 50 68 73
MAP 63 80 85
42 weeks
SBP 85 98 102
DBP 50 65 70
MAP 62 76 81
40 weeks
SBP 80 95 100
DBP 50 65 70
MAP 60 75 80
38 weeks
SBP 77 92 97
DBP 50 65 70
MAP 59 74 79
36 weeks
SBP 72 87 92
DBP 50 65 70
MAP 57 72 77
34 weeks
SBP 70 85 90
DBP 40 55 60
MAP 50 65 70
32 weeks
SBP 68 83 88
DBP 40 55 60
MAP 49 64 69
30 weeks
SBP 65 80 85
DBP 40 55 60
MAP 48 63 68
28 weeks
SBP 60 75 80
DBP 38 50 54
MAP 45 58 63

Continued

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 TABLE 2. (Continued )

POSTCONCEPTUAL AGE 50th PERCENTILE 95th PERCENTILE 99th PERCENTILE

26 weeks
SBP 55 72 77
DBP 30 50 56
MAP 38 57 63

This table provides estimated values for blood pressures after 2 weeks of age in infants of 26 to 44 weeks postconceptual age. The 95th and 99th percentile
values are intended to serve as a reference to identify infants with persistent hypertension who may require treatment. Data are based on several studies
using both Doppler and oscillometric blood pressure measurements. DBPdiastolic blood pressure; MAPmean arterial blood pressure; SBPsystolic
blood pressure.
Reproduced with permission from Pediatric Nephrology 2012. Copyright Springer.

values are above the 99th percentile for postconceptual age,
it should certainly warrant further investigation.
NORMAL BP IN PRETERM AND TERM INFANTS
There are no comprehensive data dening normal BP values
in preterm and term neonates. Several studies have been
performed to determine the norms, but almost all have
major drawbacks or used different methods of BP measure-
ment, which limit our ability to compare data between
studies. For preterm infants, the most commonly used
BP normative value table is presented in Table 2, which
was developed by pooling and extrapolating data from 7
studies, of which 4 used oscillometric methods and the
remainder used Doppler methods for measuring BP. (14)
For term infants up to age 12 months, the commonly used
reference for BP data is derived from the Report of the Second
Task Force on Blood Pressure Control in Children (1987),
which pooled data from various studies to establish these
norms. In all these studies, the BPs were measured using a
Doppler instrument, which may not be transferable to oscillo-
metric measurements commonly used today. (13) These data
are shown in Table 3A for boys and Table 3B for girls.
We pooled data from 3 newer and 1 older study for term
infants and compiled the data presented in Table 4. All 4
studies used oscillometric devices for BP measurement. (15)
(16)(17)(18) An older study by Tan (18) using the oscillo-
metric method was reported differently for the awake and
asleep states. Only awake values are presented in this table.
Asleep values were minimally lower. Values were reported

TABLE 3A. BP Values Measured with Doppler in Term Boys Less Than 1
Year of Age (13)
AGE IN MONTHS 0 1 2 3 4 5 6 7 8 9 10 11 12

SBP 72 84 90 90 90 90 90 90 90 90 90 90 90
th
50 percentile
DBP 56 53 50 50 52 53 54 54 55 56 57 57 57
SBP 87 101 106 106 106 106 106 106 106 106 106 106 106
th
90 percentile
DBP 68 65 63 63 63 65 66 67 68 68 69 69 69
SBP 91 103 110 110 110 110 110 110 110 110 110 110 110
th
95 percentile
DBP 72 68 66 66 66 70 71 72 72 72 73 73 74

BPblood pressure; DBPdiastolic blood pressure; SBPsystolic blood pressure.

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TABLE 3B. BP Values Measured with Doppler in Term Girls Less Than 1
Year of Age (13)
AGE IN MONTHS 0 1 2 3 4 5 6 7 8 9 10 11 12

SBP 66 83 87 88 90 90 90 90 90 90 90 90 90
50th percentile
DBP 55 53 52 52 53 53 53 53 54 54 54 54 54
SBP 76 98 101 104 105 106 106 106 106 106 106 105 105
th
90 percentile
DBP 68 65 64 64 65 65 66 66 66 67 67 67 67
SBP 91 103 105 106 107 110 110 110 110 110 110 110 110
th
95 percentile
DBP 72 68 67 67 68 70 70 72 72 72 72 72 72

BPblood pressure; DBPdiastolic blood pressure; SBPsystolic blood pressure.

as mean standard deviation (SD). Mean was assumed as
the 50th percentile, 2 SDs as the 95th percentile, and 3 SDs
as the 99.7th percentile. (18) Similar assumptions about
mean and SDs were made by Pejovic et al using oscillo-
metric measurements. (17)
EPIDEMIOLOGY
Although the American Academy of Pediatrics does not rec-
ommend routine BP evaluation in healthy term neonates, (19)
BP measurements are important in infants admitted to the
NICU, because they are at a higher risk for hypertension. (12)
Hypertension has been reported to have a variable but low
incidence in newborns. The incidence is reported to be around
0.2% in healthy term newborns and up to 3% in the infants in
NICUs. (1)(20)(21)(22) The exact prevalence of hypertension
in premature infants is not known but a study from Houston
reported that 1.4% preterm compared with 1% term infants
required antihypertensive therapy during NICU stay. (23)
ETIOLOGY
Over the years, several factors have been identied as being
either risks or direct etiologic factors for hypertension in
newborns. Table 5 lists the various risk factors and causes
of hypertension in neonates.
Renal parenchymal and vascular anomalies account
for the majority. (12)(20)(22) Umbilical arterial catheter
related thromboemboli are known to be associated with
neonatal hypertension (1)(24)(25) with longer duration re-
lated to more thrombus formation. (26) Vascular endothelial
disruption during umbilical artery catheter placement
leads to thrombus formation (27) in the renal vasculature,
which increases renin and aldosterone production due
to decreased renal perfusion. (2)(28) Thus, the length of
the arterial catheter may not be as important as catheter
placement per se. Renin and aldosterone also increase
salt and water retention, further exacerbating the hyper-
tension. It is important to note that thrombus formation
may not always be evident on radiologic studies.
Renal vein thrombosis may present with hypertension.
The classic triad of gross hematuria, thrombocytopenia, and
palpable ank (renal) mass occurs in only 13% of patients at
presentation. (29) Thus, presence of any of these signs in
high-risk patients, for example, infants of diabetic mothers
or those with factor V Leiden mutation, should prompt in-
vestigation for this complication.
Congenital anomalies of the kidney and urinary tract
(CAKUT) have also been associated with hypertension in
infants, for example, autosomal recessive and less commonly,
autosomal dominant polycystic kidney disease, multicystic
dysplastic kidney, ureteropelvic junction obstruction, and
urethral obstruction. Autosomal recessive polycystic kidney
disease usually presents with severe hypertension in the
rst year after birth, requiring multiple agents to manage.
Acquired renal parenchymal abnormalities, eg, interstitial
nephritis and cortical necrosis, can also lead to hypertension,
but not as frequently as CAKUT. (27)
The commonest association with nonrenal hyper-
tension in infants is chronic lung disease and broncho-
pulmonary dysplasia. Hypertension is reported to have a high
incidence of 13% to 43% in neonates with bronchopulmonary

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 TABLE 4. Pooled Mean BP Values for Normal Term Infants Less Than 1
Year Old as Measured with Oscillometric Devices from Various
Studies (15)(16)(18)
RANGE 50th PERCENTILE 90th PERCENTILE 95th PERCENTILE 99.7th PERCENTILE

Day 1
SBP 46-94 66 81 89
DBP 24-57 43 54 74
MAP 31-63 50 62 71
Day 2
SBP 46-91 68 78 84 93
DBP 2758 43 49 57 67
MAP 3768 52 58 66 76
Day 3
SBP 51-93 71 88 99
DBP 26-61 45 59 68
MAP 36-70 55 71 82
Day 4
SBP 60-88 72 89 97
DBP 34-57 47 62 73
MAP 41-65 56 71 81
Day 5
SBP 74 91 99
DBP 48 64 73
MAP 58 75 84
Day 6
SBP 73 89 97
DBP 47 63 64
MAP 58 74 83
Day 7
SBP 71 81 86
DBP 46 56 61
MAP 54 64 66
Day 30
SBP 77 87 87
DBP 50 58 62
MAP 59 67 71

Continued

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TABLE 4. (Continued )

RANGE 50th PERCENTILE 90th PERCENTILE 95th PERCENTILE 99.7th PERCENTILE

6 months
SBP 72131 102 116 120
DBP 3481 63 73 75
MAP 4899 75 84 87
12 months
SBP 75130 101 114 118
DBP 4184 64 75 78
MAP 5594 75 85 89

BPblood pressure; DBPdiastolic blood pressure; MAPmean arterial blood pressure; SBPsystolic blood pressure.

dysplasia. (30)(31) Although the exact mechanism is un-
known, it is thought to be related to increased systemic
arterial stiffness. (32) As expected, corticosteroid treatment
for such patients has been shown to contribute to tran-
sient hypertension. (33)
Medication-induced hypertension, when present, is usu-
ally transient and is generally expected to resolve when the
inciting medication is discontinued. (27) Idiopathic hyper-
tension has been reported to have a variable incidence of
5% to 57% in various studies. (1)(12)(23)

TABLE 5. Etiology and Risk Factors for Neonatal Hypertension

Maternal factors: Maternal hypertension, antenatal steroid exposure, maternal BMI >30, maternal diabetes, abnormal uteroplacental perfusion
Prematurity
Low birthweight
Perinatal hypoxia
Renal disease
Renal vascular, eg, renal artery thrombosis (due to umbilical artery catheter placement) or renal vein thrombosis, bromuscular dysplasia, renal
artery stenosis, compression of one or both renal arteries externally (eg, by tumors)
Renal parenchymal, eg, polycystic kidney disease, acute tubular or cortical necrosis, acute kidney injury
Cardiac disease, eg, PDA, coarctation of thoracic aorta
Medications: Steroids, indomethacin, vasopressors, bronchodilators
Parenteral nutrition: Excess volume, sodium overload, hypercalcemia
ECMO
Bronchopulmonary dysplasia
Endocrine disorders, eg, congenital adrenal hyperplasia, hyperaldosteronism, hyperthyroidism
Neoplastic disorders, eg, neuroblastoma, Wilms tumor
Intraventricular hemorrhage
Cytochrome P450 (CYP2D6) CC genotype in preterm infants
Pain
Hemolytic uremic syndrome
Idiopathic

BMIbody mass index; ECMOextracorporeal membrane oxygenation; PDApatent ductus arteriosus.

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 CLINICAL FEATURES OF HYPERTENSION IN NEONATES
In most cases, hypertension in neonates is detected as
a result of routine continuous monitoring in the NICU.
Because the incidence of hypertension is so low in normal
term infants, hypertension in this cohort is incidentally
discovered when the infant presents to a tertiary care
center for various symptoms and receives an evaluation
of vital signs, including BP measurement. Most patients do
not exhibit the usual symptoms of hypertension that older
children do, and symptoms and signs are often difcult to
differentiate from those of concurrent medical conditions,
such as cardiorespiratory failure, feeding difculties, irri-
tability, and gastrointestinal symptoms.
INVESTIGATION AND DIAGNOSTIC EVALUATION
A general approach to evaluation of a hypertensive neonate
is outlined in the Figure. Once recognized, a diagnostic
evaluation should be undertaken to determine the etiology
of hypertension (Table 6). Renal parenchymal or renovas-
cular causes account for the vast majority of cases in which
an etiology is identied; therefore, it is important that this
system be included in the initial evaluation in all infants. (1)
As the sensitivity and detail obtained by prenatal ultraso-
nography improve, many CAKUT are prenatally diagnosed.
These infants are at higher risk of developing hypertension
and should be monitored in the NICU and following
discharge.
A thorough history and physical examination should
assist in determining the etiology of the hypertension
(Table 5), and once hypertension is detected, historical
information may need to be reviewed. Attention should
be focused on the cardiovascular, abdominal, and genito-
urinary systems during a targeted physical examination.
Usually, dysmorphic features suggestive of genetic disor-
ders or syndromes would have been apparent by the time
hypertension manifests. Infants must be evaluated for
coarctation of the aorta (cardiac murmurs, 4-extremity
BPs, femoral pulses, brachiofemoral delay), and renal

Figure. Approach to the hypertensive neonate.

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TABLE 6. Diagnostic Evaluation of Infants with Hypertension
Historya 1. Maternal
a. Steroids, cocaine, heroin
b. Hypertension, diabetes mellitus, obesity
2. Prenatal oligo- or polyhydramnios
3. Renal anomalies on prenatal ultrasounds
4. Postnatal medications administered to the infants: Steroids, adrenergic agonists, indomethacin, caffeine
5. History of umbilical catheterization
Targeted physical examinationa 1. Volume status and weight trends
2. Dysmorphic features suggestive of a syndrome or genetic abnormality, eg, external ear abnormalities
and/or preauricular pit(s) in BOR syndrome
3. Cardiovascular
a. 4-extremity BP
b. Murmurs
c. Femoral and radial/brachial pulses
4. Genitourinary and renal
a. Abdominal masses (renomegaly)
b. Abdominal wall anomalies
c. Bruits
d. Genitalia (congenital adrenal hyperplasia)
Laboratory investigations 1. Urinalysisa
2. Electrolytes, calcium, BUN, creatininea
3. Additional investigations guided by clinical suspicion
a. Thyroid studies
b. Plasma renin activity and aldosterone
c. Cortisol level
d. 11-deoxycortisol and 11-deoxycorticosterone
e. Plasma and urine catecholamines, metanephrines and normetanephrines
Radiologic studies 1. Aortic and renal ultrasound with Dopplera
2. VCUG
3. CT angiogram to evaluate aorta and renal arteries
4. Nuclear medicine studies
a. DMSA or MAG3 scans
b. Captopril renal scan
5. Cranial imaging with ultrasound or MRI
Cardiology 1. Echocardiogram

BORbranchio-otorenal; BPblood pressure; BUNblood urea nitrogen; CTcomputed tomography; DMSAdimercaptosuccinic acid; MAG3
mercaptoacetyltriglycine; MRImagnetic resonance imaging; VCUGvoiding cystourethrography.
a
First-line investigations in all patients.

parenchymal and renovascular abnormalities like abdom-
inal masses and bruits.
All infants with hypertension should have a urinalysis,
and measurement of electrolytes, blood urea nitrogen,
creatinine, and calcium, and radiologic examination should
include aortic, renal, and bladder ultrasonography with
Doppler. These studies will identify almost all infants with
CAKUT. Further investigation should be guided by clinical
suspicion.
Echocardiography may be helpful in evaluating for
coarctation of the aorta. Longstanding and more severe
hypertension may lead to hypertensive cardiomyopathy,
which may manifest as left ventricular hypertrophy, dila-
tion, and/or dysfunction. When present, end-organ dys-
function should prompt a more thorough investigation for
a cause, and the management to achieve normal BP should
be more aggressive.
MANAGEMENT
Treatment of hypertension should be individualized de-
pending on the severity and etiology. We recommend work-
ing in conjunction with consultant pediatric nephrologists
and/or cardiologists, as deemed appropriate, to manage

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 TABLE 7A. Selected Antihypertensive Agents for Intravenous Use (34)
CLASS OF DRUG DRUG USUAL DOSE NOTES AND PRECAUTIONS

Vasodilators
Calcium channel blockers
b-adrenergic blockers
a- and b-adrenergic blockers
ACE-inhibitors
Hydralazine 0.10.5 mg/kg/dose IV every 68 hours
Max 2 mg/kg/dose
Sodium nitroprusside Start 0.2 mg/kg/min infusion
Max 10 mg/kg/min
Nicardipine 0.5-2 mg/kg/min infusion
Esmolol Term neonates 07 days old:
50 mg/kg/minute infusion; titrate dose
by 25 to 50 mg/kg/min every 20 min
Term neonates 8 to 28 days: Initial 75
mg/kg/minute; titrate dose by
50 mg/kg/minute every 20 min
Max 500 mg/kg/min
Propranolol Initial: 0.01 mg/kg/dose every 68 hours
Max 0.15 mg/kg/dose every 68 hours
Labetalol 0.1-1 mg/kg/dose IV every 46 hours or
0.253 mg/kg/hour infusion
Enalaprilat 5-10 mg/kg/dose every 824 hours
May cause tachycardia and edema
Renal failure, prolonged use >72 hours
and/or doses >2 mg/kg/min lead to
thiocyanate and cyanide toxicity
Do not use max dose for more than
10 min
May cause tachycardia and edema
Extravasation of esmolol can cause skin
necrosis
May lead to hyperkalemia, especially in
presence of renal failure. Monitor serum
potassium
Use with caution in bronchospastic disease
Follow closely for bradycardia
Use with caution in patients with
congestive heart failure and
bronchospastic disease
Use with caution in patients with
hyponatremia, hypovolemia, severe
congestive heart failure, decreased renal
function, or in those receiving diuretics
Avoid use in preterm infants
Do not use in neonates with GFR <30
mL/min/1.73 m2
Monitor serum sodium, potassium and
creatinine

Use is considered off-label. ACEangiotensin-converting enzyme; GFRglomerular ltration rate; IVintravenous.

infants with hypertension. The timing of antihypertensive
therapy is controversial and data regarding the benet of
treatment of milder hypertension are lacking. The natural
history of hypertension when it presents in neonates is
unique compared with older children. Most infants re-
quire treatment for only short periods, rarely more than
6 months. In a large study by Blowey et al, (3) with over 700
NICU infants with hypertension, the median exposure to
antihypertensive therapy was 10 days. Thus, the benets
of treatment of mild hypertension that is usually transient,
is unclear.
Most experts agree that severe hypertension, greater than
the 99th percentile for postconceptual age and/or sex and/or
size, should be managed with pharmaceutical agents. Long-
standing persistent hypertension in neonates can lead to
sequelae such as left ventricular hypertrophy, encephalop-
athy, and retinopathy. (3) No agents have been studied in
neonates and very few in older children, so most clinicians
use these agents off label.
In general, severe and/or symptomatic hypertension
should be treated with intravenous agents. Milder hyper-
tension can be treated with oral medications. The most
commonly used agents are vasodilators like hydralazine,
angiotensin-converting enzyme inhibitors, and calcium
channel blockers (Table 7A and Table 7B). Other classes
of agents that can be used include a- and b-adrenergic
antagonists, diuretics, and central a-agonists (Table 7A
and Table 7B). Angiotensin-converting enzyme inhibitors
should be avoided in preterm infants, those with acute renal
failure, and those with hyperkalemia.
Reversible and treatable factors contributing to hyper-
tension should be appropriately addressed. For example,
steroids should be reduced and discontinued when
able, and uid overload should be managed. Surgical or

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TABLE 7B. Selected Antihypertensive Agents for Oral Use (34)
CLASS OF DRUG DRUG USUAL DOSE NOTES AND PRECAUTIONS

Calcium channel blockers Amlodipine 0.10.5 mg/kg/day PO given once daily May cause tachycardia and edema.
Younger children <6 years have greater
weight-based clearance and volume
of distribution
ACE-inhibitors Captopril Term neonates 07 days old: Initiate 0.01 Use with caution in patients with
mg/kg/dose PO every 812 hours hyponatremia, hypovolemia, severe
congestive heart failure, decreased
renal function, or in those receiving
diuretics
Term neonates >7 days: Initial: 0.050.1 Avoid use in preterm infants
mg/kg/dose PO every 824 hours
Max 0.5 mg/kg/dose PO every 624 hours Do not use in neonates with GFR <30
mL/min/1.73 m2
Enalapril 0.04 to 0.1 mg/kg/day PO every 1224 Monitor serum sodium, potassium and
hours creatinine.
Max 0.27 mg/kg/day in neonates, 0.58
mg/kg/day in infants.
Lisinopril 0.07 to 0.1 mg/kg/dose PO once daily
Max 0.5 mg/kg/day PO
b-adrenergic blockers Propranolol 0.25 mg/kg/dose PO every 68 hours May lead to hyperkalemia, esp. in
presence of renal failure. Monitor
serum potassium.
Max 5 mg/kg/day PO Use with caution in bronchospastic
disease.
Follow closely for bradycardia.
a- and b-adrenergic Labetalol 13 mg/kg/day PO every 12 hours Use with caution in patients with
blockers Max 1012 mg/kg/day congestive heart failure and
bronchospastic disease.
Diuretics Chlorothiazide 2040 mg/kg/day PO every 12 hours Monitor for hypercalcemia, hypokalemia,
hypochloremic alkalosis,
hyponatremia, and hypomagnesemia.
Spironolactone 13 mg/kg/day PO every 1224 hours Caution in renal failure
Monitor for hyperkalemia
Central a agonist Clonidine 310 mg/kg/day PO every 812 hours May cause CNS depression and
bradycardia
Max 25 mg/kg/day PO Avoid abrupt discontinuation, which
may cause severe rebound
hypertension
Vasodilators Hydralazine 0.251 mg/kg/dose PO every 68 hours May cause tachycardia and edema
Max 7.5 mg/kg/day PO
Minoxidil 0.10.2 mg/kg PO once daily Very potent vasodilator usually reserved
for severe refractory hypertension
Max 1 mg/kg/day PO every 1224 hours May cause uid retention, pericardial
effusion and tachycardia

Use is considered off-label. CNScentral nervous system; POoral route.

interventional radiologic management may be required for
renal artery stenosis.
Decisions regarding the need for umbilical arterial cath-
eters, and use of potential nephrotoxins, especially amino-
glycosides and nonsteroidal anti-inammatory agents like
indomethacin, should be carefully considered in NICU
infants, weighing the risks and benets. Preterm infants
and those who are small for gestational age are already
predisposed to chronic kidney disease and hypertension
due, in part, to reduced nephron endowment. Nephronogene-
sis continues postnatally in preterm infants until 36
weeks estimated gestational age, and injury to developing

Vol. 18 No. 6 JUNE 2017 e367

 nephrons secondary to any insult, whether hypoxia, hypo-
tension, and/or nephrotoxin exposure, leads to more sig-
nicant and chronic sequelae.
CONCLUSION
Hypertension in normal neonates is rare; however, certain
groups of infants are at higher risk and should be mon-
itored. Most data regarding normal BP in neonates are old
and based on Doppler measurements, which cannot be
used to interpret data obtained with oscillometric devices
commonly used in NICUs and community pediatrician
ofces today. Furthermore, the diagnosis of hypertension
is a statistical one rather than outcomes based, and thus the
degree of BP elevation requiring treatment has not been
clearly delineated. Severe and long-standing hypertension
can lead to end-organ damage and should be appropriately
managed.
When possible, use of potential nephrotoxins and umbil-
ical arterial catheters should be avoided in infants at higher
risk for hypertension, such as those with underlying known
CAKUT, preterm and small-for-gestational age infants, as
risk of hypertension increases even further. Most infants
with hypertension will have no identiable cause, and in
those in whom a cause is recognized, renal parenchymal
and renovascular causes are the most common.
Therapy should be targeted to etiology. Data pertaining to
pharmacokinetics and pharmacodynamics of antihyperten-
sive drugs in neonates require further study to optimize
dosing guidance. When indicated, most neonates require
antihypertensives only transiently, with longer-term therapy
required by those with underlying renal or renovascular
abnormalities. Longer-term outcomes data are required to
guide the benet of therapy in newborn infants.
American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Formulate a differential diagnosis for an infant with systemic
hypertension in early infancy.
Know the management of an infant with systemic hypertension,
including adverse effects of management.
Know the factors that regulate systemic blood pressure in term
and preterm infants and know the normal range of pressures and
pressure patterns.
Know the clinical and diagnostic features of an infant with
systemic hypertension, including laboratory and imaging studies.
e368 NeoReviews
References
1. Singh HP, Hurley RM, Myers TF. Neonatal hypertension. Incidence
and risk factors. Am J Hypertens. 1992;5(2):5155
2. Buchi KF, Siegler RL. Hypertension in the rst month of life.
J Hypertens. 1986;4(5):525528
3. Blowey DL, Duda PJ, Stokes P, Hall M. Incidence and treatment of
hypertension in the neonatal intensive care unit. J Am Soc
Hypertens. 2011;5(6):478483
4. de Swiet M, Dillon MJ, Littler W, OBrien E, Padeld PL, Petrie JC.
Measurement of blood pressure in children: recommendations of a
working party of the British Hypertension Society. BMJ. 1989;299
(6697):497
5. Nascimento MC, Xavier CC, Goulart EM. Arterial blood pressure of
term newborns during the rst week of life. Braz J Med Biol Res.
2002;35:905911
6. Babbs CF. Oscillometric measurement of systolic and diastolic
blood pressures validated in a physiologic mathematical model.
Biomed Eng Online. 2012;11:56
7. Papadopoulos G, Oldrp B, Mieke S. [Arterial blood pressure
measurement with oscillometric instruments in newborns and
infants]. Anaesthesist. 1994;43(7):441446
8. Park MK, Menard SM. Accuracy of blood pressure measurement by
the Dinamap monitor in infants and children. Pediatrics. 1987;79
(6):907914
9. Lalan S, Blowey D. Comparison between oscillometric and intra-
arterial blood pressure measurements in ill preterm and full-term
neonates. J Am Soc Hypertens. 2014;8(1):3644
10. Shimokaze T, Akaba K, Saito E. Oscillometric and intra-arterial
blood pressure in preterm and term infants: extent of discrepancy
and factors associated with inaccuracy. Am J Perinatol. 2015;32
(3):277282
11. Nwankwo MU, Lorenz JM, Gardiner JC. A standard protocol for
blood pressure measurement in the newborn. Pediatrics. 1997;99
(6):E10
12. Seliem WA, Falk MC, Shadbolt B, Kent AL. Antenatal and postnatal
risk factors for neonatal hypertension and infant follow-up. Pediatr
Nephrol. 2007;22(12):20812087
13. National High Blood Pressure Education Program Working Group
on Hypertension Control in Children and Adolescents. Update on
the 1987 Task Force Report on High Blood Pressure in Children and
Adolescents: a working group report from the National High Blood
Pressure Education Program. Pediatrics. 1996;98(4 pt 1):649658
14. Flynn JT. Neonatal hypertension: diagnosis and management.
Pediatr Nephrol. 2000;14(4):332341
15. Kent AL, Kecskes Z, Shadbolt B, Falk MC. Normative blood pressure
data in the early neonatal period. Pediatr Nephrol. 2007;22
(9):13351341
16. Kent AL, Kecskes Z, Shadbolt B, Falk MC. Blood pressure in the rst
year of life in healthy infants born at term. Pediatr Nephrol. 2007;22
(10):17431749
17. Pejovic B, Peco-Antic A, Marinkovic-Eric J. Blood pressure in non-
critically ill preterm and full-term neonates. Pediatr Nephrol.
2007;22(2):249257
18. Tan KL. Blood pressure in full-term healthy neonates. Clin Pediatr
(Phila). 1987;26(1):2124
19. American Academy of Pediatrics Committee on Fetus and
Newborn. American Academy of Pediatrics Committee on
Fetus and Newborn: routine evaluation of blood pressure,
 hematocrit, and glucose in newborns. Pediatrics. 1993;92
(3):474476
20. Adelman RD. Neonatal hypertension. Pediatr Clin North Am.
1978;25(1):99110
21. Watkinson M. Hypertension in the newborn baby. Arch Dis Child
Fetal Neonatal Ed. 2002;86(2):F78F81
22. Friedman AL, Hustead VA. Hypertension in babies following
discharge from a neonatal intensive care unit: a 3-year follow-up.
Pediatr Nephrol. 1987;1(1):3034
23. Sahu R, Pannu H, Yu R, Shete S, Bricker JT, Gupta-Malhotra M.
Systemic hypertension requiring treatment in the neonatal
intensive care unit. J Pediatr. 2013;163(1):8488
24. Plumer LB, Kaplan GW, Mendoza SA. Hypertension in infants: a
complication of umbilical arterial catheterization. J Pediatr. 1976;89
(5):802805
25. Merten DF, Vogel JM, Adelman RD, Goetzman BW, Bogren HG.
Renovascular hypertension as a complication of umbilical arterial
catheterization. Radiology. 1978;126(3):751757
26. Boo NY, Wong NC, Zulkii SS, Lye MS. Risk factors associated with
umbilical vascular catheter-associated thrombosis in newborn
infants. J Paediatr Child Health. 1999;35(5):460465
Parent Resources from the AAP at HealthyChildren.org
High Blood Pressure in Children: https://www.healthychildren.org/English/health-issues/conditions/heart/Pages/High-Blood-Pressure-in-
Children.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
27. Dionne JM, Abitbol CL, Flynn JT. Hypertension in infancy:
diagnosis, management and outcome. Pediatr Nephrol. 2012;27
(1):1732
28. Kilian K. Hypertension in neonates: causes and treatments.
J Perinat Neonatal Nurs. 2003;17(1):6574, quiz 7576
29. Zigman A, Yazbeck S, Emil S, Nguyen L. Renal vein thrombosis: a
10-year review. J Pediatr Surg. 2000;35(11):15401542
30. Anderson AH, Warady BA, Daily DK, Johnson JA, Thomas MK.
Systemic hypertension in infants with severe bronchopulmonary
dysplasia: associated clinical factors. Am J Perinatol. 1993;10
(3):190193
31. Abman SH, Warady BA, Lum GM, Koops BL. Systemic
hypertension in infants with bronchopulmonary dysplasia. J Pediatr.
1984;104(6):928931
32. Sehgal A, Malikiwi A, Paul E, Tan K, Menahem S. Systemic arterial
stiffness in infants with bronchopulmonary dysplasia: potential
cause of systemic hypertension. J Perinatol. 2016;36:564569.
33. Smets K, Vanhaesebrouck P. Dexamethasone associated systemic
hypertension in low birth weight babies with chronic lung disease.
Eur J Pediatr. 1996;155(7):573575
34. Pediatric and Neonatal Lexi-Drugs Online. Available at: http://
online.lexi.com
Vol. 18 No. 6 JUNE 2017 e369
 NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click Journal CME from Gateways orange main menu or go directly to: http://www.
aappublications.org/content/journal-cme.

1. A female infant born at 28 weeks gestational age is in the NICU and receiving parenteral NOTE: Learners can take
nutrition and nasal continuous positive airway pressure. She is receiving blood pressure NeoReviews quizzes and
measurement by both arterial catheter and oscillometric device. Which of the following claim credit online only
statements regarding blood pressure measurement in patients such as this is correct? at: http://Neoreviews.org.
A. The oscillometric device will most likely have lower systolic and diastolic pressures
compared with the arterial catheter. To successfully complete
B. Direct arterial blood pressure measurement via arterial catheter is the most reliable 2017 NeoReviews articles
method in critically ill neonates. for AMA PRA Category 1
C. Small-forgestational age infants will usually have an overestimate of systolic blood CreditTM, learners must
pressure using an oscillometric device. demonstrate a minimum
D. Feeding or pacier sucking will usually cause a decrease in the blood pressure. performance level of 60%
E. In contrast to adults and older children, sleeping infants will typically have systolic or higher on this
blood pressure higher than when awake. assessment, which
2. A term infant with hypoxic-ischemic encephalopathy is in the NICU and is noted to have measures achievement of
hypertension. As you evaluate the infant, the differential diagnosis includes renal vein the educational purpose
thrombosis. Which of the following statements regarding this condition is correct? and/or objectives of this
A. The classic triad of gross hematuria, thrombocytopenia, and palpable ank mass activity. If you score less
occurs in 95% of patients. than 60% on the
B. Infants of diabetic mothers and those with factor V Leiden mutation have higher assessment, you will be
risk for this condition. given additional
C. The diagnosis is only possible if an umbilical arterial catheter has been placed. opportunities to answer
D. This is likely a result of volume overload that occurred during resuscitation. questions until an overall
E. This condition is often associated with hemophilia or von Willebrand disease. 60% or greater score is
3. A male infant born at 27 weeks gestational age is now 10 weeks old and remains in the achieved.
NICU. He is receiving oral and gavage feedings and nasal cannula oxygen. He has had a
complicated NICU course, with intraventricular hemorrhage and an episode of suspected This journal-based CME
necrotizing enterocolitis that was treated medically. Which of the following conditions has activity is available
the most common nonrenal association with hypertension? through Dec. 31, 2019,
A. Necrotizing enterocolitis. however, credit will be
B. Retinopathy of prematurity. recorded in the year in
C. Intraventricular hemorrhage. which the learner
D. Central line infection and sepsis. completes the quiz.
E. Bronchopulmonary dysplasia.
4. A 3-day-old term female infant presents to the NICU with poor feeding and is noted to have
hypertension. On physical examination, there appear to be weak femoral pulses. You are
planning a diagnostic investigation. Which of the following statements concerning
evaluation of a neonate with hypertension is correct?
A. The utility of laboratory tests in hypertension is questionable and blood tests
should only be obtained if there is a specic abnormality suspected.
B. If a prenatal ultrasound were to show normal kidneys, no further information would
be obtained from a postnatal scan.
C. An echocardiogram may be helpful to evaluate for coarctation of the aorta.
D. The vast majority of cases of hypertension in neonates are related to sepsis.
E. To prevent false-positive data, this patient should have blood pressure monitored
at most once a day, and only while peacefully sleeping.
5. A female infant born at 25 weeks gestational age is now 4 weeks old. The nurse reports
that the infant has been hypertensive on the last 2 blood pressure measurements, and on
further review, you note that the blood pressure has had an increasing trend over the past
few days. A diagnostic evaluation is pursued and no clear etiology is found. Which of the
following statements regarding treatment and prognosis is correct?

e370 NeoReviews
A. In observational studies, it has been shown that preterm infants who receive
antihypertensive medications in the initial NICU hospital course have a strong
likelihood (>50%) of requiring lifelong antihypertensive therapy.
B. Angiotensin-converting enzyme inhibitors should be avoided in preterm infants,
those with acute renal failure, and those with hyperkalemia.
C. a- and b-adrenergic agonists are the most effective antihypertensive drugs in
preterm infants.
D. Nephrogenesis stops at approximately 24 weeks gestational age, and therefore,
subsequent postnatal therapies will have little clinical benet in this population.
E. There is no indication or role for oral antihypertensive medications in the NICU.

Vol. 18 No. 6 JUNE 2017 e371

 Neonatal Urogenital Issues: Evaluation
and Management
Gino J. Vricella, MD,* Douglas E. Coplen, MD*
*St Louis Childrens Hospital and Washington University School of Medicine, St Louis, MO

Education Gap
Clinicians need to recognize the clinical manifestations of anatomic
abnormalities of the kidneys and urinary tract in neonates in order to
guide evaluation and management.

Abstract
The urinary and genital tracts are affected by more anomalies than any other
organ systems. Very few of these abnormalities require urgent neonatal
intervention, but recognition of clinical ndings is important for directing
appropriate evaluation and management. This article addresses renal,
bladder, and genital abnormalities noted in newborns. Neonatal
management of exstrophy/epispadias complex, prune belly syndrome, and
myelomeningocele is discussed. The differential diagnoses of abdominal
masses and introital masses are presented.

ANTENATAL HYDRONEPHROSIS

Prenatal ultrasonographic imaging identies hydronephrosis and other renal

anomalies in up to 1% of infants. A recent review of congenital anomalies of the
AUTHOR DISCLOSURE Drs Vricella and
kidney and urinary tract provides an excellent birds-eye view of the spectrum Coplen have disclosed no nancial
of urinary tract anatomic abnormalities but does not focus on neonatal eval- relationships relevant to this article. This
commentary does not contain a discussion
uation and management. (1)
of an unapproved/investigative use of a
Bladder distention, hydronephrosis, and oligohydramnios are potential commercial product/device.
indications for fetal intervention if identied early in the pregnancy and
testing indicates that renal function is salvageable.(2) If fetal intervention is ABBREVIATIONS
CIC clean intermittent
performed, delivery should be planned at a tertiary care center because of the
catheterization
high likelihood of renal insufciency and some degree of pulmonary com-
hCG human chorionic gonadotropin
promise despite successful decompression of the urinary tract. In utero MIS mllerian inhibitory substance
shunts often dislodge, and emergent intervention is required postnatally PUV posterior urethral valve
to retrieve intraperitoneal stents or to excise eviscerated omentum or bowel UTI urinary tract infection
(Fig 1). VACTERL vertebral defects-anal atresia-
cardiovascular anomalies-
Regardless of the degree of renal dilation and/or bladder distention, fetal
tracheoesophageal stula with
intervention is contraindicated in the presence of normal amniotic uid (Fig 2). esophageal atresia-radial and
Delivery at a tertiary care center should be arranged. Urgent decompression can renal dysplasia-limb defects
be performed postnatally if clinically indicated. VCUG voiding cystourethrography

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Figure 1. A. Infant with prune belly syndrome and urethral atresia. Vesicoamniotic shunt is appropriately positioned between the umbilicus and pubic
bone. B. Eviscerated and edematous omentum (*) secondary to transperitoneal shunt placement and dislodged shunt. A second shunt (arrow) was
placed through the left lower quadrant into the bladder. This demonstrates the difculty with placement of a shunt in the preferred location.

Almost all cases of unilateral hydronephrosis can be
observed for the rst several weeks after delivery. Antibiotic
prophylaxis may be started at birth though the benet of
prophylaxis is a subject of great debate. (3) As long as the
physical examination ndings are normal and the child is
clinically well, renal ultrasonography is typically performed
7 to 10 days after birth. Depending on the ndings, voiding
cystourethrography (VCUG) and/or renal scanning are typ-
ically performed at 4 to 6 weeks of age.
POSTERIOR URETHRAL VALVES
Posterior urethral valves (PUVs) are the most common
lower urinary tract obstructions and occur in 1 in 5,000
to 1 in 8,000 male infants. Prenatally this diagnosis should
be suspected in any male fetus with persistent bladder
distention and hydronephrosis. These infants should be
delivered at a tertiary care center or transferred immediately
after birth to a center with pediatric urologic care. Post-
natally, boys with unexplained respiratory distress should be
evaluated for pulmonary hypoplasia secondary to obstruc-
tive uropathy. The bladder is typically palpably distended.
The observed urinary stream is not always abnormal. An
abdominal ultrasonography can be performed, and demon-
strates varying degrees of hydronephrosis and a distended
thick-walled bladder (Fig 3).
A 3.5F or 5F feeding tube should be placed per urethra
into the bladder. Positioning can be conrmed with bedside
ultrasonography. An umbilical artery catheter should not be
placed per urethra because it is comparatively rigid and has

Figure 2. Magnetic resonance imaging scan shows

marked bilateral hydronephrosis and normal
amniotic uid. Other images show a distended
bladder. With normal amniotic uid, no prenatal
intervention is indicated.

Vol. 18 No. 6 JUNE 2017 e373

 Figure 3. A. Left kidney shows diffuse caliectasis and cortical thinning (SFU grade IV/IV). B. Ultrasound images show a thick-walled bladder and bilateral
ureteral dilation. Given these ultrasound ndings, voiding cystourethrography must be performed to rule out posterior urethral valves.
only a very small lumen. Intravenous antibiotics are started.
If possible, nephrotoxic medications are avoided. Once the
catheter is placed, urine output is monitored. Serum elec-
trolytes and creatinine are serially monitored. Metabolic
acidosis, if present, is treated. The creatinine may initially
increase, but if there is good urine output and metabolic
acidosis is treatable, then observation with catheter drainage
is indicated while the boys condition stabilizes. Urinomas
and urinary ascites should resolve with bladder decompres-
sion and do not require directed intervention/drainage.
Once stable, the infant should be transported to radiology
for VCUG. If PUVs are conrmed, then the catheter is left
in situ pending surgical intervention (Fig 4).
PUVs are thin membranes that emanate from the
vermontanum and are obstructive during antegrade uri-
nary ow. More rarely, the obstruction is a small aperture
in a circumferential diaphragm (Fig 5). Most near-term or
full-term infants have a urethra that is large enough to
allow cystoscopy and endoscopic valve ablation. Ablation
Figure 4. Voiding lms showing a dilated prostatic urethra,
hypertrophied bladder neck, and obstruction secondary to posterior
urethral valves.
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can be performed with a cold knife, electrocautery, or laser.
After ablation, a catheter may be left in place for 24 to 48
hours. Circumcision decreases the risk of urinary tract
infection (UTI) so we typically recommend circumcision
in these boys. If cystoscopy is not technically possible, then
a cutaneous vesicostomy is created. The dome of the
bladder is exteriorized and sewn to the skin midway
between the pubic bone and umbilicus. Urine drains
through the incision into the diaper (Fig 6). If the bladder
is very muscular and thick, then intermittent catheterization
of the stoma may be required for a short time. In the past,
cutaneous ureterostomies were created in patients with
PUVs with high-grade hydronephrosis and renal insuf-
ciency. Because there is almost never an obstruction above
the level of the bladder (at the ureterovesical junction),
proximal diversion is now rarely performed.
After valve ablation, the boys are maintained on anti-
biotic prophylaxis. Even in the absence of reux, the upper
tract dilation and bladder urinary stasis are large risk
factors for UTIs. They are followed jointly with nephrol-
ogy. Despite adequate ablation, many of these children
have signicant bladder dysfunction. Intermittent cathe-
terization is started in some boys if they have large
residuals or urine-concentrating defects (nephrogenic di-
abetes insipidus) that place the kidneys at risk for further
deterioration. (4)
ABDOMINAL MASS
The vast majority of abdominal masses in infants arise
from the urinary tract. Hydronephrosis or multicystic dys-
plasia are the most common causes of renal enlargement.
A dilated, muscular bladder is identied in boys with PUVs
(as described earlier). Diffuse abdominal distention with-
out mass may be secondary to urinary ascites. The ascites
will resolve with appropriate relief of urinary tract obstruc-
tion (typically secondary to valves). Rarely, massive unilateral
hydronephrosis requires urgent postnatal decompression
Figure 5. A. Endoscopic view of type 1 posterior urethral valve leaets. B. Endoscopic view of type III urethral valve, a small aperture (*) in a diaphragm
that traverses the urethra.
to facilitate appropriate oxygenation. Percutaneous drainage
is preferred (Fig 7). Once decompressed, the ipsilateral renal
function can be assessed and denitive management de-
layed until other comorbidities have been addressed and the
infant has been stabilized.
Autosomal Recesssive Polycystic Kidney Disease
Bilateral marked renal enlargement and respiratory insuf-
ciency are hallmarks of autosomal recessive polycystic
kidney disease. Renal enlargement is rapid and symmetric
secondary to collecting duct cysts. The incidence is 1 in
10,000 to 50,000 live births. Oligohydramnios is com-
mon, and results in dysmorphic facies and limb defor-
mities. The severity is variable, but up to 30% of affected
newborns die of pulmonary hypoplasia in the rst few days
after birth. (5) (Fig 8)
Renal Vein Thrombosis
Renal vein thrombosis is a rare nding in neonates who
have low perfusion pressure, polycythemia, and dehydra-
tion. The clot starts in peripheral renal vessels and propa-
gates centrally, though it rarely reaches the vena cava. The
diagnosis is suggested by renal enlargement, hematuria,
Figure 6. Cutaneous vesicostomy is positioned midway between the
pubic symphysis and umbilicus. This drains urine into the diaper. This
does not restrict normal bathing. The vesicostomy is typically closed
between 6 and 12 months of age at the time of valve ablation.
anemia, and thrombocytopenia. Approximately 20% of in-
fants with gross hematuria have renal vein thrombosis and
20% have bilateral involvement.
Ultrasonography shows an enlarged kidney (Fig 9). The
thrombus may be visualized. Treatment focuses on rehy-
dration and correction of electrolyte abnormalities. Anti-
coagulation (heparin or streptokinase) is rarely used in
unilateral renal vein thrombosis because of signicant
bleeding complications. Treatment may decrease loss of
renal function and may be used in bilateral involvement
to prevent end-stage renal disease but this has not been
shown to be efcacious. (6)
Adrenal Hemorrhage
Adrenal hemorrhage occurs in infants with perinatal
stressors like prolonged labor, birth trauma, and macrosomia.
This may coexist with renal vein thrombosis. The neonate
may have anemia, shock, and an abdominal mass. An
avascular suprarenal mass is identied on ultrasonography
(Fig 10). Magnetic resonance imaging may be required to
differentiate the mass from a neuroblastoma. In boys, the
blood occasionally tracks down the retroperitoneum along the
course of the testicular vasculature, resulting in scrotal ecchy-
mosis and swelling. Involution of the mass on serial ultra-
sonography supports the diagnosis. No specic treatment is
indicated and this rarely results in adrenal insufciency. (7)
Congenital Mesoblastic Nephroma
Congenital mesoblastic nephroma is a solid tumor that
is typically identied prenatally. (8) Polyhydramnios re-
sults in supranormal uterine size and is the indication
for fetal ultrasonography. Although the mass may be
locally invasive, treatment is radical nephrectomy alone
(Fig 11). (9)
Vol. 18 No. 6 JUNE 2017 e375
 Figure 7. A. Prenatal image showing massive dilation of the left kidney. Amniotic uid was normal. B. Postnatal image showing marked abdominal
distention that was affecting respiration. C. Appearance of abdomen after placement of a percutaneous nephrostomy at the bedside. D. Volume of urine
that was drained out of the kidney. Subsequent renal scan demonstrated 30% left function and a pyeloplasty was performed in the neonatal period.

Hydrocolpos hydronephrosis are identied in both conditions. How-

Hydrocolpos can be hard to differentiate from bladder disten-
tion on physical examination, but abdominal ultrasonography
will typically differentiate between the 2. Uterine distention
occurs secondary to either vaginal obstruction (imperforate
hymen, vaginal agenesis, etc) or retrograde distention with
urine in girls with a urogenital sinus anomaly (Fig 12). (See
management later in this article.)
PRUNE BELLY SYNDROME
It is difcult to differentiate prune belly syndrome from
PUVs on prenatal imaging, because distended bladders and
ever, the diagnosis of prune belly syndrome is apparent in
the delivery room (Fig 13). A deciency of abdominal mus-
culature gives the childs abdomen a wrinkled, prunelike
appearance. Bilateral nonpalpable undescended testes are
present. Associated anomalies can involve the respiratory
tract, gastrointestinal tract, cardiovascular system, and
musculoskeletal system. (10)
If amniotic uid was normal prenatally or the infant
voids shortly after birth, urgent catheterization is not re-
quired because of the lack of bladder outlet obstruction.
Ultrasonography is performed and typically demonstrates
tortuous, dilated ureters, and renal dysmorphism. The

Figure 8. A. Markedly enlarged echogenic kidney with no corticomedullary differentiation and cysts in a newborn with autosomal recessive polycystic
kidney disease (ARPKD). B. Chest radiograph of newborn with ARPKD and hypoplastic lungs. Note the small lung volume and bilateral chest tubes
placed for pneumothoraces.

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Figure 9. Computed tomographic scan demonstrating a markedly
enlarged left kidney with delayed excretion of contrast secondary to
venous obstruction. A subsequent ultrasound scan showed an atrophic
left kidney.
bladder is markedly distended. The bladder is easily mas-
saged (or tickled) through the abnormal abdominal wall
and this almost always generates bladder contraction and
urination.
Laboratory studies assess baseline renal function. A
cystogram is obtained to evaluate for reux and to exclude
urethral obstruction. Most newborns with prune belly
syndrome are given maintenance antibiotic prophylaxis
and observed. If there is urethral atresia, renal insuf-
ciency, or UTI, then a cutaneous vesicostomy is the pre-
ferred bladder management. Given the marked urinary
stasis, prophylactic antibiotics are used even in the absence
of vesicoureteral reux.
BLADDER EXSTROPHY
Classic bladder exstrophy affects the abdominal wall, pelvic
bones, anus, and genitalia. The bladder is open and the
Figure 10. A. Grayscale image of right kidney. There is a mass above the right kidney. B. Doppler image shows no ow in the mass above the kidney
consistent with adrenal hemorrhage.
Figure 11. Magnetic resonance image of a right congenital mesoblastic
nephroma. This large solid mass was identied prenatally.
ventral urethra is visualized. In boys, the phallus is fore-
shortened and there is dorsal curvature (Fig 14). Girls have
a bid clitoris and an anteriorly displaced vaginal orice
(Fig 15). The umbilicus is lower on the abdomen than
usual, positioned just above the apex of the defect. There is
widening (diastasis) of the symphysis pubis and outward
rotation of ischia, resulting in increased distance between
the hips and outward rotation of acetabula and lower
extremities. The short, broad perineum pushes the anus
anteriorly but the anus is normally positioned in the
musculature, so an anoplasty is not indicated. Inguinal
hernias may also be present.
Delivery room management of these neonates should
focus on limiting trauma to the open mucosa. The umbilical
cord should be tied with soft cloth umbilical tape rather than
the plastic umbilical clamp and the bladder defect should be
covered with nonadherent plastic wrap to minimize trauma
and drying (Fig 14B). This allows urine to ow out and
Vol. 18 No. 6 JUNE 2017 e377
 Figure 12. A. Transverse ultrasound image of the pelvis demonstrates a distended vagina with dependent debris posterior to the bladder (BL) that is
anteriorly displaced. B. Longitudinal image demonstrates the distended vagina and deviated bladder. C. More cephalad image shows the cervix and
distended uterus.
avoids irritation from diapers. Irrigation of the defect is not
necessary and broad-spectrum antibiotics are only indicated
around the time of closure. The infant should be transferred
to a facility with pediatric urologists and orthopedic sur-
geons in a timely manner. A secure closure requires re-
approximation of the pubic rami (Fig 16). There may be
some benet to closure in the rst 72 hours after birth but
Figure 13. Newborn with prune belly syndrome. Note that distended
bladder is visible through the thinned abdominal wall.
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bladder exstrophy is not a surgical emergency. Infants are
immobilized from 4 to 6 weeks after closure. (11)
CLOACAL EXSTROPHY
The classic constellation of anomalies that are noted in
children with cloacal exstrophy includes exstrophy of the
bladder, complete phallic separation, wide pubic diastasis,
exstrophy of the terminal ileum between the 2 halves of the
bladder, a rudimentary hindgut, imperforate anus, and the
presence of an omphalocele (Fig 17). Many children also have
spinal abnormalities (lipomeningocele, myelomeningocele,
spina bida, and isolated cord tethering).
Cloacal exstrophy is a more complex anomaly than
classic bladder exstrophy. Immediate management is
directed toward stabilization. In the past, gender reassign-
ment was considered in boys with cloacal exstrophy and a
diminutive phallus. However, it is now well accepted that
in utero testosterone imprints the brain and that these boys
should be raised as males with the small chance that
gender conversion would be required in the future. Neo-
natal omphalocele closure is recommended to prevent
untimely rupture and is typically combined with intestinal
diversion. Formerly, initial attempts focused on ileostomy
with resection of the hindgut remnant. Ileostomies are
associated with chronic uid and sodium loss. The infants
develop hyperaldosteronism related to dehydration. They
Figure 14. A. Classic bladder exstrophy in a male. Bladder mucosa is prolapsing and obscuring the phallus. B. Plastic wrap is used to cover the bladder
plate to decrease irritation in the diaper.
have poor weight gain and metabolic acidosis, so an
attempt should be made to use the hindgut remnant to
provide additional length of bowel for uid absorption. At
the initial stage of omphalocele closure, if it is determined
that bladder and abdominal wall closure may not be
accomplished, the bladder halves are approximated in
the midline without further dissection and the defect is
converted to a bladder exstrophy.
These infants are critically ill and often require paren-
teral nutrition because of marked foreshortening of the
intestinal tract. Given the coexisting spinal cord abnormal-
ities, most will have a permanent colostomy and require
some type of reconstruction to achieve urinary continence.
SPINAL DYSRAPHISM
Most spinal dysraphism cases are identied on fetal ultra-
sonography. In some centers, intrauterine fetal surgery
and closure are performed. Fetal intervention does not
alter bladder function and all these children have a neu-
rogenic bladder. Open myelomeningocele is readily iden-
tied at birth. The level of lesion does not correlate with the
neurologic defect. After birth, surgery is performed within
the rst 2 to 3 days. Once an indwelling catheter is
Figure 15. A. Female bladder exstrophy (note the bid clitoris). B. Female bladder exstrophy immediately after closure.
removed, clean intermittent catheterization (CIC) is initi-
ated and renal ultrasonography is performed. If catheter
residuals are routinely greater than 20 to 30 mL, then this
regimen is maintained every 4 to 6 hours. At 2 to 3 months
of age, urodynamic study is performed to further evaluate
bladder function. (12) These studies measure bladder
compliance, detrusor function, and capacity. If there is
marked detrusor overactivity or discoordination between
the detrusor and external sphincter (dyssynergia) that
results in bladder pressures greater than 40 cm H2O, then
oxybutynin and CIC are indicated. There is good evidence
that prophylactic treatment with CIC and anticholinergics
decreases the risk of renal injury and bladder deterioration.
(13)(14)
IMPERFORATE ANUS
Imperforate anus is rarely an isolated abnormality. As
part of the vertebral defectsanal atresiacardiovascular
anomaliestracheoesophageal stula with esophageal
atresiaradial and renal dysplasialimb defects (VACTERL)
association, renal and vertebral/spinal anomalies are fre-
quently identied. (15) Ultrasonography is performed to
evaluate for hydronephrosis, renal agenesis, and renal
Vol. 18 No. 6 JUNE 2017 e379
 Figure 16. Postoperative immobilization using A) mermaid restraints, or B) a modied spica cast.

dysplasia. If the collecting system and/or ureters are
found to be dilated, then VCUG is performed to evaluate
for reux. VCUG may also conrm the location of the
rectourethral or rectovesical stula. There is a high incidence
of neuropathic bladder related to vertebral anomalies and
tethered spinal cord. Spinal ultrasonography assesses the
level of the conus medullaris, which is normally at the L2
level in the newborn. If there is any question, a spinal
magnetic resonance imaging scan can be obtained later in
infancy. A diverting, as opposed to loop, colostomy is per-
formed to decrease the risk of UTI secondary to urinary tract
seeding by the rectourethral stula. Rarely, urine reux into
the mucus stula is seen, and reabsorption causes meta-
bolic acidosis. Urodynamic study should be performed at 3 to
4 months of age to assess bladder function in patients with
high lesions and/or spinal abnormalities.
SCROTAL ENLARGEMENT
A noncommunicating hydrocele is the most common
cause of neonatal scrotal enlargement and is identied
in up to 5% of term infants. Firm scrotal enlargement is
almost always secondary to the presence of hydroceles, and
transillumination may help in clarifying the diagnosis;
however, extravaginal torsion (rotation of spermatic cord
and tunica vaginalis) must be considered (Fig 18). Perinatal
spermatic cord torsion is a term applied to infants regard-
less of whether the event occurred before or after birth.

Figure 17. Cloacal exstrophy. A. The hindgut has prolapsed between the 2 bladder halves. B. The hindgut has been separated from the bladder halves
and a colostomy has been created. At this point, a decision can be made to proceed with closure of the bladder exstrophy or reapproximation of the
bladder plates and delayed closure.

e380 NeoReviews
Figure 18. A. Symmetric scrotal enlargement in a newborn. Ecchymosis and scrotal wall edema differentiate this from a straightforward hydrocele. B.
Extravaginal torsion of the left testicle. Note demarcation point in cord. The entire processus vaginalis is twisted.

Torsion of the entire cord occurs before xation of the tunica ureterocele. In older girls, urethral prolapse and vaginal
vaginalis and dartos within the scrotum. This event most rhabdomyosarcoma (botryoid or grapelike mass) are also in
commonly occurs well before delivery, yielding a vanishing the differential. Usually physical examination of external
testis or a hemosiderin-containing nubbin. The atrophic testis genitalia is diagnostic but renal and bladder (pelvic) ultra-
is almost invariably found in the scrotum, but less commonly, sonography can be used to conrm the diagnosis.
in the inguinal canal. If the event occurs during or shortly after
delivery, examination is consistent with a hard, painless testis Urethral Cyst
that is xed to the overlying erythematous or dark scrotal skin This is an opalescent cyst arising from the posterior
with or without edema. A coexisting hydrocele can often com- urethra (Fig 19). Even with a large cyst, a normal hymenal
plicate physical examination. Scrotal imaging may be obtained ring can be identied posteriorly. The cyst is typically
in cases of suspected perinatal torsion, but its usefulness and asymptomatic, but rarely, there is some suggestion of
reliability are questionable. The infant is typically asymptom- partial urethral obstruction (bladder distention, dribbling
atic. The ndings rarely develop after a normal newborn stream, and incomplete bladder emptying). The cyst wall is
examination. squamous and the contents are desquamated squamous
There is no consensus regarding the best treatment for cells. The cysts arise from the paraurethral glands and
perinatal testicular torsion. Some advocate elective explo- the presence at birth is felt to be secondary to maternal
ration, because the testicle is not salvageable in most estrogenic stimulation. Because the cyst is asymptomatic,
cases, metachronous torsion is rare, the risk of anesthesia it can be observed with a high likelihood of spontaneous
is increased, and there is a potential surgical risk to resolution/rupture. If the cyst persists or appears to be
injuring the remaining testis during orchiopexy. (16)
(17)(18)(19) If a contralateral hydrocele precludes clin-
ical evaluation of the testicle, then contralateral scrotal
exploration and orchiopexy should be performed to
decrease the risk of anorchia. Others advocate for imme-
diate exploration to offer possible partial or complete
testicular salvage (19)(20)(21) and point to cases of un-
expected contralateral torsion or atrophy found at explo-
ration. (22)(23)(24) When torsion is suspected after a
documented normal postnatal scrotal examination, it is
somewhat less controversial. Most surgeons would
advocate for prompt exploration as would be performed
for cases of intravaginal torsion.

INTROITAL MASS IN A FEMALE INFANT

For interlabial masses in neonates, the differential diagnosis

includes urethral cysts, imperforate hymen, and prolapsing Figure 19. Bulge of the urethral cyst is anterior to a normal hymenal ring.

Vol. 18 No. 6 JUNE 2017 e381

 Figure 20. A. Acute-onset inamed introital mass consistent with a prolapsed ureterocele. Renal and bladder ultrasound scan will conrm the presence
of a distended bladder and most commonly a renal duplication with hydroureteronephrosis. The ureterocele can be aspirated at the bedside with
prompt decompression and relief of bladder outlet obstruction. B. Appearance of same introitus 12 hours later.
symptomatic, then aspiration with an 18-gauge needle is
typically denitive.
Prolapsed Ureterocele
Rarely an ectopic ureterocele will prolapse. This is an
inamed mass with venous congestion (Fig 20). The infant
is uncomfortable secondary to bladder outlet obstruction.
The parents may note grunting and strangury. UTI and
sepsis are often present. Ultrasonography conrms the
presence of upper urinary tract and bladder distention.
The ureterocele can be aspirated. The decompressed
ureterocele will retract into the bladder. After the sepsis
is treated, VCUG is performed to evaluate for reux.
Figure 21. Noninamed opalescent mass occluding the introitus.
Ultrasonography will conrm the presence of a dilated vagina and
uterus (see Fig 12).
e382 NeoReviews
Ultrasonography performed 1 month later should show
decreased upper tract dilation. Subsequent open ureterocele
excision and reconstruction may be indicated for recurrent
infections and/or persistent vesicoureteral reux.
Imperforate Hymen
Imperforate hymen is the most common congenital vag-
inal obstruction. On examination, the distensible mem-
brane bulges between the labia. This is inferior to the
urethral opening. By denition, the hymenal opening is
absent (Fig 21). A palpable abdominal mass (distended
uterus) is often present. The distention is secondary to
mucoid secretions induced by maternal estrogen. Pelvic
ultrasonography will reveal distention of the vagina and
uterus. The bladder is typically anteriorly displaced and
may also be distended. Incision of the hymen is denitive.
There is typically no scarring or long-term sequela related
to the neonatal vaginal and uterine distention. If not
identied in infancy, this will present with amenorrhea
in adolescence.
HYPOSPADIAS
Hypospadias occurs in approximately 1 in 200 male in-
fants. The phenotype is widely variable (Figs 22 and 23).
If the phallus is small, there may be concerns regard-
ing androgen synthesis and/or androgen action; however,
if the testes (gonads) are descended, historically, a disorder

Figure 22. Distal shaft hypospadias.
of sexual differentiation is not a concern. However, if one
or both gonads are undescended and/or nonpalpable,
genital ambiguity is present; a multidisciplinary evalua-
tion and management approach involving endocrine,
urologic, gynecologic, genetic, psychologic, and ethical
teams is indicated.
Although an urgent referral is not required for evalua-
tion of hypospadias, parents are often very anxious regard-
ing the diagnosis and may wish to meet with a urologist in
the rst 1 to 2 months after birth. Even boys with a very
small urethral meatus have no voiding symptoms or dif-
culties in infancy. The incidence of UTI is not higher,
presumably because the prepuce does not completely
cover the urethral meatus. Circumcision should be
delayed in most boys with hypospadias, but it can be safely
performed in boys with an intact prepuce megameatus
variant because the foreskin is not required for
reconstruction.
GENITAL AMBIGUITY
Genital ambiguity is noted when the phallus is neither
male nor female in appearance (Fig 23). The appearance
may vary widely in patients with the same condition, so
denitive diagnosis cannot be based on physical appear-
ance alone. The size and shape of the phallus and the
location of the urethral meatus are noted. A well-developed
phallus suggests the presence of circulating high levels of
androgens and a functioning androgen receptor. Elevated
corticotropin may cause hyperpigmentation of the external
genitalia. As described earlier, palpation for the presence
of gonadal tissue is imperative for the initial differential
diagnosis.
Particular attention is given to the maternal medica-
tions used just before or during pregnancy. A family history
should be obtained regarding genital defects and/or sudden
infant death.
Laboratory Evaluation
A karyotype may be available within 24 to 72 hours de-
pending on the institution. Infants should be evaluated
for hypoglycemia, hyponatremia, hyperkalemia and met-
abolic acidosis, and chemical imbalances that can develop
with untreated congenital adrenal hyperplasia. A rapid
assay for 17-hydroxyprogesterone should be performed
to rule out 21-hydroxylase deciency
Radiographic Studies
Abdominal and pelvic ultrasonography is the primary test
obtained in the neonatal period. This will usually demonstrate
mllerian structures lying behind the bladder in most cases of
ovarian, ovotesticular, and mixed gonadal dysgenesis. Ultraso-
nography may also be used to assess for the location of the
gonads, but this is most sensitive when the gonads are in the
inguinal canal. A genitogram (simultaneous VCUG and vagino-
gram) is extremely useful in determining the presence of a
vagina, the vaginal size and conguration, and the level at which
the vagina opens into the urogenital sinus (Fig 24). A cervical
impression at the apex of the vaginal vault is typically identied.
NORMALLY FORMED PHALLUS AND NONPALPABLE
GONADS
In rare instances, a female (46XX) is completely virilized
with a Prader V phallus and nonpalpable gonads. Con-
genital adrenal hyperplasia must be excluded in these
infants. Most of these children are normal males with
undescended testes, whereas 1% to 2% of these boys
have anorchia secondary to testicular regression/antenatal
torsion. Human chorionic gonadotropin (hCG) stimula-
tion tests and pituitary functional investigations are
helpful in infants with nonpalpable gonads who fail to
demonstrate the appropriate neonatal rise in testoster-
one. (25) A positive test result conrms the presence of
functional testicular tissue. A negative response to the
initial hCG stimulation test is associated with a 15%
false-negative rate, that is, functioning testicular tissue
is present, with little to no increase in testosterone in
response to hCG.
Vol. 18 No. 6 JUNE 2017 e383
 Figure 23. Genital ambiguity. A and B. Single urogenital opening. Gonads are not palpable so evaluation for congenital adrenal hyperplasia is required.
C. Hypospadias with scrotal asymmetry. There is a descended testicle on the left and a nonpalpable gonad on the right in a child with mixed gonadal
dysgenesis D. Isolated clitoromegaly secondary to androgen exposure after feminization of the urogenital sinus in an infant with ovotesticular disorder
of sexual differentiation,

Determination of mllerian inhibitory substance (MIS) (>5 ng/mL) are indicative of testicular function. (26)
can aid in determining if functional testicular tissue is Low or undetectable levels of MIS would suggest either
present. Specically, serum MIS values that are normal anorchia or the presence of dysgenetic gonads.

ABSENCE OF VOIDING

Figure 24. Genitogram in congenital adrenal hyperplasia demonstrates
conuence of the urethra and vagina into a distal common channel
(urogenital sinus).
Most children will void within the rst 24 hours after birth.
(27) If the child is clinically well, and the bladder is not
palpably distended, continued observation is advisable.
Gentle stimulation of the lower abdomen may cause a blad-
der contraction and urination. Ultrasonography can be per-
formed if the bladder is distended or if there are other
clinical concerns. If the bladder is distended and/or hydro-
nephrosis is identied, then catheterization and urologic
evaluation are indicated. Recent newborn circumcision or
hypospadias should not adversely affect urination. Cathe-
terization is unnecessary because the child will eventually
void.

e384 NeoReviews

American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Recognize the clinical manifestations of anatomic abnormalities
of the kidneys and urinary tract in infants.
Know the clinical manifestations, laboratory features, and
therapeutic management of an infant with ambiguous genitalia,
not including congenital adrenal hyperplasia.
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Vol. 18 No. 6 JUNE 2017 e385
 Index of Suspicion in the Nursery
AUTHOR DISCLOSURE Drs Kurada and
Joseph have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
e386 NeoReviews
1 The Inconsolable Infant in the NICU
Sravanti Kurada, MD,* Tessy Joseph, MD
*Division of Neonatal-Perinatal Medicine, Brookdale University Hospital Center, Brooklyn, NY, and
Division of Neonatology, John Stroger Hospital of Cook County, Chicago, IL
PRESENTATION
A female infant is born at 30 weeks of gestation via vaginal delivery due to
imminent labor. The infant receives 1 dose of surfactant in the delivery room for
respiratory distress, after which she is transferred to the NICU for further care.
Anthropometric measurements at birth are: weight, 595 g; length, 29 cm; and
head circumference, 23.5 cm. Birthweight, length, and head circumference are
below the 5th percentile for the corresponding gestational age. Wide forehead, 2
natal teeth on the mandibular ridge, hypertonia of all extremities, grade 2 systolic
murmur, and bilateral inguinal hernias are noted on examination. Specic
immunoglobulin M values for toxoplasma, rubella and cytomegalovirus virus
are negative. Head ultrasonography reveals no calcications or other abnormali-
ties. Skeletal survey shows no signs of perichondritis. Retinal examination to
check for signs of chorioretinal inammation that could point toward a particular
TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella,
cytomegalovirus, and herpes) infection are negative. Peripheral pulmonary
arteries are found to be mildly hypoplastic on echocardiography, which is
conducted as part of an evaluation for an audible murmur. Ultrasound imaging
of kidneys and bladder reveals no anatomic abnormalities.
The patient undergoes elective extubation 24 hours after birth. She makes a
transition to room air within 72 hours after birth. After extubation, she has a high-
pitched cry, and a hyperactive anxious disposition that requires much attention
from nursing staff and is inconsolable. She has abnormally long cry times that are
8 to 12 hours a day. Thyroid prole indicates euthyroid status. Urine toxicology
screening result is negative. Electroencephalography is age appropriate. Mag-
netic resonance imaging of the brain shows no anatomic abnormalities. Neonatal
pain score is persistently high requiring intervention. Auditory brainstem
response shows unilateral sensorineural hearing decit on the right side and
normal conduction on the left side.
Frequent abdominal distention hinders the advancement of enteral feeds.
Contrast studies do not reveal any anatomic obstruction and enteral feeds are
continued through a nasojejunal tube. Most of her nutrition is given parenterally
because of repeated failures in oral feeding attempts. Swallow evaluation shows
complete lack of coordination of swallow and suck, along with failure to create suction
pressure with a good seal around the nipple, thus causing leakage of oral feeds from
the side of her mouth. Catch-up growth is not seen. Percutaneous gastrostomy tube
placement restored enteral feeds, which assist in appropriate weight gain.
Repeat echocardiography at 4 weeks reveals mildly hypoplastic pulmonary
trunks and supravalvular pulmonary stenosis. Balloon dilation of the pulmonary
valve is performed to reduce the pressure gradient across the stenosis.
 Karyotype analysis reveals 46,XX and chromosomal
microarray conrms the diagnosis.
DISCUSSION
Diagnosis
Cri-du-chat could be considered as part of the differential
diagnosis because of the high-pitched cry and microceph-
aly. The differential diagnosis includes Williams syndrome
(WS) because of the pulmonary stenosis, unilateral senso-
rineural hearing loss, and short stature.
The microarray revealed 7q11.23 microdeletion encom-
passing the elastin ELN gene, which is characteristic of WS.
WS is now recognized to be a multisystem genomic disorder
caused by a homozygous microdeletion of chromosome
7q11.23. The deleted portion of the WS gene includes the
ELN gene, which codes for structural protein elastin.
All of the following features point toward a condition with
a genetic etiology: feeding problem, anxious disposition,
inconsolable crying during hospital stay, bilateral inguinal
hernia, sensorineural hearing loss, decreased gut motility,
lack of suck-swallow coordination for oral feeds requiring
gastrostomy to advance enteral feeds, peripheral pulmonary
stenosis with supravalvular pulmonary stenosis requiring
balloon dilation, and short stature.
The Condition
The incidence of WS is 1 in 10,000 live births. The facial
features are described as eln facies with a broad forehead
and a wide mouth. The incidence of auditory problems,
including hypersensitivity and sensorineural hearing loss,
is 50% to 90%. Malocclusion and microdontia are the
reported dental malformations with a high incidence of
85% to 95%. Early postnatal teeth is not a well-known entity
and not commonly seen in WS.
Twenty-ve percent of patients with supravalvular aortic
stenosis have WS, which makes it a very specic nding.
Pulmonary arterial stenosis is the second most common
cardiovascular abnormality seen in WS. Supravalvular pul-
monary stenosis, although rare, is seen in affected infants.
Other major blood vessels such as the renal arteries have
also been reported to be affected. Hypertension is another
problem that would be evident in adolescents.
Feeding difculties seen in most affected children be-
comes the most common gastrointestinal manifestation of
the WS. Constipation is the second most common gastro-
intestinal manifestation.
Lax skin and hernias that are inguinal or umbilical in
location are commonly seen. Calcium metabolism issues, hy-
pothyroidism, and type 1 diabetes mellitus are also seen rarely.
Most affected children have joint hypermobility and
contractures that result in an awkward gait. Central hypo-
tonia and peripheral hypertonia with hyperactive deep ten-
don are found in children with WS.
Cognition is affected almost universally. Developmental
delay is expected in 95% of the affected children. Affected
children have defects in the visuospatial constructive cog-
nition. Attention-decit/hyperactivity disorder and general-
ized anxiety disorder are seen in older children. We believe
this anxiety manifested, even at an early age, as inconsolable
crying in our patient. Overfriendliness, a gregarious per-
sonality, and an empathetic nature are also commonly
observed.
Management
The American Academy of Pediatrics published guidelines in
2001 for the evaluation and primary care of children with WS.
Special considerations were mentioned and categorized by
age from birth to adolescence. Baseline evaluation and inte-
gration of communication among the cardiologist, primary
care physician, nephrologist, child psychiatrist, and therapist
is emphasized. Pediatric orthopedics should be involved from
early childhood for frequent surveillance for kyphosis, scoli-
osis, and early detection and prevention of problems that lead
to awkward gait. Most common cause for mortality after the
third decade of life is cardiovascular in origin.
Lessons for the Clinician
A neonate who is symmetrically small for gestational age
with no ndings of in utero TORCH (toxoplasmosis,
other [syphilis, varicella-zoster, parvovirus B19], rubella,
cytomegalovirus, and herpes) infections should be eval-
uated for genetic causes of the condition.
Neurologic examination of growing premature infants
including disposition should be done elaborately on a
regular basis to keep a close watch on interval changes.
Supravalvular aortic and pulmonary arterial stenosis is
strongly associated with Williams syndrome, which can
be conrmed by 7q11.23 sequencing.
American Board of Pediatrics
Neonatal-Perinatal Content
Specication
Recognize clinical manifestations and laboratory methods for
diagnosis of the microdeletion syndromes.
Vol. 18 No. 6 JUNE 2017 e387
 Suggested Readings
Committee on Genetics. American Academy of Pediatrics: health care
supervision for children with Williams syndrome. Pediatrics.
2001;107(5):11921204
Lowery MC, Morris CA, Ewart A, et al. Strong correlation of elastin
deletions, detected by FISH, with Williams syndrome: evaluation of
235 patients. Am J Hum Genet. 1995;57(1):4953
e388 NeoReviews
Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL. Natural
history of Williams syndrome: physical characteristics. J Pediatr.
1988;113(2):318326
Teixeira MC, Monteiro CR, Velloso RL, Kim CA, Carreiro LR. Behavioral
and cognitive phenotype of children and adolescents with
Williams-Beuren Syndrome. Pro Fono. 2010;22(3):215220
 Index of Suspicion in the Nursery
AUTHOR DISCLOSURE Drs Krasaelap and
Kannikeswaran have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
An Infant with Poor Weight Gain and
2 Persistent Tachycardia
Amornluck Krasaelap, MD,* Nirupama Kannikeswaran, MD*
*Department of Pediatrics and Division of Emergency Medicine, Childrens Hospital of Michigan, and
Wayne State University, Detroit, MI
CASE PRESENTATION
An 8-week-old-term female infant presents with a 2-day history of nasal conges-
tion, cough, and difculty breathing. The mother denies fever and any change
in feeding or wet diapers. Initial vital signs show a rectal temperature of 99.8F
(37.7C), heart rate of 190 to 210 beats/min, respiratory rate of 70 to 80
breaths/min, oxygen saturation of 95% in room air, and blood pressure of
128/78 mm Hg. The patient is noted to be small for age (3,650 g, 7th percentile)
with normal height and head circumference. She is in moderate respiratory distress
with intercostal retractions but clear lungs. She is tachycardic, with good pulses and
perfusion. No murmurs, gallop, or organomegaly were noted. She is administered
aerosolized albuterol/ipratropium, high-ow oxygen through nasal cannula, and
20 mL/kg of normal saline bolus, with minimal improvement in cardiorespiratory
status. Results of chest radiography and capillary blood gas measurement are
normal. The nasal swab is positive for respiratory syncytial virus. The patient is trans-
ferred to the pediatric intensive care unit for respiratory syncytial virus bronchiolitis.
Patient was born at 38 weeks to a 27-year-old gravida 3, para 3-0-0-3 mother,
who reported regular prenatal care without any medical problems. The infants
birthweight was appropriate for gestational age (3,430 g). However, after dis-
charge, her weight gain was poor (<2 g/day) despite absence of feeding difculty
and change to a concentrated formula (25 calorie/ounce).
During her admission to the intensive care unit, respiratory distress and
tachycardia persist despite the administration of 3 additional 20-mL/kg uid
boluses. Serial capillary blood gases are unremarkable. Electrocardiography shows
sinus tachycardia without pre-excitation pathway. Blood culture is negative. Echo-
cardiography and abdominal ultrasonography are also unremarkable.
The infants respiratory status normalizes on hospital day 3, but she remains
tachycardic, with a heart rate of up to 180 beats/min. She tolerates high-calorie
formula well but no signicant weight gain is observed (6 g/day). Results of thyroid
function tests (TFTs) are consistent with hyperthyroidism (thyrotropin [TSH]
<0.008 mIU/mL, free thyroxine [ fT4] 5.2 ng/dL [66.9 pmol/L]).
Review of maternal records revealed that the mother was diagnosed with
Graves disease (GD) at 8 weeks of pregnancy. Maternal TFTs at 18 weeks showed
an elevated fT4 (8.1 ng/dL [104 pmol/L]) with an undetectable TSH level. Thyroid-
stimulating immunoglobulin (TSI) was signicantly elevated (>500%). Though
asymptomatic, she was started on treatment with methimazole. Serial fetal
ultrasonography showed normal growth and anatomy. Serial nonstress test
showed normal baseline fetal heart rate of 110 to 160 beats/min, with normal
Vol. 18 No. 6 JUNE 2017 e389
 variability and accelerations. Last maternal TFTs 1 month
before delivery showed normalized fT4 with a suppressed
TSH level.
Given the history of maternal GD, the patients poor
weight gain, and laboratory results consistent with hyper-
thyroidism, a diagnosis of neonatal hyperthyroidism is
made.
CASE PROGRESSION
The patient started treatment with methimazole 0.5 mg/kg
per day and propranolol 0.5 to 1 mg/kg per day as recom-
mended by the endocrinologist. Two days after therapy, her
heart rate normalized to 120 to 140 beats/min and weight
gain improved to 60 g/day.
At the 2-week follow-up, the patient continued to dem-
onstrate excellent weight gain (35 g/day). Resting heart rate
was 130 beats/min. Repeat TFTs showed normalized fT4 and
TSH levels with elevated TSI (216%), consistent with neo-
natal hyperthyroidism.
DISCUSSION
The prevalence of GD in pregnancy is 0.2%. Neonatal
hyperthyroidism occurs in 1% to 12.5% of these pregnan-
cies, whereas 3% of pregnancies result in asymptomatic
hyperthyroidism, (1) resulting in a prevalence of neonatal
hyperthyroidism between 1 in 4,000 and 1 in 50,000
pregnancies. (1)
Neonatal hyperthyroidism is usually secondary to trans-
placental passage of TSI, a type of thyroid receptor antibody,
from a mother with an autoimmune thyroid disorder. This
causes transient hyperthyroidism secondary to limited clear-
ance of maternal TSIs from the infants circulation until
8 to 20 weeks. (1) Thyroid hormone levels usually normal-
ize by 48 weeks after birth. (2) Less common forms caus-
dominantly inherited TSH receptor mutations (3) and muta-
tions of the stimulating G protein in McCune-Albright
syndrome. (4) Risk factors for developing neonatal hyper-
thyroidism are summarized in Table 1. (1)
Signs and symptoms of fetal and neonatal hyperthyroid-
ism (Table 2) are nonspecic and can be confused with
sepsis or heart disease. Symptoms usually manifest by 10
days after birth, (5) but can be apparent after birth or delayed
up to 45 days. (6) Mortality rates can be as high as 12% to
20% in undiagnosed hyperthyroidism due to heart failure,
TABLE 2. Signs and Symptoms of Fetal and
Neonatal Hyperthyroidism
Fetal
Intrauterine growth restriction
Prematurity
Fetal tachycardia (heart rate >160 beats/min)
Fetal goiter
Nonimmune hydrops from cardiac failure
Intrauterine death
Neonatal
Persistent acrocyanosis
Goiter, tracheal obstruction
Periorbital edema, lid retraction, and exophthalmos
Tachycardia, arrhythmia, congestive heart failure, systemic/
pulmonary hypertension
Microcephaly, craniosynostosis, frontal bossing, triangular-
shaped face
Advanced bone age
Irritability, jitteriness, and restlessness
Diaphoresis, ushing

ing persistent neonatal hyperthyroidism are secondary to Excessive appetite

Frequent vomiting and diarrhea
Hypoglycemia
TABLE 1. Neonates at High Risk for Neonatal Poor weight gain
Hyperthyroidism
Hyperbilirubinemia, hepatic cholestasis
Mothers with clinical thyrotoxicosis or those receiving thionamide Hepatosplenomegaly (with or without congestive heart failure)
therapy during third trimester
Hyperviscosity syndrome
Elevated maternal thyroid-stimulating immunoglobulins (>2-3
times normal) between 20 and 24 weeks of pregnancy Thrombocytopenia, petechiae

Mothers with a previous infant with neonatal hyperthyroidism Lymphadenopathy

Family history of thyrotropin receptor mutation Infections

Evidence of fetal thyrotoxicosis Death

e390 NeoReviews
and less commonly due to tracheal compression, infections,
and thrombocytopenia. (1) Long-term effects of undiag-
nosed hyperthyroidism include craniosynostosis, intellec-
tual impairment, and growth restriction.
Newborn screening is not a reliable measure to detect
infants with hyperthyroidism because it is designed to
detect elevated TSH levels seen in primary hypothyroid-
ism. Testing for neonatal hyperthyroidism in infants of
mothers with GD depends on the maternal TSI levels. No
testing is recommended for those infants whose maternal
TSIs are negative. If maternal TSIs are positive or unavail-
able, cord blood should be tested. Low- or high-risk infants
with normal cord blood TSI can be discharged and no
specic follow-up is needed. (7) If cord blood TSI is abnor-
mal, TFTs should be measured at 3 to 5 days after birth
unless clinical signs warrant earlier testing. If initial TFTs
are normal, it is repeated between days 10 and 14, and
at 4 weeks and 2 to 3 months to identify infants with
delayed-onset hyperthyroidism. (7)
Treatment of asymptomatic infants with hyperthyroid-
ism remains controversial. (7) Symptomatic infants should
be treated, given the long-term effects of hyperthyroidism
and low risk of medication-induced hypothyroidism.
(1)(7) The mainstay of treatment is methimazole with
an initial dose of 0.625 mg twice daily (0.4 mg/kg per
day) for a term newborn. (7) Methimazole is preferred over
propylthiouracil because of the latters association with liver
failure. Methimazole acts by blocking thyroid hormone syn-
thesis and hence clinical effects might be delayed until thyroid
hormone storage is depleted. A strong iodine solution (Lugol
solution 1 drop every 8 hours or potassium iodide 1 drop daily)
can be added to block the immediate release of hormone in
severe cases. Prednisolone, 2 mg/kg per day, can be added
to suppress the deiodination process and replenish gluco-
corticoids during the hypermetabolism period. In patients
with severe sympathetic overstimulation, propranolol
2 mg/kg per day in 2 divided doses for 1 to 2 weeks can be
added. (7)
Infants receiving treatment need weekly follow-up
until symptoms and TFTs stabilize, and every 2 weeks
thereafter. (7) Most infants require medical treatment
for 4 to 8 weeks, while those with persistent neonatal
hyperthyroidism secondary to TSH mutations may require
ablative treatment.
Lesson for the Clinician
Neonatal hyperthyroidism is a rare condition but can result
in serious morbidity or even death in infants if undiag-
nosed. This diagnosis should be considered, particularly in
infants born to mothers with autoimmune hyperthyroid-
ism with elevated thyroid-stimulating immunoglobulin.
American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Know the relationship between fetal and maternal thyroid
physiology.
Identify the etiology, clinical manifestations, laboratory features,
and management of neonatal thyrotoxicosis.
References
1. Ogilvy-Stuart AL. Neonatal thyroid disorders. Arch Dis Child Fetal
Neonatal Ed. 2002;87(3):F165F171
2. Sunshine P, Kusumoto H, Kriss JP. Survival time of circulating long-
acting thyroid stimulator in neonatal thyrotoxicosis: implications for
diagnosis and therapy of the disorder. Pediatrics. 1965;36(6):
869876
3. Schwab KO, Gerlich M, Broecker M, Shlemann P, Derwahl M,
Lohse MJ. Constitutively active germline mutation of the thyrotropin
receptor gene as a cause of congenital hyperthyroidism. J Pediatr.
1997;131(6):899904
4. Yoshimoto M, Nakayama M, Baba T, et al. A case of neonatal McCune-
Albright syndrome with Cushing syndrome and hyperthyroidism.
Acta Paediatr Scand. 1991;80(10):984987
5. OHearlihy C. Neonatal thyrotoxicosis with long acting thyroid
stimulator-protector. Ir Med J. 1977;70(4):124125
6. Zakarija M, McKenzie JM, Munro DS. Immunoglobulin G inhibitor
of thyroid-stimulating antibody is a cause of delay in the onset of
neonatal Graves disease. J Clin Invest. 1983;72(4):13521356
7. van der Kaay DC, Wasserman JD, Palmert MR. Management of
neonates born to mothers with Graves disease. Pediatrics. 2016;
137(4):e20151878
Vol. 18 No. 6 JUNE 2017 e391
 Index of Suspicion in the Nursery
AUTHOR DISCLOSURE Drs McCrary, Tatum,
and Wechsler have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device. Dr Page was
supported by an NIH training grant
(5T32AI007217-33). Dr Greenberg was
supported by an NIH training grant
(5T32HD043029-13). Dr Balikcioglu was
supported by Eunice Kennedy Shriver
National Institute of Child Health & Human
Development of the National Institutes of
Health under award number 4K12HD043494-
14, Duke Childrens Miracle Network and Duke
Private Diagnostic Clinic Enhanced Academics
in a Basic Laboratory Environment (ENABLE)
career development program.
e392 NeoReviews
Respiratory Distress and Tachycardia in a
3 Preterm Neonate
Andrew W. McCrary, MD,* Laura C. Page, MD, Gregory H. Tatum, MD,*
Rachel G. Greenberg, MD, MHS, Stephanie Burns Wechsler, MD,*x
Pinar Gumus Balikcioglu, MD
Divisions of *Pediatric Cardiology, Pediatric Endocrinology, Neonatal-Perinatal Medicine, and
x
Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC
PRESENTATION
A 31-week-gestation male infant is delivered vaginally in the setting of preterm
labor and chorioamnionitis. The pregnancy was remarkable for late prenatal care,
but no other complications. Maternal antenatal testing results were normal and
the mother denied any signicant medical history. The infant is initially stunned,
but quickly recovers, with Apgar scores of 1 and 7 at 1 and 5 minutes, respectively.
His size is appropriate for gestational age and his vital signs in the intensive care
nursery include a temperature of 98.8F (36.5C), pulse of 172 beats/min, right
lower extremity blood pressure of 76/34 mm Hg, respiratory rate of 62 breaths/
min, and oxygen saturation of 98% on nasal continuous positive airway pressure
support at 5 cm H2O and 21% fraction of inspired oxygen. On examination, the
infants anterior fontanelle is soft, at, and approximately 1 ngertip in size. His
lungs are clear despite a mildly increased respiratory effort, including grunting
and subcostal retractions. He has normal rst and second heart sounds, a gallop
rhythm, and no murmurs, and his liver is palpable 4 cm below the right costal
margin.
On investigation, chest radiography demonstrates an enlarged cardiac silhou-
ette (Fig 1), and echocardiography shows ndings consistent with restrictive
cardiomyopathy, normal systolic function, but impaired diastolic function (Fig 2).
Given this rare nding, pediatric cardiology is consulted, which recommends
conducting a comprehensive cardiomyopathy genetic testing panel. During his
rst week after delivery, the infant develops frequent ventricular ectopic beats and
mild hypotension, necessitating volume resuscitation. His baseline heart rate
shows a higher trend, toward a mean of 200 beats/min, and his tachycardia fails
to respond to multiple uid boluses. The team is also unable to wean him off the
respiratory support. A milrinone infusion is started to relax the myocardium and
augment cardiac output.
DISCUSSION
Given the infants persistent tachycardia, thyroid disease is considered and
evaluated. The thyrotropin level is decreased at 0.01 mIU/mL (normal, 0.34
5.66 mIU/mL) and the levels of total triidothyronine (total T3) and free thyroxine
(fT4) are markedly elevated (280 ng/dL [4.3 nmol/L; normal, 80178 ng/dL,

Figure 1. Chest radiograph demonstrating enlarged cardiac silhouette
obscuring lung elds.
1.22.7 nmol/L] and 5.83 ng/dL [75 pmol/L; normal 0.52
1.21 ng/dL, 6.715.5 pmol/L], respectively). Although his
mother again denies medical problems, the team sus-
pects neonatal Graves disease and starts methimazole and
propranolol.
The infants heart rate normalizes on treatment for
hyperthyroidism and he quickly weans off respiratory sup-
port and milrinone (Fig 3). Repeat echocardiography dem-
onstrates improving diastolic function. Interestingly, the
comprehensive cardiomyopathy panel returns with a muta-
tion in the RYR2 gene. Mutations in the RYR2 gene have
been associated with increased risk of developing cate-
cholaminergic polymorphic ventricular tachycardia as well as
arrhythmogenic right ventricular cardiomyopathy. However,
Figure 2. Apical 4-chamber echocardiogram demonstrating enlarged
right and left atria bilaterally.
the results of a functional analysis show that this infants
mutation is unlikely to have clinical signicance.
Before discharge, propranolol is discontinued and the
infants diastolic function and chamber sizes completely
normalize. His mother is found to have active Graves
disease and a goiter that has been covered by scarves and
clothing with high necklines. The infants methimazole is
discontinued at 5 months of age and he has not had any
further thyroid dysfunction.
The Condition
Neonatal Graves disease is a rare disorder that occurs when
maternal thyrotropin receptor antibody (TRAb) crosses the
placenta to reach the fetus. The estimated incidence of
neonatal Graves disease is 1 in 25,000 to 50,000; only
0.2% of pregnant women have Graves disease and only
1% to 5% of their infants develop neonatal hyperthyroidism.
(1)(2) Clinical manifestations of neonatal Graves disease
include irritability, hyperactivity, ushing, poor weight gain,
tachycardia, hyperthermia, diarrhea, frontal bossing, trian-
gular facies, small anterior fontanelle and less commonly,
heart failure, exophthalmos, cholestasis, thrombocytopenia,
and hyperammonemia. (1)(2)(3)(4) A goiter is another sign
of neonatal Graves disease, but can be difcult to detect in
neonates. Therefore, thyroid ultrasonography should be
used in suspected cases. (5) While reversible dilated cardio-
myopathy can be seen in thyrotoxicosis, restrictive cardiac
physiology, as was seen in this case, has not been described
previously. (6)
Diagnosis
The timing of neonatal symptom development depends
on the mothers use of an antithyroid medication such as
methimazole. In the case of untreated mothers, including
those who have had thyroidectomies or radioactive iodine
ablation, the neonate may be symptomatic at birth and have
abnormal thyroid function tests within the rst week after
delivery. (5) Conversely, infants born to mothers taking
antithyroid medications may not manifest symptoms until
1 to 3 weeks after birth because of the drugs ability to cross
the placenta. Importantly, infants with neonatal Graves
disease may be euthyroid on the state newborn screen.
Laboratory evaluation can assist in the diagnosis and help
predict the clinical course. Thyroid stimulating index assays
specically detect the presence of stimulating antibodies by
measuring cyclic adenosine monophosphate production.
(7) TRAb assays are competition-based, meaning they detect
the presence of TRAb but cannot distinguish between
stimulating, blocking, and neutral antibodies. (7) A negative
TRAb nding in an infant is reassuring against future
Vol. 18 No. 6 JUNE 2017 e393
 Figure 3. Heart rate trend from birth to 12 days after delivery.
development of neonatal Graves disease, and these in-
fants can have standard pediatric care without addi-
tional thyroid monitoring. (5) Not surprisingly, high
maternal serum TRAb levels late in pregnancy increase
the likelihood that an infant will develop neonatal Graves
disease. (5)
Management
Infants with neonatal Graves disease are commonly treated
with a b-blocker and an antithyroid medication. (3) Methi-
mazole is the preferred pediatric antithyroid agent because
propylthiouracil carries a black box warning for hepatotox-
icity. (8) More severe cases of neonatal Graves disease may
require iodine (Lugol solution) to inhibit thyroid hormone
release and/or glucocorticoids to reduce the conversion of
fT4 to the more active T3. (9)(10)
Infants with neonatal Graves disease should be closely
followed by a pediatrician and pediatric endocrinologist to
monitor weight gain and thyroid function tests. Maternal
TRAb levels in the infant typically wane between 3 and 12
weeks, and in most infants, the disease resolves spontane-
ously during this period, allowing methimazole to be dis-
continued. (1) The transient nature of neonatal Graves
disease should be emphasized to parents because fre-
quent laboratory evaluations are necessary to ensure that
the infants do not become hypothyroid with methimazole
treatment.
Lessons for the Clinician
Vital sign abnormalities may be the rst indicator of
underlying thyroid disease.
Neonatal Graves disease can present various pheno-
types. Cardiac manifestations may be tachycardia alone,
but evidence of cardiomyopathy (dilated or restrictive)
is possible.
e394 NeoReviews
American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Know the anatomy and pathophysiology (including genetics) of
an infant with a condition affecting myocardial performance.
Identify the etiology, clinical manifestations, laboratory features,
and management of neonatal thyrotoxicosis.
References
1. Srinivasan S, Misra M. Hyperthyroidism in children. Pediatr Rev.
2015;36(6):239248
2. Polak M, Luton D. Fetal thyroidology. Best Pract Res Clin Endocrinol
Metab. 2014;28(2):161173
3. Khadora MM, Al Dubayee M. Neonatal Graves disease with unusual
metabolic association from presentation to resolution. BMJ Case
Rep. 2014;2014.
4. Regelmann MO, Sullivan CK, Rapaport R. Thyroid vise in an infant
with neonatal Graves disease. Pediatrics. 2013;132(4):e1048e1051
5. Besancon A, Beltrand J, Le Gac I, et al. Management of neonates
born to women with Graves disease: a cohort study. Eur J Endocrinol.
2014;170(6):855762.
6. Forfar JC, Muir AL, Sawers SA, Toft AD. Abnormal left ventricular
function in hyperthyroidism: evidence for a possible reversible
cardiomyopathy. N Engl J Med. 1982;307(19):11651170
7. Barbesino G, Tomer Y. Clinical review: clinical utility of TSH
receptor antibodies. J Clin Endocrinol Metab. 2013;98(6):22472255
8. Bahn RS, Burch HB, Cooper DS, et al; American Thyroid Association;
American Association of Clinical Endocrinologists. Hyperthyroidism
and other causes of thyrotoxicosis: management guidelines of the
American Thyroid Association and American Association of Clinical
Endocrinologists. Endocr Pract. 2011;17(3):456520
9. Correia MF, Maria AT, Prado S, Limbert C. Neonatal thyrotoxicosis caused
by maternal autoimmune hyperthyroidism. BMJ Case Rep. 2015;2015.
10. Vliet G, Deladoey J. Disorders of the thyroid in the newborn and
infant. In: Sperling M, ed. Pediatric Endocrinology. 4th ed.
Philadelphia, PA: Saunders; 2014;chap 7:186201.e.1.

Delivery Room Management of a Neonate
AUTHOR DISCLOSURE Drs Sloan, Blue, and
Vachharajani have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device.
Video Corner
with Inspiratory Stridor
Patrick Sloan, MD,* Brittany Blue, MD,* Akshaya Vachharajani, MD*
*Washington University School of Medicine and St Louis Childrens Hospital, St Louis, MO
QUESTION
In this video, the neonatology team placed an oral airway to relieve the neonates
respiratory distress associated with inspiratory stridor. Which of the following
intervention/s could also be helpful to relieve these symptoms? Note: More than 1
option might be correct.
A. Insertion of a laryngeal mask airway
B. Insertion of a nasopharyngeal airway or a nasal trumpet
C. Nasogastric placement of a Replogle tube for continuous suction
D. Placement of the newborn in a supine position
E. Reattempt at endotracheal intubation with a stylet inserted into the endo-
tracheal tube
Video. Click here to view the video. Reproduced with permission of Akshaya Vachharajani, MD, FAAP,
and The Saigh Foundation Pediatric Simulation Center, St. Louis Childrens Hospital, Washington
University School of Medicine. Copyright 2017.
CRITIQUE
Stridor represents obstructed ow within the airway that can be heard during the
inspiratory phase, expiratory phase, or both phases. The neonate in this video has
inspiratory stridor. Stridor during inspiration suggests an extrathoracic or upper airway
obstruction. The causes of upper airway obstruction in a neonate include tongue
displaced posteriorly (as occurs with Pierre-Robin sequence), anomalies of the larynx
(such as laryngomalacia, laryngeal hemangioma, and vocal cord edema), and vocal cord
palsy. The 2 most common causes of inspiratory stridor in a neonate are laryngomalacia
and vocal cord palsy. A laryngeal cyst is a rare cause of inspiratory stridor. Congenital
tracheal stenosis (as a result of complete tracheal rings) and tracheomalacia in the
extrathoracic portion of the trachea can also result in inspiratory stridor. Stridor
associated with vocal cord pathology can be distinguished from other causes because
it results in a hoarse or absent cry.
Vol. 18 No. 6 JUNE 2017 e395
 Expiratory stridor is caused by an intrathoracic airway
obstruction involving the mediastinal structures such as
the aorta (eg, abnormalities of the aortic arch, vascular
rings), heart (eg, enlargement of the left atrium), and
mediastinal lymph nodes (eg, node enlargement). Trache-
omalacia of the intrathoracic portion of the trachea can
lead to expiratory stridor.
Biphasic stridor is most often caused by subglottic ste-
nosis (congenital or acquired) or a subglottic hemangioma.
The neonate in this video most likely has inspiratory
stridor as a result of micrognathia, an excessively small
mandible. (1) Micrognathia is a characteristic of the Pierre-
Robin sequence, along with glossoptosis and a U-shaped
cleft palate. (2) The combination of the reduced mandib-
ular size and posterior displacement of the tongue into the
hypopharynx in neonates with Pierre-Robin sequence can lead
to an upper airway obstruction. (3) During the immediate
postnatal period, neonates with severe upper airway obstruc-
tion may demonstrate respiratory distress, as evidenced by
suprasternal, intercostal, or subcostal retractions, and inspi-
ratory stridor as well as oxygen desaturations in the supine
position. (4)
In anticipation of delivery of an infant with a possible
upper airway obstruction, the neonatology team should
prepare the following equipment:
an oropharyngeal airway
a nasopharyngeal airway
a laryngeal mask airway
an endotracheal tube
Following delivery, if the infant has physical examination
ndings that are suggestive of an upper airway obstruction,
especially in the presence of micrognathia, retrognathia, or
glossoptosis, the neonatology team should consider placing
the neonate in the prone or side-lying position. This will use
gravity to bring the tongue forward and may alleviate the ob-
struction. If positioning changes are unsuccessful at relieving
the infants symptoms, the neonatology team should consider
placing an alternate airway, which may include an oropharyn-
geal, nasopharyngeal, or laryngeal mask airway. All of these
airways are designed to bypass the upper airway obstruction. To
place an oral airway, the clinician should measure the distance
from the corner of the infants mouth to the angle of the
mandible (below the earlobe). To measure a nasopharyngeal
airway, the clinician should measure from the tip of the in-
fants nostril to the angle of the mandible and ensure that the
diameter of the airway is smaller than that of the nares.
If placement of the alternate airway is unsuccessful
at relieving a newborns upper airway obstruction, endo-
tracheal intubation should be considered. However, the glot-
tis may be difcult to visualize via direct laryngoscopy.
e396 NeoReviews
Alternative methods to visualize the airway, such as the use
of a video laryngoscope, can also be considered, as well as
assistance from a difcult or advanced airway team. A trache-
ostomy may be needed if the airway obstruction cannot be
bypassed.
Severe upper airway obstruction identied prenatally
should prompt a team approach with an advanced airway
team present at the delivery, as well as consideration of an ex
utero intrapartum treatment procedure. (5)
The video reveals opportunities to improve the communi-
cation among the team members. These include the following:
A. The team leader responsible for the airway intervention
addressed one of the team members by name, which is
an excellent approach to communicating in an emergent
situation. However, the team leader could have indicated
the sizes of the laryngeal blade and endotracheal tube
that he desired.
B. The team member who provided the laryngoscope
closed the communication loop by verbalizing the size of
the endotracheal tube but could have also stated the size
of the laryngoscope blade that he provided.
C. The team leader responsible for the airway intervention
could have specically addressed the third team member
with the request to increase the supplemental oxygen.
D. The third team member increased the supplemental
oxygen but could have announced her action and closed
the communication loop.
The video demonstrates how knowledge sharing can still
occur in an emergent scenario; this occurred when the third
team member questioned why different-sized oral airways
may be needed and the most experienced person on the
team provided a response.
Correct Responses
A and B. Inspiratory stridor in a neonate might be decreased by
placing the infant in a prone position, insertion of a laryngeal
mask airway, or placement of a nasopharyngeal airway or a
nasal trumpet. A stylet inserted within the endotracheal tube is
likely to increase the risk of injury to the vocal cords without
improving the chance of successful intubation.
American Board of Pediatrics Neonatal-
Perinatal Content Specications
Know the proper approach to airway management in the delivery room.
Know the various causes of stridor in the newborn and how to
assess severity.
ACKNOWLEDGMENT
We wish to thank Sarah Weyhrich, RN (Clinical Education
Specialist, Saigh Pediatric Simulation Center) and Bryan
Camp (Media Services at St Louis Childrens Hospital, St
Louis, MO) for the production and editing of the video. We
wish to thank Ms Jessica Hutchens and Mr Keith Patten for
participating in the video.
References
1. Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff and
Martins Neonatal-Perinatal Medicine: Diseases of the
Congenital Diseases of the Kidneys: Prognosis and Treatments: 1. C; 2. B; 3. E; 4. D; 5. A.
Fetus and Infant. Philadelphia, PA: Elsevier/Saunders;
2015
2. Breugem CC, Evans KN, Poets CF, et al. Best practices for
the diagnosis and evaluation of infants with Robin sequence:
a clinical consensus report. JAMA Pediatr. 2016;170(9):894902
3. Cielo CM, Montalva FM, Taylor JA. Craniofacial disorders associated
with airway obstruction in the neonate. Semin Fetal Neonatal Med.
2016;21(4):254262
4. Thimmappa B, Hopkins E, Schendel SA. Management of
micrognathia. NeoReviews. 2009;10(10);e488e493
5. Ryan G, Somme S, Crombleholme TM. Airway compromise
in the fetus and neonate: prenatal assessment and
perinatal management. Semin Fetal Neonatal Med. 2016;21
(4):230239
ANSWER KEY FOR JUNE 2017 NEOREVIEWS
Neonatal Hypertension: 1. B; 2. B; 3. E; 4. C; 5. B.
Vol. 18 No. 6 JUNE 2017 e397

AUTHOR DISCLOSURE Drs Guerrero, Winter,
and Borders have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device.
e398 NeoReviews
Strip of the Month
Placental Abruption Case Report
Karla Daniela Guerrero, MD,* Michelle D. Winter, MD,* Ann Borders, MD
*Department of Obstetrics and Gynecology and Division of Maternal-Fetal Medicine, NorthShore University
HealthSystem, Evanston, IL, and Department of Obstetrics and Gynecology, University of Chicago, Pritzker
School of Medicine, Chicago, IL
ELECTRONIC FETAL MONITORING CASE REVIEW SERIES
Electronic fetal monitoring (EFM) is a popular technology used to establish fetal
well-being. Despite its widespread use, the terminology used to describe patterns
seen on the monitor has not been consistent until recently. In 1997, the National
Institute of Child Health and Human Development (NICHD) Research Planning
Workshop published guidelines for interpretation of fetal tracings. This publi-
cation was the culmination of 2 years of work by a panel of experts in the eld of
fetal monitoring and was endorsed in 2005 by both the American College of
Obstetricians and Gynecologists (ACOG) and the Association of Womens Health,
Obstetric and Neonatal Nurses (AWHONN). In 2008, ACOG, NICHD, and the
Society for Maternal-Fetal Medicine reviewed and updated the denitions for fetal
heart rate (FHR) patterns, interpretation, and research recommendations. Fol-
lowing is a summary of the terminology denitions and assumptions found in the
2008 NICHD workshop report. Normal values for arterial umbilical cord gas
values and indications of acidosis are dened in Table 1.
Assumptions from the NICHD Workshop
Denitions are developed for visual interpretation, assuming that both the FHR
and uterine activity recordings are of adequate quality
Denitions apply to tracings generated by internal or external monitoring devices
Periodic patterns are differentiated based on waveform, abrupt or gradual (eg, late
decelerations have a gradual onset and variable decelerations have an abrupt onset)
Long- and short-term variability are evaluated visually as a unit
Gestational age of the fetus is considered when evaluating patterns
Components of FHR do not occur alone and generally evolve over time
DEFINITIONS
Baseline FHR
Approximate mean FHR rounded to increments of 5 beats/min in a 10-minute
segment of tracing, excluding accelerations and decelerations, periods of
marked variability, and segments of baseline that differ by >25 beats/min
In the 10-minute segment, the minimum baseline duration must be at least
2 minutes (not necessarily contiguous) or the baseline for that segment is
indeterminate
Bradycardia is a baseline of <110 beats/min; tachycardia is a baseline of >160
beats/min
Sinusoidal baseline has a smooth sine wave-like undulating pattern, with waves
having regular frequency and amplitude
TABLE 1. Arterial Umbilical Cord Gas Values
pH PCO2 (mm Hg)
Normal* 7.20 (7.15 to 7.38) <60 (35 to 70)
Respiratory acidosis <7.20 >60
Metabolic acidosis <7.20 <60
Mixed acidosis <7.20 >60
*Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695.
Baseline Variability
Fluctuations in the baseline FHR of 2 cycles per minute,
uctuations are irregular in amplitude and frequency,
uctuations are visually quantitated as the amplitude of
the peak to trough in beats/min
Classication of variability:
Absent: Amplitude range is undetectable
Minimal: Amplitude range is greater than undetectable to
5 beats/min
Moderate: Amplitude range is 625 beats/min
Marked: Amplitude range is >25 beats/min
Accelerations
Abrupt increase in FHR above the most recently deter-
mined baseline
Onset to peak of acceleration is <30 seconds, acme is 15
beats/min above the most recently determined baseline
and lasts 15 seconds but <2 minutes
Before 32 weeks gestation, accelerations are dened by an
acme 10 beats/min above the most recently determined
baseline for 10 seconds
Prolonged acceleration lasts 2 minutes but <10 minutes
Late Decelerations
Gradual decrease in FHR (onset to nadir 30 seconds)
below the most recently determined baseline, with nadir
occurring after the peak of uterine contractions
Considered a periodic pattern because it occurs with uterine
contractions
Early Decelerations
Gradual decrease in FHR (onset to nadir 30 seconds)
below the most recently determined baseline, with nadir
occurring coincident with uterine contraction
Also considered a periodic pattern
PO2 (mm Hg) BASE EXCESS
20 10 (2.0 to 9.0)
Variable 10
Variable 10
Variable 10
Variable Decelerations
Abrupt decrease in FHR (onset to nadir <30 seconds)
Decrease is 15 beats/min below the most recently de-
termined baseline lasting 15 seconds but <2 minutes
May be episodic (occurs without a contraction) or periodic
Prolonged Decelerations
Decrease in the FHR 15 beats/min below the most
recently determined baseline lasting 2 minutes but <10
minutes from onset to return to baseline
Decelerations are tentatively called recurrent if they
occur with 50% of uterine contractions in a 20-
minute period
Decelerations occurring with <50% of uterine contrac-
tions in a 20-minute segment are intermittent.
Sinusoidal FHR Pattern
Visually apparent, smooth sine wavelike undulating pat-
tern in the baseline with a cycle frequency of 3 to 5 per
minute that persists for 20 minutes.
Uterine Contractions
Quantied as the number of contractions in a 10-minute
window, averaged over 30 minutes.
Normal: 5 contractions in 10 minutes
Tachysystole: >5 contractions in 10 minutes
INTERPRETATION
A 3-tier FHR interpretation system has been recommended
as follows:
Category I FHR tracings: Normal, strongly predictive of
normal fetal acid-base status and require routine care.
These tracings include all of the following:
Vol. 18 No. 6 JUNE 2017 e399
 Baseline rate: 110 to 160 beats/min
Baseline FHR variability: Moderate
Late or variable decelerations: Absent
Early decelerations: Present or absent
Accelerations: Present or absent
Category II FHR tracings: Indeterminate, require evalua-
tion and continued surveillance and reevaluation. Examples
of these tracings include any of the following:
Bradycardia not accompanied by absent variability
Tachycardia
Minimal or marked baseline variability
Absent variability without recurrent decelerations
Absence of induced accelerations after fetal stimulation
Recurrent variable decelerations with minimal or mod-
erate variability
Prolonged decelerations
Recurrent late decelerations with moderate variability
Variable decelerations with other characteristics, such
as slow return to baseline
Category III FHR tracings: Abnormal, predictive of abnor-
mal fetal acid-base status and require prompt intervention.
These tracings include:
Absent variability with any of the following:
Recurrent late decelerations
Recurrent variable decelerations
Bradycardia
Sinusoidal pattern
Data from Macones GA, Hankins GDV, Spong CY, Hauth
J, Moore T. The 2008 National Institute of Child Health and
Human Development workshop report on electronic fetal
monitoring. Obstet Gynecocol. 2008;112:661-666 and Ameri-
can College of Obstetricians and Gynecologists. Intrapartum
Figure 1. Electronic fetal monitoring strip 1.
e400 NeoReviews
fetal heart rate monitoring: nomenclature, interpretation, and
general management principles. ACOG Practice Bulletin No.
106. Washington, DC: American College of Obstetricians and
Gynecologists; 2009.
We encourage readers to examine each strip in the case
presentation and make a personal interpretation of the
ndings before advancing to the expert interpretation
provided.
CASE PRESENTATION
A 29-year-old gravida 4, para 3 woman at 35 weeks and 6
days of gestation with a history of iron-deciency anemia
presents to labor and delivery with complaints of uid
leakage. Her prenatal course is complicated by ultrasound
ndings of markedly dilated loops of bowel suggesting
bowel obstruction (maximum diameter of 27 mm) and mod-
erate polyhydramnios with amniotic uid index of 33.2 cm
2 days before presentation. An estimated fetal weight of
2,913 g (56th percentile) is found on the same ultrasound
scan. She had recent consultations with maternal-fetal
medicine, neonatology, and pediatric surgery in prepara-
tion for a vaginal delivery.
On admission, her membranes are grossly ruptured with
clear uids, and a diagnosis of preterm premature rupture
of membranes (PPROM) is made. She reports good fetal
movement and denies vaginal bleeding or painful contrac-
tions. Maternal hemoglobin on admission is 7.6 g/dL (76
g/L). Vaginal examination reveals a 2-cm dilated cervix, with
25% effacement and 3 fetal station. Cephalic presentation
of the fetus is conrmed on bedside ultrasonography. She is
admitted to labor and delivery for expectant management.
The patient starts treatment with antibiotics for group B
Streptococcuspositive status. Figure 1 demonstrates fetal
heart tracing on admission.
Figure 1. Electronic fetal monitoring strip 1.
Findings in Fig 1 were as follows:
Variability: Moderate
Baseline rate: 145 beats/min
Episodic pattern: Accelerations
Uterine contractions: Absent
Interpretation: Category I
Figure 2. Electronic fetal monitoring strip 2
Differential diagnosis: Well-oxygenated fetus
Action: Expectant management
The patient requests an epidural for pain control. Fetal heart
tracing continues to be reassuring at category I. The patient
starts having regular contractions every 2 minutes without
augmentation; therefore, expectant management is continued.
Vol. 18 No. 6 JUNE 2017 e401
 Figure 2. Electronic fetal monitoring strip 2

Findings on Fig 2 were as follows: Action: Reposition from supine to right lateral position

Variability: Periods of minimal followed by overall moder- Nursing staff alternate the patient to the right lateral
ate variability position. She continues to have regular contractions. Vag-
Baseline rate: 155 beats/min inal examination is repeated and shows no cervical change.
Episodic pattern: One late deceleration with spontaneous Overall fetal heart tracings are reassuring with moderate
return to baseline variability. Labor is continued. In the next 1.5 hours, con-
Uterine contractions: Every 1 to 2 minutes tractions become infrequent. Oxytocin is started and titrated
Interpretation: Category II for augmentation per institutional protocol.

Figure 3. Electronic fetal monitoring strip 3

e402 NeoReviews
Figure 3. Electronic fetal monitoring strip 3
Findings on Fig 3 were as follows:
Variability: Moderate
Baseline rate: 125 beats/min
Episodic pattern: Accelerations
Uterine contractions: Irregular
Interpretation: Category I
Differential diagnosis: Well-oxygenated fetus
Figure 4. Electronic fetal monitoring strip 4
Action: Continue with labor augmentation
Repeat vaginal examination shows an unchanged cervix,
now for more than 6 hours. No signs or symptoms of
infection are present. Oxytocin is currently being admin-
istered at 7 mL/h and continues to be increased per
protocol. She remains comfortable with the epidural in
place.
Vol. 18 No. 6 JUNE 2017 e403
 Figure 4. Electronic fetal monitoring strip 4

Findings on Fig 4 were as follows: Differential diagnosis: Well-oxygenated fetus

Action: Close fetal heart monitoring, continue with expec-
Variability: Moderate
tant management
Baseline rate: 135 beats/min
Episodic pattern: Accelerations with nonrecurrent vari- Contractions have become more consistent. Oxytocin is
able decelerations administered at 18 mL/h and is increased to 20 mL/h at
Uterine contractions: Every 3 to 4 minutes this time.
Interpretation: Category II

Figure 5. Electronic fetal monitoring strip 5

e404 NeoReviews
Figure 5. Electronic fetal monitoring strip 5

Findings on Fig 5 (top) were as follows: and the patient is normotensive. Oxytocin is administered at
20 mL/h. Maternal repositioning, intravenous uid bolus,
Variability: Moderate
and supplemental oxygen via facemask are provided. How-
Baseline rate: 145 beats/min
ever, subsequent variable decelerations follow, with a nadir
Episodic pattern: Severe variable decelerations and late
in the 60s and decreasing baseline variability in between
decelerations with return to baseline in between contractions
contractions. Oxytocin is stopped. A fetal scalp electrode and
Uterine contractions: Every 3 minutes
intrauterine pressure catheter are placed. Vaginal examina-
Interpretation: Category II
tion shows a cervix that is 3 cm dilated, 25% effaced, and
Differential diagnosis: Placental insufciency, maternal
at high fetal station. With the following deceleration, the
hypotension, placental abruption
patient is repositioned to a hands and knees position.
Action: Preparation for cesarean delivery
Between contractions, the decelerations recover but de-
Findings on Fig 5 (bottom) were as follows: creased baseline variability persists. Given the minimal
cervical change remote from delivery and nonreassuring
Variability: Moderate
fetal well-being, the patient is counseled regarding urgent
Baseline rate: 155 beats/min
cesarean delivery. The risks, benets, and alternatives of
Episodic pattern: Recurrent severe variable decelerations
the surgery are explained, all questions are addressed,
with a nadir in the 60s, return to baseline between con-
and written consent is obtained.
tractions, late deceleration
Uterine contractions: Every 3 minutes
Outcome
Interpretation: Category II
A female infant weighing 2,600 g is delivered via urgent
Differential diagnosis: Placental insufciency, maternal
cesarean delivery. The patient had a low transverse primary
hypotension, placental abruption
cesarean delivery and postpartum tubal ligation, compli-
Action: Preparation for cesarean delivery
cated by postpartum hemorrhage. The estimated blood loss
The resident and attending physician are called into the was 1,300 mL. Bicornuate uterus and placental abruption, as
room for late deceleration. Maternal vital signs are stable evidenced by a clot on the maternal surface of the placenta,

Vol. 18 No. 6 JUNE 2017 e405

 are noted during delivery. Apgar scores are 5 and 7 at 1 and 5
minutes, respectively. Neonatal interventions include facial
oxygen of 50%, continuous positive airway pressure via mask
at 5 centimeters of water pressure for 4 minutes, and oral/
nasal suction in the delivery room. The neonate is taken to
the infant special care unit. Blood gas results are consistent
with respiratory acidosis (Table 2). Abdominal radiogra-
phy shows paucity of bowel gas, consistent with jejunal
atresia. The infant is given nothing by mouth and provided total
parenteral nutrition. Surgical repair of her jejunal atresia is
completed on the following day. Her follow-up abdominal radi-
ography status after surgery is reassuring and shows a non-
obstructive gas pattern. Approximately 1 month after delivery
with ongoing care in the NICU, the infant is discharged from
the hospital in stable condition. Postoperative maternal hemo-
globin is found to be 6.6 g/dL (66 g/L). She receives a trans-
fusion with 1 unit of packed red blood cells before discharge.
Her postpartum care is otherwise uncomplicated and she is
discharged in stable condition on postpartum day 4.
DISCUSSION
This case highlights many risk factors that may have con-
tributed to the patients diagnosis of placental abruption.
Multiple risk factors have been associated with placental
abruption, including advanced maternal age, cigarette smok-
ing, cocaine and drug use, multiple gestations, premature
rupture of membranes, polyhydramnios, oligohydramnios,
chorioamnionitis, uterine malformation, hypertension, and
many others, with a history of placental abruption having the
highest risk. (1)(2)(3)(4) In this case, the diagnosis of fetal
jejunal atresia likely led to the obstruction of amniotic uid
passage and decreased intestinal surface area available for
reabsorption, resulting in polyhydramnios. (5) Polyhydram-
nios is a known risk factor for preterm PPROM secondary to
TABLE 2. Neonatal Blood Gas Ranges Compared with the Patients Blood
Gas Results Showing Respiratory Acidosis
pH PCO2, mm Hg
Normal 7.20 <60
Respiratory acidosis <7.20 >60
Metabolic acidosis <7.20 <60
Mixed acidosis <7.20 >60
Patient results
Arterial 7.09 80
Venous 7.12 73
e406 NeoReviews
uterine overdistension. (6) In the setting of polyhydramnios
likely leading to PPROM, the risk of placental abruption
was increased. (3)(7)(8) It has been suggested that a quick
decrease in uterine volume and intrauterine pressure, as
seen in cases of PPROM, could lead to disruption of placen-
tal site attachment, predisposing patients to placental abrup-
tion. (9) In a retrospective cohort study, Ananth et al (10)
reviewed 11,771 pregnancies and found 441 to be associated
with placental abruption (incidence of 0.87%). The study
showed that pregnancies associated with PPROM had a
3.58-fold higher risk of abruption compared with those
having intact membranes.
Moreover, this case emphasizes the importance of under-
standing fetal heart tracing abnormalities that may be as-
sociated with placental abruption and the need to proceed
with timely delivery. In a case-control study, Tikkanen et al
(4) evaluated 198 cases of placental abruption and discov-
ered that most cases presented with vaginal bleeding (70%)
or abdominal pain (50%). They also noted that these tradi-
tional symptoms were absent in 1 of every 5 cases. FHR
abnormalities described as bradycardia, repetitive late or
variable decelerations, reduced variability, or sinusoidal
FHR patterns are described in multiple studies and are
good indicators for prompt delivery. (1)(3)(4) This empha-
sizes the importance of close FHR monitoring, as it may
often be the only contributing signal guiding physicians to a
timely delivery in the setting of placental abruption. In a
small case-control study of 33 patients with severe placen-
tal abruption and fetal bradycardia, a longer decision-to-
delivery interval (>20 minutes) was shown to be associated
with poorer perinatal outcomes. (11) Another retrospective
case-control study of 222 patients with placental abruption
found that 62% of patients had abnormal fetal heart tracings
(main abnormal nding: persistent late decelerations and
prolonged decelerations) and fetal bradycardia was the most
PO2, mm Hg BASE EXCESS
60 10
Variable 10
Variable 10
Variable 10
14 9.0
20 8.3
signicant predictor of fetal acidemia. (12) In addition, FHR
patterns, specically absent variability and bradycardia, are
correlated to the severity of abruption, resulting 5-minute
Apgar score, and fetal umbilical artery pH. Importantly,
however, it has been recorded that up to 20% of FHR
tracings in cases of placental abruption may be reassuring,
(13) therefore other clinical signs such as pain or vaginal
bleeding should be used in clinical decision-making.
Improved understanding of both the clinical signs and
FHR tracing abnormalities associated with placental abrup-
tion is necessary because the decision to proceed with
urgent delivery is critical to decrease poor maternal and
fetal outcomes.
American Board of Pediatrics
Neonatal-Perinatal Content
Specications
Know the signicance of polyhydramnios, and the management
of pregnancy when it is diagnosed.
Know the diagnosis and management of maternal/fetal blood
loss such as placenta previa, placenta abruption, vasa previa, and
maternal-fetal hemorrhage.
References
1. Fahey JO. The recognition and management of intrapartum fetal
heart rate emergencies: beyond denitions and classication.
J Midwifery Womens Health. 2014;59(6):616623
2. Tikkanen M. Placental abruption: epidemiology, risk factors
and consequences. Acta Obstet Gynecol Scand. 2011;90
(2):140149
3. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol.
2006;108(4):10051016
4. Tikkanen M, Nuutila M, Hiilesmaa V, Paavonen J, Ylikorkala O.
Clinical presentation and risk factors of placental abruption. Acta
Obstet Gynecol Scand. 2006;85(6):700705
5. Heydanus R, Spaargaren MC, Wladimiroff JW. Prenatal ultrasonic
diagnosis of obstructive bowel disease: a retrospective analysis.
Prenat Diagn. 1994;14(11):10351041
6. Golan A, Wolman I, Sagi J, Yovel I, David MP. Persistence of
polyhydramnios during pregnancy: its signicance and correlation
with maternal and fetal complications. Gynecol Obstet Invest.
1994;37(1):1820
7. Nelson DM, Stempel LE, Zuspan FP. Association of prolonged,
preterm premature rupture of the membranes and abruptio
placentae. J Reprod Med. 1986;31(4):249253
8. Chen KC, Liou JD, Hung TH, et al. Perinatal outcomes of
polyhydramnios without associated congenital fetal anomalies after
the gestational age of 20 weeks. Chang Gung Med J. 2005;28
(4):222228
9. Hung TH, Hsieh CC, Hsu JJ, Lo LM, Chiu TH, Hsieh TT. Risk
factors for placental abruption in an Asian population. Reprod Sci.
2007;14(1):5965
10. Ananth CV, Oyelese Y, Srinivas N, Yeo L, Vintzileos AM. Preterm
premature rupture of membranes, intrauterine infection, and
oligohydramnios: risk factors for placental abruption. Obstet
Gynecol. 2004;104(1):7177
11. Kayani SI, Walkinshaw SA, Preston C. Pregnancy outcome in severe
placental abruption. BJOG. 2003;110(7):679683
12. Matsuda Y, Ogawa M, Konno J, Mitani M, Matsui H. Prediction
of fetal acidemia in placental abruption. BMC Pregnancy Childbirth.
2013;13:156
13. Usui R, Matsubara S, Ohkuchi A, et al. Fetal heart rate pattern
reecting the severity of placental abruption. Arch Gynecol Obstet.
2008;277(3):249253
Vol. 18 No. 6 JUNE 2017 e407
 Visual Diagnosis
Rash in a Newborn
Lauren M. Davidson, DO, MA,* Vivien Carrion, MD,* Ilene L. Rothman, MD,
Nathalie Morales, MS
Departments of *Neonatology and Pediatric Dermatology, Women and Childrens Hospital
of Buffalo, SUNY-Buffalo, Buffalo, NY; SUNY Upstate Medical University, College of
Medicine, Syracuse, NY

THE CASE

A female term newborn presents with a generalized rash with eroded and crusted
skin lesions.

Prenatal and Birth Histories

Born to a 34-year-old gravida 2, para 1 Nepali woman
Maternal history was signicant for a positive puried protein derivative test
and negative chest radiograph. She received treatment with isoniazid for 1 year
before the pregnancy
Prenatal history was unremarkable
Maternal screening: Blood type B positive, syphilis nonreactive, hepatitis B
surface antigen negative, human immunodeciency virus (HIV) negative,
rubella immune, group B Streptococcus negative
Estimated gestational age: 40 weeks and 1 day
Spontaneous vaginal delivery. A double nuchal cord was noted. Rupture of
membranes at the time of delivery with clear amniotic uid; no maternal
fever
Apgar score: 9 at 1 and 5 minutes; no resuscitation required
Birthweight3.021 kg (20th percentile), birth head circumference33.5 cm
(20th percentile), birth length48.5 cm (20th percentile)

Presentation
Immediately after birth, the neonate was noted to have crusted and eroded skin
lesions over the entire body. The neonate was admitted to the NICU for further
evaluation of the skin lesions, concerns for possible sepsis, and isolation pre-
cautions. The infant was active and stable in room air.

CASE PROGRESSION

Vital Signs
Heart rate: 147 beats/min
Respiratory rate: 59 breaths/min
Blood pressure: 62/24 mm Hg with a mean of 37 mm Hg
Oxygen saturation: 97%
AUTHOR DISCLOSURE Drs Davidson, Carrion, Temperature: 98.06F (36.7C)
and Rothman, and Ms Morales have disclosed
no nancial relationships relevant to this
Physical Examination
article. This commentary does not contain a
discussion of an unapproved/investigative Skin: Widespread crusted papules from scalp to feet, including palms and soles
use of a commercial product/device. (Figs 1 and 2). The lesions were of varying size and stage. There were 2 yellow

e408 NeoReviews
 uid-lled vesicles with erythematous bases on the lower
abdomen and 2 additional large uid-lled vesicles on the
right buttock. Negative Nikolsky sign.
Head: Anterior and posterior fontanelles open and at;
molding; caput
Eyes: No mucosal lesions or crusting, no scleral erythema,
no periorbital lesions
Oral cavity: Pink, moist mucosa; no lesions noted
Respiratory: Clear, equal breath sounds bilaterally; no
increased work of breathing
Cardiovascular: Normal heart sounds; regular rate and
rhythm; no murmurs or gallops
Abdomen: Soft, nondistended; no hepatosplenomegaly or
masses palpable
Genitourinary: Normal term female with patent anus; no
anal lesions
Neurologic: Normal tone and reexes consistent with
gestational age
Skeletal: Hips normal, extremities without deformity,
spine intact without deformity

Laboratory Studies
White blood cell count: 16,400/mL (16.4  109/L) with 51%
Figure 2. Crusted papules and vesicles on soles.
segmented neutrophils, 27% bands, 17% lymphocytes
Hemoglobin: 17.8 g/dL (178.0 g/L)
Hematocrit: 55.8% Other testing for infection was performed
Platelet count: 288  103/mL (288  109/L)
Serum glucose: 64 mg/dL (3.5 mmol/L) Differential Diagnosis
C-reactive protein: <0.20 mg/L negative (<0.02 mg/dL Staphylococcus aureus infection
negative) Congenital epidermolysis bullosa
Prothrombin time: 16.3 seconds Herpes simplex virus
Activated partial thromboplastin time: 32.0 seconds Cytomegalovirus
Fibrinogen: 328 mg/dL (9.64 mmol/L) Congenital self-healing Langerhans cell histiocytosis
International normalized ratio: 1.32 Group B Streptococcus infection
Blood culture: Pending Myelodysplasia associated with trisomy 21 syndrome
Urine culture: Pending Syphilis
Congenital candidiasis

Actual Diagnosis
The infants skin biopsy revealed self-healing Langerhans cell
histiocytosis (LCH), also known as Hashimoto-Pritzker disease

Management
The neonatology team performed additional testing for an
infectious cause of the skin lesions. This included:
Urine cytomegalovirus culture
Nasal swab for methicillin-resistant Staphylococcus aureus
Umbilical swab for methicillin-resistant Staphylococcus
Figure 1. Widespread crusts and erosions in a newborn. aureus

Vol. 18 No. 6 J U N E 2 0 1 7 e409

 Herpes simplex virus eye, nasal, rectal, skin cultures
Toxoplasma immunoglobulin (Ig) G and IgM
Culture of vesicular skin lesion
The infant initially started treatment with ampicillin,
gentamicin, and acyclovir. Shortly after admission, the ampi-
cillin was discontinued and the infant received oxacillin
instead. A repeat complete blood cell count 12 hours after
birth revealed a white blood cell count of 27,800/mL (27.8 
109/L) with 75% segmented neutrophils, 10% bands and
10% lymphocytes, and a platelet count of 256  103/mL
(256  109/L). The laboratory studies noted earlier were
negative.
The pediatric dermatology team was consulted and ob-
tained 2 skin specimens for biopsy on day 2 after birth. One
Figure 4. Mononuclear cells show diffuse, strong expression of CD1a,
was taken from a lesion on the right lower leg and the second
which indicated congenital self-healing histiocytosis
was from a lesion on the left anterior thigh. The infant (immunohistochemistry for CD1a, original magnication 200).
remained well throughout her NICU stay. The skin biopsy
results were pending at the time of discharge but ultimately
revealed the diagnosis of LCH based on the inltration of LCH known as congenital self-healing LCH (CSHLCH),
Langerhans cells in the papillary dermis with focal overlying also known as congenital self-healing reticulohistiocytosis
ulceration. Pathology results in conjunction with the infants or Hashimoto-Pritzker syndrome. (1) Although the progno-
subsequent benign course were consistent with self-healing sis is good, clinicians should be cautioned that the patient
LCH. This infants histologic ndings are shown in Figs 3 should be followed for the possibility of systemic involve-
through 5. (The slides were obtained from the patients biopsy ment or for recurrence of skin ndings. (2)
and provided by Paul Bogner, MD, at Roswell Park Cancer Cutaneous lesions of CSHLCH manifest at birth or
Institute.) within the rst 2 months after birth, with resolution of
skin lesions over a 3- to 4-month period. Physical exami-
WHAT THE EXPERTS SAY nation ndings are varied and may be notable for vesi-
cles or erythematous papules. A skin biopsy is required
The diagnosis of LCH is based on histopathology. Exclusion for diagnosis. Based on a retrospective case series of 19
of systemic involvement, which may require a period of children who presented with cutaneous ndings in the
observation, supports the diagnosis of the benign form of

Figure 5. Mononuclear cells have abundant cytoplasm, nuclei with a

reniform or grooved appearance, and occasional mitotic gures.
Figure 3. Small nodules of large mononuclear cells lie under and around Scattered eosinophils are present in the background (hematoxylin-
the ulcer (hematoxylin-eosin, original magnication 100). eosin, original magnication 400).

e410 NeoReviews
rst 4 weeks after birth and were then subsequently
diagnosed with LCH, the most common initial skin
lesions were erythematous, often crusted, vesiculopustules.
(3) One-third of the 19 patients had disease limited to the
skin and/or mucous membranes. CSHLCH is a diag-
nosis of exclusion. Caution must be exercised before making
a diagnosis of CSHLCH, because more aggressive forms of
LCH may mimic the congenital self-healing form of
LCH.
Skin lesions presenting in the neonatal period can result
from various causes, making the nal diagnosis of the
newborn rash a difcult one. The initial approach includes
evaluation for benign conditions, infectious etiologies, and
inherited disorders. (4) Transient neonatal pustular melanosis,
a relatively common and benign condition, presents at birth
with very thin-walled pustules and hyperpigmented macules
primarily on the chin, neck, chest, and buttocks, and less
often on the palms and soles. The pustules are so supercial
that most are not still intact at birth. Rather, the residual
postinammatory hyperpigmented macules predominate.
In addition, the disorder rarely presents with associated
crusts. (5)(6)
A herpes simplex virus (HSV) infection may present with
skin, eye, and mucous membrane involvement. Lesions
usually appear 10 to 12 days after birth when acquired
during birth or can be present at birth with presumed
intrauterine acquisition. HSV lesions are evident as
vesicles that sometimes evolve into pustules. (7) Vesicles
are grouped or clustered, and multinucleated giant cells
can be observed microscopically. Viral culture or DNA
polymerase chain reaction is diagnostic. Herpetic ulcer-
ations have been reported on the feet of some infants,
but they are not common in the immediate postnatal
period.
Some forms of epidermolysis bullosa (EB) congenita are
in the differential diagnosis of this newborn rash. However,
the hallmark of EB is skin fragility resulting in blistering
or erosion of the skin with minimal trauma, a distinctive
feature in contrast to LCH. (8)(9)
ACKNOWLEDGMENT
We wish to thank Dara Brodsky, MD, Assistant Editor,
Visual Diagnosis, Video Corner; Assistant Professor, Beth
Israel Deaconess Medical Center, Harvard Medical School,
Boston, MA.
American Board of Pediatrics
Neonatal-Perinatal Content
Specication
Know the cutaneous and laboratory manifestations and
management of Langerhans cell histiocytosis.
References
1. Battistella M, Fraitag S, Teillac DH, Brousse N, de Prost Y, Bodemer
C. Neonatal and early infantile cutaneous Langerhans cell
histiocytosis: comparison of self-regressive and non-self-regressive
forms. Arch Dermatol. 2010;146(2):149156
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