part

6
The Neonate
73
Neonatal Morbidities of Prenatal and
Perinatal Origin
JAMES M. GREENBERG, MD | VIVEK NARENDRAN, MD, MRCP (UK), MBA |
JENNIFER M. BRADY, MD | AMY T. NATHAN, MD | BETH B. HABERMAN, MD
Obstetrical Decisions and Neonatal
Outcomes
The nature of obstetrical practice requires consideration of
two patients: mother and fetus. Their intrinsic biological
interdependence creates unique challenges not typically
encountered in other realms of medical practice. Often there
is a paucity of objective data to support the evaluation of risks
and benefits associated with a given clinical situation, forcing
obstetricians to rely on their clinical acumen and experience.
Family perspectives must also be integrated in clinical decision-
making, along with the advice and counsel of other clinical
providers. In this chapter, we review how to best utilize
neonatology expertise in the obstetrical decision-making
process.  these infants may have significant hypoglycemia, polycythemia,
The Perinatal Consultation and the
Role of the Neonatologist
Optimal perinatal care derives from collaboration between
the obstetrician and neonatologist during pregnancy, and
especially around the time of labor, to eliminate ambiguity and
confusion in the delivery room and to ensure that patients and
families understand the rationale for obstetrical and postnatal
management decisions. The neonatologist can provide
information regarding risks to the fetus associated with delaying
or initiating preterm birth and can identify the optimal location
for delivery to ensure that skilled personnel are present to
support the newborn infant.
In addition to contributing information about gestational-
age-specific outcomes, the neonatologist can also anticipate
neonatal complications related to maternal disorders such as
diabetes mellitus, hypertension, and multiple gestation and can
define treatment pathways for fetal conditions such as congenital
infections, alloimmunization, or congenital anomalies. When a
lethal condition or high risk of death in the delivery room is
anticipated, the neonatologist can assist with the formulation of
a birth plan, develop parameters for delivery room intervention,
and make plans for palliative care.
Preparing parents by describing delivery room management
and resuscitation of a high-risk infant can demystify the process
and reduce some of the fear anticipated by the expectant family.
Making parents aware that premature infants are susceptible
to thermal instability will reduce their anxiety when the
newborn is rapidly moved after birth to a warming bed. The
need for resuscitation is determined by careful evaluation
of cardiorespiratory parameters and appropriate response
according to published Neonatal Resuscitation Program
guidelines.1  production and function. However, preterm infants born to
1410
Common Morbidities of Pregnancy
and Neonatal Outcome
Complications of pregnancy that affect infant well-being may
be immediately evident after birth, such as hypotension related
to maternal hemorrhage, or may present hours later, such as
hypoglycemia related to maternal diabetes or thrombocytopenia
related to maternal preeclampsia. Anemia and thyroid disorders
related to transplacental passage of maternal immunoglobulin
(Ig) G antibodies to platelets or thyroid, respectively, may
present several days after delivery.
Diabetes during pregnancy is a prototypic example.2 Infants
born to women with diabetes are often macrosomic, increasing
the risk of shoulder dystocia and birth injury. After delivery,
and electrolyte disturbances, which require close surveillance
and treatment. Lung maturation is delayed in the infant of a
diabetic mother (IDM), increasing the incidence of respiratory
distress syndrome (RDS) at a given gestational age. The IDM
also has delayed neurologic maturation, with decreased tone
typically leading to delayed onset of feeding competence.
Less common complications include an increased incidence
of congenital heart disease and skeletal malformations. Most
neonatal complications of maternal diabetes are managed
without long-term sequelae but may prolong length of hospital
stay. Anticipatory guidance for parents can decrease anxiety
and improve readiness for hospital discharge. Neonatal
complications for the IDM are a function of maternal glycemic
control. Thus careful screening of pregnant women by
physicians and adherence to treatment regimens by patients will
reduce neonatal morbidity due to maternal diabetes. In Table
73.1 we summarize other morbidities of pregnancy and their
effects upon neonatal outcome. The list is not exhaustive and
does not incorporate how multiple morbidities may interact
to create additional complications. Any of these problems may
contribute to increased length of hospital stay after delivery as
well as long-term morbidity.
Chorioamnionitis has diverse effects upon the fetus and
neonatal outcome. It is associated with preterm prelabor
rupture of membranes and, therefore, preterm birth. Elevated
levels of proinflammatory cytokines may predispose neonates
to cerebral injury.3 Though suspected or proven neonatal
sepsis is more common in the setting of chorioamnionitis,
many neonates born to mothers with histologically proven
chorioamnionitis are asymptomatic and appear unaffected,
with normal pregnancy outcomes. Animal models and
associated epidemiologic data suggest that chorioamnionitis
can accelerate fetal lung maturation as measured by surfactant

Table Morbidities of Pregnancy and Their Effects on
73.1 Neonatal Outcome
Pregnancy Morbidity Neonatal Outcome
Preeclampsia/chronic SGA, thrombocytopenia,
hypertension polycythemia
Congenital viral infection Thrombocytopenia, SGA,
intracranial calcifications,
developmental delay
Smoking SGA, polycythemia
Opioid use disorder Feeding difficulties, hyperirritability,
hypertonia, seizures
Obesity LGA, hypoglycemia, feeding
difficulties
Underweight Preterm birth
pPROM with Pulmonary hypoplasia
oligohydramnios
LGA, Large for gestational age; pPROM, preterm premature rupture of
the membranes; SGA, small for gestational age;.
mothers with chorioamnionitis are more likely to develop
bronchopulmonary dysplasia (BPD).4–7 The neonatal
consequences of chorioamnionitis are likely related to the
timing, severity, and extent of the infection and the associated
inflammatory response.
The effects of preeclampsia on the neonate are well known
and include fetal growth restriction, hypoglycemia, neutropenia,
thrombocytopenia, polycythemia, and electrolyte abnormalities
such as hypocalcemia. Most of these problems relate to placental
insufficiency with diminished oxygen and nutrient delivery to
the fetus. With delivery and supportive care, most of these will
resolve with time, although some patients will require treatment
with intravenous calcium and/or glucose in the early neonatal
period. Similarly, severe thrombocytopenia may require platelet
transfusion therapy. Some studies suggest that preeclampsia
may protect against intraventricular hemorrhage (IVH) in
preterm infants, perhaps because of maternal treatment or other
unknown factors.8 In contrast to intrauterine inflammation,
preeclampsia does not appear to accelerate lung maturation.
Predicting the consequences of maternal preeclampsia on
neonatal outcome remains difficult.8
Maternal autoimmune disease may affect the neonate
through transplacental transfer of autoantibodies. The extent
of antibody transfer drives severity of symptoms. Treatment is
supportive and based on the affected neonatal organ system.
For example, maternal Graves disease may cause neonatal
thyrotoxicosis requiring treatment with propylthiouracil or
beta-­blockers. Maternal lupus or connective tissue disease is
linked to congenital heart block that may require long-­term
atrial pacing after delivery. Myasthenia gravis during pregnancy
can promote a transient form of the disease in the neonate.
Supportive therapy during the early neonatal period will address
most issues associated with maternal autoimmune disorders.
Passively transferred autoantibodies gradually clear from the
neonatal circulation with a half-­life of 2–3 weeks. Preterm birth
and small for gestational age are more likely among neonates
born to mothers with autoimmune disorders.9
Neonatal outcome associated with maternal nutritional
status during pregnancy is of growing interest. The Dutch
famine of 1944–45 created a unique circumstance for studying
the consequences of severe undernutrition during pregnancy
(caloric intake less than 1000 kcal/day). Mothers experienced
significant third-­ trimester weight loss and offspring were
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1411
underweight.10 Low maternal body mass index (BMI) is
associated with increased risk of preterm birth.11 There is
now growing evidence that infants undernourished during
fetal life have higher risk for development of “adult” diseases
such as atherosclerosis and hypertension. Poor maternal
nutrition during intrauterine life may cause the fetus to
modify metabolic pathways and blood pressure regulatory
systems, with long-­term health consequences lasting into late
childhood and beyond.12
Conversely, maternal overnutrition as defined by excessive
caloric intake predisposes mothers to insulin resistance and
large-­for-­
gestational-­
age infants. In general, maternal BMI
and birth weight have increased over time, even though mean
gestational age at delivery has declined.13–16 Elevated maternal
BMI is associated with excess stillbirth and neonatal mortality
and may increase the risk for preterm birth.17 Maternal obesity
(BMI >30) is a risk factor for cerebral palsy among a term
population.18 The effects of maternal BMI on outcomes among
preterm neonates are less clear. Some studies report an elevated
risk of adverse neurodevelopmental outcomes, whereas others
do not detect a link with maternal BMI.19,20
Neonates from a multifetal gestation are, on average, smaller
at a given gestational age than their singleton counterparts.
They are also more likely to deliver before term and therefore
are more likely to experience complications associated with
low birth weight and prematurity described elsewhere in this
chapter. Identical twins may also experience conditions unique
to multiple gestation such as twin-­twin transfusion syndrome.
The associated discordant growth and additional problems of
anemia, polycythemia, congestive heart failure, and hydrops
may further complicate the clinical course following delivery,
even after amnioreduction or selective fetoscopic laser
photocoagulation. Of additional concern are cerebral lesions
such as periventricular white matter injury and ventricular
enlargement that may occur more frequently in the setting of
twin-­twin transfusion syndrome.21 Additional epidemiologic
studies and long-­term follow-­up are needed to further our
understanding.
Congenital malformations present significant challenges for
caregivers and families. Prenatal diagnosis offers opportunity to
plan for delivery room management and provide anticipatory
guidance. Choosing the site of delivery should be based
on optimizing availability of appropriate expertise. The
neonatologist can facilitate appropriate delivery coverage and
ensure availability of appropriate equipment, medications,
and personnel. Table 73.2 summarizes some of the important
considerations associated with neonatal management of
congenital malformations. Management considerations
include availability of expertise and equipment needed for
optimal management. This list reflects the importance of
multidisciplinary input for optimal management of patients
with congenital malformations. Typically, such patients are
best delivered in a setting with experienced delivery room
attendants. If needed consultative services or equipment are
not readily available, arrangement should be made for prompt
transfer to a tertiary center. Successful transports depend upon
clear communication between centers. For example, prompt
notification of the delivery of an infant with gastroschisis
ensures that the delivering hospital will provide adequate IV
hydration and protection of exposed viscera, while alerting the
referral center to make pediatric surgery expertise immediately
available upon arrival.
1412 Part 6  The Neonate
Table Neonatal Management of Congenital
73.2 Malformations
Malformation Management Considerations
Clefts Alternative feeding devices (e.g.,
Haberman feeder), genetics
evaluation, occupation/physical
therapy
Congenital Skilled airway management, pediatric
diaphragmatic surgery, immediate availability of
hernia mechanical ventilation, nitric oxide,
ECMO
Upper airway Skilled airway management,
obstruction/ otolaryngology, genetics evaluation/
micrognathia management, immediate availability
of mechanical ventilation,
tracheostomy tube placement
Hydrops/hydrothorax/ Skilled airway management, nitric
peritoneal effusion oxide, ECMO, chest tube placement,
paracentesis, immediate availability
of mechanical ventilation
Ambiguous genitalia Endocrinology, urology, genetics
available for immediate evaluation
Neural tube defects Sterile moist dressing to cover defect
and prevent desiccation, IV fluids,
neurosurgery, urology, orthopedics
evaluation/management
Abdominal wall Saline-­filled sterile bag to contain
defects exposed abdominal contents
and prevent desiccation, IV
fluids, pediatric surgery, genetics
evaluation/management
Cyanotic congenital IV access, prostaglandin E1, immediate
heart disease availability of mechanical ventilation
ECMO, Extracorporeal membrane oxygenation; IV, intravenous.
In the setting of premature labor, mothers are frequently
treated with antibiotics and tocolytic agents. Maternal
medications administered during pregnancy for nonobstetric
diseases can have a significant impact on the neonate. A
common challenge in many centers evolved from the treatment
of opiate-­addicted mothers with methadone or buprenorphine.
The symptoms of neonatal abstinence syndrome (NAS, also
called neonatal opioid withdrawal syndrome [NOWS]) vary
as a function of the degree of prenatal opiate exposure and
age after delivery.22 Many infants will appear neurologically
normal at delivery, only to exhibit symptoms later, on the first,
second, or even third day of postnatal life. Infants with NAS/
NOWS typically demonstrate irritability, poor feeding, loose,
frequent stools, and, in severe cases, seizures. Treatment options
include nonpharmacologic intervention (swaddling, minimal
stimulation), methadone, morphine, buprenorphine, or
nonnarcotic drugs such as phenobarbital or clonidine, the latter
as adjunct therapy with opioids. Often these infants require
hospitalization for many days or weeks until their irritability
is under sufficient control to allow for care in a home setting.
Diagnostic criteria, management strategies, and treatment of
NAS/NOWS continue to evolve.23
There is clinical evidence that neonates may also exhibit
similar symptoms following withdrawal from antenatal nicotine
exposure.24 Maternal smoking during pregnancy is also strongly
associated with low birth weight and sudden, unexpected infant
death.25
The consequences of other illicit drug use during pregnancy
have been widely studied but are more difficult to assess
due to diagnostic challenges and confounding variables.
Maternal cocaine abuse has been associated with obstetrical
complications such as placental abruption. In the neonate,
vascular compromise is suspected to predispose these patients
to cerebral infarcts and bowel injury.26 Developmental delay and
behavioral problems are also noted, although associated factors
such as poverty, lack of prenatal care, and low socioeconomic
status clearly contribute as well. Methamphetamine use during
pregnancy is associated with low birth weight, diminished linear
growth, small head circumference, and structural alterations of
the central nervous system.27
Neonatal anemia may be a consequence of perinatal
events such as placental abruption, ruptured vasa previa, or
fetal-­maternal transfusion. At delivery, the neonate may be
asymptomatic or display profound effects of blood loss including
high-­output heart failure or hypovolemic shock. The duration
and extent of blood loss along with any fetal compensation
determines neonatal clinical status at delivery and subsequent
management. In the delivery room, prompt recognition of acute
neonatal blood loss and transfusion with O-­negative blood can
be a lifesaving intervention.
Alloimmune hemolytic disorders such as Rh hemolytic disease
and ABO incompatibility can cause neonatal morbidity ranging
from uncomplicated hyperbilirubinemia to severe anemia,
hydrops, and high-­output congestive heart failure. Rh hemolytic
disease is now uncommon, but it still must be considered as a
cause of unexplained hydrops, anemia, or heart failure in infants
born to Rh-­negative mothers, especially if there is a possibility of
maternal sensitization. ABO incompatibility is common, with up
to 20% of all pregnancies potentially at risk for hyperbilirubinemia.
The responsible isohemagglutinins have weak affinity for
blood group antigens. Therefore the degree of hemolysis and
subsequent jaundice varies from patient to patient. Indirect
immunoglobulin (Coombs) testing has limited value in predicting
clinically significant jaundice. The typical neonatal morbidity is
hyperbilirubinemia requiring treatment with phototherapy.
Prematurity
The mean duration of a spontaneous singleton pregnancy is
282 days or 40 menstrual weeks (38 postconceptional weeks).
An infant delivered prior to completion of the 37th week of
gestation is considered preterm (World Health Organization
definition). Infant morbidity and mortality increase with
decreasing gestational age at birth. Preterm birth remains the
primary driver of global neonatal intensive care admissions
and infant mortality. The risk of poor outcome, defined as
death or lifelong handicap, increases dramatically as gestational
age decreases, especially for very-­ low-­birth-­weight infants.
The interplay between birth weight and gestational age, first
documented by Lemons and colleagues and updated by Fanaroff
and colleagues,28,29 remains valid today. (Fig. 73.1). Those born
significantly below or above a weight appropriate for gestational
age experience additional mortality risk.
Complications of Prematurity
Beyond increased mortality risk, prematurity is also associated
with increased risk of morbidity in nearly every major organ
system.29 Bronchopulmonary dysplasia, retinopathy of
prematurity, necrotizing enterocolitis, and intraventricular
hemorrhage are almost exclusively linked to the preterm state.
Intrauterine growth restriction and increased susceptibility to
 73  Neonatal Morbidities of Prenatal and Perinatal Origin 1413

Males (n=6563) Females (n=6493)

1600 1600

0.05
1400 1400

1200 1200
Birthweight (grams)

Birthweight (grams)
1000 0.05 1000

0.1 0.05
800 800
0.2 0.1
0.3
0.4 0.2
600 0.5 600 0.3
0.6
0.7 0.4
0.8 0.5
0.6
0.9 0.7
400 0.8
400 0.9

22 24 26 28 30 32 22 24 26 28 30 32
Gestational age (weeks) Gestational age (weeks)
Figure 73.1  Estimated mortality risk by birth weight and gestational age based on singleton infants born in NICHD Neonatal Research Network
Centers between 1997 and 2002. Numeric values represent age-­and weight-­specific mortality rates. (Used with permission of the American Academy of
Pediatrics. Very low birth weight outcomes of the National Institute of Health and Human Development Neonatal Research Network). See reference 29.

is no doubt that the US preterm birth rate remains persistently

Table Common Complications of Prematurity by
73.3 Organ System
elevated when compared with other developed countries.30
Explanations for our high preterm birth rates are complex
Organ System Morbidity and deserve close scrutiny. Among those closely associated
Pulmonary Respiratory distress syndrome (RDS)
with obstetric clinical practice include improvements in
Bronchopulmonary dysplasia (BPD) dating associated with use of early gestation ultrasound,31 an
Pulmonary hypoplasia increase in multifetal gestation associated with rising maternal
Apnea of prematurity age,32 use of assisted reproductive technology, and an increase
Cardiovascular Patent ductus arteriosus (PDA) in indicated preterm births.33 This last category has major
Apnea and bradycardia
Hypotension import because decisions affecting the timing of delivery can
Gastrointestinal/ Necrotizing enterocolitis (NEC) have a profound impact on neonatal outcome. Depending
liver Dysmotility/reflux on other factors such as fetal weight and antenatal steroid
Feeding difficulties exposure, the risk of death prior to hospital discharge roughly
Hypoglycemia
Central nervous Intraventricular hemorrhage (IVH)
doubles when gestational age decreases from 25 weeks to 24
system Periventricular leukomalacia weeks.34 Therefore delaying delivery even for a few days may
Cerebral palsy substantially improve neonatal outcome, especially prior to
Attention deficit disorders 32 weeks, with the caveat that the intrauterine environment
Visual Retinopathy of prematurity remains safe to support fetal physiologic integrity. In certain
Skin Excess insensible water loss
Hypothermia clinical circumstances with high potential for preterm delivery,
Immune/ Increased incidence of sepsis/meningitis the quality of the intrauterine environment may be difficult to
hematologic Anemia of prematurity assess. Three common examples are preterm/prelabor rupture
of membranes (Chapter 39), placental abruption (Chapter 43),
and preeclampsia (Chapter 45). In each situation, allowing
infection are not restricted to the preterm infant but promote gestation to continue is accompanied by an uncertain risk of
additional morbidity and mortality risk for the immature infant. rapid change in maternal status with a corresponding increasing
Table 73.3 summarizes common complications of prematurity risk of fetal compromise. Tests of fetal well-­being are discussed
by organ system. in Chapters 32 and 33 and patient safety in Chapter 46. We must
Although certain changes in vital statistics methodology emphasize that the neonatologist can be a valuable partner as
make direct decade by decade comparisons cumbersome, there these clinical challenges evolve.
1414 Part 6  The Neonate

During the first decade of the 21st century, disturbing Table

epidemiologic data emerged in the context of rising preterm birth 73.4 Complications of Prematurity
rates in the United States. Among all preterm births (defined as Incidence
delivery at less than 37 weeks’ gestational age), the fastest growing Complication of Incidence in Early in Late
segment was between 34 and 36 weeks’ gestation. Notably, the Prematurity Preterma Pretermb
peak gestational age at delivery in the United States had shifted Respiratory distress 10%–80% depending <5%
from 40 weeks in 1991 to 39 weeks in 2002.35 This was despite syndrome on gestational
no concordant increase in preeclampsia or chorioamnionitis age, antenatal
corticosteroid
over that same period. Further investigation determined that treatment
this population of late preterm infants experienced significantly Bronchopulmonary 22% <1500 g42,43 Uncommon
higher morbidity and mortality risk, although these risks were dysplasia
often perceived to be of limited clinical significance at the level Retinopathy of ∼20% <1500 g35,36, 44
of an individual patient.36 Note that extremely preterm infants, prematurity
Intraventricular 12% <1500 g28,29 Rare
typically defined as those born prior to 32 weeks’ gestation and/ hemorrhage with
or weighing less than 1500 g, comprise 1%–2% of all deliveries, ventricular dilation
and the late preterm population accounts for 8%–9% of all births. or parenchymal
Thus even uncommon morbidity in the late preterm population involvement
can generate a significant impact on the health care system. Necrotizing 5%–7% <1500 g28,29 Uncommon
enterocolitis
Subsequent epidemiologic investigation has verified the Patent ductus 30% <1500 g28,29 Uncommon
vulnerability of the late preterm population relative to term arteriosus
infants and led to the implementation of obstetric practice Feeding difficulty >90% 10%–15%36
guidelines meant to eliminate elective deliveries prior to 39 Hypoglycemia NA 10%–15%36
weeks’ gestation.37,38 Though progress has ensued,39 elective late aDefined as <32 weeks and/or <1500 g.
preterm birth remains a contributor to the US preterm birth bDefined as 32–38 weeks and/or 1500–2500 g.
rate. Some have advocated for and even implemented a hard-­
stop approach in the labor and delivery setting empowering
any involved provider to notify maternity center leadership to In addition to the clinical management issues associated with
initiate a standardized, real-­time peer review.40 preterm birth noted above, the role of key social determinants
It is also important to recognize that delivery prior to 39 of health must be noted as a central driver of excessive preterm
weeks must be balanced against the risk of stillbirth during the birth rates in the United States. The racial disparity of preterm
remaining pregnancy. A recent historical cohort study evaluated birth (and infant mortality) is particularly disturbing.45 In the
the interplay between risk of stillbirth and late preterm/early United States, Black infants are more than twice as likely to
term birth. In a 2-­year period following implementation of deliver early compared to their White counterparts, a disparity
rules designed to reduce elective delivery prior to 39 weeks, the that is not explained away by demographic factors such as
investigators found a stable overall perinatal mortality rate with insurance status, income, or educational attainment.46 Racism
a very small but significant increase in stillbirths accompanied in many manifestations, including systemic versions, is now
by a comparably significant decrease in infant deaths.41 recognized as a driver of the racial disparities of birth outcomes.
Most neonatal complications of late preterm birth are Strategies to remediate these challenges are urgently needed
easily treated, but their economic and social consequences and will require the same rigorous thinking and investment
are substantial, and long-­ term sequelae are incompletely traditionally applied to other major health care challenges such
understood. For example, brain growth and development as cancer and heart disease. 
proceed rapidly during the third trimester and continue for the
first several years of life. An infant born at 35 weeks’ gestation Decisions at the Threshold of Viability
has approximately one-­half the brain volume compared to a
term infant. Although IVH is unusual after 32 weeks’ gestation, Decisions regarding treatment of infants at the “limit of
the periventricular white matter and other regions of the viability” are often the most difficult for families and health
central nervous system continue to undergo rapid myelination care professionals. The challenge stems from the lack of clarity
during the third trimester of pregnancy. Studies demonstrate in defining that limit, which has decreased by approximately
a clear association between late preterm birth and long-­term 1 week every decade over the past 40 years in the United
neurodevelopmental concerns such as learning disabilities States. Among developed countries, most identify the limit of
and attention deficit disorders. Additional neurologic and extrauterine viability at 22 to 25 weeks’ gestation.47,48
epidemiologic study is needed to establish mechanistic Clinical decision making at these gestational ages typically
connections between late preterm delivery and these long-­term centers around a dichotomy of immediate medical intervention
outcomes. Table 73.4 provides a summary of complications at the time of birth versus palliative or so-­called comfort care.
of prematurity, comparing early preterm versus late preterm Taking time to gather relevant objective information and share
populations. Later preterm infants also experience excess infant that information among the obstetric and neonatal providers
mortality compared to their full-­term counterparts: the infant is crucial and should be a priority. The objective basis of the
mortality rate for infants born at 34–36 weeks’ gestation is presumed gestational age should be verified and discussed.
approximately threefold higher than those delivered at 40 weeks. Ideally, counseling should be based upon local outcome data
Clearly, ongoing scrutiny of immediate and long-­term birth and up-­to-­date experience. If known, estimated fetal weight and
outcomes related to recently established practice guidelines is gender are important variables that impact predicted survival
still essential. and major morbidity risk. Other variables to consider are noted

Table Key Variables Driving Outcomes for
73.5 Extremely Premature Infants
Variable Comment
Gestational age Small variations impact survival and
morbidity
Fetal/neonatal weight Small variations impact survival and
morbidity
Antenatal steroid Growing recognition of importance to
treatment survival50
Delivery site Survival advantage with delivery at a
specialty perinatal center
Transport Higher morbidity and mortality risk with
intercenter transport
Comorbidities For example, congenital malformations
in Table 73.5. At present, there is clear consensus that infants
born prior to 22 weeks’ gestation do not survive, regardless
of resuscitative efforts. Beginning at 22 0/7 weeks, survival is
documented, although data are difficult to interpret due to
variation in resuscitation practices.49 Evidence-­based calculators
designed to estimate survival and long-­ term outcomes are
useful tools but should not be the sole resource used to counsel
families (see https://www.nichd.nih.gov/research/supported/
EPBO/use).
Obviously, at extremely early gestational ages, a decision not
to attempt resuscitation always results in mortality for the infant.
Long-­term outcome data are also dependent on follow-­up rates,
the duration of follow-­up, and the quality of developmental
testing. Finally, outcome is clearly driven by the site of delivery.
Although under ideal circumstances, all periviable deliveries
should take place at a specialty perinatal center, some do not.51
Availability of state-­ of-­
the-­
art resuscitation equipment and
skilled, experienced delivery room personnel clearly impacts
outcomes, although quantitative data are very limited. The
published recommendations of a joint workshop convened by
the Eunice Kennedy Shriver National Institute of Child Health
and Human Development52 remain relevant at the time of this
writing and, along with other published guidelines,53,54 can be
construed as foundational documents for caregivers working
with families under these extremely challenging circumstances.
Planning for Delivery
Ideally, discussion between physicians and parents should begin
prior to birth in a nonemergency situation and should include
obstetric and neonatal providers. If simultaneous presence is not
possible, it is imperative that obstetric and neonatal providers
communicate directly prior to delivery to ensure clarity and
consistency of intent. Even during active labor, communication
with the family should be initiated as a prelude to postdelivery
discussions. The family should understand that plans for delivery
management are based upon maternal and fetal considerations.
Outcome data are typically very limited and are based upon
populations of similar individuals (e.g., cohorts of 23-­ week
gestation infants, rather than an individual). Finally, it should
be emphasized that additional information available only after
delivery, such as actual birth weight and neonatal physical findings,
may modify a previously predicted predelivery prognosis.
Neonatal Resuscitation at the Threshold of Viability
As emphasized earlier, a birth plan developed by the parents
in collaboration with obstetrical and pediatric/neonatology
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1415
providers should be established. The neonatologist will provide
information about planned interventions in the delivery room,
transfer to the neonatal intensive care unit, anticipated initial
hospital course, and the significance of potential complications
in the context of prior experience with neonates of similar
gestational age, weight, and clinical circumstances. Even when
time does not permit such discussions, the neonatologist should
carefully assess gestational age at delivery and the response to
initial resuscitation. This information can be instrumental
in assisting families regarding viability or nonviability of
an extremely premature infant. Even though resuscitation
measures for extremely preterm neonates follow standard
Neonatal Resuscitation Program (NRP) protocols, every
effort should be made to engage the participation of the most
clinically experienced neonatal provider to evaluate gestational
age, estimate weight, assess response to resuscitative efforts, and
provide medical leadership for the delivery room care team to
support decision making. In cases when a precipitous delivery
occurs and no family communication is possible, the physician/
provider should employ their best judgment to initiate
resuscitation until a parent can be brought into the discussion,
erring on the side of resuscitative measures if the appropriate
course is initially uncertain. 
Who Decides?
It is generally recognized that parents are the surrogate decision
makers who should determine the goals of care for their
newborn child. Decisions regarding lifesaving treatment should
emphasize what is believed to be best for the newborn and are
greatly impacted by the provided expertise of knowledgeable
health care providers.55 Some recent legislative dictums
have emphasized an imperative toward resuscitation for any
liveborn infant.56 Such imperatives are likely to evolve over
time. Providers should be proactive in knowledge of current
institutional, local, and national regulatory norms. Every effort
should be made to utilize up-­to-­date locally relevant outcome
data. It is important to note that health care providers tend to
be pessimistic about outcomes based solely on recollections of
their experience and subjective reasoning.57
Clinicians can assist parents by providing (1) technical
information (evidence-­ based outcome data, prognostic
information), (2) individual clinical information (specific data
regarding their newborn), and (3) theoretical background
(ethical guidelines, local experience). It is crucially important
to remember that parents bring profound emotional and
psychological investment to their comprehension and decision-­
making processes. They also often lack technical expertise
needed to evaluate outcome data and convert that into a risk/
benefit framework that is consistent with their values. Finally,
parents typically bring powerful instincts to advocate for
treatment, no matter how futile. The phenomenon of selective
listening is common. If possible, written documentation of key
concepts for future reference and discussion may be helpful. In
rare circumstances when clinical providers and parents come
into conflict about resuscitation, involvement of an institutional
ethics committee may be helpful. Legal remedies should be a
last resort. 
Ethics and Moral Distress
Though decisions about resuscitation should ideally be
individualized to each circumstance and family, ethical
frameworks can provide an important foundation. The Nuffield
1416 Part 6  The Neonate
Council on Bioethics report “Critical Care Decisions in Fetal and
Neonatal Medicine: Ethical Issues” published in 200658 remains
one of the most comprehensive, although some evolution of
thought regarding the precise threshold of viability has ensued
since the time of publication. The cornerstone ethical principles
of medical care, autonomy, beneficence, nonmaleficence, and
justice remain relevant and should be a starting point.
We have already emphasized the importance of collaboration
between neonatal and obstetric providers. Nonetheless, moral
distress, the ethical confrontation between a plan of care and
one’s own ethical principles, can occur despite best efforts to
achieve consensus. This is most likely to occur when providers
on the same care team have differing personal values and
moral principles. Education and communication in the form of
debriefing sessions, workshops, and ethics training are important
tools to ensure that the resilience and optimal functionality of
the health care team.59 There is no formula or guideline that can
be consistently applied to each clinical situation. Clinicians will
benefit their patients and families by taking time to consider the
large body of literature focused on care of the periviable infant,
while listening carefully to each family. It is also important to
emphasize that clinical decision making regarding care for the
periviable infant does not end in the delivery room. Several
complications of prematurity listed in Table 73.4 may present
in devastating fashion during the hours and days following
delivery, most notably severe IVH, bowel perforation, and
respiratory failure with air leak. For an extreme preterm infant,
transitioning from delivery room to NICU is the beginning of a
long medical journey taking from months to years.  The presence of fluid in the fissures is a common nonspecific
Respiratory Problems
No aspect of the transition from fetal to neonatal life is more
dramatic than the process of pulmonary adaptation. In a
normal term infant, the lungs expand with air, pulmonary
vascular resistance rapidly decreases, and vigorous, consistent
respiratory effort ensues within a minute of separation
from the placenta. The process is dependent upon crucial
physiologic mechanisms including production of functional
surfactant, dilatation of high-­resistance pulmonary arterioles,
bulk transfer of fluid from airspaces, and physiologic closure
of the ductus arteriosus and foramen ovale. Complications
such as prematurity, infection, neuromuscular disorders,
developmental defects, or complications of labor may interfere
with the transition to normal neonatal respiratory function.
Below, common respiratory problems of neonates are reviewed.
Transient Tachypnea of the Newborn
Definition
Transient tachypnea of the newborn (TTN), commonly known
as “wet lungs,” is a mild condition affecting term and late
preterm infants. This is the most common “respiratory cause” of
admission to the special care nursery. Transient tachypnea of the
newborn is self-­limiting, with no risk of recurrence or residual
pulmonary dysfunction. It rarely causes hypoxic respiratory
failure secondary to persistent pulmonary hypertension of the
newborn.60  usually given IV fluids and not fed orally until their tachypnea
Pathophysiology
During the last trimester, a series of physiological events lead to
changes in the hormonal milieu of the fetus and its mother to
facilitate neonatal transition. Rapid clearance of fetal lung fluid
is essential for successful transition to air breathing. The bulk
of this fluid clearance is mediated by transepithelial sodium
reabsorption through amiloride-­sensitive sodium channels in
the respiratory epithelial cells.61 The mechanisms for such an
effective “self-­resuscitation” soon after birth are not completely
understood. Traditional explanations based on Starling forces
and vaginal squeeze for fluid clearance account only for a
fraction of the fluid absorbed. 
Risk Factors
This condition is classically seen in infants delivered late
preterm/early term, especially after cesarean birth before the
onset of spontaneous labor. Absence of labor is accompanied
by impaired surge of endogenous steroids and catecholamines
necessary for a successful transition. Additional risk factors such
as multiple gestations, excessive maternal sedation, prolonged
labor, and complications resulting from excessive maternal fluid
administration have been less consistently observed. 
Clinical Presentation
The clinical features of TTN include a combination of grunting,
tachypnea, nasal flaring, and mild intercostal and subcostal
retractions along with mild central cyanosis. The grunting
can be prominent and sometimes misdiagnosed as respiratory
distress syndrome secondary to surfactant deficiency. The
chest x-­ray usually shows prominent perihilar streaking that
represents engorged pulmonary lymphatics and blood vessels.
finding. Clinical symptoms rapidly improve in the first 24–48
hours after birth. TTN is a diagnosis of exclusion, and it is
important that other potential causes of respiratory distress in
the newborn be excluded. The differential diagnosis of TTN
includes pneumonia/sepsis, air leaks, surfactant deficiency, and
congenital heart disease. Other rare diagnoses are pulmonary
hypertension, meconium aspiration, and polycythemia.62 
Diagnosis
This is primarily a clinical diagnosis. Chest x-­rays typically
demonstrate mild pulmonary congestion, with hazy lung
fields. The pulmonary vasculature may be prominent. Small
accumulations of extrapleural fluid, especially in the minor
fissure on the right side, may be seen. Ultrasound of the lung is
increasingly used to diagnose TTN.63 
Management
Prenatal prevention strategies include antenatal betamethasone
prior to late preterm infant birth and elective cesarean birth
between 37 and 39 weeks. This intervention decreases all
common causes of neonatal respiratory morbidities; however,
potential long-­term adverse effects of this intervention need
to be closely monitored.64,65 Current American Academy of
Pediatrics (AAP) guidelines66 recommending scheduling of
elective cesarean births after 39 completed weeks of gestation
should significantly reduce the incidence of TTN. Postnatal
management is mainly supportive. Supplemental oxygen is
provided to keep the O2 saturations greater than 90%. Infants are
resolves. Rarely, infants may need continuous positive airway
pressure to relieve symptoms. Diuretic therapy is not effective;
fluid restriction and inhaled beta-­agonists (salbutamol) have
been tried with limited success.67,68

A: TTN
Figure 73.2  Chest x-­ray appearance of transient tachypnea of the newborn (TTN) (A) and respiratory distress syndrome (RDS) (B). The radiographic
characteristics of TTN include perihilar densities with good aeration, bordering on hyperinflation. In contrast, neonates with RDS have diminished
lung volumes on chest x-­ray reflecting atelectasis associated with surfactant deficiency. Diffuse “ground glass” infiltrates along with air bronchograms
make the cardiothymic silhouette indistinct.
Neonatal Implications
TTN can contribute to significant morbidity related to delayed
initiation of oral feeding, which may in turn interfere with
parental bonding and establishment of successful breastfeeding.
The hospital stay is prolonged for mother and infant. Recently,
studies have found an association between TTN and wheezing/
asthma in later childhood60 (Fig. 73.2).  gestational age at rupture and delivery and parental wishes
Pulmonary Hypoplasia
Lung development begins during the first trimester when the
ventral foregut endoderm projects into adjacent splanchnic
mesoderm (see Chapter 3). Branching morphogenesis, epithelial
differentiation, and acquisition of a functional interface for gas
exchange ensue through the remainder of gestation and are
not completed until the second or third year of postnatal life.
Clinical conditions associated with pulmonary hypoplasia and
approaches to prevention and treatment are discussed here.
Perturbation of lung development at any time during
gestation may lead to clinically significant pulmonary
hypoplasia. Two general pathophysiologic mechanisms
contribute to pulmonary hypoplasia: extrinsic compression
(e.g., congenital diaphragmatic hernia) and neuromuscular
dysfunction (e.g., myotonic dystrophy). There is no gold
standard clinical diagnostic method to diagnose pulmonary
hypoplasia. Computed tomography (CT) is commonly used to
confirm the clinical suspicion. Postmortem pathological criteria
such as lung weight to body weight and radial alveolar count
have been used in clinical research.69
Oligohydramnios, whether due to periviable preterm
prelabor rupture of membranes (pPROM) or diminished
fetal urine production (renal agenesis), can lead to severe
pulmonary hypoplasia. pPROM in the periviable period
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1417
B: RDS
occurs during the canalicular phase of fetal lung development
and drives pulmonary hypoplasia. Prediction of clinical
outcome is difficult in these infants. The reduction in
branching morphogenesis and surface area for gas exchange
may be lethal or clinically imperceptible. The degree of
pulmonary hypoplasia and neonatal survival depend on
for resuscitation. In a recent review, Gibson and colleagues
reported significant mortality risk in infants born to women
with periviable (20–25 weeks) PROM and oligohydramnios.
Therapeutic interventions such as amnioinfusion and
resealing technologies do not currently show benefit and are
undergoing further investigation.70
The degree of pulmonary hypoplasia in congenital
diaphragmatic hernia (CDH) is directly related to the extent
of herniation. Large hernias occur earlier in gestation. In most
cases, the contralateral lung is also hypoplastic.71 Recent studies
document some degree of catch-­ up lung growth following
delivery. The interplay of the three salient pathophysiologic
processes in CDH (pulmonary hypoplasia, pulmonary
hypertension, and ventricular dysfunction) determines the
baby’s survival. Prenatal diagnosis of pulmonary hypoplasia is
discussed in Chapter 22.
Postnatal treatment for pulmonary hypoplasia is largely
supportive. A subset of infants with profound hypoplasia will
have insufficient surface area for effective gas exchange. These
patients typically display profound hypoxemia, respiratory
acidosis, pneumothorax, and pulmonary interstitial emphysema
shortly after delivery. At the other end of the spectrum, some
infants will have no clinical evidence of pulmonary insufficiency
at birth but have diminished reserves when stressed. In between
is a cohort of patients with respiratory insufficiency responsive
to mechanical ventilation and pharmacologic support. Typically,
1418 Part 6  The Neonate
these patients have adequate oxygenation and ventilation,
suggesting adequate gas exchange capacity. However, many
develop pulmonary hypertension. The pathophysiologic
sequence begins with limited cross-­sectional area of resistance
arterioles, followed by smooth muscle hyperplasia in these same
vessels.
Early use of pulmonary vasodilators such as nitric oxide
is the mainstay of management for increased pulmonary
vasoreactivity. Optimizing pulmonary blood flow reduces the
potential for hypoxemia thought to stimulate pathologic medial
hyperplasia. If oxygenation, ventilation, and acid-­base balance
are maintained, nutritional support over time can allow sufficient
lung growth to support the infant’s metabolic demands. In many
cases the process is lengthy, requiring mechanical ventilation
and treatment with pulmonary vasodilators such as sildenafil,
bosentan, prostaglandin E1, epoprostenol, or treprostinil for
weeks to months. Prenatal prognostic indicators for CDH
such as percentage predicted lung volume and lung-­head ratio
measurements on fetal magnetic resonance imaging (MRI) are
useful for guiding management and parental counseling.72  weeks’ gestation with a high risk for preterm delivery within
Respiratory Distress Syndrome
Respiratory distress syndrome (RDS) is a significant cause of
early neonatal mortality and long-­term morbidity. However,
in the last 3 decades, significant advances have been made
in its management with a consequent decrease in associated
morbidity and mortality.
Perinatal Risk Factors
The classic risk factors for RDS are prematurity and low birth
weight. In 2017, according to Vermont Oxford Network the
incidence of RDS was around 80% at 28 weeks increasing up
to 90% at 24 weeks. Factors that negatively affect surfactant
synthesis include maternal diabetes, perinatal asphyxia,
cesarean delivery without labor, and genetic factors (Caucasian
race, history of RDS in siblings, male sex, and surfactant
protein B deficiency).73 Congenital malformations that lead
to lung hypoplasia such as CDH or giant omphalocele are also
associated with significant surfactant deficiency. 
Prenatal Assessment of Fetal Lung Maturity and
Treatment
The need for assessing fetal lung maturity was considered
critical in timing delivery of high-­risk pregnancies to minimize
respiratory morbidity associated with immature lungs. There
were a number of biochemical, functional, and physical
lung maturity tests performed on amniotic fluid obtained by
amniocentesis or from pooled vaginal secretions after rupture
of the membranes; however, none of them individually or
collectively had a clinically significant sensitivity or specificity
to detect lung maturity.74 The most widely used tests were
lamellar body count (LBC), the L/S ratio, and PG test
(phosphatidylglycerol). The less commonly used tests were
surfactant/albumin ratio (TDx FLM), foam stability test, and
lung profile. Studies found that neonates delivered late preterm
despite mature fetal lung testing were at increased risk for RDS,
hyperbilirubinemia, and hypoglycemia; hence, recent American
College of Obstetricians and Gynecologists (ACOG) and
Society for Maternal-­Fetal Medicine (SMFM) guidelines cite the
unreliability of these tests and advised clinicians to discontinue
the practice of performing routine amniocentesis for fetal lung
maturity testing in suboptimally dated and medically indicated
or nonmedically indicated early deliveries.75,76
Quantitative ultrasound (quantusFLM) is a new technique
increasingly used to detect fetal lung texture to predict lung
maturity.77 The fetal lung is visualized at the level of the
four-­chamber cardiac view and images uploaded to a cloud-­
based database where it is quickly analyzed, and results are
transmitted back. This technique has been validated in a large
prospective multicenter study to have reliable (reproducible)
and accurate results comparable to prior invasive methods.78
Magnetic resonance imaging and MRI spectroscopy are being
investigated to measure lipid content of amniotic fluid but not
clinically used due to high cost and maternal discomfort while
obtaining images.
Antenatal steroids (ANS) are the most effective prenatal
intervention to mature fetal lungs and reduce associated neonatal
morbidity and mortality.79 The most popular treatment is to use
a 1:1 mixture of betamethasone phosphate and betamethasone
acetate (Celestone) in pregnant women between 24 and 34
7 days. A single rescue course is recommended for threatened
preterm birth if >7 days after a previous full course of steroids.
The use of ANS has now expanded to threatened late preterm
births (34–37 weeks) and to elective cesarean delivery without
labor at term to reduce respiratory morbidity. Betamethasone
and dexamethasone have been compared in well-­designed large
trials and found to be equally effective with no difference in
neurosensory impairment at 2 years.80,81
More recently, potential long-­term adverse effects of ANS
have been shown in both animals and human epidemiological
studies. Large cohort studies from Finland and Canada have
shown an increase in behavioral-­emotional and psychological
development effects, anxiety, and depression in long-­ term
follow-­up studies of infants who received ANS.82 To reduce
ANS exposure, investigations are currently ongoing to examine
a lower dose of betamethasone (full dose versus half dose) and
to evaluate betamethasone acetate alone to reduce the peak
concentrations obtained when combined with betamethasone
phosphate.83 
Clinical Presentation of RDS
Symptoms are typically evident in the delivery room, or shortly
thereafter, including tachypnea, nasal flaring, subcostal and
intercostal retractions, cyanosis, and expiratory grunting.
The characteristic expiratory grunt is secondary to expiration
through a partially closed glottis, providing continuous
distending airway pressure to maintain functional residual
capacity (thereby preventing alveolar collapse). These signs
of respiratory difficulty are not specific to RDS and can occur
from a variety of pulmonary and nonpulmonary causes such
as transient tachypnea, air leaks, congenital malformations,
hypothermia, hypoglycemia, anemia, polycythemia, or metabolic
acidosis. Progressive worsening of symptoms in the first 2–3
days followed by recovery characterizes the typical clinical
course. This timeline (curve) is modified by administration
of exogenous surfactant with a more rapid recovery. Classic
radiographic findings include low-­volume lungs with a diffuse
reticulo-­
granular pattern and air bronchograms. Point-­ of-­
care lung ultrasound is being increasingly used in Europe to
diagnose and determine severity of RDS.84,85 The diagnosis can
be established chemically by measuring surfactant activity in
tracheal or gastric aspirates, but this is not routinely done.83,86

Management Principles
General Measures. Infants are managed in an incubator or
under a radiant warmer in a neutral thermal environment to
minimize oxygen requirement and consumption. Arterial oxy-
gen tension (PaO2) is maintained between 50 and 80 mm of
mercury with saturations between 90% and 95%. Hypercarbia
and hyperoxia are avoided. Heart rate, blood pressure, respira-
tory rate, and peripheral perfusion are monitored closely. As
sepsis cannot be excluded, screening blood culture and com-
plete blood counts with differential counts are performed and
infants are started on broad-­spectrum antibiotics for 48 hours,
until culture results are available.  mittent positive ventilation (SNIPPV) and heated humidified
Surfactant Therapy. Surfactant replacement is one of the safest
and most effective interventions in neonatology. The first suc-
cessful clinical trial of surfactant use was reported in 1980 using
surfactant prepared from an organic solvent extract of bovine
lung to treat 10 infants with RDS.87 By the early 1990s, widespread
use of surfactant led to a progressive decrease in RDS-­associated
mortality. Three strategies for treatment are commonly used: (1)
prophylactic surfactant, in which surfactant is administered via
endotracheal tube before the first breath to all infants at risk of
developing RDS; (2) rescue therapy, where surfactant is given
via endotracheal tube after the onset of respiratory signs; and
(3) minimally invasive methods of surfactant administration for
infants on noninvasive ventilation.88 The advantages of prophy-
lactic administration include a better distribution of surfactant
when instilled into a partially fluid-­filled lung along with the
potential to decrease trauma related to resuscitation. Avoiding
treatment of unaffected infants and related cost savings are the
advantages of rescue therapy. Less-­invasive methods of surfac-
tant administration include nebulization, instillation into the
pharynx before the first breath, and administration via laryn-
geal mask or thin catheter. The thin catheter method allows the
instillation of surfactant into a spontaneously breathing infant
(better surfactant distribution), without the disruption of nasal
continuous positive pressure, and potentially avoids positive
pressure–induced lung injury.89 Biologically active surfactant
can be prepared from bovine, porcine, human, or synthetic
sources. When administered to patients with surfactant defi-
ciency and RDS, all of these preparations show improvement
in oxygenation and a decreased need for ventilator support,
along with decreased air leaks and death. The combined use of
antenatal corticosteroids, noninvasive ventilation, and postnatal
surfactant has significantly improved neonatal outcomes.
Continuous Positive Airway Pressure. In infants with acute
RDS, continuous positive airway pressure (CPAP) prevents atel-
ectasis, minimizes lung injury, and preserves surfactant function,
allowing infants to be managed without endotracheal intubation
and mechanical ventilation. Early delivery room CPAP therapy
decreases the need for mechanical ventilation and the incidence
of long-­term pulmonary morbidity.90,91 Increasing use of CPAP
has led to decreased use of surfactant and decreased BPD. Com-
mon complications of CPAP include pneumothorax and pneu-
momediastinum. Rarely, the increased transthoracic pressure
leads to progressive decrease in venous return and decreased
cardiac output. Brief intubation and administration of surfac-
tant followed by transition to CPAP (InSurE technique) is an
additional RDS treatment strategy increasingly used in Europe
and Australia.92 Recently, the advantages of CPAP have been
combined with less-­invasive surfactant administration (LISA)
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1419
and have led to reduced need for mechanical ventilation and
BPD.93 Prospective, randomized trials in extremely-­low-­birth-­
weight infants comparing early delivery room CPAP versus
early prophylactic surfactant therapy demonstrate equivalency
as defined by death or bronchopulmonary dysphasia. Three
meta-­analyses of these trials support the superiority of delivery
room CPAP in reducing BPD.94 These findings led to the recom-
mendation by the European Association of Perinatal Medicine
and AAP to endorse delivery room CPAP as the primary mode
of respiratory support for treating RDS.95 Noninvasive respi-
ratory support techniques such as synchronized nasal inter-
high-­flow nasal cannula have been shown to be equally effective
as nasal CPAP in primary support for RDS in recent noninferi-
ority clinical trials.96–98
Mechanical Ventilation. The goal of mechanical ventilation
is to limit lung injury (volutrauma and barotrauma) without
causing progressive atelectasis while maintaining adequate
oxygenation and gas exchange. Recent evidence suggests that
volume-­targeted intermittent mandatory ventilation and high-­
frequency oscillators cause the least amount of iatrogenic lung
injury. Complications associated with mechanical ventilation
include pulmonary air leaks, endotracheal tube displacement or
dislodgement, obstruction, infection, and long-­term complica-
tions such as BPD and subglottic stenosis. 
Complications of RDS
Acute complications include pneumothorax, pneumomediasti-
num, pneumopericardium, and pulmonary interstitial emphy-
sema. The incidence of these complications has decreased
significantly with surfactant treatment. Infection, intracranial
hemorrhage, and patent ductus arteriosus occur more fre-
quently in very-­low-­birth-­weight infants with RDS. Long-­term
complications and comorbidities include BPD, poor neurode-
velopmental outcomes, and retinopathy of prematurity. Inci-
dence of these complications is inversely related to decreasing
birth weight and gestation. Studies of early inhaled nitric oxide
and supplementary inositol for prevention of long-­term BPD
failed to demonstrate significant effectiveness.99,100 
Bronchopulmonary Dysplasia
The classic form of BPD was first described101 in a group of
preterm infants who were mechanically ventilated at birth
and who later developed chronic respiratory failure with
characteristic radiographic findings on chest x-­ray. These infants
were larger, late-­preterm infants with lung changes attributed
to mechanical ventilation and oxygen toxicity. More recently,
smaller, extremely preterm infants with lung immaturity and
prenatal exposure to antenatal glucocorticoids have developed
a more subtle form, labeled the “new BPD.”102 This disease now
primarily occurs in infants less than 1000 g who have very
mild or no initial respiratory distress. The clinical diagnosis
is currently based on the need for supplemental oxygen at 36
weeks’ corrected gestational age.100,103 Recently diagnostic
criteria have been revised to improve prediction of childhood
respiratory morbidity based on mode of respiratory support at
36 weeks’ gestational age, irrespective of the level or duration
of oxygen therapy.104 Advances in pulmonary imaging are now
guiding risk stratification to predict development of BPD and to
formulate treatment strategies.105
1420 Part 6  The Neonate
Proinflammatory
Chorioamnionitis Resuscitation
Preterm
Transitional
fetal
lung
lung
Antenatal
Indomethacin
corticosteroids
Antiinflammatory
Figure 73.3  This schematic diagram depicts interaction between treatment and proposed inflammation in the pathogenesis of bronchopulmonary
dysplasia (BPD).
Clinically, the transition from RDS to BPD is subtle and
gradual. Radiographic manifestations of classic BPD include
areas of shifting focal atelectasis and hyperinflation with or
without parenchymal cyst formation. Chest x-­rays of infants
with the new BPD show bilateral haziness reflecting diffuse
microatelectasis without multiple cystic changes. These changes
lead to ventilation-­perfusion mismatching and increased work
of breathing. Preterm infants with BPD either gradually wean
off respiratory support and oxygen or continue to worsen
with progressively severe respiratory failure, pulmonary
hypertension, and a high mortality risk.
Pathophysiology
Risk factors predisposing preterm infants to BPD include
extreme prematurity, oxygen toxicity, mechanical ventilation,
and inflammation (prenatal and postnatal). The pathological
findings characterized by severe airway injury and fibrosis in
the old BPD have been replaced in the new BPD with large
simplified alveolar structures, impaired capillary configuration,
and variable degrees of interstitial cellularity and/or
fibroproliferation.106 Airway and vascular abnormalities tend to
be associated with more severe disease.
Oxygen-­induced lung injury is an important contributing factor.
Exposure to oxygen in the first two weeks of life and as chronic
therapy has been associated in clinical studies with the severity of
BPD.107,108 Similarly, in animal models, hyperoxia has been shown
to mimic many of the pathological findings of BPD. As there are
potential benefits and harm of hyperoxemia and hypoxemia,
effects of targeting two different saturation ranges from birth have
been studied in multiple clinical trials. Meta-­analysis revealed no
difference in BPD rates; however, assignment to a higher target
range reduced the risk of death and severe necrotizing enterocolitis
but increased the risk of treated retinopathy.109
Concerns regarding oxygen toxicity are reflected in the most
recent update of the neonatal resuscitation guidelines. Blended
oxygen (30%) or, if not available, room air is now recommended
for initial resuscitation of preterm infants in the delivery room,
along with continuous monitoring via pulse oximetry.110
Mechanical Sepsis
Oxygen
ventilation pneumonia
Altered
Preterm
lung
postnatal
development
lung
and BPD
Postnatal
corticosteroids
Barotrauma and volutrauma associated with mechanical
ventilation have been identified as major factors causing lung
injury in preterm infants. Surfactant replacement therapy is
beneficial in decreasing symptoms of RDS and improving survival.
The efficacy of surfactant to decrease the incidence of subsequent
BPD is less well established. Chronic inflammation and edema
associated with positive-­ pressure ventilation cause surfactant
protein inactivation leading to decreased lung compliance and
need for higher positive pressures. Newer ventilation strategies
have been developed to reduce lung injury and optimize repair
and lung growth.111 As intrauterine inflammation is increasingly
recognized as a cause of preterm parturition, antenatal
inflammation is gaining more attention in the pathogenesis of
BPD and other morbidities of prematurity. Chorioamnionitis has
been shown to be strongly associated with impaired pulmonary
and vascular growth, a typical finding in the new BPD.
Most deliveries before 30 weeks’ gestation are associated with
histological chorioamnionitis, which except for preterm initiation
of labor is otherwise clinically silent. The more preterm the
delivery, the more often histological chorioamnionitis is detected.
Increased levels of proinflammatory mediators in amniotic fluid,
placental tissues, tracheal aspirates, lung, and serum of extremely-­
low-­birth-­weight preterm infants support an important role
for both intrauterine and extrauterine inflammation in the
development and severity of BPD. The proposed interaction
between the proinflammatory and antiinflammatory influences
on the developing fetal and preterm lung is detailed in Fig. 73.3.
Several animal models and preterm studies demonstrate that
mediators of inflammation including endotoxins, tumor necrosis
factor, interleukin (IL)-­1, IL-­6, IL-­8, and transforming growth
factor alpha can enhance lung maturation but concurrently
impede alveolar septation and vasculogenesis, contributing
to the development of BPD.112–114 Chorioamnionitis alone is
associated with BPD, but the probability is increased when these
babies receive a second insult such as mechanical ventilation or
postnatal infection.5,102,115,116
Maternal genital mycoplasma infection, particularly with
Mycoplasma hominus and Ureaplasma urealyticum, is associated
 73  Neonatal Morbidities of Prenatal and Perinatal Origin 1421

with preterm delivery and BPD. The pulmonary microbiome

is emerging as an important factor in the pathophysiology of TABLE Bronchopulmonary Dysplasia Prevention
73.6 Strategies
BPD as studies reveal differences in airway microbiome in
preterm infants with and without BPD. Numerous studies have Relative Evidence/
isolated these organisms from amniotic fluid and placentas in Intervention Effectivenessa Quality of Data
women with spontaneous preterm birth (preterm birth due to Antenatal steroids + Strong
preterm labor or pPROM). Following birth, these organisms Early delivery room ++ Strong
are known to colonize and elicit a proinflammatory response surfactant
in the respiratory tract leading to BPD. Preliminary evidence Surfactant mixed with +++ Minimal
budesonide
suggests azithromycin therapy in preterm infants colonized
Less invasive surfactant ++ Moderate
with ureaplasma reduces a combined outcome of BPD and administration
death.117 Additional, more rigorous study is needed before Early caffeine ++ Moderate
broadly recommending this as an established practice. Postnatal systemic steroid ++ Moderate
The unpredictable variation in the incidence of BPD, despite Vitamin A + High
Antioxidants -­-­ Moderate
adjusting for low birth weight and prematurity, suggests a Permissive hypercapnia +++ Minimal
genetic predisposition to the occurrence and the severity of BPD. Fluid restriction ++ Moderate
Expression of genes critical to surfactant synthesis, vascular High-­frequency ventilation +/-­ Moderate
development, and inflammatory regulation are likely to play Delivery room ++++ Moderate
a role in the pathogenesis of BPD. Twin studies have recently management
Inhaled nitric oxide + Moderate
shown that the BPD status of one twin, even after correcting for Early use of continuous +++ Strong
contributing factors, is a highly significant predictor of BPD in positive airway pressure
the second twin. In this cohort, after controlling for covariates, Stem cell–based therapies ++ Minimal
genetic factors accounted for 53% of the variance in the liability Azithromycin prophylaxis ++ Minimal
for BPD. Genetic polymorphisms in the inflammatory response aRelative
effectiveness of each intervention to reduce the severity of
are increasingly recognized as important in the pathogenesis bronchopulmonary dysplasia. The range of symbols from – through
of preterm parturition (see Chapter 7) and may be similarly ++++ is based on published literature and clinical experience.
important in the genesis of inflammatory morbidities in the
preterm neonate as well.118 
exposure to high levels of oxygen, and infection prevention.
Long-­Term Complications Table 73.6 enumerates current strategies and their relative
Infants with BPD have significant pulmonary sequelae during effectiveness to prevent BPD.126 Large, controlled clinical
childhood and adolescence. Impaired lung function has trials and meta-­analyses have not consistently demonstrated
been identified in both old and new BPD survivors. Reactive a significant impact of these pharmacological and nutritional
airway disease occurs more frequently with increased risk of interventions. The multifactorial nature of BPD suggests that
bronchiolitis and pneumonia. A recent follow-­up study showed targeting individual pathways is unlikely to have a significant
significant airway obstruction in infancy that persisted at age effect on outcome. Strategies to address several pathways
24 years.119 Among preterm infants born at less than 29 weeks’ simultaneously are more promising. 
gestation, a large, multicenter study identified important
perinatal risk factors, including male gender, intrauterine Meconium-­Stained Amniotic Fluid and
growth restriction, maternal smoking, race/ethnicity, intubation Meconium Aspiration Syndrome
at delivery, and public insurance, to predict respiratory outcome
at 1 year of age.120 The significance and management of meconium-­stained amni-
BPD is an independent predictor of adverse neurological otic fluid (MSAF) have evolved with time. Meconium is pres-
outcomes. Infants with BPD exhibit lower average IQs, academic ent in the fetal intestine by the second trimester. Maturation of
difficulties, delayed speech and language development, impaired intestinal smooth muscle and the myenteric plexus progresses
visual-­motor integration, and behavior problems. Sparse data through the third trimester. Thus intrauterine passage of meco-
also suggest an increased risk for attention deficit disorders nium is unusual before 36 weeks and does not typically occur
and memory and learning deficits. Delayed growth occurs in for several days following preterm delivery. The physiologic
30%–60% of infants with BPD at 2 years. The degree of long-­ stimuli for passage of meconium are still incompletely under-
term growth delay is inversely proportional to birth weight and stood. Clinical experience and epidemiologic data suggest that
directly proportional to the severity of BPD.  a stressed fetus may pass meconium prior to birth. Infants born
through meconium-­stained amniotic fluid are likely to have
Prevention Strategies lower pH and be associated with nonreassuring fetal heart trac-
Several strategies to decrease the incidence of BPD have been ings. Meconium-­stained amniotic fluid at delivery occurs in
tried, including administration of surfactant in the delivery 4%–22% of all deliveries and occurs more frequently in post-
room, less invasive modes of surfactant administration,121 term gestation.127
administering surfactant mixed with budesonide,122 In contrast to MSAF, meconium aspiration syndrome
mesenchymal stem cells,123 early caffeine therapy,124 antioxidant (MAS) is a clinical diagnosis that, by definition, includes
superoxide dismutase, long-­chain polyunsaturated fatty acid delivery through MSAF along with respiratory distress and a
(LCPUFA)125 and vitamin A supplementation, optimizing characteristic chest x-­ray appearance. Approximately 1%–2%
fluid and parenteral nutrition, aggressive treatment of patent of deliveries with MSAF are complicated by MAS, but the
ductus arteriosus, minimizing mechanical ventilation, limiting reported incidence varies widely. The severity of the syndrome
1422 Part 6  The Neonate
is also variable. The hallmarks of severe disease are the need for
positive-­pressure ventilation and the presence of pulmonary
hypertension. Severe meconium aspiration is associated with
significant mortality and morbidity risk, including air leak,
chronic lung disease, and developmental delay.
Pathophysiology
It was believed that partial or complete airway obstruction was
the primary pathophysiological mechanism for MAS. This led to
an aggressive recommendation for perinatal airway suctioning
by obstetricians and neonatologists that was practiced from
the 1970s to 2005. However, airway obstruction is now
considered to be only one component of the multiple factors
leading to a clinical picture of MAS. Pulmonary hypertension
is a major complication of MAS. In addition, surfactant
inactivation and lung inflammation secondary to direct effects
of meconium contribute to the severity of MAS. Prevention
strategies during pregnancy include induction of labor at 41
weeks to prevent MSAF associated with postterm gestation.
A recent systematic review demonstrated fewer cases of MAS
and cesarean deliveries with induction at 41 weeks compared
with expectant management.128 Amnioinfusion to dilute thick
meconium did not affect the incidence of MAS or perinatal
morbidity in settings of appropriate peripartum surveillance.129
Prophylactic antibiotics administered to mother decrease risk
of chorioamnionitis but do not reduce the incidence of neonatal
sepsis or neonatal intensive care admissions.
Strategies to prevent MAS in the peripartum period
included suctioning of the mouth, nose, and nasopharynx
before delivery of the shoulders by the obstetricians
and elective intubation and suctioning of the trachea by
neonatologists both in vigorous and depressed newborns. In
2004 a large, randomized trial in term infants with MSAF
did not show a difference in MAS and need for mechanical
ventilation between infants who had intrapartum suctioning
compared to no suctioning.130 This trial led to the elimination
of peripartum suctioning from all international professional
guidelines. Similarly, a 2000 seminal study by Wiswell and
associates showed no difference in incidence of MAS, need
for mechanical ventilation, and mortality in vigorous infants
at birth, between infants randomized to elective intubation
and suctioning compared to expectantly managed infants.131
Following this study, postnatal endotracheal intubation and
suctioning of vigorous infants was no longer recommended
and was advocated only for depressed infants by International
Liaison Committee on Resuscitation (ILCOR). In 2015, ILCOR
and AAP further modified recommendations following
the publication of two small, randomized controlled trials
evaluating the impact of endotracheal suctioning in depressed
infants. Both studies showed no difference in the incidence
of MAS, mechanical ventilation, or mortality.132 Currently
the guidelines recommend against routine endotracheal
suctioning for both vigorous and depressed infants following
birth after MSAF.1 The delay in instituting positive-­pressure
ventilation after birth may cause more harm than benefit.
Personnel skilled in establishment of ventilation and airway
patency should attend any infant expected to be depressed at
delivery. It is interesting to note that the incidence of MAS has
clearly decreased in several centers over the past several years,
perhaps as a consequence of improvements in obstetrical
assessment and management. Our center has also experienced
a decline in MAS while concurrently pursuing a policy of
no routine tracheal suctioning for infants born through
meconium-­stained amniotic fluid.
Prevention and treatment of severe MAS has dramatically
improved in recent years, leading to decreases in neonatal
morbidity and mortality. A collaborative approach between
obstetrician and neonatologist is paramount. Therapy is
primarily directed at managing hypoxemia and respiratory
failure. Significant advances have emerged to treat pulmonary
hypertension with selective pulmonary vasodilators including
inhaled nitric oxide, sildenafil, and bosentan. These agents
not only improve oxygenation but also allow less injurious
ventilator strategies with reduced subsequent morbidity from
air leak and chronic lung disease. Early exogenous surfactant
administration is another useful treatment modality.
Antibiotics and steroids are selectively used despite no
demonstrated effectiveness.
Persistent Pulmonary Hypertension of
the Newborn
Persistent pulmonary hypertension of the newborn (PPHN)
is one of the main causes of neonatal morbidity and mortality.
Its incidence is ∼2/1000 live births in term and late preterm
infants. At delivery, the normal transition from fetal to neonatal
pulmonary circulation is mediated by a rapid, dramatic
decrease in pulmonary vascular resistance (PVR) and increase
in systemic vascular resistance (SVR) following cord clamping.
A series of coordinated events are involved to achieve an 8-­to
10-­fold increase in pulmonary blood flow including effective
clearance of lung fluid, lung aeration, oxygenation, ventilation,
and reversal of blood flow across the ductus and foramen ovale.
Failure to achieve this transition leads to persistence of high
PVR leading to PPHN. This entity is associated with multiple
etiologies primarily related to two underlying mechanisms,
pulmonary arteriolar vasoconstriction and vascular structural
remodeling. The etiologies are classified into four main
categories: (1) idiopathic (abnormally remodeled pulmonary
vasculature), (2) lung parenchymal disease (MAS, pneumonia/
sepsis), (3) abnormal transition at birth (TTN, RDS, perinatal
asphyxia), and (4) congenital lung malformation (CDH,
pulmonary hypoplasia).133 There are additional perinatal risk
factors for PPHN such as maternal drug exposure to SSRIs/
NSAIDs, maternal smoking, and uncontrolled maternal
diabetes. The underlying mechanism for the above associations
are not clearly understood.
First principles of management include addressing the
underlying etiology and treating accompanying hypoxemia
and respiratory failure. Optimal oxygenation and ventilation
through elimination of ventilation-­ perfusion mismatch is
critical. When positive-­ pressure ventilation is employed,
overdistention is avoided by focusing on preductal rather than
postductal oxygen saturations to reduce the risk of lung injury
and remodeling. Treatment of pulmonary hypertension has
been advanced by pharmacologic interventions that specifically
reduce pulmonary vascular resistance. Nitric oxide is the best
studied, with clear evidence of efficacy in term and late preterm
infants. Clinical experience with other pulmonary vasodilators
including sildenafil, bosentan, milrinone, and prostacyclin is
increasing, and they are used in certain clinical situations as
adjuvant therapy.133 Recent progress in understanding PPHN
pathophysiology in animal models has led to targeted novel
therapies currently being evaluated in clinical trials.

Gastrointestinal Problems in Neonatal
Period
Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is a devastating complication of
prematurity and the most common gastrointestinal emergency
in the neonatal period. It affects 1% to 5% of all infants admitted
to a neonatal intensive care unit (NICU).134–137 The reported
incidence is 4% to 13%138–141 in very-­low birth-­weight infants
(<1500 g). It is characterized by intestinal inflammation that
can progress to transmural necrosis and perforation. Disease
onset has an inverse relationship with gestational age, with
earlier preterm infants presenting at an older postnatal age,142
and a peak incidence at 32 corrected weeks’ gestation. Mortality
related to NEC ranges from 10% to 30% in all cases and up to
50% for infants requiring surgery.138,143–146 As more preterm
and low-­birth-­weight infants survive the initial days of life,35
the number of infants at risk of NEC has increased, though in
recent years quality improvement efforts have been successful
in reducing the incidence of NEC in even the highest risk
patients.147
Although the pathogenesis of the disease remains
incompletely understood, a variety of antenatal and postnatal
exposures have been suggested as risk factors for the development
of NEC.137,143,144,148 Early gestational age and low birth weight
are consistently related to NEC. Among prenatal factors, case
reports and retrospective reviews suggested that indomethacin
tocolysis may be associated with adverse neonatal outcomes,
including NEC.149,150 Others found no association151,152 of
indomethacin tocolysis with NEC when used as a single agent
but did find increased risk when used as part of double-­agent
tocolytic therapy. A meta-­analysis of randomized controlled
trials and observational studies from 1966 through 2004 found
no significant association between indomethacin tocolysis and
NEC in either study type, although the pooled sample size of
the published randomized controlled trials limited statistical
power.153 A retrospective cohort study of 63 infants exposed
to antenatal indomethacin found an association with early-­
onset NEC, within the first 14 days of life, after controlling for
a variety of covariates (adjusted odds ratio = 7.2; 95% CI, 2.5–
20.6).154 A larger multicenter study is needed to corroborate
these results, and the risks of indomethacin must be weighed
against benefits in delaying preterm birth. In contrast, antenatal
steroid administration has been shown to be protective against
NEC.155–157
Necrotizing enterocolitis is almost exclusively seen in
infants who have received enteral feeds. Therefore postnatal
interventions to prevent the development of NEC include
alterations in feeding type and advancements, use of human
milk, and probiotics. Decreased incidence of NEC has been
demonstrated with the use of human milk.158–163 A meta-­
analysis of randomized controlled trials evaluating use of human
milk and NEC found a fourfold decrease (RR = 0.25; 95% CI,
0.06–0.98) with the use of human milk.154 A large prospective
study of preterm neonates born before 32 weeks showed small
but significant reductions in relative risk for NEC among those
fed human milk.164 Mothers of infants at risk, particularly those
less than 32 weeks’ gestation, should be encouraged to supply
breast milk for their infants. Providing early pre-­and postnatal
counseling on use of human milk increases the initiation of
lactation and neonatal intake of mother’s milk without increasing
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1423
maternal stress or anxiety.165,166 Standardized feeding protocols
have also been shown to reduce risk of NEC.167–169
Alternations in the gut microbiome are associated with
NEC.138,170–172 Exposure to antibiotics, both antenatal and
postnatal, increases the risk of NEC as well as the risk of late-­onset
sepsis and death.173–178 Preservation of commensal bacteria is
hypothesized to protect against NEC, and several international
studies have shown benefit from the administration of probiotics
to premature infants.179–182 Although the role of probiotics
remains a promising intervention, it is still controversial, with
no consensus regarding organism or dose and lack of federal
regulations raising safety concerns about product purity and
quality assurance protocols.
Necrotizing enterocolitis may present slowly or as a sudden
catastrophic event. Abdominal distention occurs early, with
bloody stools a common presenting symptom. The radiographic
hallmark is the presence of pneumatosis intestinalis and/
or portal venous gas (Fig. 73.4). Progression may be rapid,
resulting in bowel perforation with radiographic evidence of
free air. Early management consists of bowel decompression
and intravenous antibiotics, with respiratory and cardiovascular
support as indicated. The single absolute indication for surgical
intervention is pneumoperitoneum.
For infants who survive NEC, long-­term morbidity is high,
including high rates of growth failure, neurodevelopmental
impairment, chronic lung disease, and nosocomial
infections.183–186 Duration of inpatient hospital stay and cost
are significantly increased, particularly in NEC requiring
surgical intervention.185,187,188 NEC is an independent risk
factor for development of cerebral palsy and developmental
delay.184,189,190 For infants with surgical NEC, depending on
the amount of bowel lost, there is risk of short gut syndrome
requiring parenteral nutrition and ultimately small bowel or
liver transplant or both. Necrotizing enterocolitis remains
the single most common cause of short bowel syndrome in
children.191 
Hyperbilirubinemia
Hyperbilirubinemia is common: 50% of term infants and
80% of preterm infants develop jaundice in the first week
of life.192 Bilirubin levels are elevated in neonates due to
increased production coupled with decreased clearance. The
increased production of bilirubin is related to higher rates of
red cell turnover and shorter red cell life span in the neonatal
period.193,194 Rates of excretion are lower in neonates because
of diminished activity of hepatic glucuronyl transferase, which
limits bilirubin conjugation, and increased enterohepatic
circulation. In most cases jaundice has no long-­term significance
and is even considered physiologic because bilirubin levels
remain relatively low, and the problem is transient. Less than
3% of infants have bilirubin levels which rise to greater than 15
mg/dL.195 Key risk factors for development of severe jaundice
are listed in Box 73.1.
Many important risk factors for hyperbilirubinemia originate
in the prenatal and perinatal environment. Hyperbilirubinemia
is seen more frequently in infants of diabetic mothers (IDM).
The pathogenesis of increased bilirubin in IDM infants is
uncertain but has been attributed to polycythemia as well as
increased red cell turnover.197–199 Prenatal maternal blood
group immunization may result from blood transfusion or
fetal-­
maternal hemorrhage. Though the prevalence of RhD
1424 Part 6  The Neonate
A B
Figure: 73.4  (A) Typical radiographic appearance of necrotizing enterocolitis demonstrating pneumatosis and intramural gas. (B) Intraoperative
photo of small bowel containing intramural gas.
Box 73.1   Common Clinical Risk Factors for
Severe Hyperbilirubinemia
Jaundice in the first 24 hours
Visible jaundice before discharge
Previous jaundiced sibling
Exclusive breastfeeding
Bruising, cephalohematoma
East Asian, Mediterranean, or Native American race
Maternal age >25
Male sex
Unrecognized hemolysis (i.e., ABO, Rhesus, anti-­c, C, E, Kell,
and other minor blood group antigens)
Glucose-­6-­phosphate dehydrogenase deficiency
Infant of a diabetic mother
Modified from Centers for Disease Control and Prevention. Kernic-
terus in full-­term infants—United States, 1994–1998. MMWR Morb
Mortal Wkly Rep. 2001;50(23):491–494.
immunization has significantly decreased with the advent of
prevention programs including use of Rh immune globulin,
antibodies to other blood group antigens may still occur. ABO
hemolytic disease, a common cause of severe jaundice in the
newborn, rarely if ever causes hemolytic disease in the fetus.
Other antibodies associated with hemolytic disease in the fetus
and newborn are discussed in detail in Chapter 35. It is important
to recall that a fetus that is apparently unaffected in utero may
have continued postnatal hemolysis; physicians caring for the
newborn must be informed of any maternal sensitization.
Other perinatal factors associated with severe
hyperbilirubinemia include delivery before 38 weeks. Infants
born at 36 to 37 weeks have an almost sixfold increase of
significant hyperbilirubinemia200 and require close surveillance
and monitoring, especially if breastfed.201,202 Feeding
difficulties, also common for the near-­term infant, increase this
risk still further and may result in delayed hospital discharge
or readmission for the infant. The presence of bruising or a
cephalohematoma, more common after instrumented or difficult
deliveries, will also increase risk. Polymorphisms of genes
coding for enzymes mediating bilirubin catabolism may also
contribute to the development of severe hyperbilirubinemia.203
The primary consequence of severe hyperbilirubinemia is
potential neurotoxicity. Kernicterus is a neurologic syndrome
resulting from neural necrosis and deposition of unconjugated
bilirubin in the basal ganglia and brainstem nuclei.196,204 Clinical
features may be acute or chronic, resulting in tone and movement
disorders such as choreoathetosis and spastic quadriplegia,
mental retardation, and sensorineural hearing loss.205 Several
factors influence the neurotoxic effects of bilirubin, making
prediction of outcome difficult. Bilirubin more easily enters the
brain if it is not bound to albumin or is unconjugated or there is
increased permeability of the blood-­brain barrier.205 Conditions
such as prematurity that alter albumin levels or that alter the
blood-­brain barrier such as infection, acidosis, and prematurity
affect bilirubin entry into the brain. As a result, there is no
serum level of bilirubin that predicts outcome. In early studies
of infants with Rh hemolytic disease, kernicterus developed in
8% of infants with serum bilirubin concentrations from 19 to 24
mg/dL, 33% with levels 25 to 29 mg/dL, and in 73% of infants
with levels 30 to 40 mg/dL.206
Levels of indirect bilirubin below 25 mg/dL in otherwise
term healthy infants without hemolytic disease are unlikely to
result in kernicterus without other risk factors, as indicated in
a study of 140 term and near infants with levels above 25 mg/
dL, in which no cases of kernicterus occurred.207 Kernicterus
has, however, been reported in otherwise healthy breastfed term
newborns at levels above 30 mg/dL.208 Prematurity is one of the
most important risk factors for kernicterus, both because the

blood-­brain barrier is more permeable and because the neonatal
brain appears to be more susceptible to damage.209,210 Levels
of bilirubin contributing to subtler neurologic abnormalities
remain unclear.201,211
Management of hyperbilirubinemia is aimed at the prevention
of bilirubin encephalopathy while minimizing interference with
breastfeeding and unnecessary parental anxiety. Key elements
in prevention include systematic evaluation of newborns
prior to discharge for the presence of jaundice and its risk
factors, promotion and support of successful breastfeeding,
interpretation of jaundice levels based on the hour of life,
parental education, and appropriate neonatal follow-­up based
on time of discharge.212 Treatment of severe hyperbilirubinemia
should be initiated promptly when identified. Guidelines for
treatment with phototherapy and exchange transfusion vary
with gestational age, the presence or absence of risk factors,
and the hour of life. Nomograms to guide patient management
are available from AAP.201 Kernicterus is largely preventable.
Close collaboration between prenatal and postnatal caretakers
ensures accurate dissemination of information regarding risk
factors for parents and clinical providers to facilitate prompt
recognition and treatment of significant hyperbilirubinemia. In
general, predicting nonhemolytic neonatal hyperbilirubinemia
can be based upon readily available maternal and obstetric risk
factors.213  of stay. Also, minimizing iatrogenic oral aversion is crucial.
Feeding Problems
Feeding problems related to complications of prematurity,
congenital anomalies, or gastrointestinal disorders contribute
significantly to length of stay for hospitalized newborns. In a
study of children referred to an interdisciplinary feeding team,
38% were born preterm.214 Premature infants with a history of
chronic lung disease or neurologic injury such as intraventricular
hemorrhage (IVH) or periventricular leukomalacia (PVL) and
those with a history of NEC are at the highest risk of long-­term
feeding problems. These medically complex infants often have
other comorbidities such as tracheomalacia, chronic aspiration,
and gastroesophageal reflux (GER) that interfere with normal
maturational patterns of feeding. Premature infants with
complex medical problems often require prolonged intubation
and mechanical ventilation with delayed initiation of enteral
feeding, all of which have been associated with subsequent
feeding difficulties. Because of these medical interventions
and neurologic immaturity, these infants often have difficulty
integrating sensory input. These factors combine to increase the
risk of developing oral aversion.
Infants with congenital anomalies are also at high risk of
developing feeding disorders. Infants with tracheoesophageal
fistula with esophageal atresia often have difficulty feeding due to
tracheomalacia, recurrent esophageal stricture, and GER, which
are known comorbidities of this disorder. Infants with congenital
diaphragmatic hernia (CDH) have an extremely high incidence
of oral aversion and growth problems in addition to pulmonary
complications. Surviving infants and children with CDH have
a 60%–80% incidence of associated GER that can persist into
adulthood.215,216 Often, this GER is severe, is refractory to medical
therapy, and may require a surgical antireflux procedure. Infants
with CDH often have inadequate caloric intake due to fatigue
or oral aversion and increased energy requirements leading to
poor growth. These infants typically require supplemental tube
feedings by nasogastric, nasojejunal, or gastrostomy feeding
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1425
tube. Feeding difficulties may last several years and are often
accompanied by behavioral-­based feeding difficulties.
Finally, infants with gastrointestinal abnormalities, either
congenital or acquired, frequently experience associated
feeding difficulties. Infants with conditions such as gastroschisis
with or without associated intestinal atresias often require
prolonged hospitalization because of a slow tolerance of enteral
feedings and a higher risk of NEC following gastroschisis
repair.217,218 They often have dysmotility and severe GER with
oral aversion. A small percentage of patients have long-­term
intolerance of enteral feedings and require prolonged total
parenteral nutrition (TPN). Patients requiring long-­term TPN
may develop liver injury or cholestasis and ultimately may
require liver/small bowel transplantation. Infants who develop
short bowel syndrome secondary to NEC also have difficulties
tolerating enteral feeds depending upon the length and function
of the remaining bowel. Like patients with gastroschisis, infants
with severe short bowel syndrome may require prolonged TPN
and go on to develop liver and/or intestinal failure requiring
transplantation.
Premature infants and infants with congenital anomalies
or acquired gastrointestinal abnormalities are at high risk for
long-­term feeding problems. It is important to counsel families
regarding this risk, including its impact on hospital length
Involving a feeding specialist early in a medically complex
infant’s course may lessen the impact. 
Neonatal Management of Neurologic
Problems
Hypoxic-­Ischemic Encephalopathy
Injury to the brain sustained during the perinatal period was
once thought to be one of the most common causes of death
or severe, long-­term neurologic deficits in children.219 However,
reviews of multiple studies show that only 10% of brain injuries
are related to perinatal or intrapartum events.220–222
There is increasing recognition that events occurring well
before labor contribute more significantly to the etiology of
brain injury. Despite improvements in perinatal practice over
recent years, the incidence of hypoxic-­ischemic encephalopathy
in developed countries such as the United States has remained
stable at 3–5 babies per 1000 live births.223,224 Strategies for
prevention of brain injury have been mainly supportive because
prevention has been difficult due to the lack of clinically reliable
indicators and the fact that often the initiating event occurs
prior to the onset of labor.
The pathophysiology of brain injury due to hypoxic-­ischemic
encephalopathy is initiated by the hypoxic-­ischemic event but
also affected by a “reperfusion phase” of the injury. Treatment
strategies, such as head or total body cooling, target this process
of ongoing injury that follows the initial insult.225,226
Definition of Asphyxia
The brain injury referred to as hypoxic-­ ischemic
encephalopathy occurs due to impaired cerebral blood flow
likely as a consequence of interrupted placental or umbilical
blood flow leading to impaired gas exchange.227 If gas exchange
is persistently impaired, then hypoxemia and hypercapnia
develop, with resultant fetal acidosis or what is referred to
as “asphyxia.” Severe fetal acidemia, defined as an umbilical
1426 Part 6  The Neonate
arterial pH of less than 7.00, is associated with an increased
risk of adverse neurologic outcome.228,229 However, even
with this degree of acidemia, only a small portion of infants
develop significant encephalopathy and subsequent sustained
neurologic injury.230 Therefore fetal scalp blood sampling and
umbilical cord gas data do not have great sensitivity to predict
long-­term neurologic impairment.  luminal ischemia and an increased risk of NEC. Decreased
Clinical Markers
When used in isolation, other clinical measures to identify
fetal stress, such as fetal heart rate abnormalities, MSAF, low
Apgar scores, and need for cardiopulmonary resuscitation, in
the delivery room do not reliably identify infants at high risk
of brain injury. Despite widespread use of electronic fetal heart
rate monitoring (EFM), which detects changes in fetal heart rate
related to fetal oxygenation and hemodynamic changes, there
has been no reduction in the incidence of cerebral palsy.229
In 2005, the ACOG Practice Bulletin Clinical Management
Guidelines for Obstetrician-­ Gynecologists228 concluded that
EFM has a high false-­positive rate to predict adverse outcomes
and is associated with an increase in operative deliveries without
reduction in cerebral palsy. Meconium-­stained amniotic fluid is
commonly seen during labor, but no data exist to associate it
with adverse neurologic outcome.
Apgar scores were originally introduced to identify infants
in need of resuscitation and not to predict neurologic outcome.
Apgar scores are not specific to an infant’s acid-­base status but can
also reflect drug use, metabolic disorder, trauma, hypovolemia,
infection, neuromuscular disorder, or congenital anomalies.
However, a persistently low Apgar score after 5 minutes despite
intensive cardiopulmonary resuscitation (CPR) has been
associated with increased morbidity and mortality.227,231–233
Furthermore, the combination of a low 5-­minute Apgar score
with other markers, such as fetal acidemia and the need for
CPR in the delivery room, predict a significantly increased
risk of brain injury.234,235 Perlman and Risser documented
a 340-­fold increased risk of seizures and moderate to severe
encephalopathy in association with a 5-­minute Apgar score of
≤5, delivery room intubation or CPR, and an umbilical arterial
cord pH of <7.00.235  also detect alterations in metabolites such as lactate, N-­acetyl
Neonatal Encephalopathy
Neonatal encephalopathy is clinically characterized by
depressed level of consciousness, abnormal muscle tone and
reflexes, abnormal respiratory pattern, and seizures.236 These
findings may result from a hypoxic-­ischemic event but can
also be due to a variety of other conditions such as metabolic
disorders, neuromuscular disorders, toxin exposure, and
chromosomal abnormalities or syndromes. Not all infants
with neonatal encephalopathy go on to develop permanent
neurologic impairment. The Sarnat staging system is used to
classify the degree of encephalopathy and predict neurologic
outcome.230 Infants with mild encephalopathy (Sarnat stage
1) generally have a favorable outcome. Infants with moderate
encephalopathy (Sarnat stage 2) develop long-­term neurologic
compromise in 20%–25% of cases, and infants with severe
encephalopathy (Sarnat stage 3) have a greater than 80% risk of
death or long-­term neurologic sequelae.236  that hypothermia either by selective head cooling or whole-­
Multiorgan Injury
In addition to neurologic compromise, the interruption of
placental or umbilical blood flow can result in systemic organ
injury. Animal models and clinical studies demonstrate that
the kidney is exquisitely sensitive to reductions in renal blood
flow.237,238 The result of decreased renal perfusion is acute
tubular necrosis with varying degrees of oliguria and azotemia.
Other organ systems are also sensitive to reduced blood flow.
Decreased blood flow to the gastrointestinal tract can lead to
pulmonary blood flow can result in PPHN. Lack of blood flow
to the liver can result in hepatocellular injury and impaired
synthetic function leading to hypoglycemia and disseminated
intravascular coagulation. Fluid retention and hyponatremia
can develop due to the combination of impaired renal
function and the release of antidiuretic hormone. Suppression
of parathyroid hormone release can lead to hypocalcemia
and hypomagnesemia. These electrolyte abnormalities can
further affect myocardial function. Muscle can be affected by
electrolyte abnormalities and direct cellular injury leading to
rhabdomyolysis.227 
Neuropathology
The reduction in cerebral blood flow associated with a hypoxic-­
ischemic event sets off a complex cascade of regional circulatory
factors and biochemical changes at the cellular level. Hypoxia
induces a switch from normal oxidative phosphorylation to
anaerobic metabolism, leading to depletion of high-­ energy
phosphate reserves, accumulation of lactic acid, and inability to
maintain cellular functions.227,239,240 The end result is cellular
energy failure, metabolic acidosis, release of glutamate and
intracellular calcium, lipid peroxidation, accumulation of nitric
oxide, and eventual cell death.225,236,241 Current neuroprotection
strategies used in the NICU target one or more of these
pathophysiologic processes (see later). 
Neuroimaging
Diffusion-­ weighted MRI has become the gold standard to
define the extent and potentially the timing of the brain injury.
Diffusion-­weighted techniques can detect signal changes due to
reduced brain water diffusivity within the first 24 to 48 hours
of the insult.225,242–244 Magnetic resonance spectroscopy can
aspartate, choline, and creatinine in specific regions of the brain,
indicating injury.243,245 However, MRI is difficult to perform in
an unstable patient, and therefore CT may be preferable as the
initial study for term infants and ultrasound for preterm infants. 
Neuroprotection Strategies
Brain cooling by selective cooling of the head or systemic
hypothermia is now an established therapy to reduce neurologic
injury due to neonatal hypoxic-­ischemic encephalopathy. Five
large randomized controlled trials (see246 and references therein)
collectively demonstrate significant reduction in a combined
outcome of death or long-­ term major neurodevelopmental
disability at 18 months’ follow-­up. Additional work is required
to define populations most likely to benefit from treatment,
as well as duration of the therapeutic window, optimal target
temperatures, and safety for preterm infants. Since these
studies, subsequent randomized clinical trials have shown
body cooling is associated with a reduction in death and
severe neurodevelopmental disability at 18 months of age
in term infants with moderate to severe hypoxic-­ ischemic
encephalopathy (see247 and references therein). Therefore

therapeutic hypothermia is now the standard of care for infants
36 weeks or greater with moderate to severe hypoxic-­ischemic
encephalopathy and should be initiated as soon as possible
following birth. Head cooling and total body cooling appear
equally efficacious with similar safety profiles.248
Future efforts are being focused on early identification of
those infants at the greatest risk for hypoxic-­ischemic injury
and defining the therapeutic window for effective treatment.
This was initially thought to be limited to within 6 hours of
delivery; however, ongoing studies are evaluating the benefit of
late hypothermia (>6 hours after birth). Variation in practice
among neonatologists emphasizes the need for ongoing
investigation.249 Infants at highest risk are those with evidence
of a sentinel event during labor, pronounced respiratory and
neuromuscular depression at delivery with persistently low
Apgar scores, need for delivery room resuscitation, severe
fetal acidemia defined as an umbilical artery pH <7.00 and/
or base deficit ≥16 mEq/L, and evidence of an early abnormal
neurologic exam, seizures, or an abnormal amplitude-­integrated
electroencephalography (aEEG).225,235,250–252 Potential
pharmacologic adjunctive therapies in addition to hypothermia
are being investigated.251,253  outcomes at 20 months corrected age compared to those with
Summary
Hypoxic-­ischemic brain injury due to intrapartum asphyxia
is a rare but serious cause of long-­term neurodevelopmental
disability. It is often difficult to define a specific intrapartum
episode because the initiating event may occur before the
onset of labor. Early identification of at-­risk newborns by
neuroimaging techniques, aEEG findings, history, and clinical
exam may provide an opportunity to ameliorate the effects
of ongoing brain injury using neuroprotective strategies. The
goal of these therapeutic interventions is the reduction of
long-­term neurodevelopmental disabilities, including cerebral
palsy.
Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) or germinal matrix
hemorrhage (GMH) occurs most commonly in preterm infants
and is a major cause of mortality and long-­term disability in
this population. Bleeding originates in the subependymal
germinal matrix but may rupture through the ependyma into
the ventricular system. IVH is graded into four categories:
Grade I: Bleeding localized to the germinal matrix
Grade II: Bleeding into the ventricle but the clot does not
distend the ventricle
Grade III: Bleeding into the ventricle with ventricular dila-
tion
Grade IV: Intraparenchymal extension
Incidence
Diagnosis is made most commonly by cranial ultrasound with
most hemorrhages occurring within 6 hours of birth and 90%
within the first 5 days of age.254 The incidence of IVH has
decreased significantly with improvements in perinatal care
such as maternal transfer and antenatal steroids. From 1990 to
1999, the incidence of IVH reported in infants <1000 g birth
weight was 43%, and 13% were Grade III or Grade IV. In 2000–
02, the overall incidence of IVH decreased to 22%; only 3% were
severe despite improvements in survival.255 Lower gestational
age is associated with an increased risk of severe IVH.231,248  mature the germinal matrix vasculature.267,269,270 Prophylactic
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1427
Pathogenesis
Both anatomic and physiologic factors have been implicated in
the pathogenesis of IVH. The blood supply of the germinal matrix
is provided by thin-­walled blood vessels that lack supportive
tissue. These fragile vessels are prone to rupture spontaneously
or in response to stress such as hypoxia-­ischemia, changes in
blood pressure and/or cerebral perfusion, and pneumothoraces.
In addition to these structural factors, premature infants
have an immature cerebrovascular autoregulation system
or a so-­ called pressure-­ passive circulation in response to
systemic hypotension, which makes them more susceptible to
hemorrhage.238,254,256 Immaturities in the coagulation system
and increased fibrinolytic activity of premature infants may also
play a role.256–259 
Outcomes
Although it has been generally thought that infants with
Grade I or II IVH have similar outcomes to those without
cranial ultrasound abnormalities, a recent study by Patra
and colleagues suggests that extremely-­ low-­
birth-­
weight
infants with Grade I–II IVH have worse neurodevelopmental
normal cranial ultrasounds.191 Infants with Grade III IVH have
adverse neurologic outcome in about 35% of cases. In those who
develop posthemorrhagic hydrocephalus requiring surgical
intervention, the disability rate increases to about 60%.233 Grade
IV IVH is associated with the highest mortality rates and most
are associated with a poor neurologic outcome.232 
Antenatal Prevention
The only therapies shown to decrease the incidence of IVH in
premature infants are antenatal corticosteroid administration
and maternal transfer to a tertiary care center for delivery.
Multiple studies have shown that the administration of
corticosteroids prior to preterm birth to induce lung maturity
has significantly reduced the incidence of RDS, NEC, mortality,
and severe IVH. According to a meta-­analysis of four trials of 596
infants from 24 to 33 weeks’ gestation, prenatal corticosteroid
therapy was associated with a relative risk reduction for IVH
of 0.57 (CI, 0.41 to 0.78).234 Maternal transfer to a tertiary care
center for gestational age <32 weeks has been shown to decrease
the incidence of death or major morbidity including IVH.260
Antenatal phenobarbital, vitamin K, and magnesium sulfate
have failed to demonstrate a consistent decrease in overall IVH,
severe IVH, or death.261–263 
Postnatal Prevention
The goal of postnatal prevention has been blood pressure
stabilization to prevent fluctuations in cerebral perfusion,
correction of coagulation disturbances, and stabilization of
germinal matrix vasculature.254 Postnatal administration
of phenobarbital and muscle paralysis have been shown to
stabilize blood pressure, but neither has been found to decrease
the incidence of IVH or neurologic impairment.264,265 Routine
use of paralytics to prevent IVH in ventilated preterm neonates
is not recommended. Fresh-­ frozen plasma and ethamsylate
to promote platelet adhesiveness and correct coagulation
disorders also do not reduce the incidence of IVH.262,266–268
Indomethacin remains the most promising preventive therapy
for IVH due to its ability to constrict the cerebral vasculature,
inhibit prostaglandin and free-­ radical production, and
1428 Part 6  The Neonate
indomethacin decreases the incidence of severe IVH. Follow-­up
studies have shown slight improvement in cognitive function
in infants who received prophylactic indomethacin but no
difference in the incidence of cerebral palsy.271–273 Prophylactic
indomethacin remains reserved for preterm infants at high risk
of IVH. A recent study has called into question its direct impact
upon IVH.274 
Posthemorrhagic Hydrocephalus
The most serious complication of IVH is posthemorrhagic
hydrocephalus due to obstruction of cerebrospinal fluid (CSF)
flow. This occurs when multiple blood clots obstruct CSF
reabsorption channels, leading to transforming growth factor β1
(TGFβ1)-­mediated production of extracellular matrix proteins
such as fibronectin and laminin, which ultimately lead to scar
formation.275 Progressive ventricular dilation can worsen brain
injury due to damage to periventricular white matter secondary
to increased intracranial pressure and edema.235 Therapies
such as serial lumbar punctures, diuretics, and intraventricular
fibrinolytic therapy are ineffective and may even be harmful.265
Although surgical shunt placement carries risks of shunt
complications and infection, it remains the definitive therapy
for progressive posthemorrhagic hydrocephalus.  (24–28 weeks), there are few anastomoses between the long
Summary
Intraventricular hemorrhage due to a fragile germinal matrix
and an unstable cerebrovascular autoregulatory system remains
a significant cause of neurologic morbidity in preterm infants.
Infants with cardiorespiratory complications are at highest
risk. Antenatal corticosteroids are the most effective preventive
therapy currently available. Despite significant reduction in
the incidence of severe IVH, new prevention and treatment
therapies for hydrocephalus are needed.  effects, and the presence of glutamate (see Fig. 9 on p. 146 in
Periventricular Leukomalacia
Periventricular leukomalacia (PVL) refers to injury to the deep
cerebral white matter in two characteristic patterns, described
as focal periventricular necrosis and diffuse cerebral white matter
injury. This type of brain injury typically affects premature
infants and is a common cause of cerebral palsy. Preterm infants
who have suffered an IVH and/or have cardiopulmonary
instability are at the highest risk. Other intrauterine factors
such as infection, prelabor prolonged rupture of membranes,
first-­trimester hemorrhage, placental abruption, and prolonged
tocolysis have all been associated with increased risk of PVL. The
reported incidence of PVL detected by ultrasound examination
in very-­ low-­ weight infants is 5%–15%.276 However,
birth-­
ultrasound often fails to identify subtle evidence of diffuse white
matter injury. MRI may be a more sensitive imaging study.277
Diagnosis of PVL at autopsy in preterm infants with normal
cranial imaging suggests that the true incidence of PVL may be
underestimated.
Neuropathology
Focal necrosis most commonly occurs in the cerebral white
matter at the level of the trigone of the lateral ventricles and
around the foramen of Monro.276 These sites make up the border
zones of the long penetrating arteries. Classically, these lesions
undergo a coagulative necrosis that results in cyst formation
or focal glial scars.238 The more diffuse type of injury may also
occur in conjunction with focal necrosis but is more frequently
recognized as an independent entity. Diffuse white matter
injury seems to affect premyelinating oligodendrocytes and
leads to global loss of these cells and an increase in hypertrophic
astrocytes in response to the diffuse injury.238,276,278,279 This
loss of oligodendrocytes leads to white matter volume loss and
ventriculomegaly. 
Pathogenesis
The pathogenesis of PVL is primarily by hypoxia-­ ischemia
leading to neuronal injury due to free radical exposure, cytokine
toxicity, and exposure to excessive excitatory neurotransmitters
such as glutamate.238 Vascular anatomic factors also seem to
play a role. As noted, PVL tends to occur in arterial end zones or
so-­called border zones280 (see Fig. 7 on p. 142 in reference276).
The arterial supply consists of long penetrating arteries that
terminate deep in the periventricular white matter, basal
penetrating arteries supplying the immediate periventricular
area, and short penetrating arteries supplying subcortical white
matter. Focal necrosis occurs most commonly in anterior and
posterior periventricular border zones because in premature
infants these vessels are immature. Diffuse white matter injury
may also occur due to vascular immaturity. At early gestations
and short penetrators and arterial border zones may occur in
subcortical and remote periventricular areas, resulting in a
more diffuse type of injury.276
The preterm brain is also vulnerable to ischemia due to
impaired cerebrovascular regulation. Preterm infants exhibit
a pressure-­passive circulation; a decrease in systemic blood
pressure is associated with a decrease in cerebral perfusion
leading to ischemia.276,281,282 Also, immature oligodendrocytes
seem to be more sensitive to free radical injury, cytokine
reference283). 
Clinical Outcomes
The most common long-­ term sequelae of PVL is spastic
diplegia, a form of cerebral palsy in which the lower extremities
are more affected than the upper extremities. The descending
fibers of the motor cortex, which regulate function of the lower
extremities, traverse the periventricular area and are most likely
to be injured. More severe injury with lateral extension may be
associated with spastic quadriplegia or other manifestations
such as cognitive, visual, or auditory impairments. 
Summary
PVL is a major cause of neurologic morbidity in premature
infants, especially those <1000 g birth weight. Prevention
is currently the only strategy to treat PVL. Avoidance of
fluctuations in blood pressure and cerebral vasoconstrictors
such as extreme hypocarbia are important due to the known
immaturity in cerebrovascular autoregulation of preterm
infants. Future investigational strategies targeting the cascade
of oligodendroglial death may eventually yield pharmacologic
treatments. 
Perinatal Stroke
Arterial ischemic stroke (AIS) in neonates is defined as a
cerebrovascular event around the time of birth with resultant
clinical and/or radiographic evidence of focal cerebral arterial
infarction.284 The majority occur in the distribution of the

middle cerebral artery (MCA).241,285–287 AIS accounts for
most perinatal ischemic strokes. When diagnosis is based on
symptoms in the neonatal period, the reported incidence is 1
in 4000 live births.241,288,289 The incidence of perinatal ischemic
strokes that were asymptomatic in the neonatal period and
diagnosed later is unknown.
Clinical Presentation
Neonatal seizures are the most common clinical presentation of
AIS and can be focal in origin without other signs of neonatal
encephalopathy.241,290 Many infants are systemically ill, and
the diagnosis is made with neuroimaging to rule out evidence
of hypoxic-­ischemic injury or bleeding. Neonates with focal
neurologic signs account for about 30% of cases.285,289,291–293
Perinatal stroke may also be identified retrospectively in initially
well-­appearing infants who present in later months with signs
of hemiparesis, developmental delay, or seizures.241,294 In
these cases, neuroimaging reveals a remote injury, often in the
distribution of the MCA. 
Pathophysiology and Risk Factors
The mechanisms of perinatal stroke are thought to be
multifactorial. Regional ischemia with subsequent hypoxia and
infarction clearly plays a role. Also, a relative hypercoagulable
state in newborns due to the presence of fetal hemoglobin,
polycythemia, and activation of coagulation factors in the fetus
and mother around the time of birth seems to increase the risk
of a thromboembolic event leading to stoke.241,295 Risk factors
for perinatal stroke include maternal and placental disorders,
neonatal hypoxic-­ ischemic injury, hematologic disorders,
infection, cardiac disorders, trauma, and drugs.241 However,
many mothers have no obvious risk factors at the time of
delivery.293  the prevalence of CP has remained relatively unchanged over
Neuroimaging and EEG Assessment
Although cranial ultrasound is the easiest to perform, it is not a
sensitive indicator of perinatal stroke.239 Little information exists
on prenatal cranial ultrasound. However, prenatal ultrasounds
may demonstrate areas of unilateral echolucencies, which may
represent areas later identified as prenatal stroke. CT imaging
can usually be performed readily in neonates and usually does
not require sedation. CT evidence of perinatal ischemic stroke
includes focal hypodensity with or without intraparenchymal
hemorrhage, abnormal gray white differentiation, and evidence
of volume loss or porencephaly if the injury is remote241 (Fig.
73.5).
Further diagnostic studies focused upon risk factors
for perinatal ischemic stroke should include blood tests
for coagulation disturbances and genetic predispositions,
urine toxicology for metabolic disorders and toxins such as
cocaine, echocardiogram, infectious workup including lumbar
puncture, maternal testing for acquired coagulation disorders
such as antiphospholipid antibodies, and an assessment of the
placenta.241  events such as birth asphyxia,222,304,305 and 10% follow postnatal
Outcome
Perinatal ischemic stroke is the most common cause of
hemiplegic cerebral palsy.241 Although not all survivors of
perinatal stroke suffer long-­ term disabilities, 50%–75% of
infants who suffered a perinatal stroke will have a neurologic
deficit or seizures.280,285,298–300 Lee and colleagues reported a
population-­based study of neonatal AIS showing that 32% of
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1429
infants with AIS who presented with symptoms in the neonatal
period went on to develop cerebral palsy, whereas 82% of
infants diagnosed retrospectively developed cerebral palsy.280
Because cases identified retrospectively presented because of
hemiparesis, they were more likely to be classified as having
cerebral palsy. 
Summary
Perinatal ischemic stroke is a major cause of long-­term neurologic
disability. Treatment is purely supportive, and management
is via rehabilitation focusing on muscle strengthening and
prevention of contractures. Novel neuroprotective strategies and
approaches to prevention are needed. Advanced neuroimaging
techniques to better understand how the brain reorganizes
following this type of injury are currently being utilized as
research tools. 
Cerebral Palsy
As early as 1862, William John Little described the relationship
between children with motor abnormalities and pregnancy
complications such as difficult labor, neonatal asphyxia, and
premature birth.243 Cerebral palsy (CP) is a clinical diagnosis
that refers to a group of nonprogressive motor impairments.
In 2005 the International Committee on Cerebral Palsy
Classification defined CP as “a group of developmental disorders
of movement and posture, which cause activity limitations that
are attributed to nonprogressive disturbances that occurred in
the developing fetal or infant brain. The motor disorders of CP
are often accompanied by disturbances of sensation, cognition,
communication, perception, and/or behavior, and/or by a
seizure disorder.”242 Despite improvements in perinatal care,
the past 50 years with an incidence of 1.5 to 3.5 per 1000 live
births.236,301–303
Classification
Traditionally, CP has been classified by topography based upon
the affected limb involvement (i.e., monoplegia, hemiplegia,
diplegia, triplegia, and quadriplegia) and a description of the
predominant type of tone or movement abnormality (i.e.,
spastic, dyskinetic, ataxic, hypotonic, or mixed). Recently, the
International Committee on Cerebral Palsy Classification has
proposed a new classification system that additionally considers
the presence or absence of associated impairments, other
anatomic involvement besides limbs, radiologic findings, and
causation.242 
Etiology
Cerebral palsy is a result of injury to the developing brain that
occurs during prenatal, perinatal, or postnatal life. The large
majority (75%–80%) of cases of CP have been attributed to events
during pregnancy. Ten percent are attributable to intrapartum
causes such as head injury or CNS infection.244,245 Risk factors of
CP include prematurity, multiple gestation, intrauterine growth
restriction, intracranial hemorrhage, PVL, infections, placental
pathology, genetic syndromes, structural brain abnormalities,
birth asphyxia or trauma, and kernicterus. The origins of CP
tend to be multifactorial, but in some cases no cause is identified.
Some of the more common risk factors will be discussed in
detail; however, the roles of intracranial hemorrhage, PVL, and
1430 Part 6  The Neonate

Figure 73.5  MRI with diffusion-­weighted imaging is the most sensitive, especially in the setting of early infarction. MRI may be able to demonstrate
restricted diffusion within a vascular distribution for acute stroke as well as chronic changes such as encephalomalacia, gliosis, and ventriculomegaly
for remote events. MR angiography may be useful in some cases to confirm arterial occlusion although is not commonly used unless a vascular mal-
formation is suspected. Functional MRI may be valuable in the future to understand how the brain reorganizes following perinatal stroke.285,296,297 EEG
may be useful to detect subclinical seizures that may cause secondary brain injury.285

birth asphyxia contributing to CP are discussed in a previous
section of this chapter.  will increase as well. Several authors have reported increasing
Prematurity
Prematurity and low birth weight are the most important
identifiable risk factors for CP, with an increased prevalence
of CP associated with decreasing gestational age and decreas-
ing birth weight as compared to term infants. For comparison
purposes, it is important to consider the rates of CP and neu-
rosensory impairments in term infants. Msall and associates
reported rates of disability in term infants as follows: 0.2% for
CP, 2%–3% for cognitive impairment, 0.1%–0.3% for hearing
loss, and 0.1% for visual impairment.306 With improvements in
survival for extremely-­low-­birth-­weight infants (ELBW, defined
as <1000 g birth weight), there are concerns that disability rates
neurodevelopmental disability rates for ELBW infants born
in the 1990s with rates of CP ranging from 8% to 19%, rates
of developmental disability ranging from 19% to 49%, rates of
hearing impairment from 1% to 4%, and rates of visual impair-
ment from 1% to 4%.189,307–310 When extreme prematurity is
considered, Shankaran and associates showed that surviving
infants born at the threshold of viability defined as birth weight
<750 g, gestational age <24 weeks, and a 1-­minute Apgar of ≤3
had neurodisability rates of 60% with nearly one-­third of infants
having CP.311 The increase in disability rates has been postulated
to be related to heavy use of postnatal steroids to treat neonatal
chronic lung disease and high rates of sepsis in this population.

Poor neurodevelopmental outcomes have been associated with
widespread use of postnatal steroids in the 1990s so that rou-
tine use of this therapy to treat chronic lung disease is now dis-
couraged.312–315 The association between sepsis and CP has also
been identified in multiple studies and will be discussed in a
later section.
With recent improvements in the survival of extremely
low-­gestational-­age neonates, strategies to reduce associated
morbidity are important. Decreased rates of CP have been
reported in ELBW infants born between 2000 and 2002, a
time period associated with increased use of antenatal steroids,
decreased use of postnatal steroids, and decreased incidence of
nosocomial sepsis.255 Chronic lung disease is an independent
risk factor for neurodevelopmental disability, and improved
strategies are needed. Inhaled nitric oxide for preterm infants
with respiratory failure has been studied, and improved cognitive
outcome in infants so treated has been reported,316,317 but this
has not been consistently observed in ELBW infants.318–320  intrauterine growth restriction because these cohort studies
Multiple Births
The risk of developing CP is significantly higher in multiple
gestations compared to singleton births. Data from CP registries
show that the risk for developing CP in twins is 4 to 5 times
greater than singletons. For triplets the risk is 12 to 13 times
greater.236,252,321,322 Although twins comprise only 1.6% of the
population, they have a 5%–10% incidence of CP.323,324 The
higher rate of CP in multiple births may relate to preterm birth,
along with complications associated with multiple gestation
such as placental and cord abnormalities, intraplacental
shunting, structural anomalies, and difficulties at delivery.
The incidence of CP increases as birth weight decreases.
Infants with birth weights <1500 g comprise 0.9% singletons,
9.4% twins, 32.2% triplets, and 73.3% quadruplets.252
Population-­based registries have also broken down the risks of
CP per 1000 neonatal survivors related to birth weight groups
as follows: 66.5 for infants <1000 g, 57.4 for infants 1000–1499
g, and 8.9 for infants 1500–2499 g.325 However, twins with
birth weight >2500 g have a three-­to fourfold increased risk of
developing CP compared to singletons.252 It is unclear why this
risk increases near term but is thought to be due to an increased
risk of asphyxia or fetal growth restriction that occurs more
commonly in multiples.
The risk of CP is also increased with the fetal death of a co-­
twin and is higher in same sex verses non-­same-­sex twins.326–329
Furthermore, when both twins are born alive and one twin dies
in infancy, the risk is even greater than if one twin died in utero,
again with same-­sex twins having a greater risk than non-­same-­
sex twins.252 These data suggest that monochorionicity plays
a significant role in the pathogenesis of CP, likely due to the
placental vascular anastomoses.
Finally, assisted reproductive technology (ART) remains
associated with an elevated risk for multiple gestations. The
increased risk of CP associated with ART is largely due to
the higher percentage of preterm births in such pregnancies.
However, a Danish study suggested that IVF pregnancies may
carry an increased risk of CP not attributable to birth weight or
gestation.250 Therefore this increased risk of CP associated with
ART requires further study.  and are thus risk factors for the development of CP. Intraamniotic
Fetal Growth Restriction
There is much debate in the literature whether infants with fetal
growth restriction have an increased incidence of CP. Many
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1431
authors have reported an increased risk of CP in infants who
are small for gestational age (SGA).330–335 However, fetal growth
restriction is a distinct clinical entity. Fetal growth restriction
refers to failure of a fetus to grow at a predicted rate using fetal
growth standards as opposed to neonatal growth standards.
These fetal growth standards are derived using ultrasound
measurements of healthy fetuses in utero at each gestational age
and can take into account variables such as fetal sex, ethnicity,
parity, and maternal height and weight.336–338 SGA refers to
infants who are statistically smaller than average at a given
gestational age but does not consider potential etiologies of
SGA such as chromosomal anomalies, congenital infections,
structural brain malformations, or constitutional small stature.
Furthermore, studies of risk of CP often use birth weight alone
to define their population of interest, which could explain the
observed increased risk of CP associated with low birth weight.
This increased risk of CP could actually be due to effects of
include both more mature SGA infants and preterm infants
with equivalent birth weights.339,340 Therefore the terminology
used affects how data may be interpreted.
Many studies have demonstrated that SGA in term or
preterm infants >33 weeks’ gestation have the highest risk of
developing CP.332–334 The Surveillance of Cerebral Palsy in
Europe (SCPE) Collaborative Group reported that babies born
between 32 and 42 weeks’ gestation and a birth weight <10th
percentile were four to six times more likely to develop CP than
infants with a birth weight between the 25th percentile and 75th
percentile.340,341 For infants born <33 weeks’ gestation with fetal
growth restriction, the association is less clear because this
population has the highest risk of adverse neurodevelopmental
outcome. Therefore it is difficult to separate the risk due purely
to growth restriction versus the effect of prematurity in general.
Other factors shown to increase the risk of CP include the
severity of the SGA, male gender, and asphyxia.342
Growth-­ restricted infants may be more susceptible to
intrapartum hypoxia, which then leads to adverse neurologic
outcome. Data from the Collaborative Perinatal Project showed
that infants with intrauterine growth restriction had similar
incidences of CP compared to non–intrauterine-­ growth
restricted infants when examined at 7 years of age in the absence
of intrapartum hypoxia. However, when intrapartum hypoxia
was identified, the children with intrauterine growth restriction
had an increased incidence of neurodevelopmental disability
compared to those without intrauterine growth restriction.267
The relative risk of CP due to intrapartum hypoxia was
actually lower in a study of infants who were SGA compared
with appropriate-­for-­gestational-­age (AGA) infants.335 These
conflicting results suggest that other factors may be involved. 
Perinatal Infections
Maternal, intrauterine, and neonatal infections have all been
associated with CP. Congenital viral infections such as TORCH
infections including toxoplasmosis, rubella, cytomegalovirus
(CMV), herpes simplex virus, and syphilis may account for
5%–10% of cases of CP. Maternal infection and inflammation
have been associated with an increased incidence of preterm birth
infection, also referred to as clinical chorioamnionitis, has been
associated with prelabor rupture of the fetal membranes and
subsequent preterm birth.343,344 Chorioamnionitis has also been
associated with an increased risk of developing CP via several
1432 Part 6  The Neonate
likely mechanisms. An increased risk of IVH and PVL has been
associated with maternal chorioamnionitis and pPROM in
numerous studies.345–349 Histological chorioamnionitis without
clinical signs of intraamniotic infection has also been linked
to increased risk of IVH, PVL, and CP.350–354 Potential links
between chorioamnionitis and neonatal lung disease are noted
in previous sections of this chapter.
In recent years, laboratory and clinical evidence has emerged
that supports the hypothesis that intrauterine infection and
inflammation lead to the production of proinflammatory
cytokines, which are responsible for white matter brain injury
and ultimately CP. These cytokines are potentially toxic
to developing oligodendrocytes in fetal white matter and
cause reduced myelination and subsequent white matter inj
ury.346,355,356 In addition, various cytokines could have a direct
toxic effect on cerebral white matter by increasing the production
of nitric oxide synthase, cyclooxygenase, other associated free
radicals, and excitatory amino acids.356–359 This relationship
between elevated cytokine levels and the development of white
matter injury has been seen in both preterm and term infants.
A four-­to six-­fold increased risk for white matter injury has
been associated with elevated levels of interleukin (IL)-­ 1ß
from amniotic fluid and from umbilical cord blood in preterm
infants.360,361 In a study of term infants who went on to develop
CP, stored blood samples had significantly increased levels of
the cytokines IL-­1, IL-­8, IL-­9, tumor necrosis factor-­beta, and
RANTE.362 Furthermore, the combination of intrauterine
infection and intrapartum hypoxia has been correlated with a
dramatic increase in the incidence of CP.363
Neonatal infection has also been associated with the
development of CP due to direct CNS damage (e.g., in
meningitis) or to a systemic inflammatory response syndrome
(SIRS) that leads to sepsis, shock, and multiorgan system failure.
Preterm infants who develop infection seem to be at higher
risk.364,365 A study of 6093 ELBW survivors born between 1993
and 2001 found an 8% incidence of CP among infants who did
not develop a postnatal infection and a 20% incidence of CP in
infants whose hospital course was complicated by sepsis, NEC,
or meningitis.134 The infected infants also had an extremely
high risk of cognitive impairment defined as a Bayley MDI
<70 at 18 months compared to noninfected infants, 33%–42%
versus 22%, respectively.309 Another study in ELBW survivors
found that NEC requiring surgical intervention was associated
with a significant increase in both the incidence of CP and
developmental disabilities compared to those without NEC.189  the use of antiplatelet drugs to prevent preeclampsia, potentially
Placental Abnormalities
Because the placenta serves to supply nutrients to the
developing fetus and as a barrier that protects the fetus from
influences such as infectious organisms, toxins, trauma, and
immune mediators, placental abnormalities can predispose
fetuses to adverse outcomes. Placental abnormalities associated
with CP can fall into three categories. The first encompasses
events that occur during or prior to labor also known as
“sentinel lesions,” which can cause fetal hypoxia. These lesions
include uteroplacental separation, fetal hemorrhage, and
umbilical cord occlusion.366 The next category is made up of
thromboinflammatory processes that affect fetal circulation
and include fetal thrombotic vasculopathy, chronic villitis,
meconium-­ associated fetal vascular necrosis, and fetal
vasculitis related to chorioamnionitis.366,367 The third category
includes processes that cause decreased placental reserve such
as chronic placental insufficiency, chronic villitis, chronic
abruption, chronic vascular obstruction, and perivillous
fibrin deposition.368 Evaluation of the placenta in the cause
of neonatal encephalopathy may provide some insight into
the fetal intrauterine environment and its contribution to the
neurologic impairment. 
Coimpairments
Historically, CP has been defined strictly by the anatomic
location and degree of motor impairment. However, associated
coimpairments such as disturbances in sensation, cognition,
communication, perception, and behavior are common, as are
seizures. A definition that includes coimpairments has been
proposed.242,302 A Dutch population study of children with CP
reported that 40% had seizures, 65% had cognitive deficits (IQ
<85), and 34% had visual impairments.369 Hearing impairments
and feeding difficulties are also common. 
Strategies to Reduce Cerebral Palsy
Strategies to reduce CP have focused upon preventing
asphyxia and premature birth because these factors seem to
be the most significant contributors to the development of CP.
Strategies commonly used to reduce intrapartum hypoxia such
as fetal heart monitoring, maternal oxygen administration,
repositioning, and strict guidelines for oxytocin use have not
affected the rate of CP.370 Fetal heart rate monitoring could
even increase the prevalence of CP by increasing the risk of
chorioamnionitis.371,372 Fetal heart rate monitoring increases the
rate of operative interventions without any reduction in the rate
of CP.228 Reduction of perinatal intracranial injuries associated
with the decreased use of forceps and vacuum extraction in
the last 20 years is a positive trend that may contribute to a
reduction in the incidence of CP.30,236
Preterm birth accounts for approximately 35% of CP
cases.373 Therefore it is logical that strategies to reduce the
incidence of preterm birth will reduce the incidence of CP
provided these interventions do not increase the risk of an in
utero insult. Prevention of preterm birth has proved elusive,
making strategies to reduce morbidity more immediately
promising. However, recent literature has shown that the
following strategies are helpful to reduce the rate of preterm
birth: limiting the number of embryos transferred with in vitro
fertilization, programs supporting smoking cessation, screening
and treatment of asymptomatic bacteriuria during pregnancy,
the use of progesterone to prolong pregnancy, and the use of
cervical cerclage for women with a previous preterm birth and
short cervix.58,374,375
Antenatal steroids decrease the incidences of several
morbidities strongly associated with CP, including IVH,
PVL,234,376 RDS, and chronic lung disease. Postnatal steroids
to treat neonatal chronic lung disease, however, are associated
with a significant increase risk of CP.312,377–379
Another strategy to reduce CP in preterm infants is the
administration of magnesium sulfate prior to delivery. The
proposed mechanism of benefit is the ability of magnesium
sulfate to stabilize vascular tone, reduce reperfusion injury, and
reduce cytokine mediated injury.380,381 Several observational
studies note an association between maternal administration of
magnesium sulfate either for preeclampsia or preterm labor and
a reduced risk of CP.382–385 However, other authors have reported
no protective effect of magnesium.386–392 The Australasian

Collaborative Trial of Magnesium Sulphate examined the
efficacy of magnesium sulfate given to women at risk for preterm
birth <30 weeks’ gestation solely for neuroprotection. This
study was a much larger randomized controlled trial (n = 1062)
and the authors reported a lower incidence of CP, although
not statistically significant (6.8% versus 8.2%), and no serious
harmful effects to women or their children.263 More recently,
Marret and colleagues with the PREMAG trial group showed
that magnesium sulfate given to pregnant women before 33
weeks’ gestation with planned or expected delivery within 24
hours did not show any differences in total death or severe white
matter injury at hospital discharge but was associated with
significant reductions in late death or gross motor dysfunction
at 2 years of age.393,394 The largest study (n = 2241) evaluating
the effect of magnesium sulfate for the prevention of CP by
Rouse and colleagues and the NICHD Maternal-­Fetal Medicine
Network showed a reduction in the rate of moderate or severe
CP.395 The ACOG Committee on Obstetric Practice and SMFM
issued a joint statement in 2010 recommending the use of
magnesium sulfate before anticipated early preterm birth for
fetal neuroprotection, although they did not specify a specific
gestational age. Though this recommendation remains in place,
further studies may provide additional clarification. 
Summary
Cerebral palsy is a significant adverse event with origins in
pregnancy. Many risk factors have been identified, although
sometimes no etiologic factor is found. Strategies to reduce
asphyxia and prevent preterm birth have not shown a significant
decrease in rates of CP. Because most CP is related to extremely
preterm birth and the survival rates of these ELBW infants is
improving, strategies to reduce neonatal brain injury such as
the use of antenatal steroids are currently the most promising.
Future trials of antenatal neuroprotection for preterm infants
may prove beneficial to combat inflammatory-­or cytokine-­
mediated brain injury.  publication of guidelines for intrapartum antibiotic prophylaxis
Infectious Disease Problems
Neonatal Infection
Neonatal infection is a significant cause of neonatal morbidity
and mortality in preterm and term infants. The risk of infection
is inversely related to gestational age. The clinical manifestations
of neonatal infection vary by pathogen and age of acquisition.
The spectrum of pathogens causing neonatal infection is broad
and has changed over the decades.396 However, the cornerstones
of management remain prevention whenever possible, early
detection, and focused treatment.
Compared with older children and adults, neonatal host
defense is blunted by incomplete development and experience
with self-­versus nonself-­ discrimination.397 All components
of the neonatal immune system are deficient, a circumstance
that is exacerbated by preterm delivery. Nonspecific immunity
is defective at several levels. Skin and mucosal barriers are
immature, especially in preterm infants. Levels of nonspecific
antibacterial proteins such as lysozyme and lactoferrin are low.
Neutrophil numbers are low with limited bone marrow storage
pools recruitable to clear bacteria. Key neutrophil functions
including chemotaxis, phagocytosis, and intracellular killing
are rudimentary. Thus the neonate is poorly equipped to clear
transient bacteremia and localize bacterial infection. Specific
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1433
humoral and cell-­mediated immune functions are also very
limited.
Circulating immunoglobulin levels are low compared to
adult levels. The neonate acquires virtually all circulating IgG
from the mother via transplacental transport. The bulk of this
antibody is transferred during the third trimester, making the
preterm infant profoundly deficient. B-­cell function is immature
as well. The primary antibody response to infection mediated
by the infant is production of IgM. Although T-­lymphocytes
are present at birth, their function is nearly undetectable by
standard functional assays.
The nature of neonatal immune function accounts for
the clinical manifestations of most early-­ onset infections.
Nonspecific signs such as lethargy, poor feeding, temperature
instability, decreased tone, apnea, and altered perfusion may
or may not be present. Fever is uncommon, as are localized
processes such as cellulitis, abscesses, or osteomyelitis. When
present, they are usually accompanied by bacteremia. Similarly,
bacteremia must always be presumed in neonates with culture-­
proven meningitis or urinary tract infections. 
Group B Beta Hemolytic Streptococcus
Group B beta hemolytic streptococcus (GBS) was first recognized
as a cause of early-­onset neonatal sepsis in the 1970s. By the
1990s, GBS was a leading cause of serious neonatal infections.
The organism is a common colonizing constituent of the vagina
and rectum in 15%–40% of pregnant women. GBS colonization
is more common in those with a previous history of a neonate
with GBS disease or a history of a GBS urinary tract infection.
Epidemiologic studies demonstrated that most invasive, early-­
onset neonatal GBS disease involves vertical transmission
from mother to fetus during labor. This observation led to
studies of intrapartum antibiotic prophylaxis with penicillin
G or ampicillin. The success of this strategy prompted the
by the Centers for Disease Control and Prevention (CDC).398
A follow-­up study completed in 2005 confirmed the success of
this strategy.341 Further laboratory-­based surveillance data have
shown that from 2006 to 2015 the incidence of early-­onset GBS
disease continued to decrease from 0.37 to 0.23 cases per 1000
live births.399
In 2020, guidance from the ACOG replaced prior CDC
guidelines with recommendations that all pregnant women
undergo screening for vaginal-­ rectal GBS colonization at
36 0/7 to 37 6/7 weeks’ gestation.400 Women with positive
cultures should receive intrapartum antibiotic prophylaxis
unless a cesarean delivery without labor is performed. It is
recommended that women with a history of GBS bacteriuria in
the current pregnancy or history of a prior infant with invasive
GBS disease receive antibiotic prophylaxis independent of
screening results.400 Most invasive, serious GBS cases now seen
are born to mothers with negative GBS screening cultures who
have presumably converted to GBS-­positive carrier status in the
interval between screening and delivery.401 Rapid GBS screening
technology may allow for identification of these women when
they present in labor, although reported sensitivities vary.402
There is some concern that intrapartum antibiotic
prophylaxis may be associated with a higher incidence of
serious bacterial infections later in infancy. This was most
pronounced when broad-­spectrum antibiotics were used for
intrapartum prophylaxis rather than penicillin G.403 At present,
1434 Part 6  The Neonate
the advantages of intrapartum antibiotic prophylaxis to reduce
the risk of invasive neonatal GBS disease clearly outweigh any
risks, especially if penicillin is employed. Although intrapartum
antibiotic prophylaxis has been shown to reduce the risk of
early-­onset GBS sepsis (illness onset day 0–6 of life), it has not
influenced the incidence of late-­onset GBS sepsis (illness onset
day 7–89 of life).  when holding and breastfeeding their infant. Breastfeeding is
Chorioamnionitis
The relationship between chorioamnionitis and neonatal
infection is complex and remains incompletely understood.
Some studies demonstrate a direct correlation between
chorioamnionitis and neonatal infection. Other poor neonatal
outcomes including RDS, BPD, and CP are also associated
with chorioamnionitis.116,404 However, other clinical series
and studies using animal model systems have reached the
opposite conclusion, that chorioamnionitis protects against
these same outcomes.405,406 Some of the confusion is grounded
in definitions of chorioamnionitis. Clinical chorioamnionitis,
as characterized by maternal fever and uterine tenderness,
is probably a very different pathophysiologic process from
clinically silent histologic chorioamnionitis commonly
seen in association with preterm deliveries.407,408 Whether
these represent different disease entities or simply different
manifestations of the same disease spectrum is not clear. Recent
efforts have been made to redefine intraamniotic infection
(IAI) into three categories: (1) isolated maternal fever, (2)
suspected triple I, and (3) confirmed triple I.409 Triple I refers
to intrauterine inflammation, infection, or both. Recent studies
have shown a high rate of adverse infectious outcomes in cases
of isolated maternal fever, suggesting that these women may
benefit from being treated as if they have suspected triple I.410
Despite these recent efforts to achieve a universal consensus
on clinically defining chorioamnionitis, clinical variability still
exists.  Approximately 1% of all liveborn infants are infected in utero
Viral Infections
Coronavirus Disease 2019 (COVID-­19)
Coronavirus disease 2019, or COVID-­ 19, is a viral illness
caused by a novel coronavirus, SARS-­CoV-­2, first identified
in 2019. The main route of transmission is through respiratory
droplets, with person-­ to-­
person transmission leading to a
worldwide pandemic in 2020–22. Vertical transmission in the
perinatal period has also been reported. Previous reports have
found perinatal transmission rates from mother to infant to be
approximately 2%–3%.411,412
Infection with SARS-­ CoV-­2 during pregnancy has been
associated with increased maternal morbidity. An increased
incidence of medically indicated preterm birth has also been
reported. The most common causes of preterm birth include
small for gestational age, preeclampsia/eclampsia/HELLP
syndrome, and fetal distress.413 Studies have not found an
increased rate of spontaneous preterm birth.413 In general,
neonates infected with SARS-­CoV-­2 have been described as
having mild symptoms or asymptomatic. However, a recent
report found a higher incidence of neonatal morbidities in
infants born to COVID-­ positive mothers when compared
to COVID-­ negative mothers, even when controlling for
prematurity.413 Additional studies are needed.
Current recommendations based on available evidence do
not support separating mother and infant after delivery in the
setting of an asymptomatic COVID-­positive mother. Delayed
cord clamping and skin-­to-­skin care (with mothers wearing a
mask) should be performed per practice standards. Mothers are
encouraged to perform proper hand hygiene and wear a mask
recommended. Although SARS-­CoV-­2 RNA has been found
in breast milk, viable virus has not been detected,414 and an
increased risk of neonatal infection has not been found in
breastfed infants.413
Due to the potential risk of vertical transmission, appropriate
personal protective equipment (PPE) should be used when
caring for infants born to mothers with COVID infection.
COVID PCR testing of the infant at approximately 24 and 48
hours of life is recommended. If both tests are negative, the
infant can be considered negative for COVID. If an infant is
discharged from the hospital prior to 48 hours of life, a single
COVID PCR test can be administered between 24 and 48 hours
of life. Due to rapidly changing information, it is recommended
that clinicians reference the CDC and AAP recommendations
for the most up-­to-­date guidelines. 
Cytomegalovirus
Human cytomegalovirus (CMV) is transmitted horizontally
(by direct person-­ to-­person contact with virus-­ containing
secretions), vertically (from mother to infant before, during,
or after birth), and via transfusion of blood products or organ
transplantation from previously infected donors. Vertical
transmission of CMV to infants occurs by one of the following
routes of transmission: (1) in utero by transplacental passage of
maternal blood borne virus, (2) through an infected maternal
genital tract, and (3) postnatally by ingestion of CMV-­positive
human milk.415,416
and excrete CMV at birth. Risk to the fetus is greatest in the first
half of gestation. Fetal infection can occur either after maternal
primary infection or after reactivation of infection during
pregnancy. Sequelae are far more common in infants exposed
to maternal primary infection, with 10% to 20% of infants
manifesting neurodevelopmental impairment or sensorineural
hearing loss in childhood.417 Congenital CMV infection is the
most common cause of nonhereditary sensorineural hearing loss.
Congenital CMV infection is usually clinically silent.
Some infected infants who appear healthy at birth are
subsequently found to develop hearing loss or learning
disabilities. Approximately 10% of infants with congenital
CMV infection exhibit evidence of profound involvement
at birth, including intrauterine growth restriction, jaundice,
purpura, hepatosplenomegaly, microcephaly, intracerebral
calcifications, and retinitis.418 Testing for congenital CMV
should be considered in a newborn presenting with symptoms
consistent with congenital CMV that are not otherwise
explained. Congenital CMV infection can be diagnosed based
on urine PCR testing within 3 weeks of birth. Testing of saliva
is also an available testing modality; however, urine is preferred
due to a higher false-­positive and false-­negative rate with saliva
samples.419 Testing after 3 weeks of age cannot distinguish
between congenital and postnatally acquired CMV.
Ganciclovir and valganciclovir are the first-­ line antiviral
treatment for congenital CMV. Six months of antiviral

treatment initiated after birth has been shown to improve long-­
term outcomes in infants with symptomatic congenital CMV
infection.420–422 Due to concerns for potential side effects and
longer-­term toxicity of antiviral treatment, routine treatment
of asymptomatic infants with congenital CMV and normal
hearing is not recommended at this time. However, differences
in expert opinion exist as to whether antiviral treatment should
be offered to asymptomatic infants with congenital CMV and
isolated hearing loss. Parents should be carefully counseled
before starting treatment.420,421
Infection acquired intrapartum from maternal cervical
secretions or postpartum from human milk usually is not
associated with clinical illness. Infections resulting from
transfusion of blood products with CMV-­seropositive donors
and from human milk to preterm infants have been associated
with serious systemic infections, including lower respiratory
tract infection. Transmission of CMV by transfusion to
newborn infants has been reduced by using CMV-­antibody
negative donors, by freezing erythrocytes in glycerol, or by
removal of leukocytes by filtration prior to administration.423
CMV transmission by human milk is also decreased by
pasteurization.424 However, freeze-­ thawing is probably not
effective.425 If fresh donor milk is needed for infants born to
CMV antibody–negative mothers, provision of these infants
with milk from only CMV antibody–negative women should
be pursued.  hepatitis B vaccination. However, by 1 month chronological
Hepatitis B
Hepatitis B virus (HBV) is a DNA virus whose important
components include an outer lipoprotein envelope containing
HBsAg and an inner nucleocapsid containing the hepatitis
B core antigen. Only antibody to HBsAg (anti-­HBs) provides
protection from HBV infection. Perinatal transmission of HBV
is highly efficient and usually occurs from blood exposure
during labor and delivery. In utero transmission of HBV is rare,
less than 2% of perinatal infections in most studies. Without
prophylaxis, the risk of an infant acquiring HBV from an infected
mother due to perinatal exposure is 70% to 90% for infants born
to mothers who are HBsAg and HBeAg positive. The risk is 5%
to 20% for infants born to mothers who are HBsAg positive
and HBeAg negative. Age at the time of acute infection is the
primary determinant of risk of progression to chronic HBV
infection. More than 90% of infants with perinatal infection will
develop chronic HBV infection.426 Risk of perinatal hepatitis
B infection in infants with perinatal exposure who receive
recommended immunoprophylaxis and the hepatitis B vaccine
series is approximately 1%.427
The goals of HBV prevention programs are to prevent the
acute HBV infection and to decrease the rates of chronic HBV
infection and HBV-­related chronic liver disease. Over the past
2 decades, a strategy has been progressively implemented in
the United States to prevent HBV transmission. This includes
the following components: (1) universal immunization of
infants beginning at birth, (2) prevention of perinatal HBV
infection by routine screening of all pregnant women and
appropriate immunoprophylaxis of infants born to HBsAg-­
positive women and infants born to women with unknown
HBsAg status, (3) routine immunization of children and
adolescents who have previously not been immunized, and
(4) immunization of previously nonimmunized adults at
increased risk of infection.
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1435
Two types of products are available for hepatitis B
immunoprophylaxis. Hepatitis B immune globulin (HBIG)
provides short-­term protection (3 to 6 months) and is indicated
only in postexposure circumstances. Hepatitis B vaccine
is used for preexposure and postexposure protection and
provides long-­ term protection. Preexposure immunization
with hepatitis B vaccine is the most effective means to prevent
HBV transmission. To decrease the HBV transmission rate
universal immunization is necessary. Postexposure prophylaxis
with both hepatitis B vaccine and HBIG have been shown to
be superior to prophylaxis with the hepatitis B vaccine alone.428
The effectiveness of postexposure immunoprophylaxis is related
to the time elapsed between exposure and administration.
Immunoprophylaxis is most effective if given within 12 hours
of exposure. Infants with perinatal hepatitis B exposure should
receive both the hepatitis B vaccine and HGIB within the first
12 hours of life when feasible. Serologic testing of all pregnant
women for HBsAg is essential for identifying women whose
infants will require postexposure prophylaxis immediately after
birth.
Hepatitis B vaccines are highly effective and safe. These
vaccines are 90% to 95% efficacious for preventing HBV
infection. Studies in preterm infants and low-­ birth-­weight
infants (less than 2000 g birth weight) have demonstrated
decreased seroconversion rates following administration of
age, medically stable preterm infants should be immunized,
regardless of initial birth weight or gestational age. Infants
with a birth weight of 2000 g or greater should receive the
hepatitis B vaccine within the first 24 hours of life.429 Routine
postimmunization testing for anti-­HBs is not necessary for
most infants. However, postimmunization testing for HBsAg
and anti-­HBs at 9 to 12 months of age is recommended for
infants born to HBsAg-­positive mothers.
Immunization of pregnant women with hepatitis B vaccine
has not been associated with adverse effects on the developing
fetus. Because HBV infection may result in severe disease in the
mother and chronic infection in the newborn infant, pregnancy
is not considered a contraindication to immunization. Lactation
is also not a contraindication to immunization. Breastfeeding is
considered safe in the absence of cracked and bleeding nipples
if the infant appropriately received the hepatitis B vaccine and
HBIG after birth. 
Hepatitis C
Hepatitis C virus (HCV) is a small, enveloped RNA virus that is
a significant cause of chronic liver disease in the United States.
The overall incidence of HCV infection has risen during the
opioid epidemic. Vertical transmission can lead to perinatal
acquisition in infants born to mothers who are HCV positive.
The incidence of perinatal-­acquired infection ranges from 5%
in infants born to mothers with viremia to 10% for infants with
maternal coinfection with HIV and HCV.430 Additional factors
shown to be associated with an increased incidence of perinatal
transmission include HCV infection of peripheral mononuclear
cells, high viral load, and history of IV drug use.431
Factors that may be associated with an increased risk
of perinatal HCV infection include prolonged rupture of
membranes, invasive prenatal testing, and invasive obstetric
procedures. The potential risks and benefits in each of these
situations should be considered in patient care decisions.
1436 Part 6  The Neonate
Neither mode of delivery nor breastfeeding (in the absence of
cracked and bleeding nipples) have been shown to be associated
with increased risk of transmission. Newborns with HCV are
most often asymptomatic. Unfortunately, there is no currently
available treatment for infants to decrease the incidence of
perinatal transmission. Prevention focuses on the identification
and treatment of women with HCV infection prior to pregnancy.
Maternal HCV testing is standard during pregnancy. Routine
testing is important to identify infants at risk of perinatal
infection. Follow-­up and testing of infants born to mothers
with HCV infection is crucial. Anti-­HCV IgG antibody testing
is recommended at 18 months of age in the setting of perinatal
exposure. As an alternative, RNA testing may be performed
at earlier ages. Antibody testing prior to 18 months of age is
not routinely recommended as maternal IgG antibodies could
result in false-­positive results. Children with confirmed HCV
infection need to be followed closely for progression of disease,
risk of hepatocellular carcinoma, and future eligibility for
antiviral treatment.  antiretroviral therapy achieving sustained maternal viral loads
Herpes Simplex Virus
Neonatal herpes simplex virus (HSV) infections are most
commonly due to perinatal infection, although in rare cases
intrauterine and postnatal infection can occur. Neonatal HSV
infection can be categorized into three subgroups: (1) localized
skin, eye, and mouth (SEM) disease; (2) central nervous system
(CNS) disease; and (3) disseminated disease. The SEM disease
commonly presents in the first 2 weeks of life as clusters of
vesicles, conjunctival erythema, and oral lesions, and can
progress to CNS or disseminated disease without treatment. The
CNS disease can present at 2 to 3 weeks of life as hypothermia,
irritability, lethargy, seizures, and bulging fontanelle.
Disseminated disease often presents in the first 2 weeks of life
with symptoms of multisystem organ failure. Although most
common in the first few weeks of life, all categories of neonatal
HSV can present within the first 6 weeks of life and should be
considered on the differential diagnosis of an infant presenting
with any symptoms of neonatal HSV.
In infants with suspicion for HSV, viral cultures or HSV PCR
testing should be obtained from surface swabs (conjunctiva,
mouth, nasopharynx, and rectum), any skin lesions, blood,
and CSF. Intravenous acyclovir is the recommended treatment,
with a minimum of 14 days of treatment for SEM disease and
a minimum of 21 days for CNS and disseminated disease.
Although antiviral treatment has improved survival, mortality
in disseminated disease is still approximately 30%. After
completion of the initial treatment course, oral suppressive
therapy with acyclovir is recommended for 6 months. This
has been shown to reduce SEM recurrence and improve
developmental outcomes in CNS disease.432
In 2013, AAP published guidelines on the management
of the asymptomatic neonate born to a mother with active
genital lesions at the time of delivery.433 Guidelines consider
the increased risk of transmission in a primary infection. At 24
hours of life, it is recommended that all infants born to a mother
with an active genital HSV lesion have HSV surface cultures and
blood PCR obtained. If the mother has a history consistent with
a recurrent infection, the infant can be monitored clinically
off acyclovir. In the setting of a history of concern for primary
maternal infection, HSV PCR from the CSF and LFTs should
also be obtained, and the infant should be started on IV acyclovir
while awaiting lab results and maternal serology to determine
whether infection is primary or recurrent. It is important to note
that recommendations apply regardless of mode of delivery. In
the event of an infant born to a mother with an active genital
HSV lesion, it is recommended that the clinician reference the
AAP guidelines for further detailed guidance.433 
Human Immunodeficiency Virus
Landmark studies in the 1990s434–436 demonstrated the value
of intrapartum antiretroviral therapy to reduce the risk of
maternal-­ to-­
fetal transmission of human immunodeficiency
virus (HIV). Higher maternal viral loads during pregnancy are
associated with higher risk of congenital HIV. Improvements
in the quality and availability of rapid HIV testing allows for
more timely and accurate identification of infected women and
their newborn infants. The risk of congenital HIV is reduced
to approximately 1%–2% when HIV-­positive mothers receive
of ≤1000 copies/mL during pregnancy.437 Breastfeeding is
contraindicated due to risk of transmission, unless there is no
access to clean water and infant formula.
Transplacental passage of maternal antibodies complicates
use of antibody-­ based assays for diagnosis of infection in
infants because all infants born to HIV-­seropositive mothers
have passively acquired maternal antibodies that can persist
for months. Laboratory diagnosis of HIV infection during
infancy relies on detection of virus or viral nucleic acid. Cord
blood should not be used for this early test because of possible
contamination by maternal blood. A positive result within
48 hours of birth identifies infants who have been infected in
utero. Approximately 90% of infected infants have detectable
HIV DNA at 2 weeks and nearly all HIV-­infected infants have
positive HIV DNA PCR assay results by 3 months of age. Serial
HIV DNA PCR assays should be obtained between birth and 6
months of age, with frequency and timing of testing dependent
on transmission risk level.
All infants with perinatal exposure to HIV should be started
on antiretroviral therapy as soon as possible after birth, ideally
within 6 hours. The specific antiviral regimen depends on both
maternal and infant factors. Because therapeutic options for
HIV infection continue to evolve, consultation with an expert
in pediatric HIV management is recommended. 
Rubella
Humans are the only source of infection. Peak incidence of
infection is in late winter and early spring. Before widespread
use of rubella vaccine, rubella was an epidemic disease spread via
airborne droplets, with most cases occurring in children. With
implementation of rubella vaccination programs, the incidence
of rubella has drastically decreased. Globally, congenital
rubella syndrome still occurs, with approximately 100,000
cases reported each year.393 Endemic rubella transmission
was eradicated in the Americas in 2009.438 However, potential
outbreaks among unvaccinated populations in the United
States remain a concern and raise the theoretical possibility of
exposure during pregnancy.439
Congenital rubella syndrome is characterized by a
constellation of anomalies that may include ophthalmologic
(cataracts, microphthalmos, pigmentary retinopathy, and
congenital glaucoma), cardiac (patent ductus arteriosus and

peripheral pulmonary artery stenosis), auditory (sensorineural
hearing impairment), and neurologic (meningoencephalitis,
behavioral abnormalities, and developmental delay)
abnormalities. Neonatal manifestations of congenital rubella
syndrome include fetal growth restriction, interstitial
pneumonia, radiolucent bone disease, hepatosplenomegaly,
thrombocytopenia, and dermal erythropoiesis, also termed
blueberry muffin lesions. The occurrence of congenital defects
varies with timing of the maternal infection, with infections
early in pregnancy at highest risk for congenital defects.
Detection of rubella-­specific IgM antibody usually indicates
recent postnatal infection or congenital infection in a newborn
infant; however, both false-­positive and false-­negative results
occur. Congenital infection can be confirmed by stable or
increasing rubella-­specific IgG over several months. Rubella
virus can be isolated most consistently from throat or nasal
swabs by inoculation of appropriate cell culture. Blood, urine,
cerebrospinal fluid, and pharyngeal swab specimens can also
yield virus in congenitally infected infants.
Treatment for infants with congenital rubella syndrome
includes supportive care and close follow-­up to monitor for
the development of long-­term complications. Antivirals have
not been shown to impact long-­term outcomes. Infants with
congenital rubella should be considered contagious until at
least 1 year of age, unless nasopharyngeal and urine cultures are
repeatedly negative for rubella virus. Caregivers of these infants
and children should be made aware of the potential hazard to
susceptible pregnant contacts.  to mothers with known gonococcal infection rarely develop
Sexually Transmitted Infections
Chlamydia
Chlamydia trachomatis is the most common bacterial sexually
transmitted infection in the United States. In the newborn
period, Chlamydia trachomatis is associated with conjunctivitis
and pneumonia. Acquisition of Chlamydia trachomatis occurs
in approximately 50% of infants born vaginally to infected
mothers and in some infants delivered by cesarean with
intact membranes.440 Neonatal chlamydial conjunctivitis is
characterized by ocular congestion, edema, and discharge
developing at 5–14 days of life. Pneumonia in infants is usually
an insidious afebrile illness occurring 4–12 weeks after birth.
It is characterized by a staccato cough, tachypnea, and rales on
physical examination. Pulmonary hyperinflation and infiltrates
are demonstrated on the chest radiograph.
The recommended topical prophylaxis with erythromycin, or
tetracycline for all newborn infants for gonococcal ophthalmia, will
not prevent chlamydial conjunctivitis or extraoccular infections.441
Infants with chlamydial conjunctivitis are treated with oral eryth-
romycin base or ethylsuccinate (50 mg/kg per day in four divided
doses) for 14 days or azithromycin (20 mg/kg per day as a single
dose) for 3 days. Routine treatment prophylaxis for asymptomatic
infants born to mothers with active chlamydial infections is not rec-
ommended. Infants should be monitored for symptoms and treated
if infection occurs. Treatment for chlamydial conjunctivitis should
be initiated after a confirmed diagnosis, whereas treatment for chla-
mydial pneumonia can be initiated based on a presumed clinical
diagnosis while confirmatory testing is pending.
Chlamydial conjunctivitis and pneumonia are treated similarly,
with oral erythromycin base (50 mg/kg per day in four divided
doses) for 14 days or with oral azithromycin (20 mg/kg/day) for
73  Neonatal Morbidities of Prenatal and Perinatal Origin 1437
3 days. Because the efficacy of treatment is about 80%, follow-­up
of infants is recommended. In some instances, a second course of
therapy may be required. Detection and treatment of maternal C.
trachomatis infections before delivery is the most effective way to
reduce the risk of neonatal conjunctivitis and pneumonia.
Gonococcal Infections
Infection with Neisseria gonorrhoeae in the newborn infant
most commonly presents as purulent conjunctivitis, occurring
at 2–5 days of life. Other types of gonococcal infections include
arthritis, disseminated disease with bacteremia, meningitis,
scalp abscess, or vaginitis. Microscopic examination of gram-­
stained smears of exudates from the eyes, skin lesions, synovial
fluid, and, when clinically warranted, CSF may be useful in the
initial evaluation. Identification of gram-­negative intracellular
diplococci in these smears can be helpful if the organism is not
recovered in culture. Neisseria gonorrhoeae can be cultured from
normally sterile sites such as blood, CSF, and synovial fluid.
For routine ophthalmia neonatorum prophylaxis of
infants immediately after birth, or 1% tetracycline, or 0.5%
erythromycin ophthalmic ointment, is instilled into each eye.
Silver nitrate, though effective, causes more chemical irritation
than antimicrobials and is no longer available in the United
States. Prophylaxis may be delayed for as long as 1 hour after
birth to facilitate parent-­infant bonding.
When topical prophylaxis is administered, infants born
gonococcal ophthalmia. However, because gonococcal
ophthalmia or disseminated disease occasionally can occur
in this situation, infants born to mothers known to have an
untreated gonorrhea infection should receive a single dose of
ceftriaxone, 25 to 50 mg/kg, intravenously or intramuscularly,
not to exceed 125 mg.
Infants with clinical evidence of ophthalmia neonatorum, scalp
abscess, or disseminated disease should be hospitalized. Infants
with gonococcal ophthalmia should be evaluated for disseminated
infection. Cultures of the blood, CSF, eye discharge, or other sites of
infection should be performed to confirm the diagnosis, assess for
disseminated infection, and determine antimicrobial susceptibility.
Tests for concomitant infection with C. trachomatis, syphilis, and
HIV infection should be performed. Recommended treatment
for ophthalmia neonatorum is ceftriaxone (25–50 mg/kg,
intravenously or intramuscularly, not to exceed 125 mg) given once.
Infants with gonococcal ophthalmia should receive eye irrigations
with saline solution immediately and at frequent intervals until the
discharge is eliminated. Left untreated, gonococcal ophthalmia
can result in ulceration, scarring, and visual impairment. Topical
antimicrobial treatment alone is inadequate and is unnecessary
when recommended systemic antimicrobial treatment is provided.
Recommended therapy for arthritis and septicemia is ceftriaxone
or cefotaxime for 7 days. If meningitis is documented, treatment
should continue for a total of 10 to 14 days. Ceftriaxone should not
be used in infants receiving calcium-­containing fluids due to risk of
precipitation. Cefotaxime is the recommended agent in the setting
of significant hyperbilirubinemia due to the risk of ceftriaxone
displacing bilirubin from albumin.
Syphilis
Congenital syphilis remains a significant public health problem
in the United States. It is contracted from an infected mother via
1438 Part 6  The Neonate
transplacental transmission of Treponema pallidum at any time
during the pregnancy or delivery. Intrauterine syphilis can cause
stillbirth, hydrops fetalis, or preterm birth. Affected infants may
present with edema, hepatosplenomegaly, lymphadenopathy,
mucocutaneous lesions, osteochondritis, pseudoparalysis, rash,
or snuffles at birth or within the first 2 months of life. However,
lack of these findings does not rule out neonatal disease.
Additionally, hemolytic anemia or thrombocytopenia may be
identified on laboratory evaluation. Untreated infants, regardless
of whether they have manifestations in infancy, may develop
late manifestations, usually after 2 years of age and involving
the bones, CNS, eyes, joints, and teeth. Some consequences of
intrauterine infection may not become apparent until many
years after birth.
Definitive diagnosis is established by identification of
spirochetes by microscopic dark-­field examination or by direct
fluorescent antibody tests of lesion exudates or tissue such as the
placenta or umbilical cord. Presumptive diagnosis is possible
using nontreponemal and treponemal tests. The use of only one
type of test for diagnosis is insufficient, because false-­positive
nontreponemal tests occur with various medical conditions and
false-­positive treponemal tests can occur with other spirochetal
diseases.
No newborn infant should be discharged from the hospital
without determination of the mother’s serological status for
syphilis.442 All infants born to seropositive mothers require a
careful examination and a quantitative nontreponemal syphilis
test. The laboratory test performed in the infant should be the
same as that performed on the mother, ideally from the same
testing facility, so that comparison of titer results is facilitated. An
infant should be evaluated for congenital syphilis if the maternal
titer has increased fourfold, if the infant titer is fourfold greater
than the mother’s titer, or if the infant has clinical manifestations
of syphilis. Additionally, the infant should be evaluated if born
to a mother with positive nontreponemal and treponemal test
results if the mother has any of the following conditions: (1)
maternal syphilis has not been treated or treatment has not
been documented, (2) maternal syphilis during pregnancy was
treated with a nonpenicillin regimen, (3) maternal syphilis was
treated less than 1 month prior to delivery because treatment
failures occur and efficacy cannot be assumed, and, finally,
(4) maternal syphilis was treated before pregnancy but with
insufficient follow-­up to assess the response to treatment and
current infection status.443
Evaluation for syphilis in an infant should include a physical
examination, a quantitative nontreponemal syphilis test of
serum, a VDRL test of the CSF and analysis of the CSF for
cells and protein concentration, long bone radiographs, and a
complete blood cell and platelet count. Other clinically indicated
tests might include a chest radiograph, liver function tests,
abdominal ultrasonography, ophthalmologic examination, and
an auditory brainstem response test. Pathologic examination of
the placenta or umbilical cord using specific anti-­treponemal
antibody staining is also recommended.
Infants should be treated for congenital syphilis if they have
proven or probable disease demonstrated by one or more of the
following: (1) physical, laboratory, or radiographic evidence of
active disease, (2) positive placenta or umbilical cord test results
for treponemes using direct fluorescent antibody T. pallidum
staining or dark-­field test, (3) a reactive result on VDRL on
testing of CSF, or (4) a serum quantitative nontreponemal titer
is at least fourfold higher than the mother’s titer using the same
test and preferably the same laboratory. If the infant’s titer is less
than four times that of the mother, congenital syphilis still can
be present. When circumstances warrant evaluation of an infant
for syphilis, the infant should be treated if test results cannot
exclude infection, if the infant cannot be adequately evaluated,
or if adequate follow-­up cannot be ensured.
Infants with proven congenital syphilis should be treated
with aqueous crystalline penicillin G. The dosage should be
based on chronologic, not gestational age. The dose of penicillin
G is 100,000 to 150,000 units/kg per day administered as 50,000
U/kg per dose intravenously every 12 hours during the first
7 days of life and then every 8 hours thereafter for a total of
10 days. Alternatively, penicillin G procaine 50,000 U/kg per
day intramuscularly for 10 days may be considered; however,
adequate CSF concentrations may not be achieved with this
regimen.
A full reference list is available online at ExpertConsult.
com.