New review plus

2019

January
Question: 1
A male neonate is born at term, after a pregnancy complicated by the isolated finding of echogenic
bowel on antenatal ultrasonography. At birth, he is vigorous, and physical examination findings are
normal. He breastfeeds well. At 24 hours of age, he develops mild abdominal distention, and has a
small bilious emesis. He has not yet passed meconium. An orogastric tube is placed and
radiography is performed (Figure 1). Intravenous fluid administration is begun, specimens for
blood culture are obtained, and antibiotic treatment is started. A contrast enema is obtained
(Figure 2). His newborn genetic screening test result at 5 days of age shows an immunoreactive
trypsinogen concentration of 70 ng/mL (normal <60 ng/mL).
Of the following, the long-term outcome that is MORE likely in this infant than in others with the
same underlying genetic condition is

A.
distal intestinal obstructions

B.
growth failure

C.
infection risk

D.
poor lung function

Correct Answer: A

the neonate in the vignette has a distal ileal obstruction caused by meconium ileus. The plain
abdominal radiograph (figure 1) shows absence of air in the rectum with multiple dilated loops of
bowel, some of which appear to contain “bubbly” material (meconium mixed with air, creating a
“soap bubble” appearance). The contrast enema (figure 2) demonstrates a microcolon, and
contrast that refluxes into the terminal ileum and outlines multiple filling defects consistent with
meconium obstruction. Up to 90% of term infants with meconium ileus will eventually be found to
have cystic fibrosis (CF). Neonates with meconium ileus who do not have CF are more often
premature or growth restricted (30%) compared with neonates with meconium ileus who have CF
(4%), and are more likely to have meconium ileus complicated by intrauterine perforation leading
to meconium peritonitis than those with CF. Hyperechoic bowel noted antenatally may indicate
intestinal obstruction. Approximately 10% of fetuses with hyperechoic bowel will be found to have
CF. Approximately 20% of infants with CF will present with meconium ileus.

Cystic fibrosis is the most common life-threatening autosomal recessive disorder in the United
States, affecting 1 in 3,000 to 4,000 live births. At least 65% of cases of CF in the United States
are now diagnosed on newborn screening. The CF transmembrane conductance regulator (CFTR)
gene codes for an ion channel protein, which, in the intestine, is responsible for secretion of both
chloride and bicarbonate ions. The bicarbonate ions normally bind with calcium ions bound to
exocytosed mucins in the intestinal lumen to form normal, well-hydrated mucus. Decreased
secretion of bicarbonate results in a decreased luminal pH, creating an abnormal and dehydrating
environment in which the matrix of mucins is not disrupted appropriately, leading to excessively
thick, viscous mucus. The thick viscid meconium then leads to physical obstruction at the terminal
ileum.

Immunoreactive trypsinogen (IRT) is a pancreatic enzyme precursor that is released into the
bloodstream in the presence of pancreatic damage. As such, it is a biomarker suggestive of CF.
The IRT concentration, however, may be falsely normal in neonates with CF and meconium ileus.
Meconium ileus in a term infant, with or without a positive IRT result, is considered presumptive
evidence for CF. Genetic diagnosis using a variant-specific assay for the 23 most common CF-
causing mutations (or more) in the CFTR gene is recommended for any infant with an elevated
IRT concentration on the newborn screen, as well as for any infant with meconium ileus. Sweat
chloride testing (evaluating for evidence of CFTR dysfunction) is needed to confirm the diagnosis,
and can be performed on an infant weighing more than 2 kg, who is at least 36 weeks’ corrected
gestational age. The usual screening algorithm involves measurement of IRT on the initial
newborn screening blood spot, with either immediate genetic testing of those who have elevated
IRT concentrations, or a repeat IRT on the second newborn screen with genetic testing on that
sample if the IRT is again elevated.

Although more than 2,000 mutations in the CFTR gene have been described, most are not known
to be associated with disease. Of the mutations known to cause CF, meconium ileus is most
closely related to the presence of the F508del mutation. A neonate with 2 copies of the F508del
mutation has a 25% risk of having meconium ileus, compared with a 17% risk if only 1 copy of that
mutation is present along with another disease-causing mutation, and a 12.5% risk if 2 non-
F508del disease-causing mutations are present.

Diagnostic criteria for CF include:

• Elevated IRT on newborn screen

• Or symptoms/signs suggestive of CF (such as meconium ileus)
• Or positive family history in a parent or sibling

and

• Sweat chloride concentration ≥60 mmol/L

• Or identification of 2 CF-causing CFTR mutations in trans position

Neonates with CF who present with meconium ileus have similar outcomes for growth, incidence
of infections, and ultimate lung function as other patients with CF, but are at a greater risk for
recurrent partial distal intestinal bowel obstructions. The risk for distal intestinal obstruction
 syndrome is 50% for patients with CF and a history of meconium ileus versus 15% for the general
CF population.

PREP Pearls
• Meconium ileus in a term neonate is presumptive evidence of cystic fibrosis.

• Immunoreactive trypsinogen may be falsely normal in patients with cystic fibrosis, particularly if meconium
ileus is present.

• Demonstration of 2 cystic fibrosis–causing mutations in trans position in the CFTR gene or of abnormal
CFTR function (sweat chloride) is required for definitive diagnosis of CF.

• Infants with CF and meconium ileus are at risk for recurrent distal intestinal obstructions.

Question: 2
A male infant is born at 40 2/7 weeks of gestation to a 26-year-old primigravida mother via
cesarean delivery due to breech presentation. The pregnancy and delivery were uneventful and
the infant remained with the mother while being exclusively breastfed. On day 3 of age, just as the
clinical team was preparing to discharge the infant, the nursery received a call from the state
laboratory reporting that the infant’s newborn screening performed at 25 hours of age was positive
for phenylketonuria. The newborn screening report showed the following values:

• Phenylalanine: 195 μmol/L (normal <120 μmol/L)

• Phenylalanine-tyrosine ratio: 2.9 (normal <2)

No other abnormality is noted on newborn screening. The neonate has been feeding well and his
examination findings are within normal limits.

Of the following, the MOST appropriate next step in management for the infant in the vignette is

A.
diet modification including use of phenylalanine-free formula

B.
discharge from the hospital after a repeat newborn screen and follow-up with the primary care provider
within 2 days

C.
plasma amino acid analysis

D.
reassurance to the family that the newborn screen is likely false positive
Phenylketonuria (PKU), also known as phenylalanine hydroxylase deficiency, is a disorder of
amino acid metabolism affecting the conversion of phenylalanine to tyrosine. Phenylalanine
hydroxylase requires a cofactor (tetrahydrobiopterin: BH4) for normal enzyme function
(Figure). Untreated, PKU causes cognitive impairment secondary to high phenylalanine
concentrations in blood. Early dietary modification and pharmacologic treatment as needed are
effective in preventing cognitive impairment. First implemented in the United States in 1963,
newborn screening for PKU has been very helpful for early identification and treatment of affected
patients.

In asymptomatic infants with a positive newborn screen, further diagnostic testing is recommended
to confirm the diagnosis before medical or dietary interventions as long as definitive testing can be
immediately performed. For the infant described in the vignette, the recommended and necessary
confirmatory test is a plasma amino acid profile.

Early confirmatory testing will facilitate dietary therapy as soon as possible if the infant has PKU.
Affected infants will show a high phenylalanine concentration, along with a relatively low tyrosine
and increased phenylalanine-tyrosine ratio without evidence of generalized aminoacidemia. A
small percentage of patients have a defect in the metabolism of cofactor (BH4) rather than a
deficiency of phenylalanine hydroxylase as the cause of PKU. Urine or blood pterin analysis and
blood dihydropterin reductase assay are used to diagnose disorders of biopterin metabolism. In
patients with dihydropterin reductase deficiency, BH4 supplementation may be effective in
reducing the blood phenylalanine concentration.

It is recommended that patients with PKU be diagnosed and, if appropriate, started on a metabolic
diet no later than 2 weeks of age. Results of the plasma amino acid analysis are often available
within 7 days even in situations in which the test is sent to an outside laboratory. Hospitals with
their own biochemical genetics laboratories can usually generate results within 1 to 3 days.
Because the newborn screen is regarded as a screening result and is not diagnostic, it need not
be repeated, so as to avoid any delay in confirmatory diagnostic testing and treatment. Typically,
affected infants are healthy and appear well in the neonatal period. It is important to impress upon
the family that even if the infant is asymptomatic, follow-up and initiation of treatment within the
first 2 weeks after birth is important to prevent severe neurologic deficits in the future.

Some experts recommend keeping the phenylalanine concentrations below 300 μmol/L. Dietary
modification and use of metabolic formula with phenylalanine restriction is recommended based
on plasma amino acid assay results. Some infants with mildly elevated phenylalanine
concentrations on the newborn screen may have higher phenylalanine concentrations (> 300
μmol/L) later on plasma amino acid assay, requiring initiation of treatment. A patient diagnosed in
the neonatal period and whose condition is managed appropriately to target the recommended
phenylalanine concentration is expected to have an IQ within the normal range. For female
patients, strict metabolic control before conception and throughout gestation has been associated
with good outcomes for their neonates.

The infant’s primary care provider should be notified of the result immediately. However, there is
no justification to delay ordering the confirmatory test and await an outpatient appointment with the
primary care provider. This will only delay receipt of appropriate diagnostic information and prompt
initiation of dietary therapy, if needed.
 PREP Pearls
• Infants with phenylketonuria are generally healthy and appear well in the neonatal period.

• Plasma amino acid profile is the recommended confirmatory test for phenylketonuria.

Question: 3
The mother of an infant who was delivered vaginally at term after an uncomplicated pregnancy
asks about the risk of her infant having problems with his development. She reports that both she
and her sister had premature menopause and required in vitro fertilization to conceive. Her sister’s
son began to demonstrate delayed speech, learning disabilities, and autistic features as he
approached his second birthday and is presently being evaluated for both intellectual disability and
developmental delay. The mother describes her sister’s son as having a prominent forehead, large
ears, and long face (Figure). No other family members have intellectual or developmental delay,
though their 55-year-old father has tremors.

Of the following, the BEST estimate of the risk of the newborn in the vignette having intellectual
disability at 5 years of age is

A.
1%

B.
25%

C.
50%

D.
100%

The physical findings of a prominent forehead, large ears, and long face in the cousin of the
neonate in the vignette, combined with a family history that includes members with developmental
delay, premature menopause, and tremors suggest an underlying diagnosis of fragile X syndrome
(FXS). Fragile X syndrome is caused by an expanded CGG mutation on the FMR1 (fragile X
mental retardation 1) gene and is an X-linked dominant disease. Male infants born to mothers
carrying an FMR1 gene mutation have a 50% risk of FXS.

The general population has a CGG region varying between 6 and 44 repeats in the FMR1 gene,
with expansion of the CGG trinucleotide repeat in the gene leading to FXS (Table).
The FMR1 premutation (55-199 CGG repeats) is seen in fragile X–associated tremor ataxia
 syndrome (FXTAS) which includes intention tremors, cerebellar ataxia, parkinsonism, and
cognitive decline. It occurs after age 50 years and is both more frequent and severe in males with
the FMR1 premutation. Approximately 20% of females with the FMR1 premutation have fragile X–
associated primary ovarian insufficiency (FXPOI), which is associated with decreased ovarian
reserve and premature menopause.

The CGG repeat area in females with an FMR1 premutation may undergo expansion and then be
passed as a full FMR1 mutation to their offspring in a process termed anticipation. The risk of
expansion is associated with both a family history of FXS and the length of the maternal repeat
size. Full FMR1 mutations do not happen de novo. The FMR1 mutation in male carriers is
described as stable because there are presently no reports of expansion.

The full FMR1 mutation is associated with FXS. The 200 or more CGG trinucleotide repeats
silence the gene. This leads to the reduction or absence of the fragile X mental retardation protein
(FMRP), which plays a role in neural development. During the evaluation of children with global
developmental delay and/or intellectual disability (ID), 2% to 3% of males and 1% to 2% of
females will be found to have FXS. Conversely, nearly all males with FXS will have some degree
of ID. Autism and autism spectrum disorder are also commonly seen in children with FXS, with
some studies supporting the presence of autism in 30% of males and 20% of females with the
full FMR1 mutation. Fragile X syndrome is estimated to affect 1 in 4,000 males and 1 in 8,000
females.

The clinical findings of FXS include a prominent forehead, large ears, long face, and decreased
tone, with large testes noted in affected males at puberty. Because the clinical features are subtle,
it is recommended that fragile X testing be performed in all children with unexplained global
developmental delay and/or ID.

The family history presented in the vignette is consistent with an X-linked dominant FXS
phenotype, with the newborn’s mother and aunt having premature menopause suggestive of
FXPOI and the grandfather having tremors suggestive of FXTAS. The male newborn has a 50%
risk of inheriting an expanded FMR1 mutation, causing FXS associated with some degree of ID. If
a father with an FMR1 mutation has a daughter, she has a 100% chance of inheriting the same
(not expanded) FMR1 mutation but a less predictable risk of ID. The overall prevalence of ID in the
general population is 1% to 3%.

PREP Pearls
• Fragile X syndrome is caused by an expanded CGG mutation on the FMR1 (fragile X mental retardation 1)
gene, and is an X-linked dominant disease.

• Fragile X syndrome is estimated to affect 1 in 4,000 males and 1 in 8,000 females.

• The FMR1 premutation in female carriers may undergo expansion and pass on as a full FMR1 mutation to
their offspring due to anticipation.
Question: 4
A 38-week-gestation infant is born to a 19-year-old gravida 1, para 0 woman. Prenatal
ultrasonography findings at 24 weeks of gestation were reported as normal, with a persistent right
umbilical vein. Maternal group B Streptococcus screening result was negative. The infant is born
via vaginal delivery with clear amniotic fluid and is assigned Apgar scores of 9 and 9 at 1 and 5
minutes, respectively. He is admitted to the newborn nursery but develops respiratory distress
within the first 2 hours after birth and is transferred to the neonatal intensive care unit. Antibiotics
and nasal continuous positive airway pressure are initiated, but the respiratory distress increases,
and the infant is treated with endotracheal intubation, mechanical ventilation, and surfactant on
day 1. With worsening oxygenation on day 2, the infant is given another dose of surfactant, and is
treated with high-frequency oscillatory ventilation and inhaled nitric oxide. Echocardiography
demonstrates right-to-left flow across the patent foramen ovale, moderately dilated right atrium
and ventricle, septal bowing, mild tricuspid valve regurgitation, and bidirectional flow through the
patent ductus arteriosus. Vasopressor and fentanyl intravenous infusions are started for
decreased blood pressure and sedation, respectively. On day 3, the infant has worsening
hypoxemia. Chest radiography (Figure ) is performed.

The heart rate is 154 beats/min, systemic blood pressure is 52/34 mm Hg (mean 50 mm Hg), and
preductal and postductal oxygen saturations are 83% and 82%, respectively. Physical examination
reveals diffuse cyanosis, no heart murmur, and a peripheral capillary refill time of 3 seconds.
Laboratory findings and blood gas measurements are as follows.

High-frequency oscillator settings

• FiO2 100%

• Mean airway pressure 23

• Amplitude 40
Arterial blood gas
• pH 7.38

• PCO2 37 mm Hg

• PO2 40 mm Hg

• Base deficit 3.7

Complete blood cell count

• White blood cells 7,000/μL (7 × 109/L)

• Neutrophils 75%

• Bands 1%

• Lymphocytes 15%

• Hematocrit 43%

• Platelets 238 × 103/μL (238 × 109/L)

Of the following, the MOST likely diagnosis is

A.
idiopathic pulmonary hypertension of the newborn

B.
meconium aspiration syndrome

C.
tetralogy of Fallot

D.
total anomalous pulmonary venous return
Correct Answer: D

Total anomalous pulmonary venous return (TAPVR) accounts for 1% to 2.5% of congenital heart
disease, and can easily be missed on cursory echocardiography. The infant in the vignette has
infracardiac TAPVR, identified with a second echocardiogram obtained on day 3 after continued
clinical deterioration. The pulmonary veins in this case formed a vertical confluence descending
below the diaphragm and then flowing into the inferior vena cava via the portal vein. In TAPVR,
pulmonary and systemic venous blood are completely mixed in the right atrium, and systemic
output is dependent on an obligate right-to-left shunt at the atrial level, resulting in equal
pulmonary arterial and systemic arterial saturations of approximately 80%.

The infant in the vignette had been reported to have a persistent right umbilical vein on prenatal
ultrasonography. The incidence of this developmental variant has been reported to be about 1 in
500 infants, and some reports suggest that it is associated with additional malformations in up to
23% of cases. Therefore, targeted fetal ultrasonography and echocardiography may be indicated
when a persistent right umbilical vein is found, and an increased index of suspicion for congenital
heart disease is warranted.

If the pulmonary venous return is not obstructed, patients with TAPVR have only mild systemic
desaturation and may not be diagnosed for several weeks after birth. With obstruction, however,
as occurs commonly when the abnormal vessels descend below the diaphragm (infracardiac
type), pulmonary venous return can be restricted. This results in severe cyanosis, respiratory
distress, pulmonary edema, and congestive heart failure, typically without an audible murmur or
cardiomegaly. These signs can progress rapidly, and surgical repair is urgent. In the case
described in the vignette, there was evolving obstruction during the first 3 days after birth,
associated with deterioration of both peripheral perfusion (increased capillary refill time) and
oxygenation, progressively leading to the need for substantial respiratory and cardiovascular
support. Echocardiography with careful elucidation of pulmonary venous return is critical to the
diagnosis.
 The neonate in the vignette had pulmonary hypertension as shown by the initial echocardiographic
findings of atrial and ventricular enlargement, as well as bowing of the interventricular septum and
tricuspid valve regurgitation. However, these flow dynamics were secondary to pulmonary venous
congestion and pulmonary edema caused by obstruction to pulmonary venous drainage. In
contrast to the findings in idiopathic primary pulmonary hypertension, this infant’s oxygenation did
not improve in response to improved ventilation, use of inhaled nitric oxide, treatment with
surfactant, or use of vasopressors to improve systemic blood pressure. Lack of differential oxygen
saturations between pre- and postductal measurements is consistent with the absence of right-to-
left shunting at the ductus arteriosus, regardless of etiology.

In the vignette, the amniotic fluid was clear, so meconium aspiration was unlikely. Occasionally,
pulmonary venous congestion in TAPVR can mimic the radiographic appearance of aspiration
pneumonia. In this case, chest radiography revealed only an interstitial pattern and a small heart,
which was likely secondary to both a high mean airway pressure, and decreased cardiac filling
from obstructed TAPVR.

Tetralogy of Fallot is the most common congenital cyanotic heart lesion, accounting for 8% to 10%
of all congenital heart disease. Infants can be cyanotic or acyanotic, based on the degree of
pulmonary outflow tract obstruction, but almost all have a heart murmur. In the immediate newborn
period, infants with tetralogy of Fallot are usually hemodynamically stable, with chest radiography
showing dark lung fields (decreased pulmonary flow) and characteristic boot-shaped heart.

PREP Pearls
• Total anomalous pulmonary venous return is associated with complete mixing of pulmonary and systemic
venous blood return at the atrial level, resulting in equal pulmonary arterial and systemic arterial oxygen
saturations of approximately 80%.

• Severe cyanosis and pulmonary edema can occur rapidly when pulmonary venous return is obstructed, as
in infracardiac total anomalous pulmonary venous return when vessels pass below the diaphragm.

• Diagnosis with echocardiography is challenging because the findings—right-to-left shunting at the atrial
level, dilated right atrium and ventricle, and septal bowing—can be similar to those seen in idiopathic
pulmonary hypertension. All pulmonary veins must be thoroughly sought and documented when
echocardiography is performed.
Question: 5
A term newborn is admitted to the nursery to observe for neonatal abstinence syndrome.

During this pregnancy, the infant’s mother was treated with 120 mg/day of methadone for an
addiction to opioids. She does not have custody of her other children because of her drug
dependence and the unexplained death of her 4-year-old son the previous year.

The infant’s urine and meconium drug screens are positive only for opioids. On the third day of
hospitalization, methadone treatment was started at 0.05 mg/kg every 6 hours. However, after 3
doses, his abstinence signs persisted and methadone dosing was increased to 0.1 mg/kg every 6
hours.

Electrocardiography (ECG) was performed for an irregular heart rate (Figure 1 ). Despite the
increased dose of methadone, he continued to have significant signs of abstinence. He continues
to have increased tone, loose stools, and tachypnea. His laboratory findings are as follows.

Laboratory Test Patient Result (SI Units)

Sodium 137 mEq/L (137 mmol/L)
Potassium 4.5 mEq/L (4.5 mmol/L)
Chloride 102 mEq/L (102 mmol/L)
Ionized calcium 4.8 mg/dL (1.2 mmol/L)
Magnesium 2.1 mEq/L (1.1 mmol/L)
Glucose 85 mg/dL (12.0 mmol/L)

Of the following, the NEXT best step in management for this infant is to
A.
add clonidine

B.
add phenobarbital

C.
increase methadone

D.
switch to morphine

Correct Answer: D

The QT interval appears prolonged on the infant’s electrocardiogram (ECG). It should be

measured from the beginning of the QRS complex to the end of the T wave. The QT interval is the
ECG representation of the action potential in ventricular myocytes. Therefore, prolonged duration
of the action potential manifests as a prolonged QT interval. Although the QT interval represents
ventricular depolarization and subsequent repolarization, the length is primarily dependent on the
time for repolarization.

Depolarization is the result of rapid flow of positively charged sodium and calcium into myocardial
cells (Figure 2). The cells repolarize by the flow of positively charged potassium out of the cell.
Either increased sodium/calcium current into the cell or decreased potassium current out of the
cell results in an intracellular excess of positively charged ions and prolongation of the QT interval.
The major repolarizing channel in the heart is the delayed rectifier potassium channel, termed
IK. The IK channel has 2 functional components: 1) a rapidly activating component I Kr, and 2) a
slowly activating component IKs.

The QT interval is inherently longer at slower heart rates compared with faster heart rates;
therefore, the QT interval needs to be corrected for the heart rate. The most common modification
uses the Bazett formula. The corrected QT interval (QTc) is equal to the QT interval in seconds
divided by the square root of the preceding R-R interval in seconds (Figure 3).

At 4 days of age, a QTc of 440 milliseconds is 2 standard deviations above the mean. The infant in
the vignette has a QTc of 517 milliseconds, well above the upper limit of normal.

Congenital long QT syndrome (cLQTS) is a familial disease that can result in syncopal episodes or
cardiac arrest and death. Congenital LQTS has incomplete penetrance with variable expressivity
that often involves interaction with the environment. Patients with acquired prolongation of the QT
interval may have a genetic predisposition. These patients have clinically silent gene mutations
that lead to QT prolongation only with exposure to medications or electrolyte disturbances that
prolong the QT interval. Most mutations that result in cLQTS involve genes that encode cardiac
ion channels. Mutations in genes that encode either IKs or IKr account for 80% to 90% of cases of
cLQTS. Congenital LQTS may also result from a gain-of-function mutation in the genes encoding
cardiac sodium channels. These 3 forms of cLQTS have distinct clinical outcomes, ECG features,
and factors that trigger clinical events.
 Depolarization during the prolonged second or third phase of the action potential may lead to
polymorphic ventricular tachycardia, known as torsades de pointes (Figure 4). A QT interval
greater than 500 milliseconds is associated with a higher risk for torsades de pointes. Although
prolongation of the QT interval is more common in girls, the risk of a first cardiac event before
puberty is higher in boys. The unexplained death of the infant’s brother at 4 years of age may be
secondary to an arrhythmia from cLQTS. A screening ECG and genetic testing for cLQTS is
indicated for each member of this infant’s family.

Acquired prolongation of the QT interval may result from medications or electrolyte disturbances
such as hypocalcemia, hypokalemia, and hypomagnesemia. Prolongation of the QT interval from
hypokalemia is secondary to inactivation of IKr channels. Although the infant in the vignette had
loose stools, his electrolytes are normal. Numerous medications are associated with prolongation
of the QT interval, the majority of which block IKr. An extensive list of medications that prolong the
QT interval is maintained by an online registry at http://www.crediblemeds.org. Methadone is well
described to prolong the QT interval with a risk for torsades de pointes when prescribed for
patients with cLQTS. The patient in the vignette has a cQT of 517 milliseconds, therefore, the
methadone should be discontinued and switched to morphine.

In a clinical report on treatment of neonatal drug withdrawal, the American Academy of Pediatrics
recommends using either morphine or methadone when pharmacologic treatment for neonatal
abstinence syndrome (NAS) is indicated. Clonidine is a α2-adrenergic receptor agonist that has
been used alone or in combination with an opioid to treat NAS. However, many practitioners
choose to use phenobarbital as a second drug if an opiate does not adequately treat symptoms of
NAS. In the vignette, the infant’s urine drug screen was positive solely for opiates. Because he
was being treated with a relatively low dose of methadone, and because the undesirable side
effect of methadone treatment would not be improved by addition of another medication, there is
no indication to add a medication of a different drug class at this time. The best intervention in this
situation is to discontinue the methadone and substitute a different opioid.

PREP Pearls
• Medications that interfere with repolarization of myocardial cells may lead to fatal arrhythmias in patients
with congenital prolonged QT syndrome.

• Methadone prolongs the QT interval and should be avoided in patients with prolonged QT syndrome.
Question: 6
An infant born at 33 weeks of gestation is now 10 days old, and receiving gavage feedings and
active thermoregulation in the neonatal intensive care unit. He has prolonged unconjugated
hyperbilirubinemia with delayed and infrequent stooling. Although the newborn screen, sent at 48
hours of age, detected no abnormalities, a serum sample sent at 10 days of age to measure
thyroid-stimulating hormone and free thyroxine has abnormal findings. The concern is that the
newborn screening test does not have adequate sensitivity to detect hypothyroidism in this infant.

Of the following, the MOST likely cause of congenital hypothyroidism in this infant that could be
missed on newborn screening is

A.
absent thyroid gland

B.
central hypothyroidism

C.
subclinical hypothyroidism

D.
transient hypothyroidism

Correct Answer: B

Congenital hypothyroidism affects 1 in 3,000 to 4,000 infants globally, though the incidence varies
by region and population genetics. Newborn screening for congenital hypothyroidism began in
1974 in Quebec, Canada, and Pittsburgh, PA. Currently, all states in the United States perform
newborn screening for congenital hypothyroidism and detect about 1,400 to 1,600 cases per year.

Newborn screening for congenital hypothyroidism can be performed by measuring concentrations

of thyroid-stimulating hormone (TSH), thyroxine (T4), or both on a dried spot of blood. The aim of
newborn screening programs is rapid identification of diseases with available treatment and a
favorable cost-benefit ratio. Measurement of TSH is the most cost-effective and sensitive test for
the most prevalent forms of congenital hypothyroidism, and is the primary test used in most of
Western Europe and the United States. Newborn testing for T4 is more expensive and has a higher
false-positive rate. Screening programs using TSH are designed to identify newborns with
abnormally elevated concentrations of TSH. Newborns with conditions that may result in low or
normal TSH (some forms of central hypothyroidism, thyroglobulin-binding defects, resistance to
thyroid hormone) will not be identified. Therefore, screening using elevated TSH concentrations
alone may result in false-negative results for conditions such as thyroglobulin-binding defects and
central hypothyroidism, which do not manifest with elevated TSH. Even programs that use a
T4 concentration as the primary screen can have false-negative results, such as in subclinical
hypothyroidism. Note that due to technical reasons and reasons of market demand, newborn
screening kits measure total thyroxine, NOT free thyroxine (FT4). Of note, only Korea uses FT4 for
newborn screening.

Central hypothyroidism results in insufficient or dysfunctional TSH, from either hypothalamic or

pituitary failure. The incidence of central congenital hypothyroidism is 1 in 16,000 to 29,000
newborns. It can be associated with other midline defects (septo-optic dysplasia, cleft lip/palate),
or X-linked mutations in the immunoglobulin superfamily, member 1 gene (IGSF1). Newborn
screening programs that are based on TSH concentration alone have low sensitivity for central
 hypothyroidism. Even programs using primary T4 will often miss central hypothyroidism, because
early on, the T4 is often above the cutoff concentrations for an abnormal result.

Most states in the United States use an approach in which TSH is measured primarily (eg,
Arizona, Arkansas, Tennessee, Utah). Some perform a secondary T4 assay for those samples
having a TSH concentration above a certain cutoff (for example, Delaware). Less commonly,
states (such as Alaska) measure T4 primarily with a secondary TSH if the T4 concentration is in the
lowest 10% of samples tested. Each state’s screening methodology is voluntarily reported to the
following website https://data.newsteps.org/newsteps-web/reports/conditionsByQuery/input.action.
Testing for T4 alone results in a higher false-positive rate than either of the aforementioned
approaches.

Note that in the most common approach, in which TSH concentration is measured primarily, there
is a risk of a false-negative result in cases of hypothyroidism caused by central hypothyroidism in
which TSH is not produced in adequate amounts, in genetic conditions in which a biologically
inactive form of TSH is secreted, or in patients with thyroglobulin-binding defects.

Some states mandate a second screening specimen between 2 and 6 weeks of age for all infants.
Newborn screening programs were developed when the typical newborn stay in the hospital was
about 3 days. Today, with stays often as short as 24 hours in the hospital, newborn screening on
samples obtained before discharge may be less sensitive for many disorders, including
hypothyroidism. For example, low-birthweight infants may have a blunted or delayed postnatal
surge in TSH compared with average-weight neonates, and some term newborns with primary
congenital hypothyroidism also have a delayed rise in TSH concentrations. If the newborn screen
is sent at 24 hours of age, false-negative TSH screening results may be seen.

The most common cause of congenital hypothyroidism is thyroid dysgenesis, from an absent,
hypoplastic, or ectopic thyroid. Thyroid dysgenesis presents with elevated TSH concentration and
low T4 concentration, and would be identified on newborn screening tests. Subclinical
hypothyroidism manifests as a modestly elevated TSH with normal or low-normal T4 concentration.
The ability of the newborn screen to detect subclinical hypothyroidism depends on the screening
TSH concentration cutoff chosen and the degree of TSH elevation in the newborn. Transient
hypothyroidism can occur because of prematurity, iodine excess or deficiency, or maternal use of
antithyroid medications or amiodarone, and also presents with an elevated TSH concentration.
This is identified on TSH-based newborn screening programs. Central hypothyroidism occurs
because of pituitary or hypothalamic dysfunction and results in low TSH concentrations that would
not be identified on the most common newborn screening test which relies on elevated TSH
concentrations.

PREP Pearls
• Most newborn congenital hypothyroidism screening programs in North America and Europe rely on
elevated thyroid-stimulating hormone concentrations to determine an abnormal screening result.

• The newborn screens using thyroid-stimulating hormone (TSH) identify TSH concentrations above a certain
cutoff and are not designed to test for disorders that result in low TSH concentrations or biologically inactive
TSH.
Question: 7
A comprehensive, multidisciplinary quality improvement (QI) effort is under way to improve
medication errors in a neonatal intensive care unit . After obtaining baseline data from January
through October of year 1, the research team implemented 2 individual QI cycles with the
immediate goal of bringing the unit’s medication error rate per month to 75% of baseline, with a
stretch goal of zero medication error events per month. New processes were introduced at cycles
1 and 2. Cycle 3 represented re-education efforts. The data are presented as a control chart
(Figure 1).

Of the following, the EARLIEST time at which successful process change could be identified with a
high degree of certainty is

A.
May of year 2

B.
July of year 2

C.
January of year 3

D.
March of year 3
Quality improvement (QI) involves the identification of opportunities for improvement, collection,
and analysis of baseline data; the analysis of processes; planning and implementing change in
processes that are expected to improve outcomes; the implementation of those changes; and
follow-up measurement of data. The vignette illustrates the analysis and interpretation of QI data
using control charts.

The analysis of QI data takes several forms. Although traditional biostatistical analysis may aid in
analysis of data, continuous evaluation of performance provides greater near real-time information
based on statistically valid principles. This allows rapid sequential efforts to be undertaken to
improve outcomes. Commonly used data representation models include run charts and control
charts.

A run chart is a simple visual representation of selected outcomes with or without a mean line. In
the vignette, data presentation as a simple run chart is shown in Figure 2. While information
regarding performance can be derived from a run chart, more useful information is conveyed when
data are presented as the more powerful control chart (Figure 1).

Control charts allow the viewer to assess whether a statistically important change from baseline
performance has occurred. Components of a control chart include:

• A run chart
• A center line
o for count data: the mean of counts per period
o for rates: ([the mean of the numerators)/[the mean of the denominators])
• Upper and lower control limits (UCL and LCL) set at ± 3 × an estimate of standard deviation, Σ
(sometimes referred to as 3Σ)
• In addition to the center line and control limits, the area between the UCL and LCL may be divided
into 6 subzones, associated with probabilities of finding values within the zone by chance (Figure
3).

Control charts help define common cause and special cause variance. Common cause variance
(natural, noise, random cause) represents usual, often unidentified, random influences that affect
outcomes of the process. Special cause variance refers to rare events that affect the process and
are identified by a very low probability of occurrence. Such events fall outside the UCL or LCL
limits (ie, events that occur <1% of the time), or in specific patterns within the control lines. Special
cause variance may be attributable to a specific event influencing the process.

It is important to identify both types of events in the QI process, because improvement efforts may
require addressing either or both types of variance.

Process change may create special cause variation (the intervention itself being the special
cause) that can be identified statistically through control charts. The probability of measurements
occurring outside the zones defined by the UCL and LCL, coupled with frequency of specific event
patterns around the CL, have been used to develop rules to identify special cause variance which,
in the case of QI interventions, can identify successful process changes. Although there are
several variations of the basic rules for interpretation of control charts, all are based in statistical
analysis. Therefore, control charts represent statistically valid mechanisms to identify changes in
processes after implementation of QI interventions. Coupled with continuous data representation
in near real time, control charts rapidly identify such changes in processes without the need to wait
for final data entry after project completion.

The Shewhart rules and the Western Electric rules (a refinement of the Shewhart rules) represent
2 commonly used sets of rules for interpreting control charts, to distinguish between special cause
and common cause variations.

1. A single data point above the UCL or below the LCL

2. Nine or more consecutive data points all above or all below the center line if variance is symmetric
around the center line (use of 9 points improves the Shewhart rules reference of 8 consecutive
points to a probability of >99%)
3. Six or more consecutive data points steadily increasing or decreasing (2 consecutive points of the
same value must be counted as 1 point)
4. Fourteen or more consecutive data points, alternating up and down above or below the center line
5. Two of 3 consecutive points falling in zone A or beyond
6. Four of 5 consecutive points falling in or beyond zone B
7. Fifteen consecutive data points in zone C
8. Eight or more data points outside zone C

The application of rules to control charts varies depending on the symmetry of the estimate for
standard deviation (sigma, Σ) and the type of control chart used. Rules 1 through 4 apply to most
commonly used charts.

It is acceptable and may be advantageous to freeze control lines after process changes. In the
vignette, because cycle 2 resulted in improved process outcomes, it is reasonable to freeze the
curve at its initiation. The revised control chart is shown in Figure 4. Charts may also be
presented with control lines that fluctuate with data cycles.

Several types of control charts have been designed for the analysis and display of various types of
QI data. Guidance is available for the selection of appropriate versions of control charts on the
type of data (count or variable, events or averages, variance) in the referenced literature.

Based on the control chart shown in the vignette, a statistically relevant change in outcomes may
be identified by January of year 3, as indicated by 9 consecutive event counts falling below the
center line (rule 2) (Table).

May of year 2 represents the first measurement after process change that falls below the center
line but does not conform to a defined rule for identifying special cause variance. In July of year 2,
the medication error rate falls below the goal line. While such achievements may be important for
morale, neither is a statistically important indicator of special variance. The goal line, while useful
for data display and motivational purposes, is not a true component of control charts. Process
 change can be identified in March of year 3 based on 6 consecutive data points decreasing in
value (September and October were identical and count as 1 point) (rule 3), but is not the earliest
indicator of a successful process change. There was no period that demonstrated 4 or more
alternating data points (rule 4).

Cycle 3 represents continued data monitoring with an early attempt to reverse a possible upward
trend. Such monitoring and interventions should continue until the revised process has been well
established. Continued data monitoring will help standardize process revisions and identify
deviations related to workarounds, new personnel, alternative approaches entering practice
through variation, and other sources of variation.

PREP Pearls
• The graphical display of quality improvement data is facilitated through the use of run charts and the more
powerful control charts.

• Continuous data review is made possible by run and control charts allowing identification of the
effectiveness of change in near real time.
Question: 8
A 19-year-old woman who recently immigrated from Bangladesh was admitted to the obstetric
service in labor at 35 weeks. A purified protein derivative skin test triggered by persistent cough
during her pregnancy had an induration of 11 mm and a sputum culture showed Mycobacterium
tuberculosis sensitive to isoniazid. A triple regimen with isoniazid, rifampin, and ethambutol was
started 3 weeks ago and her sputum is now clear. The woman would like to breastfeed her
newborn.

Of the following, the MOST appropriate recommendation is that this woman can breastfeed

A.
after the addition of pyrazinamide to her treatment regimen

B.
after an additional week of treatment

C.
only expressed milk if fed by somebody else

D.
without restrictions
Tuberculosis remains a rare disease in developed countries and most cases occur in people who
come from endemic areas, mainly Asia and Central America, but also from the Russian Federation
and South Africa. The World Health Organization estimates that one-third of the world population
is infected with tuberculosis and the prevalence of active tuberculosis in pregnant and postpartum
women is more than 60 cases per 100,000 population per year in countries with the most limited
resources. The high mortality (up to 60%) and morbidity of tuberculous infection in the newborn
makes prompt diagnosis and treatment vital.

Infection with Mycobacterium tuberculosis can occur in utero and present as congenital
tuberculosis or, more commonly, is acquired after delivery via droplets from either the infected
mother or an undiagnosed family member.

Transmission in utero is extremely rare, with fewer than 400 cases described in literature. It can
occur either via hematogenous placental transfer through the umbilical vein to the fetal liver and
lungs, or via aspiration and swallowing of infected amniotic fluid in utero or intrapartum, leading to
primary infection of the fetal lungs and gut. For women who have only pulmonary tuberculosis, the
fetus is not likely to be infected before birth, but can became infected after birth via droplet spread.
Transmission of tuberculosis via breastmilk does not occur.

The tuberculin skin test (TST) is an indirect method to detect M tuberculosis infection and relies on
cellular immune response after infection. The test consists of the administration of purified protein
derivative intradermally. After inoculation, the area of induration is checked at 72 hours. The TST
will become reactive 2 to 10 weeks after initial infection, with a median interval of 3 to 4 weeks.
Depending on the presence of risk factors such as age and human immunodeficiency virus status,
the size of the induration area will confirm a positive test result. Based on current guidelines from
the Centers for Disease Control and Prevention that recommend interpretation of TST findings
based on an individual’s risk stratification (Table), an induration of 11 mm is considered a positive
TST result in this young woman who recently immigrated from an endemic area. A positive sputum
culture for M tuberculosis confirms the diagnosis and allows antimicrobial sensitivity testing.

If tuberculosis is diagnosed during pregnancy, prompt treatment is required. Treatment regimens

are complex and can include a combination of isoniazid, rifampin, and ethambutol for 9 months. If
pyrazinamide is added to the regimen, the duration of the treatment can be shortened to 6 months.
The safety of pyrazinamide during pregnancy, however, is not established.

It is important that cases of suspected or proven tuberculosis disease in women (or in

their household contacts) are reported immediately to the local health department, allowing an
investigation of all household members’ infection status to begin as soon as possible.

The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) states:

• “women with tuberculosis who have been treated appropriately for 2 or more weeks and who are
not considered contagious may breastfeed.”

The AAP Section on Breastfeeding declares that

• “breastfeeding should not occur if the mother has active (infectious) untreated tuberculosis;
however, expressed milk can be used because there is no concern about these infectious
organisms passing through the milk. Breastfeeding can be resumed when a mother with
tuberculosis is treated for a minimum of 2 weeks and is documented that she is no longer
infectious.”
 Both statements allow the woman with tuberculosis who has been adequately treated to
breastfeed her infant directly. Because the woman in the vignette has already received adequate
treatment for a Mycobacterium species sensitive to isoniazid for more than 2 weeks and had clear
sputum on follow-up, direct breastfeeding is allowed. If the woman has been treated for less than 2
weeks, she should pump her milk and have another individual feed the infant.

A regimen that includes isoniazid, rifampin, and ethambutol is considered appropriate as long as it
will be continued for 9 months, and has been administered for more than 2 weeks with
demonstration of clear sputum. Adding a fourth agent will not be necessary for the mother to
breastfeed.

Women with tuberculosis who are suspected of being contagious should refrain from
breastfeeding or having any other close contact with the infant because of potential transmission
through respiratory droplets. Separation from the infant is required if the mother has poor
compliance with treatment or has a multidrug-resistant form of tuberculosis.

Isoniazid is secreted in human milk, but no adverse effects of isoniazid have been demonstrated in
the infant. Pyridoxine supplementation is indicated for pregnant and breastfeeding women
receiving isoniazid, but not for the infant.

PREP Pearls
• A woman with tuberculosis is not considered contagious after 2 weeks of adequate treatment and
documented negative sputum.

• Breastfeeding is permitted when a woman with tuberculosis is no longer considered contagious.

• Suspected or confirmed tuberculosis needs to be reported to the local health department

February
Question: 1
A 26-week-gestation infant is being cared for in the neonatal intensive care unit. The infant was
born via urgent cesarean delivery because of a non-reassuring fetal heart tracing. The mother had
received 1 dose of betamethasone 6 hours before delivery. The infant’s initial hospital course was
notable for treatment with mechanical ventilation, surfactant administration, and dopamine infusion
due to hypotension. Serial head ultrasonography was performed throughout the infant’s hospital
stay (Figure 1, Figure 2, and Figure 3).

Of the following, the intervention MOST likely to have prevented the morbidity illustrated in the
ultrasound scans is

A.
antenatal magnesium sulfate administration

B.
antenatal vitamin K administration

C.
delayed clamping of the umbilical cord for 60 seconds

D.
indomethacin treatment beginning within 24 hours of delivery
Correct Answer: D
The infant described in the vignette developed an intraventricular hemorrhage (IVH), a serious
morbidity associated with preterm birth. Intraventricular hemorrhage is associated with impaired
long-term neurodevelopment including cerebral palsy and cognitive impairment. In premature
infants, an IVH originates from the periventricular germinal matrix and can extend into the lateral
ventricle. The ultrasound images in the vignette show an IVH with involvement of the brain
parenchyma which subsequently develops into a porencephalic cyst adjacent to the lateral
ventricle (Figure 4, Figure 5, and Figure 6).

The premature infant brain is vulnerable to IVH for several reasons. The germinal matrix consists
predominantly of neuronal and glial precursor cells, is highly vascularized, and has rapid
angiogenesis compared with other parts of the developing brain. This renders the germinal matrix
vasculature fragile and susceptible to hemorrhage because of rapid endothelial turnover and lack
of key components of the blood-brain barrier. Although the germinal matrix is present from 17 to
35 weeks’ gestation, the size of the germinal matrix is dependent on gestational age and begins to
decrease in size beginning at 24 weeks’ gestation. This, in part, explains the decreased risk of
germinal matrix hemorrhage in preterm infants born later in gestation. In addition to the fragility of
the germinal matrix vasculature, the preterm infant has limited ability to autoregulate cerebral
blood flow. This leads to significant fluctuations in cerebral blood flow as a result of changes in
systemic blood pressure or blood volume. The combination of an abundant but fragile group of
blood vessels in the brain, along with unstable cerebral blood flow and pressure contributes to the
increased risk of hemorrhage.

Prevention of IVH in premature infants has been the focus of multiple studies, and several
interventions have been investigated. Prenatal glucocorticoid administration has been shown to
decrease both the incidence and severity of IVH in multiple trials. The benefits of glucocorticoids
are believed to be due to both a stabilization of the germinal matrix blood-brain barrier and
decreased alterations in cerebral blood flow. The most benefit has been noted after a complete
course of glucocorticoids (eg, 2 doses of betamethasone) within 1 week of delivery, but benefit
has also been noted after an incomplete course.

In addition to prenatal glucocorticoids, several other interventions have been investigated to

decrease IVH, but with mixed results. Indomethacin is a nonselective cyclooxygenase inhibitor
used to treat patent ductus arteriosus in premature infants. Indomethacin has also been shown to
modulate cerebral blood flow and promote maturation of the blood-brain barrier in the germinal
matrix. Several randomized trials have demonstrated a decreased incidence of IVH in infants
treated prophylactically with indomethacin shortly after birth. A recent Cochrane review concluded
that prophylactic indomethacin decreased the incidence of grade 3 and grade 4 IVH when
compared with placebo or no drug therapy (relative risk [RR] 0.66, 95% confidence interval [CI]
0.53-0.82). Despite the decrease in IVH there was no difference in either mortality or a composite
outcome of death or severe neurodevelopmental disability at 18 to 36 months.

Another intervention with potential to decrease IVH in premature infants is delayed clamping of the
umbilical cord. Delayed cord clamping is generally defined as waiting at least 30 seconds after
delivery to clamp the umbilical cord. This allows for an increased amount of blood to be transferred
from the placenta to the infant after delivery (placental transfusion) as well as allowing for a more
gradual physiologic transition after birth. Benefits of delayed cord clamping in infants born at less
than 37 weeks’ gestation have been reported from both individual trials and systematic reviews,
including decreased mortality and decreased need for blood transfusions.

The effect of delayed cord clamping on the risk of IVH in premature infants is less clear.
A systematic review and meta-analysis published in 2018 of delayed versus early cord clamping
in premature infants included 2,834 infants, with most infants allocated to the delayed group
having the cord clamped at 60 seconds or later. This meta-analysis demonstrated a decrease in
hospital mortality (RR 0.68, 95% CI 0.52-0.90) with delayed cord clamping, but no decrease in
either any IVH (RR 0.87, 95% CI 0.75-1.00) or severe IVH (RR 0.87, 95% CI 0.59-1.27). These
 results contradict the results of a previous meta-analysis published in 2014 which demonstrated a
decreased incidence of IVH in the group of infants that received delayed cord clamping. The
primary difference in the 2 analyses was the inclusion of the Australian Placental Transfusion
Study (APTS), a study of more than 1,500 infants born before 30 weeks’ gestation randomized to
early or late cord clamping. The APTS study failed to show a reduction in grade 3 or 4 IVH with
delayed cord clamping (RR 1.35, 95% CI 0.73-2.48). While there appears to be a benefit of
delayed cord clamping for preterm infants on survival, the most recent randomized controlled trial
and subsequent meta-analysis does not show a clear benefit in reducing the risk for IVH.

Antenatal magnesium sulfate administration has not been shown to reduce the risk for IVH, though
it does have a neuroprotective effect on the preterm infant and decreases the risk for cerebral
palsy. Similarly, antenatal vitamin K administration has been investigated as a potential
intervention to decrease the risk for IVH in the preterm infant but did not show benefit.

PREP Pearls
• The combination of an abundant but fragile group of blood vessels in the brain, along with unstable cerebral
blood flow and pressure contributes to the increased risk of intraventricular hemorrhage in premature
infants.

• Prophylactic indomethacin treatment decreases the incidence of grade 3 and grade 4 intraventricular
hemorrhage.

• Although delayed cord clamping improves survival in preterm infants, there is no clear reduction in the risk
of intraventricular hemorrhage.
Question: 2
A 38-week-gestation female infant born via vaginal delivery receives positive pressure ventilation
and continuous positive airway pressure (CPAP) and is admitted to the neonatal intensive care
unit on nasal cannula oxygen for mild respiratory distress with nasal flaring, tachypnea, and
retractions. The respiratory distress resolves over the first few hours, but the infant is noted to
have multiple premature atrial contractions while undergoing telemetry. The newborn is
appropriately grown with low-set ears, hypertelorism, webbed neck, wide-spaced nipples and 4
large hyperpigmented patches, 1 each on the abdomen, back, flank, (Figure 1 and Figure 2) and
labia (not shown). There is no audible murmur.

An amniocentesis for genetic testing had been performed during pregnancy because of the
presence of a fetal cystic hygroma. The antenatal testing showed a normal karyotype and
chromosomal microarray.

Of the following, the test MOST likely to yield the diagnosis in this patient is

A.
long bone radiography

B.
methylation-specific polymerase chain reaction (PCR) for 15q11-13

C.
panel for mutations in the RAS/MAPK pathway

D.
polymerase chain reaction (PCR) for GNAS (20q.13.32)

Correct Answer: C

The patient described in the vignette has features suggestive of Noonan syndrome with multiple
lentigines (hyperpigmented macules). This disorder was previously known by the acronym
LEOPARD: multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism,
pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. The
diagnostic criteria for Noonan syndrome with multiple lentigines are met when an individual has
multiple lentigines plus 2 of these features, or 3 of these features plus a first-degree relative with
multiple lentigines.

Noonan syndrome with multiple lentigines is a rare autosomal dominant disorder. It is caused by
mutations in the protein tyrosine phosphatase PTPN11 gene (90%) or in the RAF 1 gene (5%),
which are both part of the RAS/mitogen-activated protein kinase (MAPK) pathway. The
RAS/MAPK pathway is essential in normal cell cycle regulation, differentiation, growth, and cell
senescence. Abnormalities in the RAS/MAPK pathway are termed RASopathies, and result in the
following syndromes (Figure 3 ):

• Noonan syndrome
 • Noonan syndrome with multiple lentigines
• Cardiofaciocutaneous syndrome
• Costello syndrome
• Capillary malformation–arteriovenous malformation syndrome
• Neurofibromatosis type 1
• Neurofibromatosis type 1–like syndrome
• Autoimmune lymphoproliferative syndrome

A lentigo is a small hyperpigmented macule. Although the lentigines associated with Noonan
syndrome with multiple lentigines can be present at birth, they often appear later in childhood. Up
to 70% of patients with Noonan syndrome with multiple lentigines have café-au-lait macules
(CALM) at birth. These CALM are hyperpigmented patches with a sharp border, more than 0.5 cm
in diameter. Persons with neurofibromatosis type 1 have multiple CALM presenting in early
childhood, and they develop tiny CALM in adulthood, which appear as freckles in the groin and
axillae.

The patient in the vignette had 4 hyperpigmented patches (2 of which were CALM), hypertelorism,
and electrocardiographic abnormalities (premature atrial contractions at birth and developed
supraventricular tachycardia later in the neonatal period). Genetic testing was performed on the
peripheral blood of the patient in the vignette using a Noonan panel, which analyzes multiple
genes associated with RASopathies. A mutation in the RAF1 gene was identified. Several
molecular genetic testing companies offer panels that test for multiple mutations in the RAS/MAPK
pathway. The mutation was not identified on the karyotype or the chromosome microarray
performed on amniocentesis fluid because neither of these tests can detect mutations in single
genes. The microarray can detect missing or extra pieces of chromosomes but targeted testing is
required when searching for a single gene mutation.

Prader-Willi syndrome (PWS) is caused by a loss of function in paternally derived genes on the q
arm of chromosome 15 (15q11-13). Seventy percent of cases are caused by a deletion in this area
of the paternal chromosome 15. Because the maternally derived genes in this region are
inactivated, the deletion on the paternal chromosome 15 leads to loss of function of genes in the
affected region. Another 25% of cases result from maternal uniparental disomy, in which the infant
inherits 2 copies of chromosome 15 from the mother. Because some genes are only active when
inherited from the father (paternal imprinting), an error in this region leads to loss of function and
results in the phenotypic neonatal characteristics of PWS: hypotonia, poor feeding, and
underdeveloped genitals. Older children and adults may experience obesity and delayed
development.

Diagnosis of PWS is most easily performed by methylation analysis of 15q11-13, which detects
abnormal parent-specific methylation in the region associated with PWS. Methylation testing has a
99% sensitivity for PWS. Deletions in the PWS region can also be identified using fluorescence in
situ hybridization (FISH) or chromosomal microarray, but methylation testing may be less
expensive than chromosomal microarray, and FISH has a higher false-negative rate for PWS.

Radiography of the long bones to evaluate for fibrous dysplasia may be helpful in the diagnosis of
fibrous dysplasia/McCune-Albright syndrome, caused by an activating mutation in
the GNAS1 gene, which encodes the cyclic adenosine monophosphate (cAMP) pathway–
associated G-protein, Gsα. Overproduction of cAMP stimulates growth and function of various
tissues. Affected tissues can include those derived from ectoderm, mesoderm, and endoderm, and
commonly include skin, skeleton, and certain endocrine organs. Café-au-lait macules are common
in this syndrome, and generally present in the neonatal period. They are usually multiple, large,
have very irregular borders (like the “coast of Maine”), and may follow Blaschko lines. Fibrous
dysplasia can affect the craniofacial, axial, or appendicular skeleton and can appear as limb
 discrepancy or body asymmetry in a neonate. Endocrinologic disorders include hypercortisolism,
hyperthyroidism, and excess growth hormone. Although genetic testing is available for fibrous
dysplasia/McCune-Albright syndrome, the diagnosis is generally made clinically because the
somatic nature of the mutation can lead to false-negative test results.

PREP Pearls
• Clinical manifestations of Noonan syndrome with multiple lentigines include hypertelorism, excess nuchal
tissue, electrocardiographic abnormalities, hyperpigmented macules, pulmonic stenosis, sensorineural
hearing loss, and abnormal genitalia.
Figure 3: Depiction of the signal transduction pathway and individual genes affected in each RASopathy
disorder. The Rasopathy disorder associated with each gene is indicated in red. Positive regulatory
interactions are indicated with black arrows, and negative regulatory interactions are indicated with black
blunted arrows. CFCS = cardiofaciocutaneous syndrome; CS = Costello syndrome; LS = LEOPARD
syndrome; NF1 = neurofibromatosis type 1; NFLS = neurofibromatosis type 1–like syndrome; NFNS =
neurofibromatosis NS; NS = Noonan syndrome; NS/LAH, Noonan-like syndrome with loose anagen hair;
RTK = receptor tyrosine kinase; WS = Watson syndrome.
Question: 3
A 2-day-old male infant was born at 35 weeks’ gestation via vaginal delivery after preterm labor.
The pregnancy was uncomplicated. The newborn had hypothermia after his first bath, but his
temperature improved to 36.7°C after being placed under the radiant warmer for 2 hours. He
proceeded to feed well by mouth every 3 hours. He has voided 6 times since birth and passed 3
meconium stools.

Today he has new abdominal distention with erythema of the abdominal wall.

On physical examination, his heart rate is 140 beats/min, and blood pressure is 74/38 mm Hg. The
infant does not have a murmur, and peripheral pulses are normal. His breath sounds are clear and
equal, and saturations are 98% in room air. Bowel sounds are present, but hypoactive, and he
shows signs of discomfort when the abdomen is palpated.

A nasogastric tube is placed to decompress the stomach, and a moderate amount of air and 10
mL of partially digested, nonbilious milk are removed. His combined chest and abdominal
radiograph is shown in the Figure. Blood gas shows pH 7.33, PaCO2 33 mm Hg, PaO2 75 mm Hg,
and base deficit of 4 mmol/L. His white blood cell count is 9,500/μL (9.5 × 10 9/L) with 75%
neutrophils, 15% lymphocytes, and 10% monocytes. His hematocrit is 50%, and platelet count is
230,000/μL (230 × 109/L). A blood culture performed shortly after birth because of prematurity is
negative.

Of the following, the MOST likely explanation for the origin of this newborn’s findings is a history of

A.
formula feedings

B.
nasogastric tube placement

C.
positive pressure ventilation in the delivery room

D.
rectal temperature measurement
Correct Answer: D
View Peer ResultsAverage Correct: 33.04%

The late preterm infant in the vignette has radiographic findings consistent with
pneumoperitoneum (Figure). He lacks any signs of systemic illness, and radiography shows no
pneumatosis intestinalis, as would be seen in necrotizing enterocolitis (NEC). He does not have a
history of medication exposures, such as corticosteroids and/or indomethacin, that would increase
the likelihood of spontaneous intestinal perforation. His stooling pattern and abdominal radiograph
do not suggest an underlying intestinal obstruction. Thus, iatrogenic perforation of the
gastrointestinal tract should be considered. The newborn’s symptoms started before the
nasogastric tube placement, making it unlikely to be the inciting event. A history of rectal
temperature measurement is the most likely cause for pneumoperitoneum in the neonate in the
vignette, given his clinical and radiographic history.

Late preterm newborns experience feeding problems (32%), respiratory distress (4%–29%), and
temperature instability (10%) at higher rates than term newborns, and then receive medical
interventions to address these issues. Iatrogenic injury can occur with any invasive procedure,
even those considered low-risk, such as placing a nasogastric tube or obtaining a rectal
temperature. Anterior rectal perforations have been reported from thermometer use in newborns
with suspicion for inappropriate depth or angle of insertion (not directed adequately posterior) as
the cause. Signs of peritonitis develop over hours to days after rectal perforation.

Formula feeding rather than exclusive breast milk feeding is associated with an increased risk for
NEC. The patient in the vignette is at a younger postnatal age than is typical for NEC, which is
usually diagnosed at 1 to 4 weeks of age. Term neonates with NEC tend to develop symptoms
closer to 1 week of age, but often have an additional risk factor, such as congenital heart disease.
 Gastric feeding tube placement can lead to esophageal or gastric perforation, but this tends to
occur in the extremely preterm population of infants who have more fragile and thin-walled organs.
Esophageal perforations usually occur in the thoracic or cervical portions of the esophagus, and
lead to pneumomediastinum or pneumothoraces, rather than pneumoperitoneum. Iatrogenic
gastric perforations can lead to massive pneumoperitoneum, but a distinct gastric bubble, as seen
in this patient’s radiograph, would not be present. Periods of poor perfusion or oxygenation (such
as cardiopulmonary resuscitation, hypotension) increase the risk for gastric perforation.

Although pneumothoraces can occur spontaneously or with any positive pressure ventilation after
birth, downward tracking of the free air into the peritoneal space is not common. Proper diagnosis
of this complication is important because the management consists of observation and possible
evacuation of any remaining pleural air, rather than abdominal surgery. The neonate described in
the vignette does not have respiratory distress and lacks evidence for pneumothoraces on chest
radiography.

PREP Pearls
• Iatrogenic injuries, such as perforation of the rectum by a thermometer or gastric perforation from
nasogastric tube placement, can occur.

• Consider caudal tracking of pneumothoraces into the peritoneal space as a potential cause of
pneumoperitoneum without a primary bowel injury.
ABP Content Specifications(s)/Content Area
• Recognize the clinical manifestations, diagnosis, and management of infants with perforations of the
gastrointestinal tract (including gastric and intestinal)
Question: 4
A term neonate is brought in to the emergency department (ED) at 6 days of age because of
fussiness and emesis after feedings for 24 hours. He has been difficult to console. He has had no
known fever and no exposures to sick contacts. There have been several episodes of stiffened
extremities in the 6 hours before coming to the ED, but all have been brief and have not been
associated with cyanosis.

On physical examination, he is very fussy but alert. He cries frequently and is consoled briefly with
a pacifier. The anterior fontanelle is full but not tense, and sutures are minimally separated. The
remainder of the examination findings are normal. His temperature is 37.9°C.

Blood, urine, and cerebrospinal fluid specimens are obtained for culture. A lumbar puncture shows
the following.

Laboratory Test Patient Results (SI Units)

Fluid Yellow, cloudy
Red blood cells 10,000/μL (10 × 109/L)
White blood cells 6,995/μL (6.9 × 109/L)
Neutrophils 94%
Lymphocytes 2%
Monocytes 4%
Glucose <20 mg/dL (1.11 mmol/L)
Protein 375 mg/dL (3.75 g/L)
Blood glucose 80 mg/dL (4.44 mmol/L)
Gram stain Gram-negative rods

The infant is treated with ampicillin and ceftazidime, and electroencephalography is performed,
which shows multifocal seizure foci with evidence of moderate encephalopathy. He is treated with
phenobarbital, and the seizures stop within 36 hours of admission. The cerebrospinal fluid culture
subsequently yields pan-sensitive Escherichia coli. A repeat lumbar puncture after 48 hours of
treatment is bloody, but the culture is negative. By the third day after admission, the infant is
feeding well, neurologic examination findings are normal, and no further seizures are noted
without continued anticonvulsant treatment. Cranial ultrasonography is performed after 5 days of
treatment (Figure 1).

Of the following, the factor MOST helpful in determining the need for antibiotic treatment beyond
21 days in this infant is

A.
brain magnetic resonance imaging

B.
cerebrospinal fluid parameters at 19 days

C.
reappearance of seizures after 48 hours
D.
specific organism isolated

CORRECT
View Peer ResultsAverage Correct: 37.20%

The incidence of bacterial meningitis is higher in the neonate than in any other age group. The
most common organisms causing bacterial meningitis in the neonate are group
B Streptococcus and Escherichia coli, each accounting for 30% to 40% of cases, with Listeria
monocytogenes (approximately 5%) and other gram-negative enteric bacilli accounting for the
remainder. Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides are
rare in the neonate. Staphylococcus species are unusual unless there is another site for invasive
infection or presence of a foreign body.

The mortality from bacterial meningitis has declined over recent decades, but morbidity has not
improved. The mortality rate is approximately 5% to 10% in the developed world, but 55% or more
of survivors will have serious neurodevelopmental impairment. Of these, approximately one-third
to one-half will be severely impaired, including developmental delay, seizure disorder, cerebral
palsy, and hearing or vision loss. The high risk of long-term sequelae is similar in survivors of both
gram-positive and gram-negative meningitis.
The standard treatment duration is a minimum of 14 days for uncomplicated gram-positive
meningitis and 21 days for uncomplicated gram-negative meningitis, though these
recommendations are based more on convention than evidence. Other than the minimum
recommended duration of treatment for gram-positive versus gram-negative organisms, there are
no recommendations regarding treatment duration for any specific organisms. Prolonged
treatment is recommended for complicated bacterial meningitis, defined as the presence of
ventriculitis, subdural effusion, subdural empyema, or brain abscess.

The infant described in the vignette had a good clinical response to antibiotic treatment, with
resolution of seizures within 36 hours, and return to normal feeding and behavior by 3 days.
Repeat culture of cerebrospinal fluid performed at 48 hours was negative. All of these findings
suggest an uncomplicated bacterial meningitis. Nevertheless, cranial ultrasonography (Figure 1)
showed mild ventricular enlargement and increased echogenicity of the ventricular lining,
consistent with ventriculitis. A magnetic resonance imaging (MRI) study with contrast
enhancement was then performed to further evaluate for any complications of bacterial meningitis
that would dictate a need for prolonged antibiotic treatment. The MRI scan of the neonate in the
vignette (Figure 2 and Figure 3) did show subdural empyemas with leptomeningeal
enhancement. For this reason, the duration of antibiotic treatment was extended to 6 weeks.

There is some variation in recommendations for repeating the lumbar puncture and obtaining
cranial imaging in cases of meningitis. The Committee on Infectious Diseases of the American
Academy of Pediatrics recommends a repeat lumbar puncture at 48 hours to document that the
culture is sterile, while this is not recommended in the United Kingdom if the neonate is receiving
an antibiotic appropriate for the organism and is making a good clinical recovery. If not sterile,
antibiotic treatment may need to be refined, and lumbar puncture will need to be repeated in 48 to
72 hours to document sterility. Lumbar puncture is no longer recommended near the end of the
planned treatment duration.

Brain imaging is recommended by some authors only in the case of a poor or delayed clinical
response to antibiotic treatment such as:

• Persistent fever
• Seizures extending beyond 72 hours or recurring after 72 hours of treatment
• Abnormally increasing head circumference
• Development of new neurologic signs

Such signs may indicate the presence of complicated bacterial meningitis, but are nonspecific and
not diagnostic. Prolonged seizures may be caused by other pathologies such as cerebral infarcts,
which do not require additional antibiotic treatment.

Other experts recommend contrast-enhanced MRI for all neonates with bacterial meningitis 2 to 3
days before the anticipated discontinuation of antibiotic treatment, even for those who have an
uncomplicated clinical course, as evidence of ventriculitis or subdural empyema is common, is not
well predicted by clinical parameters, and would dictate a longer treatment course. Subdural
effusions occur in 20% to 33% of children with bacterial meningitis. These are extracerebral
collections of fluid isointense to cerebrospinal fluid and without enhanced margins after contrast. If
the margins of the collection enhance with contrast, as seen in Figure 2, subdural empyema is
diagnosed. Ventriculitis occurs in almost 30% of patients with bacterial meningitis and up to 90%
of neonates with bacterial meningitis. Although cranial ultrasonography can show ventricular
enlargement, and may suggest ventriculitis, MRI will better show extracerebral fluid collections,
evidence of persistent cerebritis, areas of infarct or encephalomalacia, and degree of cortical or
white matter atrophy. Infarctions (venous or arterial) are reported to occur in up to 30% of
neonates with bacterial meningitis.
 PREP Pearls
• Long-term neurodevelopmental impairment following neonatal bacterial meningitis is common, affecting
55% or more of survivors, regardless of the organism involved.

• Repeat lumbar puncture is recommended after 24 to 48 hours of treatment to document sterility of

cerebrospinal fluid, but lumbar puncture near the end of the treatment course is not recommended.

• Contrast-enhanced magnetic resonance imaging may be indicated near the end of anticipated treatment for
any neonate with bacterial meningitis to evaluate for clinically silent complications that might dictate a
longer duration of antibiotic treatment.

Figure 2: Magnetic resonance imaging after 16 days of treatment. Axial e-THRIVE GD (with contrast).
Subdural empyema with rim enhancement (yellow arrows) and leptomeningeal enhancement (white
arrows) with contrast.
Figure 3: Magnetic resonance imaging after 16 days of treatment.

Axial T1 without contrast. Extracerebral fluid collection (arrows) without contrast. Courtesy of E. Thilo

Question: 5
A 2-day-old, 3-kg infant receives mechanical ventilation with a tidal volume of 6 mL/kg and a
positive end-expiratory pressure set at 5 cm H2O. The peak inspiratory pressure measures 17 cm
H2O and the infant is breathing at a rate of approximately 46 breaths/min. Resistance is 100 cm
H2O/L per second.

Of the following, the expiratory time needed for discharge of 95% of the tidal volume delivered to
this infant is CLOSEST to

A.
0.40 seconds
B.
0.45 seconds

C.
0.50 seconds

D.
0.55 seconds

CORRECT
View Peer ResultsAverage Correct: 34.95%

The respiratory system mechanics work to regulate the volume and distribution of ventilation.
Inflow and outflow of respiratory gases allow the air volume contained within the lungs to be
ventilated. A pressure gradient between the airway opening and the alveoli drives the flow of
gases, and is largely determined by the compliance and resistance of the respiratory system. The
time needed for equilibration of pressure throughout the respiratory system (inflation or deflation of
the lungs) is related to these mechanical characteristics, and is described by the time constant of
the respiratory system.

The time constant of the respiratory system is defined as the time needed for the alveolar pressure
(or volume) to reach 63% of a change in airway pressure (or volume). In other words, 1 time
constant equals the time it takes for alveoli to discharge 63% of the tidal volume through the
airways to the mouth or ventilator circuit. Three time constants are needed for 95% inflation or
deflation. Delivery of pressure (or volume) is complete (95%-99%) after a duration of inspiration or
expiration equivalent to 3 to 5 time constants (Figure). Shorter time constants result in shorter
times for lung inflation and deflation. Similarly, longer time constants result in longer durations
needed for lung inflation and deflation. Applied to an infant receiving mechanical ventilation, in the
presence of a long time constant, a long inspiratory and expiratory time is needed to prevent
incomplete delivery of tidal volume and/or incomplete exhalation and gas trapping (inadvertent
positive end-expiratory pressure [PEEP]). Infants with short time constants ventilate well with short
inspiratory and expiratory times and fast respiratory rates. In certain disease states, such as
bronchopulmonary dysplasia, regions of varying compliance and resistance may exist, resulting in
varying time constants throughout the lungs.

The time constant of the respiratory system is a function of both elastic and resistive forces placed
on the lungs during breathing or mechanical ventilation. Time constants are proportional to
compliance and resistance.

Compliance refers to the elasticity or distensibility of the lungs or respiratory system (lungs plus
chest wall) and is defined by the ratio of the change in lung volume to the change in distending
pressure.
Lung compliance is determined by the interdependence of elastic tissue elements and alveolar
surface tension. Infants with normal lungs have a compliance of 3 to 5 mL/cm H2O per kilogram.
Compliance is reduced in infants with respiratory distress syndrome (0.1-1 mL/cm H2O per
kilogram).

Resistance refers to the ability of the gas-conducting parts of the respiratory system to resist
airflow. Resistance relates to non-elastic properties and includes frictional resistance to airflow
(80% of lung resistance), tissue resistance (19%), and inertial forces (1%). Resistance to airflow is
directly related to the length of the airway and inversely related to the size of the airway lumen,
increasing by a power of 4 as airway diameter decreases.

Airway resistance in the normal newborn is 20 to 50 cm H2O/L per second, which is about 16-fold
that of an adult (1-2 cm H2O/L per second), whose airway lumen is approximately twice as large.
The newborn with respiratory distress syndrome has an airway resistance greater than 40 cm
H2O/L per second and the infant with bronchopulmonary dysplasia may have an airway resistance
exceeding 150 cm H2O/L per second. Airway resistance is increased with small-diameter
endotracheal tubes (approximately 100 cm H2O/L per second) and is reduced by shortening
endotracheal tube length.

For the infant in the vignette, his time constant can be calculated to determine the expiratory time
needed for discharge of 95% of his tidal volume. His weight is 3 kg, tidal volume is 6 mL/kg, PEEP
is 5 cm H2O, and peak inspiratory pressure (PIP) is 17 cm H2O. Resistance is given at 100 cm
H2O/L per second.

Therefore, for the infant in the vignette, 95% of his tidal volume is discharged in 3 time constants,
or 0.45 seconds.
 PREP Pearls
• The time needed for equilibration of pressure throughout the respiratory system (inflation or deflation of the
lungs) is described by the time constant of the respiratory system.

• Time constants are proportional to compliance and resistance.

• Three time constants are needed for 95% inflation or deflation to occur

Figure: Percentage change in pressure in relation to the time (in time constants) allowed for equilibration.
As a longer time is allowed for equilibration, a higher percentage change in pressure will occur. The same
rules govern the equilibration for step changes in volume.
Question: 6
A newborn is noted to be pale 8 hours after birth. The newborn was born to a 23-year-old gravida
1, para 1 woman by precipitous vaginal delivery at 35 weeks of gestation. She was visiting from
out of state and her prenatal records are unavailable. She describes being involved in a serious
motor vehicle accident as a child, requiring splenectomy and multiple transfusions. Available
maternal screening studies include blood type A negative, antibody positive, and human
immunodeficiency virus negative. Examination of the newborn reveals a pale, well-perfused infant
with no hepatosplenomegaly or body wall edema.

Laboratory studies include the following.

Laboratory Test Patient Result

Hemoglobin 11 g/dL (110 g/L)
Hematocrit 33%
Reticulocyte count 3.8%
Blood type A positive
Direct Coombs 3+
Bilirubin, total 6.0 mg/dL (102.6 μmol/L)
Bilirubin, direct 0.3 mg/dL (5.1 μmol/L)

Of the following, the maternal antibody MOST likely to lead to the presentation of the newborn in
the vignette is

A.
anti-C

B.
anti-D

C.
anti-Kell

D.
anti-Lewis
CORRECT
View Peer ResultsAverage Correct: 27.16%

The newborn in the vignette most likely has hemolytic disease of the fetus and newborn (HDFN)
due to maternal Kell alloimmunization. Hemolytic disease of the fetus and newborn is most
commonly associated with anti-Rhesus D (RhD), ABO, and anti-Kell (K1, K) blood group
antibodies. Newborns with anti-Kell HDFN typically have more severe anemia and a relative
reticulocytopenia than those infants with hemolytic disease caused by other blood group
antibodies. The degree of hyperbilirubinemia associated with anti-Kell HDFN is also less severe.

At least 8 of the 24 individual antigens in the Kell red cell antigen system have been linked to
HDFN. Of these, the Kell antigen (K1, K) is 1 of the 2 most common. Only 9% of whites and 2% of
 individuals of African ancestry are Kell positive. Because the majority of affected individuals are
heterozygotes, this leads to an estimated 5% risk of having an affected fetus in a Kell
alloimmunized pregnancy. It is notable that more than 50% of maternal sensitization to Kell has
occurred because of blood transfusions rather than exposure to fetal red blood cells in the
maternal circulation.

Kell alloimmunization causes fetal and neonatal disease through 2 mechanisms: 1) direct antigen-
antibody interaction leading to hemolysis, and 2) suppression of erythropoiesis through inhibition
of red blood cell precursors. Vaughan and colleagues demonstrated that anti-Kell antibodies inhibit
the growth of Kell-positive erythroid burst-forming units and colony-forming units in cord blood,
while anti-RhD antibody has no effect. This suppression of erythropoiesis is postulated to
significantly contribute to the fetal anemia seen with Kell alloimmunization, which may be
associated with hydrops. Symptomatic fetal anemia may be seen with maternal anti-Kell titers as
low as 1:8, leading to recommendations for weekly fetal Doppler measurement of middle cerebral
artery peak systolic velocity to screen for fetal anemia in at-risk pregnancies.

The newborn in the vignette most likely has HDFN due to anti-Kell alloimmunization. Although
there is an RhD setup between the mother and newborn, HDFN due to RhD incompatibility would
not be expected in this scenario. Blood is routinely typed and cross-matched for RhD antigen
before transfusion, making sensitization at the time of the auto accident unlikely. Because the
mother is a primigravida, fetal anemia due to in utero RhD sensitization is unlikely. Anti-RhC rarely
causes severe HDFN in isolation, but can be additive when RhD antibodies are present. Lewis
antibodies (Le-a, Le-b) are naturally occurring immunoglobulin M antibodies that do not cross the
placenta.

PREP Pearls
• Newborns with anti-Kell hemolytic disease of the fetus and newborn typically have more severe anemia, a
relative reticulocytopenia, and a milder degree of hyperbilirubinemia than those infants with hemolytic
disease caused by other blood group antibodies.

• Kell alloimmunization causes fetal and neonatal disease through 2 mechanisms: 1) direct antigen-antibody
interaction leading to hemolysis, and 2) suppression of erythropoiesis through inhibition of red blood cell
precursors.
Question: 7
The pediatric team covering the nursery seeks neonatology consultation regarding management
for a well-appearing infant born 60 minutes previously. The infant was born at 37 weeks’ gestation
by vaginal delivery after 10 hours of ruptured membranes. At the time of admission, the
obstetrician noted a lesion on the mother’s vulva that was suggestive of herpes simplex virus
infection. The mother denied having any genital lesions or cold sores in the past. Viral culture and
herpes simplex virus (HSV) polymerase chain reaction (PCR) testing of the maternal lesion were
performed, as well as maternal serologic testing. The mother refused cesarean delivery. Maternal
HSV-1 and HSV-2 antibodies are reported negative. Surface cultures and PCR for HSV, blood
PCR for HSV, cerebrospinal fluid cell count, chemistries and HSV PCR, and serum alanine
transferase concentration are recommended.

Of the following, the MOST appropriate management course for the newborn at this time is to

A.
monitor clinically and initiate intravenous acyclovir if the infant becomes symptomatic or virologic studies
are reported positive

B.
start intravenous acyclovir and continue for 10 days if the infant remains asymptomatic and virologic
studies are negative

C.
start intravenous acyclovir and continue for 14 days if the infant remains asymptomatic and virologic
studies are negative

D.
start intravenous acyclovir and discontinue at 48 to 72 hours if the infant remains asymptomatic and
virologic studies are reported negative
INCORRECT
Correct Answer: B
View Peer ResultsAverage Correct: 30.45%

Herpes simplex viruses (HSVs) are enveloped, double-stranded DNA viruses. There are 2 distinct
types of HSVs: HSV-1 and HSV-2, both associated with neonatal disease. Herpes simplex viruses
belong to the α herpesvirus subfamily of the Herpesviridae family. Nearly 50% of the DNA in HSV-
1 and HSV-2 is homologous, resulting in significant antigen cross-reactivity.

Herpes simplex virus infections are very common, affecting 1 in 4 to 5 adults in the United States.
The incidence of neonatal HSV infection ranges from 1 in 3,000 to 20,000 live births. Most
neonatal HSV infections are acquired peripartum (85%) with 10% occurring postnatally and 5%
antenatally.

Active HSV infection in pregnant women near delivery may cause mother-to-child transmission.
Factors associated with a greater risk of HSV transmission from mother to infant include:

· Primary HSV infection

· Lack of maternal HSV antibody

· Prolonged duration of rupture of amniotic membranes (>4-6 hours)

· Breach of mucocutaneous barrier (using fetal scalp probe)

· Premature delivery

· Vaginal delivery

It is important to consider whether the maternal HSV infection is first-episode primary, first-episode
nonprimary, or recurrent. History and physical examination alone are not able to differentiate
between primary and recurrent HSV infections, because genital infections may be asymptomatic
or may present with nonspecific symptoms. Serologic tests can reliably distinguish type-specific
HSV antibodies and help classify the type of infection (Table). As stated by the American
Academy of Pediatrics Committee on Infectious Diseases and Committee on Fetus and Newborn,
“When a genital lesion is strongly suspicious for HSV, clinical judgment should supersede the
virological test results” for the conservative purpose of prevention of neonatal infection.

To study the transmission of HSV from the mother to the infant, 40,000 women were prospectively
screened for HSV within 48 hours of delivery. The occurrence of neonatal HSV disease was
highest (57%) among infants born to mothers with a first-episode primary infection, and lowest
(2%) for mothers with recurrent HSV infection.

The increased risk for neonatal HSV disease associated with primary infection is due to:

· Lower concentration of HSV antibodies transmitted from the mother to fetus

· Lower efficacy of HSV antibodies in binding to HSV peptides

· Larger burden and longer duration of viral shedding

Neonatal HSV is associated with significant mortality and morbidity. Prognosis of neonatal HSV
infection can be significantly affected by prompt diagnosis and appropriate treatment.

The treatment of choice for neonatal HSV disease is parenteral acyclovir. The Committee on
Infectious Diseases and Committee on the Fetus and Newborn of the American Academy of
Pediatrics jointly authored a clinical report in 2013 entitled “Guidance on Management of
Asymptomatic Neonates Born to Women with Active Genital Herpes Lesions.” The report outlines
the management approach for asymptomatic infants born vaginally or via cesarean delivery to a
mother with active genital lesions suggestive of HSV (Figure 1 and Figure 2).

If there is no history of genital HSV before the pregnancy, viral type and maternal serologic status
need to be determined. In the absence of a history of HSV, genital lesions at delivery could
represent first-episode primary infection with a risk of transmission to the neonate of 57%, or first-
episode nonprimary infection with a risk of transmission to the neonate of 25%. Infants born to
women with primary active HSV genital infection are 10 to 30 times more likely to acquire HSV
infection, compared with infants born to mothers with recurrent HSV infection. A complete
evaluation including HSV surface cultures (with or without surface HSV polymerase chain reaction
[PCR]), HSV blood PCR, serum alanine aminotransferase, and cerebrospinal fluid studies
including HSV PCR, cell count, and chemistries are recommended for the infant. Treatment with
intravenous acyclovir at 60 mg/kg per day should be started at 24 hours of age and continued until
the maternal classification is determined. Evaluation and treatment before 24 hours is indicated if
the neonate develops signs and symptoms suggestive of HSV disease (fever, hypothermia,
lethargy, irritability, vesicular rash, seizures), and may be considered if amniotic membranes
 rupture more than 4 to 6 hours before delivery or if the neonate is born premature (≤37 weeks’
gestation). The infant in the vignette was born at 37 weeks' gestation with rupture of membranes
occurring 10 hours before delivery, so immediate evaluation was chosen.

If the mother has a documented or assumed first-episode primary (as for the infant in the vignette)
or first-episode nonprimary HSV infection, the neonate should be treated empirically with
intravenous acyclovir for 10 days even if the neonate's evaluation results are negative (preemptive
treatment of infection, but no proven disease). The treatment duration is 21 days for HSV infection
causing central nervous system or disseminated disease and 14 days for infants with disease
limited to the skin, eyes, and mucous membranes.

Newborns of mothers with a history of genital HSV before the pregnancy are at a low risk of
developing neonatal HSV. Screening HSV surface cultures (and surface PCR if desired) and HSV
blood PCR are recommended 24 hours after delivery, with no treatment at that time if the infant
remains asymptomatic. Neonatal surface HSV testing that is performed shortly after delivery may
have a positive result because of transient maternal contamination. To differentiate between
transient contamination and infection, the Committee on Infectious Diseases and Committee on
the Fetus and Newborn of the American Academy of Pediatrics have recommended waiting 24
hours before obtaining virologic studies in an asymptomatic newborn. Positive surface culture at
24 hours or later is considered suggestive of active replication of the virus in the newborn, rather
than mere contamination after intrapartum exposure.

PREP Pearls
• Neonates born to mothers with either first-episode primary or first-episode nonprimary active genital herpes
simplex virus (HSV) lesions are at high risk for HSV infection, and should be treated preemptively with 10
days of parenteral acyclovir treatment to prevent progression from neonatal infection to disease.

• When a genital lesion is strongly suggestive of herpes simplex virus, clinical judgment should supersede
the virologic test results for the conservative purpose of prevention of neonatal infection.

Table: Maternal Infection Classification by Genital HSV Viral Type and Maternal Serology.
Figure 1: Algorithm for the evaluation of asymptomatic neonates after vaginal or cesarean delivery to
women with active genital herpes lesions.
Figure 2: Algorithm for the evaluation of asymptomatic neonates after vaginal or cesarean delivery to
women with active genital herpes lesions.
Question: 8
A 2.6-kg black infant born at 37 weeks of gestation is readmitted to the neonatal intensive care
unit at 110 hours of age with extreme hyperbilirubinemia (total serum bilirubin 30 mg/dL [513
µmol/L]) caused by ABO incompatibility and glucose-6-phosphate dehydrogenase deficiency,
confirmed on laboratory testing. He is treated with phototherapy, an albumin infusion, intravenous
immune globulin, and double-volume exchange transfusion.

Physical examination findings on admission are significant for mild opisthotonus and hypotonia
with periods of intermittent hypertonia, all of which resolve completely by the time of discharge.

Before discharge, magnetic resonance imaging of the brain is performed which has normal
findings, without evidence of basal ganglia abnormality. An automated acoustic brainstem
response hearing screen is also unremarkable.

Of the following, the additional study MOST useful for determining a long-term treatment plan for
this infant at this time is

A.
auditory-evoked brainstem response testing at 3 months

B.
computed tomography of the brain before discharge

C.
magnetic resonance spectroscopy of the brain before discharge

D.
otoacoustic emission testing at 3 months
INCORRECT
Correct Answer: A
View Peer ResultsAverage Correct: 77.20%

The patient in the vignette exhibits signs of acute bilirubin encephalopathy (ABE), including
hypotonia, periods of hypertonia, and opisthotonus in the setting of a total serum bilirubin
concentration in a range associated with kernicterus.

Bilirubin encephalopathy refers to neurologic dysfunction related to elevated concentrations of

lipid-soluble unbound bilirubin. Encephalopathy may be divided into an acute phase (ABE) and a
chronic phase (chronic bilirubin encephalopathy [CBE]), which differ in clinical signs as well as
brain imaging characteristics. Kernicterus, in its most precise usage, refers to yellow staining of
the basal ganglia noted on pathology specimens of the brain; however, the term is also used to
describe the clinical findings of CBE. Both ABE and CBE are clinical diagnoses.

Bilirubin encephalopathy affects multiple areas of the brain spanning both grey and white matter,
including cerebral structures (globus pallidus, subthalamic nucleus, hippocampus, substantia
nigra), the cerebellum (dentate nuclei), the medulla, and cerebral and cerebellar white matter
tracts.
Acute bilirubin encephalopathy is characterized by nonspecific and sometimes subtle neurologic
findings. Prominent signs include:

• Hypotonia, hypertonia, or both

• Drowsiness
• Lethargy
• Diminished feeding
• Retrocollis (spastic neck extension)
• Opisthotonus (spastic trunk and neck extension)
• High-pitched or shrill cry
• Irritability progressing to inconsolability

Correlation of a suggestive clinical presentation with the infant’s history is critical for the diagnosis.
Important historical correlates include a bilirubin concentration above the recommended exchange
value for gestational and postnatal age, and the presence of risk factors for kernicterus.

Signs of CBE are characterized by dystonia and extrapyramidal movement disorders:

• Athetosis (slow writhing involuntary movements)

• Abnormalities in tone including
o hypotonia
o hypertonia
• Abnormal posture
• Co-contraction of opposing muscle groups
• Spasticity
• Ataxia and incoordination
• Impaired upward ocular movements
• Enamel hypoplasia of primary teeth
• Hearing impairment including localization difficulty

Significant intellectual delay is not part of isolated CBE despite such an association having been
suspected in the past.

The presence of an abnormal auditory brainstem response (ABR) is an important diagnostic

feature of CBE. Finding an abnormal ABR result at several months of age presents an opportunity
for early intervention that could improve clinical outcome. Some authors hypothesize that the
previously suspected association of CBE with intellectual delay was likely secondary to the motor
abnormalities of CBE coupled with undiagnosed hearing loss. Interventions such as sign language
and lip reading, and hearing augmentation with hearing aids or cochlear implants may improve
outcomes. Therefore, follow-up hearing evaluation in patients who have signs of ABE may guide
clinical interventions that improve developmental outcomes. Otoacoustic emission testing is not
helpful in bilirubin encephalopathy because the hearing loss is central, and otoacoustic emission
testing examines only the cochlear apparatus.

Magnetic resonance imaging (MRI) findings in ABE are sometimes thought to be important for
prognosis and predictive of the development of CBE, but these findings are variable. The T1 signal
images are most commonly abnormal in ABE. T1 intensity, however, is influenced by local
concentrations of blood and myelin in addition to bilirubin.
 Acute bilirubin encephalopathy is characterized by the MRI finding of T1 hyperintensity in the
globus pallidus (and variably, in the subthalamic nucleus, hippocampus, and the cerebellar
dentate nucleus) with normal T2 intensity in the same regions. However, timing of the study can
influence this finding because of the pathophysiologic evolution of the disease process, as can
variations in the pattern of myelination among infants. These factors compromise the sensitivity
and specificity of MRI findings and limit the prognostic usefulness of MRI in ABE. An increased T1
signal in a term neonate with high blood bilirubin concentrations could be predictive of CBE, but
may also indicate a normal variation in myelination.

In the subacute or chronic phase of bilirubin encephalopathy, beginning several weeks after the
insult, the T1 and T2 patterns reverse, showing an unremarkable T1 signal intensity and increased
T2 signal intensity in the brain regions as noted earlier. Increased T2 signal intensity in the
substantia nigra (midbrain) and dentate nucleus are additional variable findings in CBE. Increased
T2 signal intensity, when persistent, bilateral, and symmetrical, in a setting of clinical suspicion for
bilirubin encephalopathy, is highly specific for, and virtually diagnostic of, CBE. Importantly though,
while virtually diagnostic of CBE in the presence of increased T2 signal, late MRI may not
demonstrate these findings in all patients with hearing loss attributable to bilirubin encephalopathy,
and will therefore not allow early intervention for hearing loss.

Diffusion-weighted imaging MRI may show abnormalities in cases of severe ABE that correlate
with sites of expected pathologic involvement, including the motor cortex, cerebellar Purkinje cells,
brainstem structures, and white matter tracts in the cerebellum and superior thalamic radiations.
Diffusion tensor imaging and magnetic resonance spectroscopy are other imaging techniques that
may prove useful, though more studies are needed to define their roles. Computed tomographic
imaging and cranial ultrasonography may be helpful in excluding other diagnoses or coexisting
pathology, but are not useful in the specific diagnosis of CBE.

PREP Pearls
• Auditory brainstem response testing is the test of choice for assessing ototoxicity in chronic and acute
bilirubin encephalopathy.

• Identification of patients with auditory brainstem response testing abnormalities suggestive of bilirubin
toxicity may improve neurologic outcomes through early intervention for speech and language
development.

• Magnetic resonance imaging findings in acute bilirubin encephalopathy lack sensitivity and specificity
March
Question: 1
A 2,000-g infant was born at 37 weeks’ gestation to a 29-year-old primigravida by induced
spontaneous delivery due to intrauterine growth restriction and worsening maternal hypertension.
The maternal history is notable for smoking and an elevated body mass index. The infant was
transferred to the intensive care nursery 6 hours after birth for treatment of asymptomatic
hypoglycemia that did not respond to enteral feeding. At 10 days of age, she has persistent
hypoglycemia. Physical examination reveals no cardiac murmur, no hepatosplenomegaly, and
normal female genitalia. A diagnostic evaluation for sepsis is negative. The infant has
demonstrated consistent blood glucose values over 60 mg/dL (3.3 mmol/L) while receiving a
parenteral glucose infusion rate (GIR) of 9 mg/kg per minute and feeding 150 mL/kg per day of
fortified maternal breast milk. Attempts to decrease the GIR have been unsuccessful. When
hypoglycemia recurred with the last attempt to wean the GIR, the following laboratory studies were
obtained.

Laboratory Study Patient Result (SI Units) Expected Fasting Range

Glucose 44 mg/dL (2.4 mmol/L)
Insulin 6 µIU/mL (42 pmol/L) <2 µIU/mL (14 pmol/L)
Growth hormone 12 ng/mL (12 μg/L) >10 ng/mL (>10 μg/L)
Cortisol 22 µg/dL (607 nmol/L) >20 µg/dL (>552 nmol/L)
Plasma free fatty acids 14 mg/dL (0.5 mmol/L) >28-42 mg/dL (>1.0-1.5 mmol/L)
Plasma β-hydroxybutyrate 0.5 mmol/L (48 μmol/L) >1.5 mmol/L (>144 μmol/L)

A glucagon stimulation test was performed at the time of these laboratory studies. The glucose
values after injection were 52 mg/dL, 60 mg/dL, and 76 mg/dL at 10, 20, and 30 minutes,
respectively.

Of the following, the medication MOST likely to be beneficial, based on these results and clinical
presentation of the infant in the vignette, is

A.
diazoxide

B.
hydrocortisone

C.
nifedipine

D.
octreotide
INCORRECT
Correct Answer: A
View Peer ResultsAverage Correct: 85.80%

The infant in the vignette likely has perinatal stress-induced hyperinsulinism which is most
commonly treated with diazoxide if medication is required. Perinatal stress-induced
hyperinsulinism may be seen in infants who experience perinatal stressors such as intrauterine
growth restriction, prematurity, maternal hypertensive disorders of pregnancy, and birth asphyxia.
Some experts suggest that up to 10% of small-for-gestational age infants may be affected.
Hypoglycemia in at-risk infants develops shortly after birth and may resolve within 3 to 4 weeks,
although 1 study reported a median time of 6 months until resolution.

Hyperinsulinism should be suspected in a growth-restricted infant with persistent hypoglycemia,

though the many causes of neonatal hypoglycemia, including sepsis, pituitary disorders, and
metabolic diseases, must be considered (Table 1). Diagnostic testing centers on obtaining critical
laboratory values when hypoglycemia is identified on a glucose measurement, but consensus
does not presently exist on the degree of hypoglycemia and the timing within the clinical course.
One time to consider obtaining critical laboratory values is when the glucose value is less 50
mg/dL (2.7 mmol/L), the infant is receiving full enteral feeds, and the parenteral glucose infusion
rate cannot be weaned. Some or all of the laboratory studies listed in Table 2 may be obtained to
help determine the underlying cause of the hypoglycemia.

The infant in the vignette, while receiving a glucose infusion at a rate of 8 mg/kg per min or
higher, has an inappropriately high insulin concentration (plasma insulin >2 µIU/mL [>14 pmol/L])
for the serum glucose of 44 mg/dL (2.44 mmol/L), low serum fatty acid concentration (plasma free
fatty acids <28-42 mg/dL [<1-1. 5 mmol/L]), hypoketonemia (plasma β-hydroxybutyrate <1.5
mmol/L [>144 μmol/L]), and an exaggerated glycemic response to glucagon (∆ glucose >30 mg/dL
[1.66 mmol/L]).. These findings suggest an underlying diagnosis of hyperinsulinism, which, in this
case, is likely stress-induced. It should be noted that more than 20% of infants with stress-induced
hyperinsulinism may not have an inappropriately high insulin level during screening, but will still
manifest low serum fatty acid concentrations, hypoketonemia, and exaggerated glycemic
responses to glucagon as evidence of hyperinsulinism.

The most common drug used in the management of stress-induced hyperinsulinism is diazoxide.
Its use in the treatment of infantile hypoglycemia was first described in 1966. Diazoxide is a β-cell
KATP channel inhibitor, maintaining the channel open, which prevents repolarization of the
pancreatic β-cell membrane. This lack of repolarization keeps the voltage-dependent Ca2+ channel
closed and prevents insulin release. Diazoxide may be started with doses as low as 5 mg/kg per
day orally, with adjustment based on the glycemic response to treatment. In the neonatal
population, fluid retention and pulmonary edema may complicate the use of diazoxide and require
the use of a diuretic agent. This is especially common as the dosage approaches 10 mg/kg per
day. Treatment with diazoxide is typically managed along with a pediatric endocrinologist, with the
drug being discontinued with resolution of the stress-induced hyperinsulinism.

Octreotide, a long-acting analogue of somatostatin, is considered the second line of treatment for
infants with hyperinsulinism that is unresponsive to diazoxide. Both octreotide and somatostatin
hyperpolarize the pancreatic β-cell membrane, maintaining the voltage-dependent Ca2+ channel
closed and preventing insulin release. Case reports have described the use of nifedipine as a
treatment option for hyperinsulinism. As a calcium-channel blocker, nifedipine is hypothesized to
block the voltage-dependent Ca2+ channel and prevent insulin release. However, data on the safety
and efficacy of calcium channel blockers in this situation are presently limited. The use of
glucocorticoids such as hydrocortisone and dexamethasone for the acute treatment for
hypoglycemia has been reported. However, additional medications are usually required for the
long-term management of hyperinsulinism, and significant side effects are associated with long-
term use of glucocorticoids.
 PREP Pearls
• Perinatal stress-induced hyperinsulinism may be seen in infants who experience perinatal stressors such
as intrauterine growth restriction, prematurity, maternal hypertensive disorders of pregnancy, and birth
asphyxia.

• Hypoglycemia in infants with stress-induced hyperinsulinism develops shortly after birth and may resolve
within 3 to 4 weeks, though one study reported a median time of 6 months until resolution.

• The most common drug used in the management of stress-induced hyperinsulinism is diazoxide.
Question: 2
A 25-week-gestation premature male infant is evaluated by an ophthalmologist for retinopathy of
prematurity at 36 weeks’ postmenstrual age. The infant is currently receiving respiratory support
via humidified heated high-flow oxygen of 2 L/min and 35% oxygen. The examination findings are
described as “a ridge of fibrovascular tissue noted along the avascular and vascular junction, with
neovascularization extending into the vitreous in the periphery of zone II with dilation and
increased tortuosity of the posterior vessels.”

Of the following, the MOST appropriate intervention is

A.
anti–vascular endothelial growth factor intravitreal injection

B.
avoidance of hyperoxia by maintaining oxygen saturations less than 95%

C.
laser ablation therapy of the peripheral retina

D.
repeating the ophthalmologic examination in 2 weeks
INCORRECT
Correct Answer: C
View Peer ResultsAverage Correct: 53.14%

Retinopathy of prematurity (ROP) is caused by abnormal development of the retinal vasculature

that occurs after preterm birth and can result in retinal detachment and blindness. The retinal
vasculature develops posteriorly from the region of the optic nerve and progresses outward to the
periphery, with complete vascularization occurring near 40 weeks’ gestation. In premature infants,
ROP is an oxygen-regulated process that develops in 2 phases. The first phase occurs after birth
as a result of the relative hyperoxia that the premature infant encounters in comparison to the
intrauterine environment. This leads to a downregulation of vascular endothelial growth factor
(VEGF) and an arrest of retinal vascular development. As a consequence of this decrease in
vascular development, local tissue hypoxia develops, which in turn, causes an upregulation of
VEGF and subsequent vascular proliferation. This vascular proliferation causes abnormal retinal
vascular growth.

Treatment indications for ROP are based on the location and extent of abnormal retinal vessels as
well as the presence of retinal detachment. Classification of ROP is based on the International
Classification of ROP that takes into account 3 factors:

• The location of retinal vascularization, with zone 1 being the most posterior and zone 3 the most
peripheral
• A description of the degree of abnormality of the vessels at the junction of the vascular and
avascular retina
o Stage 1: A flat “demarcation line” of abnormal fibrovascular tissue
 o Stage 2: A ridge of fibrovascular tissue with both height and width
o Stage 3: Extraretinal fibrovascular proliferation that extends into the vitreous
o Stage 4: Partial retinal detachment
o Stage 5: Complete retinal detachment
• The presence of plus disease, which is defined by increased dilation and tortuosity of the posterior
vessels

Current recommendations for treatment of ROP are based on the Early Treatment of Retinopathy
of Prematurity Cooperative Group (ETROP) study. This study classifies ROP into type 1 and type
2 ROP.

• Type 1 ROP:
o Any ROP with plus disease or stage 3 ROP without plus disease in zone 1
o Stage 2 or 3 ROP with plus disease in zone 2
o Treatment is recommended
• Type 2 ROP:
o Any other classification of ROP not defined as type 1
o Followed by serial ophthalmologic examinations and treated if type 1 ROP develops

The patient in the vignette has ROP classified as zone 2 stage 3 with plus disease (type 1 ROP)
and therefore treatment is recommended rather than continued examinations.

Standard treatment for ROP is laser ablation of the peripheral retina, which prevents the
progression of abnormal vascular development and eventual retinal detachment. This treatment
results in destruction of the avascular retina, thereby ultimately reducing the visual field. It also
requires general anesthesia and has potential complications such as retinal hemorrhage, cataract
formation, and myopia. Because of these unfavorable effects, alternative treatments for ROP have
been explored.

Several studies report on the use of intravitreal injections of anti-VEGF agents for treatment of
ROP. Anti-VEGF treatment is targeted at the second phase of ROP, which is in part due to an
upregulation of VEGF production. Studies comparing laser treatment to anti-VEGF treatment and
combination treatment have shown similar short-term efficacy and safety. However, treatment with
anti-VEGF injections results in a higher rate of ROP recurrence, a need for longer follow-up
because of delayed vascularization of the retina, and possibly an increased risk of abnormal
retinal vascular development. In some cases of severe ROP in zone 1 or aggressive posterior
ROP, there may be advantages of anti-VEGF over laser treatment such as more rapid regression
of plus disease and less extensive treatment-related destruction of the retina.

Despite some potential advantages of anti-VEGF treatment, there is a lack of information about its
long-term safety and efficacy, as well as concern about potential systemic effects of intravitreal
injections of anti-VEGF agents. Because of these and other unanswered questions, the American
Academy of Ophthalmology recommends:

“Clinicians should exercise caution and offer anti-VEGF therapy only for type 1 ROP treatment in
patients in zone 1 or posterior zone 2 disease only after carefully weighing the benefits and risks
and discussing treatment options with parents.”

For the patient in the vignette who has stage 3 ROP with plus disease in the periphery of zone 2,
standard treatment with laser ablation would be most appropriate.
 Hyperoxia has been associated with ROP and a strategy to prevent ROP is to avoid hyperoxia by
maintaining oxygenation saturations in a tight target range. Once ROP is established, as in the
patient described in the vignette, the benefit of avoiding hyperoxia is less clear and would not
prevent the need for definitive treatment with laser ablation.

PREP Pearls
• Treatment indications for retinopathy of prematurity are based on the location and extent of abnormal
retinal vessels as well as the presence of retinal detachment.

• Standard treatment for retinopathy of prematurity remains laser ablation of the peripheral retina.

• Anti–vascular endothelial growth factor treatment has been investigated as an alternative to laser ablation,
and there may be advantages to this approach for patients with retinopathy of prematurity in zone 1 or
posterior zone 2.
Question: 3
A neonate prenatally diagnosed with trisomy 21 is being evaluated. In addition to the characteristic
phenotypic features of trisomy 21, she has a papulovesicular rash on her face and a protuberant
abdomen. The liver can be palpated 3.5 cm below the right costal margin. Her respiratory rate is
60 to 70 breaths/min and she has mild subcostal retractions. Her complete blood cell count is as
follows:

• Hemoglobin 11 g/dL (110 g/L)

• Hematocrit 35 %
• White blood cells 65,100/μL (65.1×109/L)
• Platelets 35,000/µL (35×109/L)

The peripheral blood smear with blasts (black arrows) is shown in Figure 1.

Of the following, the blast cells in the figure are MOST likely precursors of

A.
basophils

B.
lymphocytes

C.
megakaryocytes

D.
neutrophils
INCORRECT
Correct Answer: C
View Peer ResultsAverage Correct: 23.94%

The infant in the vignette has transient myeloproliferative disorder (TMD), a disorder of fetal
hematopoiesis that occurs in approximately 10% of newborns with trisomy 21. Most patients (80%)
have spontaneous resolution by 3 months of age. Immunotyping of the blast cells demonstrates
that TMD is a process of abnormal differentiation of megakaryocytes. The characteristic
proliferation of megakaryoblasts in TMD is exclusive to patients with full or partial trisomy 21 within
their myeloid precursor cells.

Hematopoiesis in utero occurs in the fetal liver. Neonates with TMD may develop hepatomegaly
from proliferation of megakaryoblastic cells in the liver, leading to hepatic dysfunction, respiratory
compromise, and decreased production of red blood cells and platelets. The hematologic
manifestations of TMD are anemia, thrombocytopenia, and an elevated number of peripheral
megakaryoblasts, manifested as an elevated white blood cell count. Prenatally, 5% of fetuses with
TMD develop hydrops fetalis, and postnatally, about 10% develop severe coagulopathy.
Megakaryoblastic cells in the liver produce cytokines and growth factors that stimulate the
development of hepatic fibrosis, which persists longer than the hematologic manifestations of
TMD.
 About 5% of patients with TMD develop a papulovesicular or pustular rash most commonly on the
face, which coincides with the development of myeloproliferation. Biopsies of the rash reveal
perivascular or dermal leukemic blasts with infiltration into the epidermis. The rash spontaneously
resolves with the resolution of peripheral blasts.

The infant in the vignette with trisomy 21 has numerous features of TMD including peripheral
blasts, anemia, thrombocytopenia, hepatomegaly leading to respiratory distress, and a
papulovesicular rash on the face.

Of the patients who survive TMD, approximately 25% subsequently develop acute
megakaryoblastic leukemia (AMKL), a subtype of acute myelogenous leukemia. Despite the
apparent resolution of TMD, the leukemic cells of AMKL are derived from a persistent clone of
megakaryoblastic cells in TMD. AMKL associated with trisomy 21 manifests before 5 years of age.
Infants with TMD should be monitored for the development of AMKL with a complete blood cell
count and differential every 3 months until they are 5 years old when the risk of developing AMKL
diminishes. Although children with trisomy 21 have a 500 times greater risk of developing AMKL
compared with the general population, their megakaryoblastic cells have increased sensitivity to
chemotherapeutic agents. Patients with trisomy 21 and AMKL have a 70% to 100% cure rate with
chemotherapy alone compared with the poor response of this type of leukemia in patients without
trisomy 21 (5-year event-free survival of 35%).

Children with trisomy 21 who have either TMD or AMKL have the same functionally specific
mutation of the gene encoding the hematopoietic transcription factor GATA1 in their
megakaryoblastic cells. GATA1 is expressed in multipotential hematopoietic progenitors of
erythrocytes, granulocytes, and megakaryocytes. It is an essential regulator of normal
megakaryocytic differentiation (Figure 2); it functions by regulating megakaryocytic proliferation,
cytoplasmic maturation, and the development of platelet organelles in megakaryocytes. The gene
for GATA1 is located on the X chromosome. Mutations associated with TMD and AMKL are the
result of a somatic frameshift mutation leading to a premature stop codon. The resultant truncated
GATA1 protein has lower transcriptional activation potential, which leads to an accumulation of
incompletely differentiated megakaryocytes.

The development of TMD is a 2-hit phenomenon that requires synergy between trisomy 21 and a
somatic mutation of the gene encoding GATA1. The first step is the increased gene dosage of a
critical region on the 21st chromosome that leads to accelerated early hematopoiesis. The second
step is the GATA1 mutation, which causes the generation of aberrant megakaryoblasts. Trisomy
21 accelerates abnormal megakaryocytic differentiation through both enhancement of early
hematopoiesis and upregulation of the formation of the truncated GATA1 protein, leading to the
development of TMD.

PREP Pearls
• The dysplastic cells in transient myeloproliferative disorder seen in patients with trisomy 21 are
megakaryoblasts.

• Transient myeloproliferative disorder usually resolves by 3 months of age, but 25% of cases will develop
acute megakaryoblastic leukemia, generally by 5 years of age
Question: 4
An infant born at 27 weeks’ gestation is currently 8 weeks old. His hospital course has been
complicated by respiratory distress syndrome treated with endotracheal intubation and surfactant
administration. At 26 days of age, he developed necrotizing enterocolitis that was treated with
bowel rest and broad-spectrum antibiotics for 14 days. Enteral feeds were restarted 40 days after
birth at 10 mL/kg per day and advanced very slowly, while he continued to receive parenteral
nutrition, including a 20% intravenous soy-based fat emulsion. He is currently receiving oxygen
through high-flow nasal cannula at 3 L/min, enteral feeds of breast milk at a volume of 40 mL/kg
per day, and parenteral nutrition for a total fluid volume of 160 mL/kg per day. His total and direct
bilirubin are now 5.2 mg/dL (88.9 μmol/L) and 2.8 mg/dL (47.9 μmol/L), respectively.

Of the following, the intervention MOST beneficial in improving this infant’s cholestasis is

A.
enteral feeds

B.
fish oil emulsion

C.
intravenous fat emulsion restriction

D.
ursodeoxycholic acid
CORRECT
View Peer ResultsAverage Correct: 65.92%

Parenteral nutrition–associated liver disease (PNALD) is a complication of prolonged use of

parenteral nutrition (PN). It is defined as a conjugated bilirubin concentration greater than 2 mg/dL
(34.2 μmol/L) after the use of PN for at least 2 weeks, when other causes of liver disease have
been excluded. The incidence of PNALD varies between 25% and 60% among those receiving
prolonged PN, and correlates directly with the duration of PN. The cause of PNALD is likely
multifactorial and risk factors include prematurity, small for gestational age, lack of enteral feeds,
abdominal surgeries, and sepsis.

Elements of PN have been implicated in the pathogenesis of liver disease, including a high
glucose infusion rate, and toxicity from amino acids (methionine, tryptophan, phenylalanine) and
microelements (copper, manganese).

In addition, evidence suggests that the lipid emulsion component of PN plays a role in the
pathogenesis of PNALD. Currently, in the United States, the most widely used form of intravenous
lipid emulsion (ILE) is a soybean-based lipid emulsion rich in omega-6 fatty acid (linoleic acid). An
excessive intake of omega-6 fatty acid from the soybean-based products triggers an increased
production of arachidonic acid (a precursor of proinflammatory factors), and increases the risk for
chronic inflammation, liver cholestasis, and possible hepatic fibrosis. Soybean-based lipid
emulsions are also very rich in phytosterols, plant-based sterols that belong to the plant cell
membrane. In rats, phytosterols reduce bile acid secretion and inhibit secretory function, activate
Kupffer cells and downregulate the sterol transporter, thus triggering liver injury. Also, soybean-
based lipid emulsions contain low amounts of α-tocopherol which has a known antioxidant effect.

Currently, there are 2 approaches regarding the use of ILE for treating PNALD. The first approach
is a reduction in the amount of intravenous fat administered. This is a common strategy, though
supporting evidence is inconclusive. A few studies show some reduction in conjugated bilirubin
when using a lower daily amount of ILE. However, lipid restriction carries the risk of essential fatty
acid deficiency and potential consequences involving long-term neurodevelopment.

A second approach is the use of a non–soybean-based ILE. Fish oil emulsions were first used in
Germany and have been associated with a reduction in PN-associated cholestasis. Fish oil
emulsions contain omega-3 fatty acids which have increased antioxidant activity. The high content
of α-tocopherol in these products also has a protective effect on lipid peroxidation. Globally,
studies using these fish oil ILEs have demonstrated an improvement in cholestatic parameters.
However, because the studies are confounded by concurrent soy-based emulsion dose reduction
and advancement of enteral feedings, evidence in support of fish oil emulsions is felt to be of low
quality. Currently in the United States, the use of parenteral fish oil emulsions for patients with
PNALD is restricted to compassionate use or investigational protocols through the US Food and
Drug Administration. Similarly, enteral fish oil is being investigated. Small case series have shown
resolution of PNALD in preterm infants after the use of enteral fish oil, but this therapeutic strategy
cannot be recommended yet.

Ursodeoxycholic acid (UDCA) is a naturally occuring hydrophilic bile acid used to treat cholestatic
conditions in adults and children. Ursodeoxycholic acid stimulates bile flow, protects hepatocytes
from bile-mediated damage, and replaces toxic hydrophobic bile acids in the bile pool. The
absorption in preterm infants is poor and is even worse in the presence of hepatic injury. A small
study demonstrated a consistent decrease in bilirubin concentration that reached a plateau after 2
weeks of treatment in 10 preterm infants with PNALD. A larger retrospective study of 118 infants
demonstrated that UDCA effectively decreased the concentration of conjugated bilirubin. However,
American Society for Parenteral and Enteral Nutrition guidelines from 2014 conclude that “The
evidence to use UDCA for the treatment of elevated liver enzymes in children with PNALD is of
very low quality and is confounded by the presence of enteral feedings along with treatment with
UDCA. The desirable effect of the reduction of liver indices has to be weighed against the
unknown efficacy of the treatment.”

Enteral feeds play an important role in the liver disease associated with PN. Without enteral
stimulation, there is a decrease in the secretion of gut hormones such as cholecystokinin,
important in gallbladder contraction, with a secondary reduction in bile flow and biliary stasis.
Providing calories by route of enteral feeds also allows for reduced exposure to PN, thus
decreasing the risk of liver disease. In a large study comparing the duration of PN use of less than
28 days with that of more than 100 days, the incidence of liver disease increased from 14% to
86%. Both early enteral nutrition within the first week after birth and earlier resumption of enteral
nutrition after necrotizing enterocolitis (NEC) were shown to be beneficial in reducing PNALD. A
retrospective study published in 2015 involving preterm infants with NEC who developed
cholestasis demonstrated that enteral nutrition within 6 days of birth decreased the development of
liver disease and resumption of enteral nutrition within 3 weeks after the diagnosis of NEC
hastened the resolution of cholestasis. This study did not find any role for specific PN components
in the development or resolution of cholestasis.

Evidence shows that breast milk is the optimal enteral nutrition in reducing PNALD. A
retrospective study published in 2013 comparing the effect of different enteral feeding regimens
found that breast milk had a protective effect against the development of PNALD in infants who
received parenteral nutrition for more than 4 weeks.
 Currently the strategy found to be most effective in both preventing and treating liver disease
associated with PN is the provision of enteral feeds.

PREP Pearls
• Enteral nutrition is the most important factor in prevention and treatment of parenteral nutrition–associated
liver disease
Question: 5
A 1,500-g neonate who was born at 31 weeks’ gestation with moderate respiratory distress is now
12 hours old and is being treated with 6 cm H2O of nasal continuous positive airway pressure
(NCPAP), with an FiO2 of 0.26. The infant has mild subcostal retractions when disturbed, but is
otherwise comfortable, and good air entry is heard in all lung fields. Chest radiography shows
inflation to the ninth rib posteriorly and mildly hazy lung fields. A high-flow nasal cannula is being
considered for ease of care and to facilitate holding by the infant’s mother. Differences between a
high-flow nasal cannula and NCPAP are being discussed.

Of the following, a high-flow nasal cannula is MOST likely to be effective by improving

A.
dead space washout

B.
distending airway pressure

C.
expiratory resistance

D.
metabolic work of conditioning inhaled gas
INCORRECT
Correct Answer: A
View Peer ResultsAverage Correct: 43.32%

The use of blended, heated, humidified high-flow nasal cannula (HHHFNC) for the noninvasive
respiratory support of neonates with mild-to-moderate respiratory distress syndrome or for
postextubation support after a period of mechanical ventilation is increasing. The definition of high-
flow nasal cannula is any flow greater than 1 L/min, but HHHFNC specifically refers to nasal
cannula flow that uses blended oxygen, is heated to 37oC, is humidified to 100%, and is provided
at a flow rate of 2 L/min or more.

Several reviews and meta-analyses of randomized controlled trials have concluded a similar
efficacy or noninferiority of HHHFNC, generally provided at flows of 3 to 8 L/min, to nasal
continuous positive airway pressure (NCPAP) for the initial treatment of respiratory distress
syndrome and for postextubation support, with the strongest evidence for postextubation support.
The number of extremely premature infants (<28 weeks of gestation) included in the trials was,
however, limited. An additional noninferiority trial published subsequent to these reviews indicates
that HHHFNC may not be as effective as NCPAP for initial treatment of respiratory distress
syndrome. Of those infants randomized to HHHFNC, 25% failed treatment (needing either NCPAP
or intubation) compared with 13% of those assigned to NCPAP. In general, the use of HHHFNC
compared with NCPAP has been found to result in similar outcomes for death or
bronchopulmonary dysplasia and a similar need for intubation (failure of noninvasive support), with
a lower incidence of nasal trauma and possibly, though not consistently, pneumothorax. There are
no consistent differences in secondary outcomes such as duration of respiratory support, length of
time on supplemental oxygen, length of time to full oral feedings, length of hospitalization, or
occurrence of necrotizing enterocolitis or sepsis.
 Although the mechanism of action of HHHFNC is not certain, Dysart et al discussed 5 potential
mechanisms:

• Reduction of inspiratory resistance in the nasopharynx

• Washout of nasopharyngeal dead space
• Provision of positive airway distending pressure
• Improved conductance and pulmonary compliance
• Reduced metabolic work

Of these, washout of the nasopharyngeal dead space is likely the principal mechanism, thereby
reducing the overall dead space in the airway. Reduced dead space makes alveolar ventilation a
greater proportion of minute ventilation and results in improved efficiency of respiratory efforts.
The use of high-flow nasal cannula in adult patients with chronic obstructive pulmonary disease is
as effective as a transtracheal catheter for dead space washout, allowing reduced respiratory
rates, higher arterial oxygen concentrations, and improved exercise tolerance, without change in
tidal volume. Hypercapnia, and apnea triggered by hypercapnia, are frequent reasons for
neonates to fail attempts at noninvasive ventilation, and may be decreased with improved
efficiency of respiratory efforts.

The use of HHHFNC reduces inspiratory resistance associated with collapse of the nasopharynx
during inspiration by providing flows that meet or exceed the patient’s maximal inspiratory flow.
Expiratory resistance is not expected to change, provided the nasal cannula prongs are
appropriately sized and the mouth is permitted to open. It is recommended that the cannula
prongs fill approximately 50%, and no more than 80%, of the nares and that the mouth not be held
shut. This allows adequate egress of gas flow to occur, permitting dead space washout and
avoiding excessive and unregulated positive airway pressure. Studies measuring work of
breathing and lower esophageal pressures as an approximation of distending airway pressure
have demonstrated similar effects on work of breathing with HHHFNC at 3 to 5 L/min as with
NCPAP at 6 cm H2O, but at lower esophageal pressures, indicating that provision of distending
pressure is not the main mechanism for the effect of HHHFNC.

Elimination of the need for the nasopharynx to warm and humidify the inhaled gases decreases
metabolic work and caloric expenditure, and may decrease oxygen need and carbon dioxide
production slightly, but is not likely to be the main mechanism for HHHFNC efficacy. Heating and
humidifying the inhaled gas can prevent bronchoconstriction in response to high flows of cool, dry
gases, and can improve compliance compared with the use of less well-humidified gases, but this
is not likely to contribute substantially.

While HHHFNC has not been shown to be either inferior or superior to NCPAP, several experts in
the field of noninvasive support of ventilation have published a consensus of their approaches to
using HHHFNC in neonates. A summary of their consensus findings is provided in the Table. All
participants agreed with the use of HHHFNC for postextubation support of neonates of 28 weeks’
gestation or more, and for making a transition from NCPAP. However, there was majority but not
complete agreement on the use of HHHFNC for initial support of neonatal respiratory distress
syndrome (4 of 6 experts in support). There was also general agreement on using initial flow rates
of 4 to 6 L/min, depending on infant size, postnatal age, and degree of respiratory distress and
oxygen need, with increases or decreases based on work of breathing and FiO2 required. There
was no agreement on when or from what flow rate to make the transition from HHHFNC to low-
flow cannula or ambient air.

PREP Pearls
• Heated, humidified high-flow nasal cannula is as effective as nasal continuous positive airway pressure for
postextubation respiratory support of neonates of 28 weeks’ gestation or more.
• Heated, humidified high-flow nasal cannula improves efficiency of alveolar ventilation, likely by causing
dead space washout, despite supplying less distending pressure than nasal continuous positive airway
pressure.
Question: 6
A 1,900-g male infant was born via induced vaginal delivery at 34 2/7 weeks’ gestation to a 30-
year-old gravida 1 woman. The pregnancy was complicated by severe preeclampsia the day
before delivery. Labor was augmented by oxytocin and artificial rupture of membranes occurred 8
hours before delivery. Group B Streptococcus status was unknown and the mother received 6
doses of penicillin G intravenously during labor. There was no concern for chorioamnionitis.

In the delivery room, the infant received continuous positive airway pressure and positive pressure
ventilation. Apgar scores were 5 and 7 at 1 and 5 minutes, respectively.

At the time of admission to the neonatal intensive care unit, the infant required no respiratory
support. He was not started on antibiotics due to the maternal reason for delivery, adequate
antibiotic prophylaxis for group B Streptococcus, and well appearance.

Twenty-four hours after birth, the infant became hypotensive. Three hours earlier, the infant was
noted to have poor color and a blood sample was sent for culture, complete blood cell count, and
C-reactive protein. Antibiotics were started, and two 10-mL/kg normal saline boluses were given to
the infant. Vasopressor treatment was started, and cerebrospinal fluid analysis performed several
hours later. The blood culture showed growth of Escherichia coli. Forty-eight hours after the blood
culture was sent, the sensitivities became available (Table 1). The patient’s laboratory results are
shown (Table 2).

Of the following, the MOST appropriate antibiotic(s) for this patient is

A.
cefotaxime

B.
ceftriaxone

C.
gentamicin

D.
meropenem
orrect Answer: A
View Peer ResultsAverage Correct: 52.63%

The pathogens most commonly implicated in early-onset neonatal sepsis are group
B Streptococcus (GBS), Listeria monocytogenes, Enterococcus, and Escherichia coli. A
recommended empiric regimen for suspected early-onset sepsis in neonates is ampicillin and
gentamicin. Up to 94% of bacterial isolates in neonates with early-onset sepsis are susceptible to
ampicillin and/or gentamicin. Ampicillin and gentamicin are synergistic in treating infections caused
by GBS and L monocytogenes.

For the infant in the vignette, the E coli isolate was resistant to ampicillin; therefore, continuing the
combination of ampicillin and gentamicin is not appropriate. Ampicillin resistance among infants
with early-onset E coli has increased in the last decade, and gentamicin resistance is strongly
associated with ampicillin resistance. Ampicillin remains the antimicrobial agent of choice for
meningitis due to ampicillin-sensitive strains of E coli. This patient did not appear to have
meningitis, as indicated by lack of cerebrospinal fluid (CSF) pleocytosis, negative Gram stain, and
negative CSF culture.

Although the isolate in the vignette was sensitive to meropenem and piperacillin-tazobactam, both
of these antimicrobials have broad anaerobic coverage, which is not needed for the patient in the
vignette. Empiric anaerobic coverage is considered for necrotizing enterocolitis when gut mucosal
integrity is compromised. However, these antimicrobials should not be unnecessarily used,
because they will decrease normal gut flora as well, altering the gut microbiome. The infant gut
microbiome plays important roles in immune function and endocrine and neurologic pathways, and
is important for infant neurodevelopment. The microbiome influences the hypothalamic-pituitary-
adrenal axis by influencing cortisol secretion and stress response development. Gut bacteria
interact with vagus nerve receptors, thus communicating with the central nervous system.

Cephalosporins are not routinely used for empiric treatment of early-onset neonatal sepsis for the
following reasons:

• Cephalosporins are not effective against L monocytogenes.

• The combination of ampicillin and a third-generation cephalosporin is not more effective than the
combination of ampicillin and gentamicin for treatment of sensitive organisms.
• Routine use of cefotaxime can result in emergence of cephalosporin resistance in gram-negative
species.
• Cephalosporin use results in more overgrowth of Candida species than use of aminoglycosides.
• Infants treated with a combination of ampicillin and cefotaxime have a 1.5-fold increase in mortality
compared with those treated with ampicillin and gentamicin.
 The addition of a third-generation cephalosporin to ampicillin and gentamicin is indicated for
infants with suspected meningitis or other factors that raise suspicion for an ampicillin-resistant
infection. Gentamicin penetrates poorly into the CSF when the blood-brain barrier is intact.
Cerebrospinal fluid penetration is improved during meningitis (when the blood-brain barrier is
weakened) and when a β-lactam is used concomitantly. Gentamicin is often used with ampicillin or
a third-generation cephalosporin for treatment of meningitis, and is stopped as the second agent
when CSF sterility is achieved. Gentamicin is not generally used for the sole treatment of
meningitis because it is thought that the CSF penetration cannot be assured.

In the infant in the vignette, the strain of E coli was resistant to ampicillin, but was sensitive to a
third-generation cephalosporin. Although ceftriaxone was listed on the standard sensitivity panel, it
is not recommended in neonates because of binding to albumin and potential displacement of
bilirubin, thus increasing risk for acute bilirubin toxicity. Cefotaxime is a good choice in this patient
because third-generation cephalosporins have good CSF penetration and are highly active against
susceptible E coli. They are not active against L monocytogenes, Enterococcus species,
or Pseudomonas species. Cefepime, a fourth-generation cephalosporin, has similar efficacy
against Pneumococcus as do third-generation cephalosporins, but increased activity against
gram-negative enterics. It would provide broader coverage to the patient in the vignette than
cefotaxime, but would not affect gut anaerobes. Cefepime would be a good choice in this patient if
cefotaxime were unavailable.

PREP Pearls
• Ampicillin is the treatment of choice for ampicillin-sensitive Escherichia coli isolates in neonates.

• The incidence of ampicillin-resistant E coli is increasing in neonates.

• Cefotaxime (alternatively cefepime) is appropriate for the treatment of susceptible E coli when ampicillin
resistance is present
Question: 7
A female neonate is born at 39 weeks' gestation to a 32-year-old primiparous woman via
spontaneous vaginal delivery after an uneventful pregnancy. Apgar scores are 8 and 9 at 1 and 5
minutes, respectively. Birthweight is 3,390 g. No gross anomalies are identified on initial physical
examination. The neonate has respiratory distress at 10 minutes of age and is admitted to the
neonatal intensive care unit. She receives respiratory support with nasal continuous positive
airway pressure for the first 2 hours after birth, followed by endotracheal intubation and
synchronized intermittent mandatory ventilation due to worsening respiratory status and labile
oxygen saturations. Her oxygen saturation is 83% in the lower limbs and 91% in the right upper
wrist. Chest radiography, blood gas measurement, and echocardiography are ordered. She is
diagnosed with persistent pulmonary hypertension of the newborn. Her medical management
includes inhaled nitric oxide, intravenous milrinone infusion, and intravenous dopamine infusion.

Of the following, the MECHANISM of action by which intravenous milrinone infusion may improve
this infant’s condition is

A.
increased cyclic adenosine monophosphate (cAMP) by inhibition of phosphodiesterase 3A

B.
increased cAMP by stimulation of adenylate cyclase

C.
increased cyclic guanosine monophosphate (cGMP) by inhibition of phosphodiesterase 5A

D.
increased cGMP by stimulation of guanylate cyclase
INCORRECT
Correct Answer: A
View Peer ResultsAverage Correct: 61.94%

Persistent pulmonary hypertension of the newborn (PPHN) is seen in approximately 2 per 1,000
live-born infants. Persistent pulmonary hypertension of the newborn occurs due to failed
circulatory adaptation after birth and is characterized by elevated pulmonary vascular resistance
and labile oxygenation because of reduced pulmonary blood flow and extrapulmonary right-to-left
shunting of blood.

Pulmonary hypertension and reduced pulmonary blood flow are normal physiologic states in the
fetus because the organ for gas exchange is the placenta and not the lungs. In the fetus, the
majority of blood flow from the right ventricle is shunted to the aorta via the patent ductus
arteriosus, with a small proportion of cardiac output perfusing the fetal lungs. After birth, there is
both an increase in the systemic arterial resistance and a decrease in the pulmonary vascular
resistance. Clamping of the umbilical cord stops the blood flow to the low-resistance placental
circulation and contributes to an increase in the systemic arterial resistance. Multiple mechanisms
are responsible for a reduction in the pulmonary vascular resistance. Ventilation of the lungs with
an associated increase in oxygenation is considered the strongest stimulant for the reduction in
pulmonary vascular resistance.
 In addition, endothelial-derived mediators aid in reducing pulmonary vascular resistance. There is
an increase in the expression of endothelial nitric oxide synthase (eNOS) that contributes to nitric
oxide–induced pulmonary vasodilation. A reduction in pulmonary vascular resistance leads to an
8-fold increase in the pulmonary blood flow. Increased pulmonary blood flow is associated with an
increase in the left atrial pressure and closure of the foramen ovale. The change in the dynamics
of systemic and pulmonary pressure leads to a reversal of blood flow from right-to-left in utero to
left-to-right across the ductus arteriosus after circulatory adaptation in the early postnatal period.

Management of PPHN includes optimal lung volume recruitment, surfactant replacement when
indicated, avoidance of respiratory and metabolic acidosis, reduction of pain/agitation,
cardiovascular support through the maintenance of adequate intravascular volume and judicious
use of vasopressors, and pulmonary vasodilator treatment.

Various pulmonary vasodilators have been used in the treatment of neonates with PPHN. The
most commonly used pulmonary vasodilator is inhaled nitric oxide (iNO), a selective pulmonary
vasodilator with no significant effect on the systemic blood pressure. Inhaled nitric oxide improves
the ventilation-perfusion matching by increasing perfusion of the ventilated segments of the lungs.
Multiple studies evaluating iNO note a significant improvement in oxygenation in neonates with
PPHN, with a reduced need for extracorporeal membrane oxygenation (ECMO). The US Food and
Drug Administration has approved the use of iNO in term and late preterm infants (>34 weeks’
gestation) with PPHN. Inhaled nitric oxide is usually initiated at a dose of 20 parts per million.
Higher doses are not recommended because of an association with an increase in the
concentrations of nitrogen dioxide and methemoglobin. Inhaled nitric oxide acts by stimulating the
guanylate cyclase, leading to an increase in cyclic guanosine monophosphate (cGMP).

In addition to iNO, other commonly used medications to reduce pulmonary vascular resistance in
neonates with PPHN are sildenafil, milrinone, and prostacyclin. The mechanism of action of these
medications is shown in Figure 1. Both cGMP and cyclic adenosine monophosphate (cAMP) are
pulmonary vasodilators. cGMP can be increased by either stimulation of guanylate cyclase (iNO)
or by reducing its breakdown by phosphodiesterase 5A (sildenafil). cAMP can be increased by
either stimulation of adenylate cyclase (prostacyclin) or by reducing its breakdown by
phosphodiesterase 3A (milrinone). Bosentan, another medication that is sometimes used in the
management of chronic pulmonary hypertension, acts by blocking endothelin 1 receptor.

In the presence of normal systemic blood pressure and ventricular dysfunction, iNO use may
worsen pulmonary edema. Under these circumstances, intravenous milrinone infusion may be
helpful (Figure 2). Milrinone, a phosphodiesterase 3A inhibitor, increases the concentration of
cAMP in pulmonary smooth muscle, systemic smooth muscle, and cardiac muscle. Milrinone may
improve cardiac function and reduce pulmonary vascular resistance. Unlike iNO, milrinone is not a
selective pulmonary vasodilator and its use may be associated with systemic hypotension.

PREP Pearls
• Inhaled nitric oxide and sildenafil treat pulmonary hypertension by altering cyclic guanosine
monophosphate concentrations.

• Milrinone and prostacyclin treat pulmonary hypertension by altering cyclic adenosine

monophosphate concentrations.
Figure 1: Pulmonary vasodilators and vasoconstrictors. AC = adenylate cyclase; cAMP = cyclic adenosine
monophosphate; cGMP = cyclic guanosine monophosphate; COX = cyclooxygenase; eNOS = endothelial nitric oxide
synthase; ET-1 = endothelin 1; IP = prostacyclin receptor; NO = nitric oxide; PDE5 = phosphodiesterase 5; PGI =
prostacyclin; sGC = soluble guanylate cyclase
.h

Figure 2: Management of neonates with persistent pulmonary hypertension of the newborn. ECMO =
extracorporeal membrane oxygenation; IV = intravenous; LR = lactated ringers solution; NO = nitric oxide;
OI = oxygenation index; Paw = mean airway pressure; PEEP = positive end-expiratory pressure; PGE1 =
prostaglandin E1; PGI2 = prostaglandin I2; PO-OG = per oral or orogastric.
Question: 8
A 26-day-old convalescing extremely preterm infant is noted not to move her left leg. On physical
examination, she has erythema and swelling of her left lower extremity. Movement of the left leg is
painful. Plain radiography of the leg shows no fracture or focal abnormality. Her white blood cell
count is 17,000/μL (17 × 109/L), and a C-reactive protein is 36.9 mg/dL (3,514 nmol/L). Blood
cultures are positive for Staphylococcus aureus. Ten days later, a follow-up radiograph of the left
lower leg is obtained (Figure 1).

Of the following, the MOST likely primary focus of infection in this infant is the

A.
epiphysis

B.
medullary compartment

C.
metaphysis

D.
physis
INCORRECT
Correct Answer: C
View Peer ResultsAverage Correct: 58.50%

The infant in the vignette has clinical and radiographic findings consistent with osteomyelitis of her
left tibia. She has erythema and swelling of the affected extremity, and associated pain and
diminished spontaneous movement. Plain radiography 10 days into the infection demonstrates an
extensive periosteal reaction along the proximal aspect of her tibia (Figure 2).

Osteomyelitis refers to inflammation of bone caused by infection. In neonates, osteomyelitis

typically is an acute process, resulting from hematogenous dissemination of a pathogen in the
course of bacteremia. Direct inoculation from heel capillary blood sampling or indirect
contamination from surrounding soft tissue infection also provide routes for microorganisms to
reach skeletal tissues. In the neonate, risk factors for osteomyelitis include prematurity,
complicated delivery, skin infection, central venous catheters, and anomalies of the urinary tract.
The most common causative organism is Staphylococcus aureus, implicated in up to 85% of
cases. This predominance may be related to the capacity of S aureus to express bacterial
adhesions that promote attachment to extracellular bone matrix. Other pathogens to consider in
the neonate include Streptococcus agalactiae, Streptococcus pneumoniae, enteric gram-negative
bacteria, and Candida albicans.

Because of the rich vascular supply, the metaphyseal region of the long bone is most often the
primary focus of neonatal osteomyelitis. Infecting organisms travel to metaphyseal capillary loops
adjacent to the cartilaginous physis or growth plate. In this region, arterioles make abrupt turns
and blood flows slowly, providing pathogens an ideal environment for replication and subsequent
local inflammation. The large vascular space and thin spongy structure of the infant’s metaphyseal
cortex permit early decompression of infection into the subperiosteal space. The medullary cavity,
 or bone marrow compartment, seldom is involved in neonatal osteomyelitis. In addition, the
metaphyses of children younger than 18 months are vascularized by persistent fetal transphyseal
vessels that penetrate the cartilaginous growth plates and end in the epiphyses and joint spaces.
Consequently, osteomyelitis in neonatal long bones often leads to epiphysitis, resulting in severe
and usually irreparable damage to the cartilaginous growth plate. Septic arthritis is a common
sequela, particularly when the hip joint is involved, because the metaphysis is intracapsular at the
hip joint. By 18 months of age, the vascular connections between the metaphysis and epiphysis
are obliterated, and the cartilaginous growth plate provides a barrier, reducing the spread of
infection. Figure 3 shows the immature circulation of the neonatal long bones.

In the neonate, osteomyelitis most frequently affects the femur (39% of cases), followed by the
humerus (18%), tibia (14%), radius (5%), and maxilla (4%). Multiple bone involvement is common
in the neonate, occurring in 33% or more of cases. Vertebral involvement is rare in the neonate.

Laboratory and radiographic studies aid in the diagnosis of osteomyelitis. At presentation, the
peripheral white blood cell count may be normal or elevated, (average count of 17,000/μL [17 ×
109/L]). C-reactive protein concentration is elevated in 98% of cases, peaks within 48 hours of
infection, and returns to normal 7 to 10 days after appropriate treatment. Blood and bone cultures
identify the pathogen in up to 80% of cases.

During the first few days of infection, plain radiography may demonstrate swelling of soft tissues
around the site of infection. The first distinct evidence of bone involvement includes periosteal and
lytic changes, and requires involvement of at least one-third of the bony matrix. Unlike older
children in whom radiographic changes are delayed up to 3 weeks, the neonate with osteomyelitis
almost always demonstrates radiographic evidence of bone destruction after 7 to 10 days.
Because of efficient vasculature, the reparative phase begins within 2 weeks and involves the
formation of subperiosteal bone. Bone destruction may continue, with rapid absorption of necrotic
foci and deposition of new bone. Remodeling of the shaft takes several months (Figure 4). A
skeletal survey helps to identify multiple sites of infection.

Ultrasonography may detect periosteal thickening and subperiosteal collections as early as 48

hours after onset of infection, but a normal study does not exclude osteomyelitis. Skeletal
scintigraphy, using technetium-labeled methylene diphosphonate isotope, is 80% to 100%
sensitive within 72 hours of the onset of infection. Scintigraphy is useful for detecting multiple foci
of infection, and for cases in which suspicion is high, but radiographic or ultrasonographic results
are equivocal. Computed tomography provides good definition of cortical bone, is sensitive for
early detection of bony changes, and is helpful in diagnosing osteomyelitis of the skull associated
with an infected cephalohematoma. Magnetic resonance imaging (MRI) affords excellent anatomic
detail of muscle, soft tissue, and contrasting bone, without exposing the infant to ionizing radiation.
In addition, MRI aids in early detection of inflammatory or destructive intramedullary disease, and
is useful for evaluating vertebral and growth plate involvement.

PREP Pearls
• Because of the rich vascular supply, the metaphyseal region of the long bone is most often the primary
focus of neonatal osteomyelitis.