This document summarizes common neonatal morbidities that can result from complications during pregnancy and delivery. It discusses how conditions like diabetes, hypertension, infection, and nutritional imbalances in the mother can negatively impact the health of the newborn. The summary provides management considerations for treating infants born with various medical issues and outlines how close collaboration between obstetric and neonatal clinicians is important for counseling families and ensuring the best outcomes for both mother and baby.

1. Chapter 58
Neonatal Morbidities of Prenatal and
Perinatal Origin
James M. Greenberg, MD, Vivek Narendran, MD, Kurt R. Schibler, MD,
Barbara B. Warner, MD, Beth Haberman, MD, and Edward F. Donovan, MD
Obstetric and Postnatal Common Morbidities
Management Decisions of Pregnancy and
The nature of obstetric clinical practice requires consideration of two Neonatal Outcomes
patients: mother and fetus. The intrinsic biologic interdependence of
one with the other creates challenges not typically encountered in Complications of pregnancy that affect infant well-being may be
other realms of medical practice. Often, there is a paucity of objective immediately evident after birth, such as hypotension related to mater-
data to support the evaluation of risks and benefits associated with a nal hemorrhage, or may manifest hours later, such as hypoglycemia
given clinical situation, forcing obstetricians to rely on their clinical related to maternal diabetes or thrombocytopenia related to maternal
acumen and experience. Family perspectives must be integrated in preeclampsia. Anemia and thyroid disorders related to transplacental
clinical decision making, along with the advice and counsel of other passage of maternal IgG antibodies to platelets or thyroid, respectively,
clinical providers. In this chapter, we review how to best use neonato- may manifest days after delivery.
logic expertise in the obstetric decision-making process. Diabetes during pregnancy serves as an example. Infants born to
Optimal perinatal care often derives from collaboration between women with diabetes are often macrosomic, increasing the risk of
the obstetrician and neonatologist during pregnancy and especially shoulder dystocia and birth injury. After delivery, these infants may
around the time of labor to eliminate ambiguity and confusion in the have significant hypoglycemia, polycythemia, and electrolyte distur-
delivery room and to ensure that patients and families understand the bances, which require close surveillance and treatment. Lung matura-
rationale for obstetric and postnatal management decisions. The neo- tion is delayed in the infants born to women with diabetes, increasing
natologist can provide information regarding risks to the fetus associ- the incidence of respiratory distress syndrome (RDS) at a given gesta-
ated with delaying or initiating preterm delivery and can identify the tional age. Infants of diabetic mothers may also have delayed neuro-
optimal location for delivery to ensure that skilled personnel are logic maturation, with decreased tone typically leading to delayed
present to support the newborn infant. feeding competence. Less common complications include an increased
In addition to contributing information about gestational age– incidence of congenital heart disease and skeletal malformations.
specific outcomes, the neonatologist can anticipate neonatal com- These neonatal complications are typically managed without long-
plications related to maternal disorders such as diabetes mellitus, term sequelae, but they are not without consequences, such as pro-
hypertension, and multiple gestations or to prenatally detected fetal longed hospital stay. Neonatal complications for the infant of a woman
conditions such as congenital infections, alloimmunization, or devel- with diabetes are a function of maternal glycemic control. Careful
opmental anomalies. When a lethal condition or high risk of death in antenatal attention to optimal control of blood glucose can reduce
the delivery room is anticipated, the neonatologist can assist with the neonatal morbidity due to maternal diabetes.
formulation of a birth plan and develop parameters for delivery room Table 58-1 summarizes other morbidities of pregnancy and their
intervention. effects on neonatal outcome. The list is not exhaustive and does not
Preparing parents by describing delivery room management and take into account how multiple morbidities may interact to create
resuscitation of a high-risk infant can demystify the process and reduce additional complications. All of these problems may contribute to
some of the fear anticipated by the expectant family. Premature infants increased length of hospital stay after delivery and to long-term
are susceptible to thermal instability and are moved rapidly after birth morbidity.
to a warming bed to prevent hypothermia while assessing the infant’s Chorioamnionitis has diverse effects on the fetus and neonatal
cardiorespiratory status and vigor. The need for resuscitation is deter- outcome. It is associated with premature rupture of membranes
mined by careful evaluation of cardiorespiratory parameters and and preterm delivery. Elevated levels of proinflammatory cytokines
appropriate response according to published Neonatal Resuscitation may predispose neonates to cerebral injury.2 Although suspected or
Program guidelines.1 proven neonatal sepsis is more common in the setting of chorioamnio-

2. 1198 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
TABLE 58-1 MANAGEMENT CONSIDERATIONS ASSOCIATED WITH NEONATAL MANAGEMENT OF
CONGENITAL MALFORMATIONS
Malformation Management Considerations
Clefts Alternative feeding devices (e.g., Haberman feeder), genetics evaluation, occupational or physical
therapy
Congenital diaphragmatic hernia Skilled airway management, pediatric surgery, immediate availability of mechanical ventilation,
nitric oxide, ECMO
Upper airway obstruction or micrognathia Skilled airway management, otolaryngologic evaluation, genetics evaluation and management,
immediate availability of mechanical ventilation
Hydrothorax Skilled airway management, nitric oxide, ECMO, chest tube placement, immediate availability of
mechanical ventilation
Ambiguous genitalia Endocrinology, urologic consultation, genetic profile available for immediate evaluation
Neural tube defects Dressings to cover defect, IV fluids, neurosurgery, urologic evaluation, orthopedics evaluation
and management
Abdominal wall defects Saline-filled sterile bag to contain exposed abdominal contents, IV fluids, pediatric surgery,
genetics evaluation and management
Cyanotic congenital heart disease IV access, prostaglandin E1, immediate availability of mechanical ventilation
ECMO, extracorporeal membrane oxygenation; IV, intravenous.
nitis, many neonates born to mothers with histologically proven day). Mothers experienced significant third-trimester weight loss, and
chorioamnionitis are asymptomatic and appear uninfected. Animal offspring were underweight.8 There is growing evidence that infants
models and associated epidemiologic data suggest that chorioamnio- undernourished during fetal life are at higher risk for “adult” diseases
nitis can accelerate fetal lung maturation, as measured by surfactant such as atherosclerosis and hypertension. Poor maternal nutrition
production and function. However, preterm infants born to mothers during intrauterine life may signal the fetus to modify metabolic path-
with chorioamnionitis are more likely to develop bronchopulmonary ways and blood pressure regulatory systems, with health consequences
dysplasia (BPD).3-5 The neonatal consequences of chorioamnionitis are lasting into late childhood and beyond.9 Conversely, maternal overnu-
likely related to the timing, severity, and extent of the infection and the trition (i.e., excessive caloric intake) predisposes mothers to insulin
associated inflammatory response. resistance and large-for-gestational-age infants.10,11
The effects of preeclampsia on the neonate include intrauterine Neonatal anemia may be a consequence of perinatal events such as
growth retardation, hypoglycemia, neutropenia, thrombocytopenia, placental abruption, ruptured vasa previa, or fetal-maternal transfu-
polycythemia, and electrolyte abnormalities such as hypocalcemia. sion. At delivery, the neonate may be asymptomatic or display pro-
Most of these problems appear related to placental insufficiency, with found effects of blood loss, including high-output heart failure or
diminished oxygen and nutrient delivery to the fetus. With delivery hypovolemic shock. The duration and extent of blood loss along with
and supportive care, most of these problems will resolve with time, any fetal compensation typically determine neonatal clinical status at
although some patients will require treatment with intravenous delivery and subsequent management. In the delivery room, prompt
calcium or glucose, or both, in the early neonatal period. Similarly, recognition of acute blood loss and transfusion with type O, Rh-
severe thrombocytopenia may require platelet transfusion therapy. negative blood can be a lifesaving intervention.
Preeclampsia may protect against intraventricular hemorrhage (IVH) Neonates from a multifetal gestation are, on average, smaller at a
in preterm infants, perhaps because of maternal treatment or other given gestational age than their singleton counterparts. They are also
unknown factors.6 Unlike intrauterine inflammation, preeclampsia more likely to deliver before term and therefore are more likely to
does not appear to accelerate lung maturation.7 experience the complications associated with low birth weight and
Maternal autoimmune disease may affect the neonate through prematurity described in this chapter. Monochorionic twins may expe-
transplacental transfer of autoantibodies. Symptoms are a function of rience twin-twin transfusion syndrome. The associated discordant
the extent of antibody transfer. Treatment is supportive and based on growth and additional problems of anemia, polycythemia, congestive
the affected neonatal organ systems. For example, maternal Graves heart failure, and hydrops may further complicate the clinical course
disease may cause neonatal thyrotoxicosis requiring treatment with after delivery, even after amnioreduction or fetoscopic laser occlusion.
propylthiouracil or β-blockers. Maternal lupus or connective tissue Cerebral lesions such as periventricular white matter injury and ven-
disease is linked to congenital heart block that may require long-term tricular enlargement may occur more frequently in the setting of twin-
pacing after delivery. Myasthenia gravis during pregnancy occasionally twin transfusion syndrome.12 Additional epidemiologic studies and
results in a transient form of the disease in the neonate. Supportive long-term follow-up are needed to further address this issue.
therapy during the early neonatal period addresses most issues associ- Congenital malformations present significant challenges for care-
ated with maternal autoimmune disorders. Passively transferred auto- givers and families, and prenatal diagnosis is an opportunity to provide
antibodies gradually clear from the neonatal circulation with a half-life anticipatory guidance. The neonatologist can facilitate delivery cover-
of 2 to 3 weeks. age and ensure availability of appropriate equipment, medications, and
Neonatal outcome associated with maternal nutritional status personnel. Table 58-1 summarizes some of the important consider-
during pregnancy is of growing interest. The Dutch famine of 1944 to ations associated with management of congenital malformations and
1945 created a unique circumstance for studying the consequences of reflects the importance of multidisciplinary input. Typically, these
severe undernutrition during pregnancy (i.e., caloric intake <1000 kcal/ patients are best delivered in a setting where experienced delivery

3. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1199
room attendance is available. If the needed consultative services and
equipment are not readily available, arrangement should be made for Complications of Prematurity
prompt transfer to a tertiary center. Successful transports depend Besides increased mortality risk, prematurity is associated with an
on clear communication between centers, for example, regarding increased risk for morbidity in almost every major organ system. BPD,
delivery of an infant with gastroschisis, so that the delivering retinopathy of prematurity, necrotizing enterocolitis, and IVH are par-
hospital provides adequate intravenous hydration and protection ticularly linked to preterm births. Intrauterine growth restriction and
of exposed abdominal organs, and the referral center can mobilize increased susceptibility to infection are not restricted to the preterm
pediatric surgical intervention immediately on arrival of the infant but are complicated in the immature infant. Table 58-2 sum-
infant. marizes common complications of prematurity by organ system.
In settings of premature, preterm, or prolonged rupture of mem- The rate of preterm birth increased by 30% between 1983 and
branes and premature labor, mothers are frequently treated with anti- 2004, from 9.6% to 12.5%. Three major causes have been identified
biotics and tocolytic agents. Maternal medications administered during to explain the rise (see Chapter 29): improved gestational dating asso-
pregnancy for non-obstetric diseases can have a significant impact on ciated with increased use of early ultrasound,16 the substantial rise in
the neonate. A common challenge in many centers is the treatment of multifetal gestation associated with assisted reproductive technology,
opiate-addicted mothers on methadone. The symptoms of neonatal and an increase in “indicated” preterm births.17 The latter category is
abstinence syndrome vary as a function of the degree of prenatal opiate important because decisions affecting the timing and management of
exposure and age after delivery. Many infants appear neurologically preterm delivery can have a profound effect on neonatal outcome.
normal at delivery, only to exhibit symptoms later on the first or The risk of death before birth hospital discharge doubles when the
second day or extrauterine life. Infants with neonatal abstinence syn- gestational age decreases from 27.5 weeks (10%) to 26 weeks (20%).
drome typically demonstrate irritability, poor feeding, loose and fre- Delaying delivery even for a few days may substantially improve
quent stools, and in severe cases, seizures. Treatment options include outcome, especially before 32 weeks, assuming that the intrauterine
nonpharmacologic intervention (e.g., swaddling, minimal stimula- environment is safe to support the fetus. However, in some clinical
tion), methadone, or non-narcotic drugs such as phenobarbital. These situations with a high potential for preterm delivery, it is difficult to
infants often require hospitalization for many days or weeks until their assess the quality of the intrauterine environment. Three common
irritability is under sufficient control to allow for care in a home examples are preterm, premature rupture of membranes (see Chapter
setting. There is clinical evidence that neonates may also exhibit similar 31), placental abruption (see Chapter 37), and preeclampsia (see
symptoms after withdrawal from antenatal nicotine exposure.13,14 The Chapter 35). In each case, prolonging gestation to allow continued
consequences of other illicit drug use during pregnancy have been fetal growth and maturation in utero is accompanied by an uncertain
widely studied but are difficult to assess because of difficulties with risk of rapid change in maternal status with a corresponding increased
diagnosis and confounding variables. Maternal cocaine abuse has been risk of fetal compromise. Tests of fetal well-being are discussed in
associated with obstetric complications such as placental abruption. Chapter 21, and clinical decision making in obstetrics is addressed in
Vascular compromise may predispose neonates to cerebral infarcts and Chapters 28 and 29.
bowel injury. Developmental delay and behavioral problems are Obstetric decisions about the timing of delivery in the setting of
observed, although associated factors such as poverty, lack of prenatal uncertain in utero risk are a significant contributing factor to the
care, and low socioeconomic status also contribute. increase in late preterm births, after 32 to 34 weeks. The contribution
Alloimmune hemolytic disorders such as Rh hemolytic disease of elective delivery must also be considered. Although perinatal mor-
and ABO incompatibility can cause neonatal morbidity ranging from
uncomplicated hyperbilirubinemia to severe anemia, hydrops, and
high-output congestive heart failure. Although it is uncommon, Rh
TABLE 58-2 COMMON COMPLICATIONS OF
hemolytic disease must be considered as a cause of unexplained
hydrops, anemia, or heart failure in infants born to Rh-negative PREMATURITY BY ORGAN SYSTEM
mothers, especially if there is a possibility of maternal sensitization. Organ System Morbidity
ABO incompatibility is common, with up to 20% of all pregnancies
potentially at risk. The responsible isohemagglutinins have weak Pulmonary Respiratory distress syndrome
affinity for blood group antigens, and the degree of hemolysis and Bronchopulmonary dysplasia
Pulmonary hypoplasia
subsequent jaundice varies among patients. Indirect immunoglobulin
Apnea of prematurity
(Coombs) testing has limited value in predicting clinically significant Cardiovascular Patent ductus arteriosus
jaundice. Neonatal morbidity is typically restricted to hyperbilirubine- Apnea and bradycardia
mia requiring treatment with phototherapy. Hypotension
Gastrointestinal, hepatic Necrotizing enterocolitis
Dysmotility or reflux
Prematurity Feeding difficulties
Hypoglycemia
The mean duration of a spontaneous singleton pregnancy is 280 days Central nervous system Intraventricular hemorrhage
or 40 menstrual weeks, 38 weeks after conception. An infant delivered Periventricular leukomalacia
Visual Retinopathy of prematurity
before completion of 37 weeks’ gestation is considered to be preterm
Skin Excess insensible water loss
according to the World Health Organization (WHO) definition. Infant Hypothermia
morbidity and mortality increase with decreasing gestational age at Immunologic, hematologic Increased incidence of sepsis and
birth. The risk of poor outcome, defined as death or lifelong handicap, meningitis
increases dramatically as gestational age decreases, especially for very Anemia of prematurity
low birth weight (VLBW) infants (Fig. 58-1).

4. 1200 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
Females (n 1327) Males (n 1453)
1500 1500
1400 1400
1300 1300
1200 1200
Birth weight (g)
Birth weight (g)
1100 1100
1000 1000
0.1
900 900
0.1
800 800 0.2
0.2 0.3
0.3 0.4
700 0.4 700 0.5
0.5 0.6
600 0.6 600 0.7
0.7 0.8
0.8
500 500
22 23 24 25 26 27 28 29 30 22 23 24 25 26 27 28 29 30
Gestational age (wk) Gestational age (wk)
FIGURE 58-1 Estimated mortality risk by birth weight and gestational age based on singleton infants
born in National Institute of Child Health and Human Development (NICHD) Neonatal Research Network
centers between January 1, 1995, and December 31, 1996. Numeric values represent age- and weight-
specific mortality rates per 100 births. (From Lemons JA, Bauer CR, Oh W, et al: Very low birth weight
outcomes of the National Institute of Child Health and Human Development Neonatal Research Network,
January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 107:E1, 2001. Used
with permission of the American Academy of Pediatrics.)
tality continues to decrease, in part due to a decline in stillbirths,17 Classic preterm infants, typically defined as those born before 32
interest in understanding the extent of morbidity associated with late weeks’ gestation or weighing less than 1500 g, or both, comprise only
preterm deliveries has intensified because of the large number of these 1.5% of all deliveries, whereas the late preterm population accounts
late preterm infants and the potential to avoid morbidities, such as for 8% to 9% of all births. Even uncommon complications in the later
temperature instability, feeding problems, hyperbilirubinemia requir- preterm population may represent a significant health care burden. As
ing treatment, suspected sepsis, and respiratory distress. Infants born the number of late preterm infants continues to increase, clinicians and
at 35 weeks’ gestation are nine times more likely to require mechanical policymakers will likely focus additional attention on the causes and
ventilation than those born at term.18 prevention of such deliveries (Fig. 58-2).
Most complications of late preterm delivery are easily treated, but
their economic and social effects are substantial, and long-term
sequelae are not well understood. For example, brain growth and Decisions at the Threshold of Viability
development proceed rapidly during the third trimester and continue Decisions regarding treatment of infants at the “limit of viability” are
for the first several years of life. An infant born at 35 weeks’ gestation often the most difficult for families and health care professionals. The
has approximately one-half the brain volume of a term infant. Although difficulty stems in part from the lack of clarity in defining what that
IVH is unusual after 32 weeks’ gestation, regions including the limit is, which has fallen by approximately 1 week every decade over
periventricular white matter continue to undergo rapid myelination the past 40 years. Among developed countries, most identify the limit
during this period. Studies by Stein and colleagues19 and Kirkegaard of viability at 22 to 25 weeks’ gestation.29-31 Making decisions at this
and coworkers20 demonstrate an association between late preterm early gestation requires accurate information about mortality and
delivery and long-term neurodevelopmental problems, including morbidity for this population. At 22 weeks (22 0/7days to 22 6/7 days),
learning disabilities and attention deficit disorders. Careful neurologic survival is rare and typically not included in studies of survival or
and epidemiologic studies will be required to define any mechanistic long-term outcome. Rates of survival to hospital discharge for infants
connection between late preterm delivery and these long-term born at 23 weeks’ gestation (23 0/7 to 23 6/7 days) range from 15% to
outcomes. 30%. Survival increases to between 30 and 55% for infants born at 24
Our growing recognition of the morbidity and mortality risks asso- weeks’ gestation.15,23,30,32-35 The Vermont-Oxford Network reported
ciated with preterm delivery clearly deserve close scrutiny and further weight-based survival for more than 4000 infants born between 401
study. Table 58-3 compares estimates of complication rates between and 500 g (mean gestational age of 23.3 ± 2.1 weeks) from 1996 to
preterm and late preterm infants. 2000. Survival to hospital discharge was 17%.36 Although mortality

5. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1201
TABLE 58-3 ESTIMATED COMPLICATION RATES FOR PRETERM AND LATE PRETERM INFANTS
Complication of Prematurity Incidence for Preterm Infants* Incidence for Late Preterm Infants†
Respiratory distress syndrome 65% surf Rx < 1500 g 5%
80% < 27 wk21
Bronchopulmonary dysplasia 23% < 1500 g15 Uncommon
Retinopathy of prematurity Approx 40% < 1500 g22-24
Intraventricular hemorrhage with ventricular 11% < 1500 g15 Rare
dilation or parenchymal involvement
Necrotizing enterocolitis 5-7% < 1500 g15 Uncommon
Patent ductus arteriosus 30% < 1500 g15 Uncommon
Feeding difficulty >90% 10-15%25
Hypoglycemia NA 10-15%25
*Defined as <32 weeks and/or <1500 g.
†
Defined as 32-37 weeks and/or 1500-2500 g.
NA, not available; surf Rx, surfactant treatment.
Peak Gestational Duration Perinatal Risk Index
1992
2002
Deaths per thousand
20
Percent
8
6
10
4
2
0 0
39 40 38 39 40 41 42 43
A Gestational age (completed weeks) B Gestational age (completed weeks)
FIGURE 58-2 Peak gestational age duration and risk of intrauterine fetal demise. A, Change in peak
gestational duration between 1992 and 2002. The duration of gestation decreased by a full week during
that decade, from 40 weeks to 39 weeks. B, The risk of intrauterine fetal demise increases with increasing
gestational age, especially beyond 40 weeks. The risk of intrauterine fetal demise likely influences obstetric
decision making regarding the timing of delivery in pregnancies approaching 40 weeks’ gestation. (Data
from Davidoff MJ, Dias T, Damus K, et al: Changes in the gestational age distribution among U.S: singleton
births: Impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol 30:8-15, 2006; Yudkin PL,
Wood L, Redman CW: Risk of unexplained stillbirth at different gestational ages. Lancet 1:1192-1194,
1987; and Smith GC: Life-table analysis of the risk of perinatal death at term and post term in singleton
pregnancies. Am J Obstet Gynecol 184:489-496, 2001.)
rates decline for each 1-week increase in gestational age at delivery, with delivery at a tertiary center, rather than neonatal transfer from an
long-term neurodevelopmental outcomes do not improve proportion- outlying facility.38-40 When families desire resuscitation or dating is
ately. Of infants born at less than 25 weeks’ gestation, 30% to 50% will uncertain, every attempt should be made to transfer to a tertiary center
have moderate to severe disability, including blindness, deafness, devel- for delivery. Maternal transfer to a tertiary center and administration
opmental delays and cerebral palsy.23,30,32 The National Institute of of corticosteroids (see Chapter 23) are the only antenatal interventions
Child Health and Human Development reported neurodevelopmental that have been significantly and consistently related to improved neo-
outcomes for more than 5000 infants born between 22 and 26 weeks’ natal neurodevelopmental outcomes.37 Other attempted strategies are
gestation from 1993 to 1998. Bayley mental development index (MDI) discussed in Chapter 29.
and nonverbal development index (NDI) scores improved and blind-
ness was reduced, but rates of severe cerebral palsy, hearing loss, Planning for Delivery at the Limits of Viability
shunted hydrocephalus, and seizures were unchanged.37 Ideally, discussion between physicians and parents should begin before
Birth weight and gender also affect survival rates. Higher weights birth in a nonemergent situation, and include both obstetric and neo-
within gestational age categories and female sex consistently show a natal care providers. Even during active labor, communication with the
survival advantage and better neurodevelopmental outcomes.15,37 Sur- family should be initiated as a foundation for postnatal discussions.
vival and long-term outcomes of very preterm infants are improved The family should understand that plans made before delivery are

6. 1202 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
influenced by maternal and fetal considerations and are based on
limited information. It should be emphasized that information avail-
able only after delivery, such as birth weight and neonatal physical Respiratory Problems in the
findings, may change the infant’s prognosis.30 Neonatal Period
Neonatal Resuscitation at the Limits No aspect of the transition from fetal to neonatal life is more dramatic
of Viability than the process of pulmonary adaptation. In a normal term infant, the
If time allows before delivery of an infant whose gestational age is lungs expand with air, pulmonary vascular resistance rapidly decreases,
near the threshold of viability, a thoughtful birth plan developed by and vigorous, consistent respiratory effort ensues within a minute of
the parents in consultation with maternal-fetal medicine specialists separation from the placenta. The process depends on crucial physio-
and the neonatologist should be established. The neonatologist can logic mechanisms, including production of functional surfactant, dila-
assist families in making decisions regarding a birth plan for their tion of resistance pulmonary arterioles, bulk transfer of fluid from air
infant by providing general information about the prognosis, the hos- spaces, and physiologic closure of the ductus arteriosus, foramen ovale.
pital course, potential complications, survival information, and general Complications such as prematurity, infection, neuromuscular disor-
health and well-being of infants delivered at the similar gestational ders, developmental defects, or complications of labor may interfere
age. When time does not permit such discussions, careful evaluation with neonatal respiratory function. Common respiratory problems of
of gestational age and response to resuscitation are instrumental in neonates are reviewed in the following sections.
assisting families in making decisions regarding viability or nonviabil-
ity of an extremely premature infant. The presence of an experienced
pediatrician at delivery is recommended to assess weight, gestational Transient Tachypnea of the Newborn
age and fetal status, and to provide medical leadership in decisions to
be made jointly with families.29,31 In cases of precipitous deliveries Definition
when communication with families has not occurred, physicians Transient tachypnea of the newborn (TTN), commonly known as wet
should use their best judgment on behalf of the infant to initiate resus- lungs, is a mild condition affecting term and late preterm infants. This
citation until families can be brought into the discussion, erring on the is the most common respiratory cause of admission to the special care
side of resuscitation if the appropriate course is uncertain.29,41 nursery. Transient tachypnea is self-limiting, with no risk of recurrence
Under ideal circumstances, the health care team and the infant’s or residual pulmonary dysfunction. It rarely causes hypoxic respiratory
family should make shared management decisions regarding these failure.43
infants. The American Medical Association and American Academy of
Pediatrics endorse the concept that “the primary consideration for Pathophysiology
decisions regarding life-sustaining treatment for seriously ill newborns During the last trimester, a series of physiologic events led to changes
should be what is best for the newborn,” and they recognize parents in the hormonal milieu of the fetus and its mother to facilitate neonatal
as having the primary role in determining the goals of care for their transition.44 Rapid clearance of fetal lung fluid is essential for successful
infant.1,29,42 Discussions with the family should include local and transition to air breathing. The bulk of this fluid clearance is mediated
national information on mortality as well as long-term outcomes. by transepithelial sodium re-absorption through amiloride sensitive
Parental participation should be encouraged with open communica- sodium channels in the respiratory epithelial cells.45 The mechanisms
tion regarding their personal values and goals. for such an effective “self-resuscitation” soon after birth are not com-
Decisions about resuscitation should be individualized to the case pletely understood. Traditional explanations based on Starling forces
and the family but should begin with parameters for care that are based and vaginal squeeze for fluid clearance account only for a fraction of
on global reviews of the medical and ethical literature and expertise. the fluid absorbed.
The Nuffield Council on Bioethics in the United Kingdom has pro-
posed parameters for treating extremely premature infants that parallel Risk Factors
guidance from the American Academy of Pediatrics.1,29 When gestation Transient tachypnea is classically seen in infants delivered near term,
or birth weight are associated with almost certain early death and especially after cesarean birth before the onset of spontaneous labor.46,47
anticipated morbidity is unacceptably high, resuscitation is not indi- Absence of labor is accompanied by impaired surge of endogenous
cated. Exceptions to comply with parental requests may be appropriate steroids and catecholamines necessary for a successful transition.48
in specific cases, such as for infants born at less than 23 weeks’ gestation Additional risk factors such as multiple gestations, excessive maternal
or with a birth weight of 400 g. When the prognosis is more uncertain, sedation, prolonged labor, and complications resulting from excessive
survival is borderline with a high rate of morbidity, such as at 23 to 24 maternal fluid administration have been less consistently observed.
weeks’ gestation, parental views should be supported.
Decisions regarding care of extremely preterm infants is always Clinical Presentation
difficult for all involved. Parental involvement, active listening, and The clinical features of TTN include a combination of grunting, tachy-
accurate information are critical to an optimal outcome for infants and pnea, nasal flaring, and mild intercostal and subcostal retractions along
their families. Although parents are considered the best surrogate for with mild central cyanosis. The grunting can be fairly significant and
their infant, health care professionals have a legal and ethical obligation sometimes misdiagnosed as RDS resulting from surfactant deficiency.
to provide appropriate care for the infant based on medical informa- The chest radiograph usually shows prominent perihilar streaks that
tion. If agreement with the family cannot be reached, it may be appro- represent engorged pulmonary lymphatics and blood vessels. The
priate to consult the hospital ethics committee or legal council. If the radiographic appearance and clinical symptoms rapidly improve
situation is emergent and the responsible physician concludes the within the first 24 to 48 hours. The presence of fluid in the fissures is
parents wishes are not in the best interest of the infant, it is appropriate a common nonspecific finding. TTN is a diagnosis of exclusion and it
to resuscitate against parental objection.35 is important that other potential causes of respiratory distress in the

7. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1203
newborn are excluded. The differential diagnosis of TTN includes third year of postnatal life. Clinical conditions associated with pulmo-
pneumonia or sepsis, air leaks, surfactant deficiency, and congenital nary hypoplasia and approaches to prevention and treatment are dis-
heart disease. Other rare diagnoses are pulmonary hypertension, cussed here.
meconium aspiration, and polycythemia. Perturbation of lung development at anytime during gestation may
lead to clinically significant pulmonary hypoplasia. Two general patho-
Diagnosis physiologic mechanisms contribute to pulmonary hypoplasia: extrinsic
TTN is primarily a clinical diagnosis. Chest radiographs typically dem- compression and neuromuscular dysfunction. Infants with aneuploidy
onstrate mild pulmonary congestion with hazy lung fields. The pul- such as trisomy 21 and those with multiple congenital anomalies or
monary vasculature may be prominent. Small accumulations of hydrops fetalis have a high incidence of pulmonary hypoplasia.
extrapleural fluid, especially in the minor fissure on the right side, may Oligohydramnios, whether caused by premature rupture of mem-
be seen. branes or diminished fetal urine production, can lead to pulmonary
hypoplasia. The reduction in branching morphogenesis and surface
Management area for gas exchange may be lethal or clinically imperceptible. Clinical
Management is mainly supportive. Supplemental oxygen is provided studies link the degree of pulmonary hypoplasia to the duration and
to keep the oxygen saturation level greater than 90%. Infants are severity of the oligohydramnios. Similarly, pulmonary hypoplasia is a
usually given intravenous fluids and not fed orally until their tachy- hallmark of congenital diaphragmatic hernia (CDH), caused by extrin-
pnea resolves. Rarely, infants may need continuous positive airway sic compression of the developing fetal lung by the herniated abdomi-
pressure to relieve symptoms. Diuretic therapy has been shown to be nal contents. The degree of pulmonary hypoplasia in CDH is directly
ineffective.49 related to the extent of herniation. Large hernias occur earlier in gesta-
tion. In most cases, the contralateral lung is also hypoplastic.
Neonatal Implications Lindner and associates51 report a significant mortality risk for
TTN can lead to significant morbidity related to delayed initiation of infants born to women with premature rupture of membranes and
oral feeding, which may interfere with parental bonding and establish- oligohydramnios before 20 weeks’ gestation. Their retrospective analy-
ment of successful breastfeeding. The hospital stay is prolonged for sis demonstrated 69% short-term mortality risk. However, the remain-
mother and infant. The existing perinatal guidelines50 recommend ing infants fared well and were discharged with apparently normal
scheduling elective cesarean births only after 39 completed weeks’ ges- pulmonary function. Prediction of clinical outcome is difficult for
tation to reduce the incidence of TTN (Fig. 58-3). these infants.
Prenatal diagnosis and treatment of pulmonary hypoplasia are
discussed in Chapters 18 and 24. Postnatal treatment for pulmonary
Pulmonary Hypoplasia hypoplasia is largely supportive. A subset of infants with profound
Lung development begins during the first trimester when the ventral hypoplasia have insufficient surface area for effective gas exchange.
foregut endoderm projects into adjacent splanchnic mesoderm (see These patients typically display profound hypoxemia, respiratory aci-
Chapter 15). Branching morphogenesis, epithelial differentiation, and dosis, pneumothorax, and pulmonary interstitial emphysema. At the
acquisition of a functional interface for gas exchange ensue through other end of the spectrum, some infants have no clinical evidence
the remainder of gestation and are not completed until the second or of pulmonary insufficiency at birth but have diminished reserves
A B
FIGURE 58-3 Radiographic appearance of transient tachypnea of the newborn (TTN) (A) and
respiratory distress syndrome RDS (B). The radiographic characteristics of TTN include perihilar densities
with fairly good aeration, bordering on hyperinflation. In contrast, neonates with RDS have diminished lung
volumes on chest radiographs reflecting atelectasis associated with surfactant deficiency. Diffuse “ground-
glass” infiltrates along with air bronchograms make the cardiothymic silhouette indistinct.

8. 1204 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
when stressed. In between is a cohort of patients with respiratory 50 and 80 mm Hg, with saturations between 88% and 96%. Hypercar-
insufficiency responsive to mechanical ventilation and pharmacologic bia and hyperoxia are avoided. Heart rate, blood pressure, respiratory
support. Typically, these patients have adequate oxygenation and ven- rate, and peripheral perfusion are monitored closely. Because sepsis
tilation, suggesting adequate gas exchange capacity. However, many cannot be excluded, screening blood culture and complete blood cell
develop pulmonary hypertension. The pathophysiologic sequence counts with differential counts are performed, and infants are started
begins with limited cross-sectional area of resistance arterioles, fol- on broad-spectrum antibiotics for at least 48 hours.
lowed by smooth muscle hyperplasia in these same vessels. Early use
of pulmonary vasodilators such as nitric oxide is the mainstay of man- SURFACTANT THERAPY
agement for increased pulmonary vasoreactivity. Optimizing pulmo- Surfactant replacement is one of the safest and most effective inter-
nary blood flow reduces the potential for hypoxemia thought to ventions in neonatology. The first successful clinical trial of surfactant
stimulate pathologic medial hyperplasia. If oxygenation, ventilation, use was reported in 1980 using surfactant prepared from an organic
and acid-base balance are maintained, nutritional support and time solvent extract of bovine lung to treat 10 infants with RDS.54 By the
can allow sufficient lung growth to support the infant’s metabolic early 1990s, widespread use of surfactant leads to a progressive decrease
demands. In many cases, the process is lengthy, requiring mechanical in RDS-associated mortality. Two strategies for treatment are com-
ventilation and treatment with pulmonary vasodilators such as silde- monly used: prophylactic surfactant, in which surfactant is adminis-
nafil, bosentan, or prostacyclin for weeks to months. Just as prenatal tered before the first breath to all infants at risk for developing RDS,
prognosis is difficult to assess, predicting outcome for patients with and rescue therapy, in which surfactant is given after the onset of
pulmonary hypoplasia managed in the neonatal intensive care unit is respiratory signs. The advantages of prophylactic administration
hampered by limited data. 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
Respiratory Distress Syndrome cost savings are the advantages of rescue therapy. Biologically active
RDS is a significant cause of early neonatal mortality and long-term surfactant can be prepared from bovine, porcine, human, or synthetic
morbidity. However, in the past 3 decades, significant advances have sources. When administered to patients with surfactant deficiency and
been made in the management of RDS, with consequent decreases in RDS, all these preparations show improvement in oxygenation and a
associated morbidity and mortality. decreased need for ventilatory support, along with decreased air leaks
and death.55 The combined use of antenatal corticosteroids and post-
Perinatal Risk Factors natal surfactant improves neonatal outcome more than postnatal sur-
The classic risk factors for RDS are prematurity and low birth weight. factant therapy alone.
Factors that negatively affect surfactant synthesis include maternal
diabetes, perinatal asphyxia, cesarean delivery without labor, and CONTINUOUS POSITIVE AIRWAY PRESSURE
genetic factors (i.e., white race, history of RDS in siblings, male sex, In infants with acute RDS, continuous positive airway pressure
and surfactant protein B deficiency).52 Congenital malformations that (CPAP) appears to prevent atelectasis, minimize lung injury, and pre-
lead to lung hypoplasia such as diaphragmatic hernia are also associ- serve surfactant function, allowing infants to be managed without
ated with significant surfactant deficiency. Prenatal assessment of fetal endotracheal intubation and mechanical ventilation. Early delivery
lung maturity and treatment to induce fetal lung maturity are dis- room CPAP therapy decreases the need for mechanical ventilation and
cussed in detail in Chapter 23. the incidence of long-term pulmonary morbidity.56,57 Increasing use of
CPAP has led to decreased use of surfactant and decreased incidence
Clinical Presentation of BPD.58 Common complications of CPAP include pneumothorax
Symptoms are typically evident in the delivery room, including tachy- and pneumomediastinum. Rarely, the increased transthoracic pressure
pnea, nasal flaring, subcostal and intercostal retractions, cyanosis, and leads to progressive decrease in venous return and decreased cardiac
expiratory grunting. The characteristic expiratory grunt results from output. Brief intubation and administration of surfactant followed by
expiration through a partially closed glottis, providing continuous extubation to CPAP is an additional RDS treatment strategy increas-
distending airway pressure to maintain functional residual capacity ingly used in Europe and Australia.59 Prospective, randomized trials
and thereby prevent alveolar collapse. These signs of respiratory diffi- enrolling extremely low birth weight (ELBW) infants and comparing
culty are not specific to RDS and have a variety of pulmonary and early delivery room CPAP with early prophylactic surfactant therapy
nonpulmonary causes, such as transient tachypnea, air leaks, congeni- are being conducted in the National Institute of Child Health and
tal malformations, hypothermia, hypoglycemia, anemia, polycythe- Human Development (NICHD) Neonatal Network (i.e., SUPPORT
mia, and metabolic acidosis. Progressive worsening of symptoms in trial).
the first 2 to 3 days, followed by recovery, characterizes the typical
clinical course. This timeline (curve) is modified by administration of MECHANICAL VENTILATION
exogenous surfactant with a more rapid recovery. Classic radiographic The goal of mechanical ventilation is to limit volutrauma and baro-
findings include low-volume lungs with a diffuse reticulogranular trauma without causing progressive atelectasis while maintaining
pattern and air bronchograms. The diagnosis can be established chem- adequate gas exchange. Complications associated with mechanical
ically by measuring surfactant activity in tracheal or gastric aspirates, ventilation include pulmonary air leaks, endotracheal tube displace-
but this is not routinely done.53 ment or dislodgement, obstruction, infection, and long-term compli-
cations such as BPD and subglottic stenosis.
Management
Infants are managed in an incubator or under a radiant warmer in a Complications
neutral thermal environment to minimize oxygen requirement and Acute complications include air leaks such as pneumothorax, pneu-
consumption. Arterial oxygen tension (PaO2) is maintained between momediastinum, pneumopericardium, and pulmonary interstitial

9. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1205
emphysema. The incidence of these complications has decreased sig- Because intrauterine inflammation is increasingly recognized as
nificantly with surfactant treatment. Infection, intracranial hemor- a cause of preterm parturition, antenatal inflammation is gaining
rhage, and patent ductus arteriosus occur more frequently in VLBW more attention in the pathogenesis of BPD and other morbidities of
infants with RDS. Long-term complications and comorbidities include prematurity.77 Chorioamnionitis has been strongly associated with
BPD, poor neurodevelopmental outcomes, and retinopathy of prema- impaired pulmonary and vascular growth, a typical finding in the new
turity. Incidence of these complications is inversely related to decreas- BPD.
ing birth weight and gestation. Most deliveries before 30 weeks’ gestation are associated with his-
Promising new therapies for the treatment of RDS include early tologic chorioamnionitis, which except for preterm initiation of labor
inhaled nitric oxide and supplementary inositol for prevention of is otherwise clinically silent. The more preterm the delivery, the more
long-term pulmonary morbidity (e.g., BPD).60-62 Noninvasive respira- often histologic chorioamnionitis is detected. Increased levels of pro-
tory support techniques such as synchronized nasal intermittent posi- inflammatory mediators in amniotic fluid, placental tissues, tracheal
tive ventilation (SNIPPV) and high-flow nasal cannulas are being aspirates, lung, and serum of ELBW preterm infants support an impor-
studied to decrease ventilator-associated lung injury.63,64 tant role for both intrauterine and extrauterine inflammation in the
development and severity of BPD. The proposed interaction between
the proinflammatory and anti-inflammatory influences on the devel-
Bronchopulmonary Dysplasia oping fetal and preterm lung is detailed in Figure 58-4. Several animal
The classic form of BPD was first described65 in a group of preterm models and preterm studies demonstrate that mediators of inflam-
infants who were mechanically ventilated at birth and who later mation, including endotoxins, tumor necrosis factor, IL-1, IL-6, IL-8,
developed chronic respiratory failure with characteristic radiological and transforming growth factor α can enhance lung maturation but
findings. These infants were larger, late preterm infants with lung concurrently impede alveolar septation and vasculogenesis, contribut-
changes attributed to mechanical trauma and oxygen toxicity. Smaller, ing to the development of BPD.78-81 Chorioamnionitis alone is associ-
extremely preterm infants with lung immaturity who have received ated with BPD, but the probability is increased when these infants
antenatal glucocorticoids have developed a milder form, called new receive a second insult such as mechanical ventilation or postnatal
BPD.66 This disease primarily occurs in infants weighing less than infection.82-84
1000 g who have very mild or no initial respiratory distress. The clini- Maternal genital mycoplasmal infection, particularly with Myco-
cal diagnosis is based on the need for supplemental oxygen at 36 weeks’ plasma hominis and Ureaplasma urealyticum, is associated with preterm
corrected gestational age.67 A physiologic definition of BPD based on delivery.85 Numerous studies have isolated these organisms from
the need for oxygen at the time of diagnosis has been developed.68 amniotic fluid and placentas in women with spontaneous preterm
Clinically, the transition from RDS to BPD is subtle and gradual. birth (i.e., preterm birth due to preterm labor or preterm rupture of
Radiologically, classic BPD is marked by areas of shifting focal atelec- membranes). After birth, these organisms are known to colonize and
tasis and hyperinflation with or without parenchymal cyst formation. elicit a proinflammatory response in the respiratory tract, leading to
Chest radiographs of infants with the new BPD show bilateral haziness, BPD.
reflecting diffuse microatelectasis without multiple cystic changes. The unpredictable variation in the incidence of BPD, despite
These changes lead to ventilation-perfusion mismatching and increased adjusting for low birth weight and prematurity, suggests a genetic
work of breathing. Preterm infants with BPD gradually wean off predisposition to the occurrence and the severity of BPD. Expression
respiratory support and oxygen or continue to worsen with progres- of genes critical to surfactant synthesis, vascular development, and
sively severe respiratory failure, pulmonary hypertension, and a high inflammatory regulation are likely to play a role in the pathogenesis of
mortality risk. BPD. Twin studies have shown that the BPD status of one twin, even
after correcting for contributing factors, is a highly significant predic-
Pathophysiology tor of BPD in the second twin. In this particular cohort, after control-
Risk factors predisposing preterm infants to BPD include extreme pre- ling for covariates, genetic factors accounted for 53% of the variance
maturity, oxygen toxicity, mechanical ventilation, and inflammation.69 in the liability for BPD.86 Genetic polymorphisms in the inflammatory
The pathologic findings characterized by severe airway injury and response are increasingly recognized as important in the pathogenesis
fibrosis in the old BPD have been replaced in the new BPD with large, of preterm parturition (see Chapter 28), and may be similarly impor-
simplified alveolar structures, impaired capillary configuration, and tant in the genesis of inflammatory morbidities in the preterm neonate
various degrees of interstitial cellularity or fibroproliferation.70 Airway as well.
and vascular lesions tend to be associated with more severe disease.
Oxygen-induced lung injury is an important contributing factor. Long-Term Complications
Exposure to oxygen in the first 2 weeks of life and as chronic therapy Infants with BPD have significant pulmonary sequelae during child-
has been associated in clinical studies with the severity of BPD.71,72 In hood and adolescence. Reactive airway disease occurs more frequently,
animal models, hyperoxia has been shown to mimic many of the with increased risk of bronchiolitis and pneumonia. Up to 50% of
pathologic findings of BPD. Two large, randomized trials in preterm infants with BPD require readmission to hospital for lower respiratory
infants suggested that the use of supplemental oxygen to maintain tract illness in the first year of life.87
higher saturations resulted in worsening pulmonary outcomes.73,74 BPD is an independent predictor of adverse neurologic outcomes.
Barotrauma and volutrauma associated with mechanical ventilation Infants with BPD exhibit lower average IQs, academic difficulties,
have been identified as major factors causing lung injury in preterm delayed speech and language development, impaired visual-motor
infants.75,76 Surfactant replacement therapy is beneficial in decreasing integration, and behavior problems.88 Sparse data also suggest an
symptoms of RDS and improving survival. The efficacy of surfactant increased risk for attention deficit disorders, memory and learning
to decrease the incidence of subsequent BPD is less well established. deficits. Delayed growth occurs in 30% to 60% of infants with BPD at
Chronic inflammation and edema associated with positive-pressure 2 years. The degree of long-term growth delay is inversely proportional
ventilation cause surfactant protein inactivation. to birth weight and directly proportional to the severity of BPD.

10. 1206 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
Prevention Strategies the myenteric plexus progresses through the third trimester. Intrauter-
Several strategies to decrease the incidence of BPD have been tried, ine passage of meconium is unusual before 36 weeks and does not
including administration of surfactant in the delivery room, antioxi- typically occur for several days after preterm delivery. The potential for
dant superoxide dismutase and vitamin A supplementation, optimiz- intrauterine meconium passage increases with each week of gestation
ing fluid and parenteral nutrition, aggressive treatment of patent thereafter.91 The physiologic stimuli for passage of meconium are still
ductus arteriosus, minimizing mechanical ventilation, limiting expo- incompletely understood. Clinical experience and epidemiologic data
sure to high levels of oxygen, and infection prevention. Table 58-4 suggest that a stressed fetus may pass meconium before birth. Infants
enumerates current strategies and their relative effectiveness in pre- born through meconium-stained amniotic fluid have a lower pH
venting BPD.89 Large, controlled clinical trials and meta-analysis have and are likely to have nonreassuring fetal heart tracings.92
not demonstrated a significant impact of these pharmacologic and Meconium-stained amniotic fluid at delivery occurs in 12% to 15%
nutritional interventions.90 The multifactorial nature of BPD suggests of all deliveries and occurs more frequently in post-term gestation
that targeting individual pathways is unlikely to have a significant effect and in African Americans.93
on outcome. Strategies to address several pathways simultaneously are In contrast to meconium-stained amniotic fluid, meconium aspira-
more promising (Fig. 58-4). tion syndrome is unusual. Meconium aspiration syndrome is a clinical
diagnosis that includes delivery through meconium-stained amniotic
fluid along with respiratory distress and a characteristic appearance on
chest radiographs. Approximately 2% of deliveries with meconium-
Meconium-Stained Amniotic Fluid and stained amniotic fluid are complicated by meconium aspiration syn-
Meconium Aspiration Syndrome drome, but the reported incidence varies widely.94,95 The severity of the
The significance and management of meconium-stained amniotic syndrome varies. The hallmarks of severe disease are the need for posi-
fluid has evolved with time. Meconium is present in the fetal intestine tive-pressure ventilation and the presence of pulmonary hypertension.
by the second trimester. Maturation of intestinal smooth muscle and Severe meconium aspiration is associated with significant mortality
and morbidity risk, including air leak, chronic lung disease, and devel-
opmental delay.
A relationship between meconium-stained amniotic fluid and
TABLE 58-4 BRONCHOPULMONARY DYSPLASIA meconium aspiration syndrome has been presumed since the 1960s,
PREVENTION STRATEGIES when the strategy of tracheal suctioning in the delivery room to prevent
meconium aspiration was proposed.96 By the 1970s, this practice was
Evidence or clinically established and affirmed by retrospective reviews. Oropha-
Relative Quality of ryngeal suctioning on the perineum before delivery of the chest to
Intervention Effectiveness Data complement tracheal suctioning was also recommended. However,
Antenatal steroids + Strong additional studies did not verify the benefit of tracheal suctioning.
Early surfactant ++ Strong Tracheal suctioning did not affect the incidence of meconium aspira-
Postnatal systemic steroid ++ Moderate tion syndrome in vigorous infants in large, prospective, randomized
Vitamin A + High trial.97 Another prospective, randomized, controlled study in 2514
Antioxidants − Moderate infants to determine the efficacy of oropharyngeal suctioning before
Permissive hypercapnia +++ Minimal delivery of the fetal shoulders in infants born through meconium-
Fluid restriction ++ Moderate
stained amniotic fluid also found no reduction in meconium
High-frequency ventilation ± Moderate
Delivery room management ++++ Animal data
aspiration syndrome.98 Amnioinfusion during labor to dilute the con-
Inhaled nitric oxide + Minimal centration of meconium has also been studied to prevent meconium
Continuous positive airway +++ Moderate aspiration, but a randomized trial found no reduction in the incidence
pressure used early or severity of meconium aspiration.99 These well-designed clinical
trials support the notion that meconium-stained amniotic fluid may
Pro-infammatory
Chorioamnionitis Resuscitation Mechanical Oxygen Sepsis
ventilation pneumonia
Preterm fetal Transitional Preterm Altered lung
lung lung postnatal lung development
and BPD
Antenatal corticosteroids Indomethacin Postnatal corticosteroids
FIGURE 58-4 Role of inflammation in the
pathogenesis of bronchopulmonary dysplasia Anti-infammatory
(BPD).

11. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1207
not have a true mechanistic, pathophysiologic connection with meco- hypertension tends to mimic prenatal physiology when pulmonary
nium aspiration syndrome. vascular resistance is necessarily high.
In 2001, Ghidini and Spong100 questioned the connection between First principles of management include optimal oxygenation and
meconium-stained amniotic fluid and meconium aspiration syndrome. ventilation through elimination of ventilation-perfusion mismatch.
Reports describe infants born through clear amniotic fluid with respi- When positive-pressure ventilation is employed, overdistention must
ratory distress with pulmonary hypertension and other clinical char- be avoided to minimize the risk of lung injury and BPD. Treatment
acteristics of meconium aspiration syndrome.101 Experimental data of pulmonary hypertension has been revolutionized by pharmaco-
suggest that factors promoting fetal acidosis and hypoxemia promote logic interventions that specifically reduce pulmonary vascular resis-
remodeling of resistance pulmonary arteries. These same factors can tance. Of these, nitric oxide is the best studied, with clear evidence of
promote intrauterine meconium passage. However, the remodeling, efficacy for treatment of pulmonary hypertension in the setting
perhaps exacerbated by inflammation from infection or by meconium, of meconium aspiration syndrome or sepsis.107 Clinical experience
produces a clinical syndrome called meconium aspiration syndrome.102,103 with other pulmonary vasodilators, including sildenafil, bosentan,
The incidence of meconium aspiration syndrome has decreased in and prostacyclin, is increasing and has proved useful in certain clini-
several centers over the past several years, perhaps a consequence cal situations.108
of improvements in obstetric assessment and management,104,105 Excessive proliferation of medial smooth muscle or its presence in
including a reduction in the incidence of post-term deliveries. vessels ordinarily devoid of smooth muscle complicates the treatment
Our center has experienced a decline in meconium aspiration syn- of pulmonary hypertension. This pathologic remodeling can occur in
drome while concurrently pursuing a policy of no routine tracheal utero or during postnatal life. The stimuli for this process are not
suctioning for infants born through meconium-stained amniotic understood, but typically include hypoxic stress of extended duration
fluid. and volutrauma associated with mechanical ventilation. Pulmonary
Treatment of severe meconium aspiration syndrome has dramati- vasodilators become less effective as remodeling progresses, prompting
cally improved in recent years, leading to decreases in morbidity and clinicians to pursue “gentle” ventilation strategies.109 By focusing on
mortality. Significant advances have come from treatment of pulmo- preductal rather than postductal oxygen saturations, lower ventilator
nary hypertension with selective pulmonary vasodilators, including settings can be achieved, reducing the risk of remodeling.
inhaled nitric oxide, sildenafil, and bosentan. These improve oxygen-
ation and enable less injurious ventilator strategies with reduced sub-
sequent morbidity from air leak and chronic lung disease. Exogenous
surfactant administration may be another useful treatment modality. Gastrointestinal Problems in
Although the mechanism is unclear, this intervention reduces ventila-
tion-perfusion mismatch and probably reduces the risk of ventilator-
Neonatal Period
associated lung injury.106 Necrotizing enterocolitis (NEC) is a devastating complication of pre-
The current state of knowledge regarding meconium-stained amni- maturity and the most common gastrointestinal emergency in the
otic fluid and meconium aspiration syndrome presents challenges for neonatal period. It affects 1% to 5% of infants admitted to neonatal
obstetricians and neonatologists. The incidence of meconium aspira- intensive care units.110 The reported incidence is 4% to 13%111 in
tion syndrome has decreased, but the reasons for the decline are not VLBW infants (<1500 g). NEC is characterized by an inflammation
readily apparent. The Neonatal Resuscitation Program35 protocol for of the intestines, which can progress to transmural necrosis and per-
delivery room management no longer recommends tracheal suction- foration. The onset typically occurs within the first 2 to 3 weeks of
ing for vigorous infants, implying that airway management leading to life, but it can occur well beyond the first month. The mortality rate
establishment of ventilation should take precedence. Meconium or related to NEC ranges from 10% to 30% for all cases and up to 50%
other material obstructing the airway should be cleared, but suctioning for infants requiring surgery.111-114 As more preterm and low-birth-
an unobstructed airway at the expense of delaying initiation of effec- weight infants survive the initial days of life, the number of infants
tive ventilation may be deleterious. A collaborative approach between at risk for NEC has increased. From 1982 to 1992, although overall
obstetrician and neonatologist is paramount. Personnel skilled in U.S. neonatal mortality rates declined, the mortality rates for NEC
establishment of ventilation and airway patency should attend any increased.26
infant expected to be depressed at delivery. A variety of antenatal and postnatal exposures have been suggested
as risk factors for the development of NEC.112,113,115 Gestational age and
birth weight are consistently related to NEC. Among prenatal factors,
Pulmonary Hypertension indomethacin tocolysis has been most often reported. Some studies
At delivery the normal transition from fetal to neonatal pulmonary report reduced incidence of NEC in infants treated with antenatal
circulation is mediated by a rapid, dramatic decrease in pulmonary steroids.116-118
vascular resistance. Endothelial cell shape change, relaxation of pulmo- Initial trials on use of indomethacin as a tocolytic showed no
nary arteriolar smooth muscle, and alveolar gaseous distention all adverse neonatal affects although sample sizes were small.119,120
contribute to this process. Several pathologic processes, including con- Although some subsequent case reports and retrospective reviews
genital malformations, sepsis, and pneumonia, can alter this sequence suggested indomethacin might be associated with adverse neonatal
to produce neonatal pulmonary hypertension. It typically accompanies outcomes, including NEC,121,122 others found no association123,124 of
pulmonary hypoplasia when diminished surface area for gas exchange indomethacin tocolysis with NEC when used as a single agent but did
and inadequate pulmonary blood flow lead to hypoxia and remodeling find an increased risk when used as part of double-agent tocolytic
of the resistance pulmonary arterioles. These vessels are more prone therapy, even after controlling for neonatal sepsis. A meta-analysis of
to constriction under conditions of acidosis and hypoxemia, resulting randomized, controlled trials and observational studies from 1966
in the right to left shunting of deoxygenated blood characteristic of though 2004 found no significant association between indomethacin
neonatal persistent pulmonary hypertension. In neonates, pulmonary tocolysis and NEC in either study type, although the pooled sample

12. 1208 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
size of the published randomized, controlled trials limited statistical are adversely affected. NEC is an independent risk factor for develop-
power.125 There is insufficient evidence to alter use of antenatal indo- ment of cerebral palsy and developmental delay.129,130,132 For infants
methacin in relationship to NEC (see Chapter 29). with surgical NEC, depending on the amount of bowel lost, there is
Postnatal interventions to prevent the development of NEC risk of short gut syndrome requiring parenteral nutrition and, ulti-
include alterations in feeding type and advancements, oral antibiot- mately, small bowel or liver transplantation. NEC is the single most
ics, immune globulin use and vitamin supplementation. Decreased common cause of the short gut syndrome in children.27-29
incidence of NEC has been demonstrated only for human milk. A
meta-analysis of randomized, controlled trials evaluating use of
human milk and NEC found a fourfold decrease (relative risk [RR] Hyperbilirubinemia
= 0.25; 95% confidence interval [CI], 0.06 to 0.98) with the use of Hyperbilirubinemia is common; 60% of term infants and 80% of
human milk.126 Mothers of infants at risk, particularly those less than preterm infants develop jaundice in the first week of life.133 Bilirubin
32 weeks’ gestation, should be encouraged to supply breast milk for levels are elevated in neonates due to increased production coupled
their infant. Providing early prenatal and postnatal counseling on use with decreased excretion. Increased production is related to higher
of human milk increases the initiation of lactation and neonatal rates of red cell turnover and shorter red cell life span.134 Rates of
intake of mother’s milk without increasing maternal stress or excretion are lower because of diminished activity of glucoronosyl-
anxiety.127 Newer preventive interventions being explored include the transferase, limiting bilirubin conjugation, and increased enterohe-
use of probiotics and growth factors aimed at protecting the gut patic circulation. In most cases, jaundice has no clinical significance
epithelium.128 because bilirubin levels remain low, and it is transient. Less than 3%
NEC may present slowly or as a sudden catastrophic event. Abdom- develop levels greater than 15 mg/dL.133 Risk factors for development
inal distention occurs early, with bloody stools present in 25% of of severe jaundice are outlined in Table 58-5.
cases.110 The radiographic hallmark is the presence of pneumatosis Several important risk factors have their origin in the prenatal and
intestinalis or portal venous gas (see Fig. 58-2). Progression may be perinatal environment. Hyperbilirubinemia is seen more frequently in
rapid, resulting in bowel perforation with evidence of free air on the infants of mothers who are diabetic (IDM). The pathogenesis of
radiograph. Early management consists of bowel decompression, increased bilirubin in IDM infants is uncertain but has been attributed
intravenous antibiotics, and respiratory and cardiovascular support as to polycythemia as well as increased red cell turnover.136,137 Prenatally,
indicated. The single absolute indication for surgical intervention is maternal blood group immunization may result from blood transfu-
pneumoperitoneum (Fig. 58-5). sion or fetal maternal hemorrhage. Although the prevalence of Rh(D)
For infants who survive NEC, morbidity is high, including high immunization has significantly decreased with the advent of preven-
rates of growth failure, chronic lung disease, and nosocomial infec- tion programs, including use of Rh immune globulin, antibodies to
tions.129-131 Lengths of stay and hospital costs are significantly length- other blood group antigens may still occur. ABO hemolytic disease, a
ened, particularly in surgical NEC.131 Long-term neurologic outcomes common cause of severe jaundice in the newborn, rarely causes hemo-
A B
FIGURE 58-5 Diagnosis and pathology of necrotizing enterocolitis. A, Typical radiographic appearance
of necrotizing enterocolitis, demonstrating pneumatosis and intramural gas. B, Intraoperative photograph of
the small bowel, which contains intramural gas.

13. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1209
TABLE 58-5 COMMON CLINICAL RISK FACTORS brain.141 At what level more subtle neurologic abnormalities appear
FOR SEVERE HYPERBILIRUBINEMIA remains unclear.139
Management of hyperbilirubinemia is aimed at the prevention of
Jaundice in the first 24 hours bilirubin encephalopathy while minimizing interference with breast-
Visible jaundice before discharge feeding and unnecessary parental anxiety. Key elements in prevention
Previous jaundiced sibling include systematic evaluation of newborns before discharge for the
Exclusive breastfeeding presence of jaundice and its risk factors, promotion and support of
Bruising, cephalohematoma
successful breastfeeding, interpretation of jaundice levels based on the
East Asian, Mediterranean, or Native American origin or ethnicity
Maternal age >25 years
hour of life, parental education, and appropriate neonatal follow-up
Male sex based on time of discharge.139 Treatment of severe hyperbilirubinemia
Unrecognized hemolysis (i.e., ABO, Rh, c, C, E, Kell, and other should be initiated promptly when identified. Guidelines for treatment
minor blood group antigens) with phototherapy and exchange transfusion vary with gestational age,
Glucose–6-phosphate dehydrogenase deficiency the presence or absence of risk factors, and the hour of life. Nomo-
Infant of a diabetic mother grams to guide patient management are available from the American
Academy of Pediatrics.139 Kernicterus is largely preventable. It requires
Adapted from Centers for Disease Control and Prevention: Kernicterus
in full-term infants; United States, 1994-1998. Report No.: 50(23), 2001.
close collaboration between prenatal and postnatal caretakers for accu-
rate dissemination of information regarding risk factors for parents
and caregivers.
lytic disease in the fetus. Other antibodies associated with hemolytic
disease in the fetus and newborn are discussed in Chapter 26. A fetus Feeding Problems
who is apparently unaffected in utero may have continued hemolysis Feeding problems related to complications of prematurity, congenital
postnatally; physicians caring for the newborn should be notified of anomalies, or gastrointestinal disorders contribute significantly to
any maternal sensitization. length of stay for hospitalized newborns. In a study of children referred
Other perinatal factors associated with severe hyperbilirubinemia to an interdisciplinary feeding team, 38% were born preterm.145 Pre-
include delivery before 38 weeks. Infants born at 36 to 37 weeks’ gesta- mature infants with a history of neonatal chronic lung disease or neu-
tion have an almost sixfold increase of significant hyperbilirubine- rologic injury such as IVH or periventricular leukomalacia (PVL) and
mia138 and require close surveillance and monitoring, especially if those with a history of NEC are at the highest risk for long-term
breastfed.139 Feeding difficulties, also common for the near term infant, feeding problems. These medically complex infants often have other
increase this risk still further and may result in delayed hospital dis- comorbidities, such as tracheomalacia, chronic aspiration, and gastro-
charge or readmission for the infant. The presence of bruising or a esophageal reflux (GER), that interfere with normal maturational pat-
cephalohematoma, more common after instrumented or difficult terns of feeding. Premature infants with complex medical problems
deliveries, will also increase risk. Polymorphisms of genes coding for often require prolonged intubation and mechanical ventilation with
enzymes mediating bilirubin catabolism may also contribute to the delayed initiation of enteral feeding, all of which have been associated
development of severe hyperbilirubinemia.140 with subsequent feeding difficulties. These infants often have difficulty
The primary consequence of severe hyperbilirubinemia is poten- integrating sensory input because of medical interventions and neuro-
tial neurotoxicity. Kernicterus is a neurologic syndrome resulting logic immaturity. All of these factors combine to increase the risk of
from deposition of unconjugated bilirubin in the basal ganglia and developing oral aversion.
brainstem nuclei, and neuronal necrosis.141 Clinical features may be Infants with congenital anomalies are also at high risk for feeding
acute or chronic, resulting in tone and movement disorders such as disorders. Infants with tracheoesophageal fistula with esophageal
choreoathetosis and spastic quadriplegia, mental retardation, and sen- atresia often have difficulty feeding due to tracheomalacia, recurrent
sorineural hearing loss.142 A number of factors influence the neuro- esophageal stricture, and GER, which are known associates of this
toxic effects of bilirubin, making prediction of outcome difficult. disorder. Infants with CDH have an extremely high incidence of oral
Bilirubin more easily enters the brain if it is not bound to albumin, aversion and growth problems in addition to the pulmonary complica-
is unconjugated, or there is increased permeability of the blood brain tions. Surviving infants and children with CDH have a 60% to 80%
barrier.142 Conditions such as prematurity that alter albumin levels or incidence of associated GER which has been shown to persist into
that alter the blood brain barrier such as infection, acidosis, and pre- adulthood.146-151 Often, GER is severe, refractory to medical therapy,
maturity affect bilirubin entry into the brain. As a result, there is no and requires a surgical antireflux procedure. Infants with CDH often
serum level of bilirubin that predicts outcome. In early studies of have inadequate caloric intake due to fatigue or oral aversion and
infants with Rh hemolytic disease, kernicterus developed in 8% of increased energy requirements leading to poor growth. Often these
infants with serum bilirubin concentrations of 19 to 24 mg/dL, 33% infants require supplemental tube feedings by nasogastric, nasojejunal,
with levels of 25 to 29 mg/dL, and 73% of infants with levels of 30 or gastrostomy feeding tube. These feeding difficulties may last several
to 40 mg/dL.141 years and are often accompanied by a behavioral-based feeding
Levels of indirect bilirubin below 25 mg/dL in otherwise term component.
healthy infants without hemolytic disease are unlikely to result in ker- Infants with congenital or acquired gastrointestinal abnormalities
nicterus without other risk factors, as indicated in a study of 140 term often have associated feeding difficulties. Infants with conditions such
and near-term infants with levels above 25 mg/dL, in which no cases as gastroschisis with or without associated intestinal atresias often
of kernicterus occurred.143 Kernicterus has however been reported in require prolonged hospitalization because of a slow tolerance of enteral
otherwise healthy breastfed term newborns at levels above 30 mg/dL.144 feedings and a higher risk for NEC after gastroschisis repair.152,153 They
One of the most important of these risk factors is prematurity. The often have dysmotility and severe GER with oral aversion.154 A small
less mature the infant the greater the susceptibility of the neonatal percentage of patients have long-term intolerance of enteral feedings

14. 1210 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
and require prolonged total parenteral nutrition (TPN). Patients Gynecologists (ACOG) practice bulletin called “Clinical Management
requiring long-term TPN may develop liver injury or cholestasis and Guidelines for Obstetrician-Gynecologists”164 concluded that EFM has
ultimately may require liver or small bowel transplantation. Infants a high false-positive rate to predict adverse outcomes and is associated
who develop short bowel syndrome resulting from NEC also have with an increase in operative deliveries without any reduction in cere-
difficulties tolerating enteral feeds, depending on the length and func- bral palsy. Meconium-stained amniotic fluid is commonly seen during
tion of the remaining bowel. Like patients with gastroschisis, infants labor, but no data exist to associate it with adverse neurologic outcome.
with severe short bowel syndrome may require prolonged TPN and go Apgar scores were originally introduced to identify infants in need of
on to develop liver or intestinal failure requiring transplantation. resuscitation, not to predict neurologic outcome. Apgar scores are not
In summary, premature infants and infants with congenital anom- specific to an infant’s acid-base status but can reflect drug use, meta-
alies or acquired gastrointestinal abnormalities are at high risk for bolic disorder, trauma, hypovolemia, infection, neuromuscular disor-
long-term feeding problems. It is important to counsel families regard- der, and congenital anomalies. However, a persistently low Apgar
ing this risk. Minimizing iatrogenic oral aversion is crucial. Involving score after 5 minutes despite intensive CPR has been associated with
a feeding specialist early in a medically complex infant’s course may increased morbidity and mortality.162,168-170 The combination of a low
help reduce these problems. 5-minute Apgar score with other markers such as fetal acidemia and
the need for CPR in the delivery room, predicts a significantly increased
risk of brain injury.171,172 Perlman and Risser172 found a 340-fold
increased risk of seizures and associated moderate to severe encepha-
Neurologic Problems in the lopathy in association with a 5-minute Apgar score of 5, delivery room
intubation or CPR, and an umbilical arterial cord pH less than 7.00.
Neonatal Period
Neonatal Encephalopathy
Hypoxic-Ischemic Encephalopathy Neonatal encephalopathy is clinically characterized by depressed level
Injury to the brain sustained during the perinatal period was once of consciousness, abnormal muscle tone and reflexes, abnormal respi-
thought to be one of the most common causes of death or severe, ratory pattern, and seizures.155 These findings may result from a
long-term neurologic deficits in children.155 However, data show that hypoxic-ischemic event but can also be due to other conditions such
only 10% of brain injury is related to perinatal or intrapartum as metabolic disorders, neuromuscular disorders, toxin exposure, and
events.156,157 There is increasing recognition that events occurring well chromosomal abnormalities or syndromes. Not all infants with neo-
before labor contribute significantly to the cause of brain injury. natal encephalopathy go on to develop permanent neurologic impair-
Despite improvements in perinatal practice, the incidence of hypoxic- ment. The Sarnat staging system is frequently used to classify the
ischemic encephalopathy has remained stable at 1 or 2 cases per 1000 degree of encephalopathy and predict neurologic outcome.166 Infants
term births.158,159 Strategies for prevention of brain injury have been with mild encephalopathy (Sarnat stage 1) generally have a favorable
mainly supportive because prevention has been difficult because of the outcome. Infants with moderate encephalopathy (Sarnat stage 2)
lack of clinically reliable indicators and the occurrence of the initiating develop long-term neurologic compromise in 20% to 25% of cases,
event well before the onset of labor. However, because brain injury and infants with severe encephalopathy (Sarnat stage 3) have a greater
initiated by a hypoxic-ischemic event is also affected by a “reperfusion than 80% risk of death or long-term neurologic sequelae.155
phase” of injury, strategies targeting this process of ongoing injury are
being developed for neuroprotection.160,161 Multiorgan Injury
In addition to neurologic compromise, the interruption of placental
Definition of Asphyxia blood flow can result in systemic organ injury. Animal models and
The brain injury referred to as hypoxic-ischemic encephalopathy clinical studies have demonstrated that the kidney is exquisitely sensi-
occurs due to impaired cerebral blood flow likely as a consequence of tive to reductions in renal blood flow.173,174 The result of decreased
interrupted placental blood flow leading to impaired gas exchange.162 renal perfusion is acute tubular necrosis with varying degrees of oligu-
If gas exchange is persistently impaired, hypoxemia and hypercapnia ria and azotemia. Other organ systems are also sensitive to reduced
develop with resultant fetal acidosis or what has been referred to as blood flow. Decreased blood flow to the gastrointestinal tract can lead
asphyxia. Severe fetal acidemia, defined as an umbilical arterial pH of to luminal ischemia and increased risk for NEC. Decreased pulmonary
less than 7.00, is associated with an increased risk of adverse neurologic blood flow can result in persistent pulmonary hypertension of the
outcome.163,164 However, even with this degree of acidemia, only a newborn. Lack of blood flow to the liver can result in hepatocellular
small portion of infants develop significant encephalopathy and sub- injury and impaired synthetic function, leading to hypoglycemia and
sequent sustained neurologic injury.165-167 Fetal scalp blood sampling disseminated intravascular coagulation. Fluid retention and hypona-
and umbilical cord gas data do not have great sensitivity to predict tremia can develop due to the combination of impaired renal function
long-term neurologic impairment. and the release of antidiuretic hormone. Suppression of parathyroid
hormone release can lead to hypocalcemia and hypomagnesemia.
Clinical Markers These electrolyte abnormalities can further affect myocardial function.
Other clinical measures to identify fetal stress (such as fetal heart rate Muscle can be affected by electrolyte abnormalities and direct cellular
abnormalities, meconium-stained amniotic fluid, low Apgar scores, injury, leading to rhabdomyolysis.162
and need for cardiopulmonary resuscitation CPR) in the delivery
room do not reliably identify infants at high risk for brain injury when Neuropathology
used in isolation. Despite the widespread use of electronic fetal heart The reduction in cerebral blood flow associated with a hypoxic-isch-
rate monitoring (EFM) which detects changes in fetal heart rate related emic event sets off a complex cascade of regional circulatory factors
to fetal oxygenation, there has been no reduction in the incidence of and biochemical changes at the cellular level. Hypoxia induces a switch
cerebral palsy.163 In 2005, an American College of Obstetricians and from normal oxidative phosphorylation to anaerobic metabolism,

15. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1211
leading to depletion of high-energy phosphate reserves, accumulation
of lactic acid, and inability to maintain cellular functions.161,175 The end Intraventricular Hemorrhage
result is cellular energy failure, metabolic acidosis, release of glutamate IVH (i.e., germinal matrix hemorrhage) occurs most commonly in
and intracellular calcium, lipid peroxidation, build-up of nitric oxide, preterm infants and is a major cause of mortality and long-term dis-
and eventual cell death.155,161,176 It is this process of cellular injury that ability. Bleeding originates in the subependymal germinal matrix but
is being targeted for neuroprotection strategies. may rupture through the ependyma into the ventricular system. IVH
is graded into four categories:
Neuroimaging
Diffusion-weighted magnetic resonance imaging (MRI) has become Grade I: Bleeding is localized to the germinal matrix
the gold standard to define the extent and potentially the timing of the Grade II: Bleeding into the ventricle but the clot does not distend
brain injury. Diffusion-weighted techniques can detect signal changes the ventricle
due to reduced brain water diffusivity within the first 24 to 48 hours Grade III: Bleeding into the ventricle with ventricular dilation
of the insult.162,177-179 Magnetic resonance spectroscopy can also detect Grade IV: Intraparenchymal extension
alterations in metabolites such as lactate, N-acetyl aspartate, choline,
and creatinine in specific regions of the brain indicating injury.177,180 Incidence
However, MRI is difficult to perform in an unstable patient, and com- Diagnosis is made most commonly by cranial ultrasound, with most
puted tomography (CT) may be preferable as the initial study for term hemorrhages occurring within 6 hours of birth and 90% within the
infants and ultrasound for preterm infants. first 5 days of life.185 The incidence of IVH has decreased significantly
with improvements in perinatal care such as maternal transfer and
Neuroprotection Strategies antenatal steroids. From 1990 to 1999, the incidence of IVH reported
Brain cooling by selective cooling of the head or systemic hypothermia for infants with birth weights of less than 1000 g was 43%, and 13%
has been studied as a potential therapy for neonates with hypoxic- were grade III or grade IV. In 2000 and 2002, the overall incidence of
ischemic encephalopathy. The Cool Cap Study Group found no sig- IVH decreased to 22%; only 3% were severe despite improvements in
nificant improvement in survival or severe neurodevelopmental survival.186 Lower gestational age is associated with an increased risk
disability in 234 term infants with moderate to severe neonatal enceph- of severe IVH.168
alopathy and abnormal amplitude integrated electroencephalography
(aEEG) in a multicenter, randomized trial of selective head cooling.165 Pathogenesis
However, there was improvement in infants with less severe aEEG Anatomic and physiologic factors have been implicated in the patho-
changes in a subgroup analysis.165 A large, multicenter, randomized genesis of IVH. The germinal matrix is composed of thin-walled blood
trial of brain cooling using whole-body hypothermia for infants of 36 vessels that lack supportive tissue. These fragile vessels have a tendency
weeks’ gestation with moderate or severe encephalopathy found that to rupture spontaneously or in response to stress, such as hypoxia-
systemic hypothermia resulted in an 18% reduction of death or mod- ischemia, changes in blood pressure or cerebral perfusion, and pneu-
erate or severe disability at 18 to 22 months of age.181 Proposed reasons mothoraces. In addition to these structural factors, premature infants
for the greater benefit in the latter study from the NICHD Neonatal have an immature cerebrovascular autoregulation system (so-called
Research Network are earlier initiation of cooling and possible differ- pressure-passive circulation) in response to systemic hypotension,
ences in the severity of brain injury (Cool Cap study required the which makes them more susceptible to hemorrhage.174,185,187 Immatu-
additional evidence of an abnormal aEEG).165 There are insufficient rities in the coagulation system and increased fibrinolytic activity of
data to suggest that one method of brain cooling is superior to the premature infants may also play a role.169,188-190
other. Until more data are available, treatment with brain cooling is
best considered an experimental technique.167 Outcomes
Because the therapeutic window for effective treatment may be Although it has been generally thought that infants with grade I or II
limited to within 6 hours of delivery, future efforts are being focused IVH have similar outcomes to those without cranial ultrasound abnor-
on early identification of infants at the greatest risk for hypoxic- malities, extremely-low-birth-weight infants with grade I or II IVH
ischemic injury. Infants at highest risk are those with evidence of a had worse neurodevelopmental outcomes at 20 months corrected age
sentinel event during labor, pronounced respiratory and neuromuscu- compared with those with normal cranial ultrasound scans in a 2006
lar depression at delivery with persistently low Apgar scores, the report.191 About 35% of infants with grade III IVH have adverse
need for delivery room resuscitation, severe fetal acidemia (umbilical neurologic outcomes. In those who develop post-hemorrhagic
artery pH less than7.00 or base deficit of 16 mEq/L), and evidence of hydrocephalus requiring surgical intervention, the disability rate
an early abnormal neurologic examination, seizures, or an abnormal increases to about 60%.169 Grade IV IVH is associated with the highest
aEEG.161,172,182-184 mortality rates, and 80% to 90% are associated with poor neurologic
outcomes.170
Summary of Hypoxic-Ischemic Brain Injury
Hypoxic-ischemic brain injury due to intrapartum asphyxia is a rare Antenatal Prevention
but serious cause of long-term neurodevelopmental disability. It is The only therapies shown to decrease the incidence of IVH in prema-
often difficult to define a specific intrapartum event because the initiat- ture infants are antenatal corticosteroid administration and maternal
ing event may occur before the onset of labor. Early identification of transfer to a tertiary care center for delivery. Multiple studies have
at-risk newborns by neuroimaging techniques, aEEG findings, history, shown that the administration of corticosteroids before preterm deliv-
and clinical examination may provide an opportunity to ameliorate ery to induce lung maturity has significantly reduced the incidence of
the effects of ongoing brain injury using neuroprotective strategies. RDS, mortality, and severe IVH. According to a meta-analysis of four
The goal of these therapeutic interventions is the reduction of long- trials that included 596 infants of 24 to 33 weeks’ gestation, prenatal
term neurodevelopmental disabilities, including cerebral palsy. corticosteroid therapy was associated with a relative risk reduction for

16. 1212 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
IVH of 0.57 (95% CI, 0.41 to 0.78).171 Maternal transfer to a tertiary detected by ultrasound examination in VLBW infants is 5% to 15%.212
care center for gestational age less than 32 weeks decreased the inci- However, ultrasound often fails to identify the more subtle evidence
dence of death or major morbidity, including IVH.39 Antenatal pheno- of diffuse white matter injury. The incidence of PVL diagnosed at
barbital, vitamin K, and magnesium sulfate have failed to demonstrate autopsy is much higher, indicating that the true incidence of PVL is
a consistent decrease in overall IVH, severe IVH, or death.192-194 likely underestimated.
Postnatal Prevention Neuropathology
The goal of postnatal prevention has been blood pressure stabilization Focal necrosis most commonly occurs in the cerebral white matter
to prevent fluctuations in cerebral perfusion, correction of coagulation at the level of the trigone of the lateral ventricles and around the
disturbances, and stabilization of germinal matrix vasculature.185 Post- foramen of Monro.212 These sites make up the border zones of the
natal administration of phenobarbital and muscle paralysis have been long penetrating arteries. Classically, these lesions undergo a coagula-
shown to stabilize blood pressure, but neither has been found to tive necrosis that results in cyst formation or focal glial scars.174 The
decrease the incidence of IVH or neurologic impairment.195,196 Fresh- more diffuse type of injury may also occur in conjunction with focal
frozen plasma and ethamsylate to promote platelet adhesiveness and necrosis but is more frequently recognized as an independent entity.
correct coagulation disorders also do not reduce the incidence of Diffuse white matter injury seems to affect premyelinating oligoden-
IVH.194,197-199 Indomethacin remains the most promising preventive drocytes and leads to global loss of these cells and an increase in
therapy for IVH because of its ability to constrict the cerebral vascu- hypertrophic astrocytes in response to the diffuse injury.174,212-214 This
lature, inhibit prostaglandin and free radical production, and mature loss of oligodendrocytes leads to white matter volume loss and
the germinal matrix vasculature.197,200-202 Prophylactic indomethacin ventriculomegaly.
decreases the incidence of severe IVH. Follow-up studies have shown
slight improvement in cognitive function in infants who received pro- Pathogenesis
phylactic indomethacin but no difference in the incidence of cerebral The pathogenesis of PVL primarily occurs by hypoxia-ischemia leading
palsy.203-205 Prophylactic indomethacin is reserved for preterm infants to neuronal injury due to free radical exposure, cytokine toxicity, and
at high risk for IVH until further studies clarify the appropriate can- exposure to excessive excitatory neurotransmitters such as gluta-
didates for prophylaxis. mate.174 Vascular anatomic factors also seem to play a role. PVL tends
to occur in arterial end zones or so-called border zones.215 The arterial
Post-hemorrhagic Hydrocephalus supply is composed of long penetrating arteries that terminate deep in
The most serious complication of IVH is post-hemorrhagic hydro- the periventricular white matter, basal penetrating arteries, which
cephalus due to obstruction of cerebrospinal fluid (CSF) flow. This supply the immediate periventricular area, and short penetrating arter-
occurs when multiple blood clots obstruct CSF reabsorption channels, ies, which supply the subcortical white matter. Focal necrosis occurs
leading to transforming growth factor β1 (TGF-β1)–stimulated pro- most commonly in the anterior and posterior periventricular border
duction of extracellular matrix proteins such as fibronectin and zones because in premature infants these vessels are immature. Diffuse
laminin, which ultimately lead to scar formation.206 Progressive ven- white matter injury may also occur due to vascular immaturity. At
tricular dilatation can worsen brain injury because of damage to peri- early gestations (24 to 28 weeks), there are few anastomoses between
ventricular white matter resulting from increased intracranial pressure the long and short penetrators. Arterial border zones may occur in
and edema.172 Therapies such as serial lumbar punctures, diuretics, and the subcortical and remote periventricular areas, resulting in a more
intraventricular fibrinolytic therapy are ineffective and may even be diffuse type of injury.212
harmful.207 Although surgical shunt placement carries significant risk The preterm brain is vulnerable to ischemia because of impaired
of shunt complications and infection, it remains the definitive therapy cerebrovascular regulation. Preterm infants exhibit a pressure-passive
for progressive post-hemorrhagic hydrocephalus. circulation; a decrease in systemic blood pressure is associated with a
decrease in cerebral perfusion, leading to ischemia.212,216,217 Immature
Summary of Intraventricular Hemorrhage oligodendrocytes seem to be more sensitive to free radical injury, cyto-
IVH due to a fragile germinal matrix and an unstable cerebrovascular kine effects, and the presence of glutamate.
autoregulatory system remains a significant cause of neurologic mor-
bidity in preterm infants. Infants with cardiorespiratory complications Clinical Outcomes
are at highest risk. Antenatal corticosteroids are the most effective The most common long-term sequela of PVL is spastic diplegia, a form
preventive therapy available. Despite significant reduction in the of cerebral palsy in which the lower extremities are more affected than
incidence of severe IVH, new prevention and treatment therapies for the upper extremities. The descending fibers of the motor cortex,
hydrocephalus are needed. which regulate function of the lower extremities, traverse the periven-
tricular area and are most likely to be injured. More severe injury with
lateral extension may be associated with spastic quadriplegia or other
Periventricular Leukomalacia manifestations such as cognitive, visual, or auditory impairments.
PVL refers to injury to the deep cerebral white matter in two charac-
teristic patterns, described as focal periventricular necrosis and diffuse Summary of Periventricular Leukomalacia
cerebral white matter injury. This type of brain injury typically affects PVL is a major cause of neurologic morbidity in premature infants,
premature infants and is a common cause of cerebral palsy. Preterm especially those who weigh less than 1000 g at birth. Prevention is the
infants who have suffered an IVH or have cardiopulmonary instability only strategy to treat PVL. Avoidance of fluctuations in blood pressure
are at the highest risk. Other intrauterine factors, such as infection, and cerebral vasoconstrictors, such as extreme hypocarbia, is impor-
premature prolonged rupture of membranes, first-trimester hemor- tant because of the known immaturity in cerebrovascular autoregula-
rhage, placental abruption, and prolonged tocolysis, have been associ- tion of preterm infants. Investigational strategies targeting the cascade
ated with increased risk of PVL.174,208-211 The reported incidence of PVL of oligodendroglial death may be promising.

17. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1213
Pathophysiology and Risk Factors
Perinatal Stroke The mechanisms of perinatal stroke are thought to be multifactorial.
Arterial ischemic stroke (AIS) in neonates is defined as a cerebrovas- Regional ischemia with subsequent hypoxia and infarction plays a role.
cular event around the time of birth with resultant clinical or radio- A relative hypercoagulable state in newborns due to the presence of
graphic evidence of focal cerebral arterial infarction. Most occur in the fetal hemoglobin, polycythemia, and activation of coagulation factors
distribution of the middle cerebral artery.176,218-220 AIS accounts for in the fetus and mother around the time of birth seems to increase the
most perinatal ischemic strokes. When the diagnosis is based on symp- risk of a thromboembolic event leading to stoke.176,227 Risk factors for
toms in the neonatal period, the reported incidence is 1 case in 4000 perinatal stroke include maternal and placental disorders, neonatal
live births.176,221,222 The incidence of perinatal ischemic strokes that hypoxic-ischemic injury, hematologic disorders, infection, cardiac dis-
were asymptomatic in the neonatal period and diagnosed at a later orders, trauma, and drugs. Often, a combination of risk factors is
time is unknown. identified.
Clinical Presentation Neuroimaging and Electroencephalographic
Neonatal seizures are the most common clinical presentation and Assessment
usually are focal in origin without other signs of neonatal encepha- Although cranial ultrasound is the easiest to perform, it is not a sensi-
lopathy.176,223 However, some infants are systemically ill, and the diag- tive indicator of perinatal stroke.175 Little information exists on prena-
nosis is made with neuroimaging to rule out evidence of hypoxic-ischemic tal cranial ultrasound, but prenatal ultrasound scans may show areas
injury or bleeding. Neonates with focal neurologic signs account for of unilateral echolucencies, which may represent areas later identified
less than 25% of cases.218,222,224,225 as prenatal stroke. CT imaging can usually be performed readily in
Perinatal stroke may also be identified retrospectively in initially neonates and usually does not require sedation. CT evidence of peri-
well-appearing infants who present in later months with signs of hemi- natal ischemic stroke includes focal hypodensity with or without
paresis, developmental delay, or seizures.176,226 In these cases, neuroim- intraparenchymal hemorrhage, abnormal gray-white differentiation,
aging reveals a remote injury, often occurring in the middle cerebral and evidence of volume loss or porencephaly if the injury is remote
artery territory. from the time of delivery176 (Fig. 58-6).
A B
FIGURE 58-6 Diagnostic imaging studies of neonatal stroke. A, Magnetic resonance imaging study of a 6-month-old infant
demonstrates a large region of encephalomalacia involving most of the left temporal lobe and large regions of the left frontal and parietal
lobes. The distribution is consistent with a remote infarction of the left middle cerebral artery. The infant had a history of sepsis and
disseminated intravascular coagulation during the early neonatal period. An ultrasound scan when the infant was 1 day old was
unremarkable. B, Computed tomography of a 1-day-old term infant who presented with a focal seizure. The perinatal history was
unremarkable. There is loss of gray-white matter differentiation involving the right parietal and occipital regions (arrow). There is a smaller
area of involvement in the right frontal region. A cranial ultrasound examination was normal.

18. 1214 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
MRI with diffusion-weighted imaging is the most sensitive, espe- TABLE 58-6 COMPONENTS OF CEREBRAL
cially in the setting of early infarction. MRI may be able to demonstrate PALSY CLASSIFICATION
restricted diffusion within a vascular distribution for acute stroke as
well as chronic changes such as encephalomalacia, gliosis, and ven- 1. Motor abnormalities
triculomegaly for remote events (see Fig. 58-6). MR angiography may A. Nature and typology of the motor disorder: the observed
be useful in some cases to confirm arterial occlusion although it is not tonal abnormalities assessed on examination (e.g.,
commonly used unless a vascular malformation is suspected. Func- hypertonia, hypotonia) and the diagnosed movement
disorders, such as spasticity, ataxia, dystonia, or athetosis
tional MRI may be valuable in the future to understand how the brain
B. Functional motor abilities: the extent to which the individual
reorganizes after perinatal stroke.218,228,229 EEG may be useful to detect is limited in his or her motor function in all body areas,
subclinical seizures that may cause secondary brain injury.218 including oromotor and speech function
Further diagnostic studies focused on risk factors for perinatal ische- 2. Associated impairments
mic stroke should include blood tests for coagulation disturbances A. Presence of absence of associated nonmotor
and genetic predispositions, urine toxicology for metabolic disorders neurodevelopmental or sensory problems, such as seizures,
and toxins such as cocaine, echocardiography, infectious workup hearing or vision impairments, and attentional, behavioral,
including lumbar puncture, maternal testing for acquired coagulation communicative, or cognitive deficits
disorders such as antiphospholipid antibodies, and an assessment of B. Extent to which impairments interact in individuals with
the placenta.176 cerebral palsy
3. Anatomic and radiologic findings
A. Anatomic distribution: parts of the body (e.g., limbs, trunk,
Outcomes bulbar region) affected by motor impairments or limitations
Perinatal ischemic stroke is the most common cause of hemiplegic B. Radiologic findings: neuroanatomic findings on computed
cerebral palsy (CP).176 Although not all survivors of perinatal stroke tomography or magnetic resonance imaging, such as
suffer long-term disabilities, 50% to 75% of infants who suffered a ventricular enlargement, white matter loss, or brain anomaly
perinatal stroke will have a neurologic deficit or seizures.215,218,230-232 Lee 4. Causation and timing
and colleagues215 reported a population-based study of neonatal AIS A. Whether there is a clearly identified cause, as is usually the
showing that 32% of infants with AIS who presented with symptoms case with postnatal cerebral palsy (e.g., meningitis, head
in the neonatal period went on to develop CP, whereas 82% of infants injury), or when brain malformations are present
diagnosed retrospectively developed CP. Because patients identified B. Presumed time frame during which the injury occurred, if
known
retrospectively presented because of hemiparesis, they were more likely
to be classified as having CP. Adapted from Bax M, Goldstein M, Rosenbaum P, et al: Proposed
definition and classification of cerebral palsy, April 2005. Dev Med
Summary of Perinatal Stroke Child Neurol 47:571-576, 2005.
Perinatal ischemic stroke is a major cause of long-term neurologic
disability. Treatment is purely supportive, and management is rehabili-
tation focusing on muscle strengthening and prevention of contrac- hypotonic, or mixed). The International Committee on Cerebral Palsy
tures. Neuroprotective strategies and approaches to prevention are Classification proposed a new classification system that takes into
needed. Advanced neuroimaging techniques to better understand how account the presence or absence of associated impairments, other ana-
the brain reorganizes after this type of injury are being used as research tomic involvement besides limbs, radiologic findings, and causation
tools. (Table 58-6).
Etiology
Cerebral Palsy Cerebral palsy is a result of injury to the developing brain that occurs
Cerebral palsy (CP) is a clinical diagnosis that refers to a group of prenatally, perinatally, or postnatally. Between 75% and 80% of cases
nonprogressive motor impairments. As early as 1862, William John of CP have been attributed to events during pregnancy. Ten percent
Little described the relationship between children with motor abnor- are attributable to intrapartum events such as birth asphyxia,156,235,236
malities and pregnancy complications such as difficult labor, neonatal and 10% follow postnatal causes such as head injury or central nervous
asphyxia, and premature birth.177 In 2005, the International Commit- system infection.179,180 Risk factors for cerebral palsy include prematu-
tee on Cerebral Palsy Classification defined CP as “a group of devel- rity, multiple gestation, growth restriction, intracranial hemorrhage,
opmental disorders of movement and posture, which cause activity PVL, infections, placental pathology, genetic syndromes, structural
limitations that are attributed to nonprogressive disturbances that brain abnormalities, birth asphyxia or trauma, and kernicterus. The
occurred in the developing fetal or infant brain. The motor disorders origins of CP tend to be multifactorial, but in some cases, no cause is
of cerebral palsy are often accompanied by disturbances of sensation, identified. Some of the more common risk factors will be discussed in
cognition, communication, perception, and behavior and by a seizure detail. The roles of intracranial hemorrhage, PVL, and birth asphyxia
disorder.”178 Despite improvements in perinatal care, the prevalence of contributing to CP have been discussed in a previous section of this
CP has remained relatively unchanged over the past 50 years, with an chapter.
incidence of 1.5 to 2.5 cases per 1000 live births.155,233,234
Prematurity
Classification Prematurity and low birth weight seem to be the most important risk
Traditionally, CP has been classified by topography based on the factors for CP, with an increased prevalence of CP associated with
affected limb involvement (i.e., monoplegia, hemiplegia, diplegia, tri- decreasing gestational age and decreasing birth weight as compared
plegia, and quadriplegia) and a description of the predominant type with term infants. It is important first to consider the rates of CP and
of tone or movement abnormality (i.e., spastic, dyskinetic, ataxic, neurosensory impairments in term infants. Msall and coworkers237

19. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1215
reported rates of disability in term infants as follows: 0.2% for CP, 2% chorionic placentation has a significant role in the pathogenesis of CP,
to 3% for cognitive impairment, 0.1% to 0.3% for hearing loss, and likely because of placental vascular anastomoses.
0.1% for visual impairment.237 With improvements in survival for Multiple gestations have significantly increased because of assisted
ELBW infants, defined as less than 1000 g, there are concerns that dis- reproductive technology (ART). The increased risk of CP associated
ability rates will increase as well. Several investigators have reported with ART is likely because of the higher rate of preterm births because
neurodevelopmental disability rates among ELBW infants born in the ART is typically not associated with monochorionicity unless mono-
1990s. Reported rates range from 8% to 19% with CP, 19% to 49% zygotic division occurs. However, the increased risk of CP associated
with developmental disability, 1% to 4% with hearing impairment, and with ART requires further study. A Danish study suggests that IVF
1% to 4% with visual impairment.23,32,132,238-240 When extreme prema- pregnancies may carry an increased risk of CP not attributable to birth
turity is considered, Shankaran and associates181 showed that surviving weight or gestation184 (see Chapter 29).
infants born at the threshold of viability (i.e., birth weight <750 g,
gestational age <24 weeks, and a 1-minute Apgar of 3), had neurodis- Growth Restriction
ability rates of 60%, with almost one third of infants having CP. The There is much debate in the literature about whether infants with fetal
increase in disability rates may be related to heavy use of postnatal growth restriction have an increased incidence of CP. Many investiga-
steroids to treat neonatal chronic lung disease and high rates of sepsis tors have reported an increased risk of CP for infants who are small
during this period. Poor neurodevelopmental outcomes have been for gestational age (SGA).257-262 However, fetal growth restriction is a
associated with widespread use of postnatal steroids in the 1990s, and separate entity from SGA (see Chapter 34). Fetal growth restriction
routine use of this therapy to treat chronic lung disease is now discour- refers to failure of a fetus to grow at an optimal predicted rate, using
aged.31,241-243 The association between sepsis and cerebral palsy has also fetal growth standards derived from ultrasound measurements of
been identified in many studies and is discussed in a later section. healthy fetuses in utero at each gestational age. Fetal growth curves can
Because further reduction in mortality of ELBW infants is unlikely, account for variables, including fetal sex, ethnicity, parity, and maternal
strategies to reduce neonatal morbidity are increasingly important. height and weight.263-265 SGA refers to infants who weigh less than a
Decreased rates of CP have been reported in ELBW infants born given percentile (usually the 10th) for gestational age and does not take
between 2000 and 2002, a period associated with increased use of into account potential etiologies of SGA such as constitutional small
antenatal steroids, decreased use of postnatal steroids, and decreased stature, chromosomal anomalies, congenital infections, or structural
incidence of nosocomial sepsis.186 Chronic lung disease is an indepen- malformations. Studies of risk of cerebral palsy often use birth weight
dent risk factor for neurodevelopmental disability for which improved alone to define their population of interest, which may explain the
strategies are needed. Inhaled nitric oxide for preterm infants with observed increased risk of CP associated with low birth weight. This
respiratory failure has been studied, and improved cognitive outcome increased risk of CP may result from the effects of intrauterine growth
in infants treated with inhaled nitric oxide has been reported,244,245 restriction, because these cohort studies include more mature SGA
but this effect has not been consistently observed in ELBW term infants and preterm infants with equivalent birth weights.266,267
infants.246,247 The terminology used affects how the data may be interpreted.
Many studies have demonstrated that SGA term or preterm
Multiple Births infants beyond 33 weeks’ gestation have the highest risk of developing
The risk of developing CP is significantly higher in multiple gestations CP.259-261 The Surveillance of Cerebral Palsy in Europe (SCPE) Col-
compared with singleton births. Data from CP registries show that the laborative Group reported that infants born between 32 and 42 weeks’
risk for developing CP in twins is four or five times greater than single- gestation with a birth weight below the 10th percentile were four to
tons. For triplets the risk is 12 to 13 times greater.183,248-250 Although six times more likely to develop CP than infants with a birth weight
twins comprise only 1.6% of the population, they have a 5% to 10% between the 25th and 75th percentile.267,268 For infants born before 33
incidence of CP.251 The higher rate of CP in multiple births may relate weeks’ gestation with fetal growth restriction, the association is less
to preterm birth and to other complications associated with multiple clear, because this population has the highest risk of adverse neurode-
gestation such as placental and cord abnormalities, intra-placental velopmental outcome. It is therefore difficult to separate the risk
shunting, structural anomalies, and difficulties at delivery. purely due to growth restriction from the effect of prematurity in
The incidence of CP increases as birth weight decreases. Only 0.9% general. Other factors that increase the risk of CP are the severity of
of singletons weigh less than 1500 g at birth, compared with 9.4% of SGA, male sex, and perinatal asphyxia.269
twins, 32.2% of triplets, and 73.3% of quadruplets.183,252 Population- Growth-restricted infants may be more susceptible to intrapartum
based registries have also broken down the risks of CP related to birth hypoxia, which leads to adverse neurologic outcome. Data from the
weight groups as follows: 66.5 per 1000 surviving infants born weigh- Collaborative Perinatal Project showed that infants with intrauterine
ing less than 1000 g, 57.4 per 1000 surviving infants with birth weights growth restriction (IUGR) had similar incidences of CP compared
between 1000 and 1499 g, and 8.9 per 1000 surviving infants with birth with non-IUGR infants when examined at 7 years of age in the absence
weights between 1500 and 2499 g.182 However, twins with birth weight of intrapartum hypoxia. However, when intrapartum hypoxia was
above 2500 g still have a threefold to fourfold increased risk of devel- identified, children with IUGR had an increased incidence of neuro-
oping CP compared with singletons.183 It is unclear why this risk developmental disability compared with those without IUGR.197 The
remains increased near term, but it may be linked to an increased risk relative risk of CP due to intrapartum hypoxia was actually lower in a
of asphyxia or fetal growth restriction, which occurs more commonly study of infants who were SGA compared with appropriate for gesta-
in multiples. tional age (AGA) infants.262 Based on conflicting results it seems clear
The risk of CP is increased with the fetal death of a co-twin and is that other factors may be involved.
higher for same-sex twins than for different-sex twins.253-256 When both
twins are born alive and one twin dies in infancy, the risk is even Perinatal Infections
greater than if one twin died in utero, with same-sex twins having a Maternal, intrauterine, and neonatal infections have all been associ-
greater risk than different-sex twins.183 These data suggest that mono- ated with cerebral palsy. Congenital viral infections such as toxoplas-

20. 1216 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
mosis, rubella, cytomegalovirus (CMV), herpes simplex virus, and category includes processes that cause decreased placental reserve,
syphilis may account for 5% to 10% of CP cases.270 Maternal infection such as chronic placental insufficiency, chronic villitis, chronic abrup-
and inflammation has been associated with an increased incidence of tion, chronic vascular obstruction, and perivillous fibrin deposition.293
preterm birth and are risk factors for the development of CP. Intra- Evaluation of the placenta in the cause of neonatal encephalopathy
amniotic infection, also referred to as clinical chorioamnionitis, has may provide some insight into the fetal intrauterine environment and
been associated with preterm labor, preterm premature rupture of the its contribution to the neurologic impairment.
fetal membranes, and subsequent preterm birth.271,272 Chorioamnio-
nitis also has been associated with an increased risk for developing CP Coexisting Impairments
through several likely mechanisms. An increased risk of IVH and PVL Historically, CP has been defined strictly by the location and degree of
has been associated with maternal chorioamnionitis and premature motor impairment. However, associated coimpairments such as dis-
rupture of membranes in numerous studies.210,211,273-275 Histologic cho- turbances in sensation, cognition, communication, perception, and
rioamnionitis without clinical signs of intra-amniotic infection has behavior are common, as are seizures. A new definition that includes
also been linked to increased risk of IVH, PVL, and CP.276-280 coimpairments has been proposed.178,234 A Dutch population study of
Laboratory and clinical evidence has emerged that supports the children with CP reported that 40% had seizures, 65% had cognitive
hypothesis that intrauterine infection and inflammation leads to the deficits (IQ < 85), and 34% had visual impairments.294 Hearing impair-
production of proinflammatory cytokines, which are responsible for ments and feeding difficulties are also common.
white matter brain injury and ultimately for CP. These cytokines are
potentially toxic to developing oligodendrocytes in fetal white matter Strategies to Reduce Cerebral Palsy
and cause reduced myelination and subsequent white matter Strategies to reduce CP have focused on asphyxia and premature birth
injury.270,273,281,282 Various cytokines may have a direct toxic effect on because these factors seem to be the most amenable to intervention to
cerebral white matter by increasing the production of nitric oxide prevent CP. Strategies commonly used to reduce intrapartum hypoxia
synthase, cyclooxygenase, other associated free radicals, and excitatory such as fetal heart monitoring, maternal oxygen administration, repo-
amino acids.270,282-285 This relationship between elevated cytokine levels sitioning, and strict guidelines for oxytocin use have not affected the
and the development of white matter injury has been seen in both rate of CP. Fetal heart rate monitoring increases the rate of operative
preterm and term infants. A fourfold to sixfold increased risk for white interventions without reducing the rate of CP164 and may theoretically
matter injury has been associated with elevated levels of interleukin increase the prevalence of CP by increasing the risk of chorioamnio-
(IL) 1β from amniotic fluid and from umbilical cord blood in preterm nitis.295,296 Reduction of perinatal intracranial injuries associated with
infants.2,286 In a study of term infants who went on to develop CP, the decreased use of forceps and vacuum extraction in the past 20 years
stored blood samples had significantly increased levels of the cytokines is a positive trend that may contribute to a reduction in the incidence
IL-1, IL-8, IL-9, tumor necrosis factor β, and RANTES.287 The of CP.155,297
combination of intrauterine infection and intrapartum hypoxia has Preterm birth accounts for approximately 35% of cerebral palsy
been correlated with a dramatic increase in the incidence of CP.288 cases.298 Strategies to reduce the incidence of preterm birth have been
Neonatal infection has been associated with the development of CP sought to reduce the incidence of CP, provided the risk of an in utero
due to direct central nervous system damage, e.g., in meningitis, or to insult is not increased by prolonging pregnancy. Prevention of preterm
a systemic inflammatory response syndrome (SIRS) that leads to birth has proved elusive, making strategies to reduce morbidity more
sepsis, shock, and multiorgan system failure.270 Preterm infants who immediately promising. Antenatal steroids decrease the incidence of
develop infection seem to be at higher risk.289,290 A study of 6093 ELBW several morbidities strongly associated with cerebral palsy, including
survivors born between 1993 and 2001 found an 8% incidence of CP IVH, PVL,171,299 RDS, and chronic lung disease. Postnatal steroids used
among infants who did not develop a postnatal infection and a 20% to treat neonatal chronic lung disease, however, are associated with a
incidence of CP in infants whose hospital course was complicated by significantly increased risk of CP.241,300-302
sepsis, NEC, or meningitis.240 The infected infants also had an extremely Another strategy under study to reduce CP in preterm infants is
high risk of cognitive impairment, defined as a Bayley MDI score less the administration of magnesium sulfate before delivery. The pro-
than 70 at 18 months compared with noninfected infants (33% to 42% posed beneficial mechanism is the ability of magnesium sulfate to sta-
versus 22%).240 Another study of ELBW survivors found that NEC bilize vascular tone, reduce reperfusion injury, and reduce cytokine
requiring surgical intervention was associated with a significant mediated injury.303,304 Several observational studies have found an
increase in both the incidence of CP and developmental disabilities association between maternal administration of magnesium sulfate
compared with those without NEC.129 (given for preeclampsia or preterm labor) and a reduced risk of
CP.305-308 However, other investigators have reported no protective
Placental Abnormalities effect of magnesium.309-314 The Australasian Collaborative Trial of
Because the placenta supplies nutrients to the developing fetus and Magnesium Sulphate examined the efficacy of magnesium sulfate
serves as a barrier that protects the fetus from influences such as infec- given to women at risk for preterm birth less than 30 weeks’ gestation
tious organisms, toxins, trauma, and immune mediators, placental solely for neuroprotection. This study was a much larger, randomized,
abnormalities can predispose fetuses to adverse outcomes. Placental controlled trial (N = 1062), and the investigators reported a lower
abnormalities associated with CP can fall into three categories. The incidence of CP, although the difference was not statistically significant
first encompasses events that occur during or before labor, also known (6.8% versus 8.2%), and no serious harmful effects to women or their
as sentinel lesions, that can cause fetal hypoxia. These lesions include children.194 Although the use of prenatal magnesium sulfate cannot be
uteroplacental separation, fetal hemorrhage, and umbilical cord recommended based on this study alone, this intervention is being
occlusion.291 The next category is made up of thromboinflammatory further investigated (see Chapter 29). A large, 10-year NIH trial of
processes that affect fetal circulation and include fetal thrombotic intrapartum administration of magnesium sulfate as neuroprotective
vasculopathy, chronic villitis, meconium-associated fetal vascular agent found a reduced rate of moderate to severe cerebral palsy among
necrosis, and fetal vasculitis related to chorioamnionitis.291,292 The third survivors at 2 years of age who received antenatal magnesium.315

21. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1217
Summary of Cerebral Palsy rioamnionitis. Clinical chorioamnionitis, as characterized by maternal
Cerebral palsy is a significant adverse event with origins in pregnancy. fever and uterine tenderness, is probably a very different disease from
Many risk factors have been identified, although sometimes no etio- clinically silent histologic chorioamnionitis commonly seen in preterm
logic factor is found. Strategies to reduce asphyxia and prevent preterm deliveries. Whether these represent different disease entities or differ-
birth have not shown a significant decrease in rates of CP. Because most ent manifestations of the same disease spectrum is not evident. The
CP is related to extremely preterm birth and the survival rates of these fetal response to infection has important consequences for neonatal
ELBW infants is improving, strategies to reduce neonatal brain injury, outcome. Studies using proteomic analysis of amniotic fluid show
such as the use of antenatal steroids, are the most promising. Future promise for relating the diagnosis of chorioamnionitis to the neonatal
trials of antenatal neuroprotection for preterm infants may prove ben- clinical course.321,322
eficial to combat inflammation- or cytokine-mediated brain injury.
Group B b-Hemolytic Streptococci
Infection with group B β-hemolytic streptococci (GBS) was first rec-
Infectious Disease Problems ognized as a cause of early-onset neonatal sepsis in the 1970s. By the
in the Neonatal Period 1990s, GBS was a leading cause of serious neonatal infections. The
organism is a common colonizing constituent of the vagina and rectum
Neonatal infection is a significant cause of neonatal morbidity and in 10% to 30% of pregnant women. GBS colonization is more common
mortality in preterm and term infants. The risk of infection is inversely in African-American women and those with a previous history of a
related to gestational age. The clinical manifestations of neonatal infec- neonate with GBS disease or a history of a GBS urinary tract infection.
tion vary by pathogen and age of acquisition. The spectrum of patho- Epidemiologic studies demonstrate that most invasive, early-onset
gens causing neonatal infection is broad and has changed over the neonatal GBS disease involves vertical transmission from the mother
decades.316 However, the cornerstones of management remain preven- to the fetus during labor. This observation led to studies of intrapar-
tion when possible, early detection, and focused treatment. tum antibiotic prophylaxis with penicillin G or ampicillin. The success
Compared with older children and adults, neonatal host defense is of this strategy prompted the publication of guidelines for intrapartum
blunted by incomplete development and experience with self versus antibiotic prophylaxis by the Centers for Disease Control and Preven-
non-self discrimination.317 All components of the immune system are tion.323 A follow-up study completed in 2005 confirmed the success of
deficient. Nonspecific immunity is defective at several levels. Skin and this strategy.324 Most infants with invasive, serious GBS now seen are
mucosal barriers are immature, especially in preterm infants. Levels of born to mothers with negative GBS screening cultures who have pre-
nonspecific antibacterial proteins such as lysozyme and lactoferrin are sumably converted to GBS-positive carrier status in the interval
low. Neutrophil numbers are low, with limited storage pools available between screening and delivery.325 In the future, rapid GBS screening
to clear bacteria. Key neutrophil functions, including chemotaxis, technology may allow for identification of these women when they
phagocytosis, and intracellular killing, are limited. The neonate is present in labor.326 There is some concern that intrapartum antibiotic
poorly equipped to clear transient bacteremia and localize bacterial prophylaxis may be associated with a higher incidence of serious bacte-
infection. Specific humoral and cell-mediated immune functions are rial infections later in infancy. This was most pronounced when broad-
also limited. Circulating immunoglobulin levels are very low compared spectrum antibiotics were used for intrapartum prophylaxis rather
with adult levels. The neonate acquires virtually all of its circulating IgG than penicillin G.327 The advantages of intrapartum antibiotic prophy-
from the mother through transplacental transport. The bulk of this laxis to reduce the risk of invasive neonatal GBS disease clearly out-
antibody is transferred during the third trimester, making the preterm weigh any risks, especially if penicillin is employed.
infant profoundly deficient. B-cell function is immature as well. The
primary antibody response to infection mediated by the infant is pro-
duction of IgM. Although T lymphocytes are present at birth, their Viral Infections
function is almost undetectable by standard functional assays.
The nature of neonatal immune function accounts for the clinical Cytomegalovirus
manifestations of most early-onset infections. Nonspecific signs such Human cytomegalovirus (CMV) is transmitted horizontally (i.e.,
as lethargy, poor feeding, temperature instability, decreased tone, direct person-to-person contact with virus-containing secretions) and
apnea, and altered perfusion may or may not be present. Fever is vertically (i.e., from mother to infant before, during, or after birth) and
uncommon, as are localized processes such as cellulitis, abscesses, or through transfusion of blood products or organ transplantation from
osteomyelitis. When present, they are usually accompanied by bacte- previously infected donors. Vertical transmission of CMV to infants
remia. Similarly, bacteremia must always be suspected in neonates with occurs by one of the following routes of transmission: in utero by
meningitis or urinary tract infections. transplacental passage of maternal blood borne virus, through an
infected maternal genital tract, and postnatally by ingestion of CMV-
positive human milk.328,329
Chorioamnionitis Approximately 1% of all liveborn infants are infected in utero and
The relationship between chorioamnionitis and neonatal infection is excrete CMV at birth. Risk to the fetus is greatest in the first half of
complex and remains incompletely understood. Some studies demon- gestation. Although fetal infection can occur after maternal primary
strate a direct correlation between chorioamnionitis and neonatal infection or after reactivation of infection during pregnancy, sequelae
infection. Other poor neonatal outcomes, including RDS and BPD, are are far more common in infants exposed to maternal primary infec-
associated with chorioamnionitis.84,318 However, other clinical series tion, with 10% to 20% of infants manifesting neurodevelopmental
and studies using animal model systems reach essentially the opposite impairment or sensorineural hearing loss in childhood.330
conclusion—that chorioamnionitis protects against these same out- Congenital CMV infection is usually clinically silent. Some infected
comes.319,320 Some of the confusion is grounded in definitions of cho- infants who appear healthy at birth are subsequently found to develop

22. 1218 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
hearing loss or learning disabilities. Approximately 10% of infants with exposure protection and provides long-term protection. Pre-exposure
congenital CMV infection exhibit evidence of profound involvement immunization with hepatitis B vaccine is the most effective means
at birth, including intrauterine growth restriction, jaundice, purpura, to prevent HBV transmission. To decrease the HBV transmission
hepatosplenomegaly, microcephaly, intracerebral calcifications, and rate universal immunization is necessary. Postexposure prophylaxis
retinitis.331 Although ganciclovir has been used to treat some infants with hepatitis B vaccine and HBIG or hepatitis B vaccine alone effec-
with congenital CMV infection, it is not recommended routinely tively prevents infection after exposure to HBV. The effectiveness of
because of insufficient efficacy data. One study of ganciclovir treat- postexposure immunoprophylaxis is related to the time elapsed
ment provided to infants with congenital CMV with central nervous between exposure and administration. Immunoprophylaxis is most
system involvement suggested that treatment decreased progression of effective if given within 12 to 24 hours of exposure. Serologic testing
hearing impairment.332 Because of the potential toxicity of long-term of all pregnant women for HBsAg is essential for identifying women
ganciclovir therapy, additional investigation is required before a rec- whose infants will require postexposure prophylaxis beginning at
ommendation can be made. birth.
Infection acquired during pregnancy from maternal cervical secre- Hepatitis B vaccines are highly effective and safe. These vaccines
tions or after delivery from human milk usually is not associated with are 90% to 95% efficacious for preventing HBV infection. Studies in
clinical illness. Infections resulting from transfusion of blood products preterm infants and low-birth-weight infants (<2000 g) have demon-
with CMV-seropositive donors and from human milk to preterm strated decreased seroconversion rates after administration of hepatitis
infants have been associated with serious systemic infections, includ- B vaccination. However, by 1 month chronological age medically
ing lower respiratory tract infection. Transmission of CMV by transfu- stable preterm infants should be immunized, regardless of initial birth
sion to newborn infants has been reduced by using CMV-antibody weight or gestational age. Routine postimmunization testing for anti-
negative donors, by freezing erythrocytes in glycerol, or by removal of HBs is not necessary for most infants. However, postimmunization
leukocytes by filtration before administration.333 CMV transmission by testing for HBsAg and anti-HBs at 9 to 18 months is recommended
human milk can be decreased by pasteurization.334 However, freeze- for infants born to HBsAg-positive mothers.
thawing is probably not effective.335 If fresh donor milk is needed for Immunization of pregnant women with hepatitis B vaccine has not
infants born to CMV-antibody negative mothers, provision of these been associated with adverse effects on the developing fetus. Because
infants with milk from only CMV-antibody negative women should HBV infection may result in severe disease in the mother and chronic
be considered. infection in the newborn infant, pregnancy is not considered a contra-
indication to immunization. Lactation is also not a contraindication
Hepatitis B to immunization.
HBV is a DNA virus whose important components include an outer
lipoprotein envelope containing antibody to hepatitis B surface antigen Herpes Simplex Virus
(HBsAg) and an inner nucleocapsid containing the hepatitis B core Neonatal herpes simplex virus infections range from localized skin
antigen. Only antibody to HBsAg (anti-HBs) provides protection from lesions to overwhelming disseminated disease. The latter has a case-
HBV infection. Perinatal transmission of HBV is highly efficient and fatality rate in excess of 50%, even with prompt initiation of antiviral
usually occurs from blood exposure during labor and delivery. In utero therapy. Vertical transmission is the likely mode of transmission
transmission of HBV is rare, accounting for less than 2% of perinatal for most cases. Mothers with a history of previous disease appear
infections in most studies. The risk of an infant acquiring HBV from to convey at least some type-specific immunity to the neonate.
an infected mother as a result of perinatal exposure is 70% to 90% for Most mothers of severely infected infants have no recognized history
infants born to mothers who are HBsAg and HBeAg positive. The risk of HSV and no evidence of active disease on physical examination.
is 5% to 20% for infants born to mothers who are HBeAg negative. No screening protocols for HSV are available, and there is no
Age at the time of acute infection is the primary determinant of risk vaccine.337,338
of progression to chronic HBV infection. More than 90% of infants
with perinatal infection will develop chronic HBV infection. Between Human Immunodeficiency Virus
25% and 50% of children infected between 1 to 5 years of age become Landmark studies339,340 in the 1990s demonstrated the value of intra-
chronically infected, whereas only 2% to 6% of older children or adults partum antiretroviral therapy to reduce the risk of maternal to fetal
develop chronic HBV infection.336 transmission of human immunodeficiency virus (HIV). Improve-
The goals of HBV prevention programs are to prevent the acute ments in the quality and availability of rapid HIV testing holds promise
HBV infection and to decrease the rates of chronic HBV infection and for timely and accurate identification of infected women and their
HBV-related chronic liver disease. Over the past 2 decades a strategy newborn infants. The risk of congenital HIV is reduced to approxi-
has been progressively implemented in the United States to prevent mately 1% when HIV-positive mothers receive antiretroviral therapy
HBV transmission. This includes the following components: universal during labor and treatment is continued for the neonate within 12
immunization of infants beginning at birth, prevention of perinatal hours of delivery, Breastfeeding is contraindicated, unless there is no
HBV infection by routine screening of all pregnant women and appro- access to clean water and infant formula.
priate immunoprophylaxis of infants born to HBsAg-positive women Laboratory diagnosis of HIV infection during infancy depends on
and infants born to women with unknown HBsAg status, routine detection of virus or viral nucleic acid. Cord blood should not be used
immunization of children and adolescents who have previously not for this early test because of possible contamination by maternal blood.
been immunized, and immunization of previously nonimmunized A positive result identifies infants who have been infected in utero.
adults at increased risk of infection. Approximately 93% of infected infants have detectable HIV DNA at 2
Two types of products are available for hepatitis B immunoprophy- weeks, and almost all HIV-infected infants have positive HIV DNA
laxis. Hepatitis B immune globulin (HBIG) provides short-term pro- PCR assay results by 1 month of age. A test within the first 14 days of
tection (3 to 6 months) and is indicated only in postexposure age can facilitate decisions regarding initiation of antiretroviral therapy.
circumstances. Hepatitis B vaccine is used for pre-exposure and post- Transplacental passage of antibodies complicates use of antibody-

23. CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1219
based assays for diagnosis of infection in infants because all infants birth. It is characterized by a staccato cough, tachypnea, and rales on
born to HIV-seropositive mothers have passively acquired maternal physical examination. Pulmonary hyperinflation and infiltrates are
antibodies. demonstrated on the chest radiograph.
Antiretroviral therapy is indicated for most HIV-infected children. Topical prophylaxis with silver nitrate, erythromycin, or tetracy-
Initiation of therapy depends on virologic, immunologic, and clinical cline for all newborn infants to avert gonococcal ophthalmia does not
criteria. Because HIV infection is a rapidly changing area, consultation prevent chlamydial conjunctivitis or extraocular infections.343 Infants
with an expert in pediatric HIV is recommended. with chlamydial conjunctivitis are treated with oral erythromycin base
or ethylsuccinate (50 mg/kg per day in four divided doses) for 14 days.
Rubella Alternatively, oral sulfonamides may be used after the immediate neo-
Humans are the only source of infection. Peak incidence of infection natal period for infants who do not tolerate erythromycin. Because the
is in late winter and early spring. Before widespread use of rubella efficacy of treatment is about 80%, follow-up of infants is recom-
vaccine, rubella was an epidemic disease with most cases occurring in mended. In some instances, a second course of therapy may be
children. The incidence of rubella has decreased 99% from the prevac- required.
cine era. Although the number of susceptible people has decreased Chlamydial pneumonia is treated with oral azithromycin (20 mg/
since introduction and widespread use of rubella vaccine, serologic kg/day) for 3 days or erythromycin base or ethylsuccinate (50 mg/kg
surveys indicate that approximately 10% of the U.S. population older per day in four divided doses) for 14 days. Detection and treatment of
than 5 years is susceptible. The percentage of susceptible people who C. trachomatis infections before delivery is the most effective way to
are foreign born or from areas with poor vaccine coverage is higher. reduce the risk of neonatal conjunctivitis and pneumonia.
The risk of congenital rubella syndrome is highest among infants of
women born outside the United States. Epidemiologic data suggests Gonococcal Infections
that rubella is no longer endemic in the United States.341 Infection with Neisseria gonorrhoeae in the newborn infant usually
Congenital rubella syndrome is characterized by a constellation involves the eyes. Other types of gonococcal infections include arthri-
of anomalies, which may include ophthalmologic (i.e., cataracts, tis, disseminated disease with bacteremia, meningitis, scalp abscess, or
microphthalmos, pigmentary retinopathy, and congenital glaucoma), vaginitis.
cardiac (i.e., patent ductus arteriosus and peripheral pulmonary artery Microscopic examination of Gram-stained smears of exudates
stenosis), auditory (i.e., sensorineural hearing impairment), and neu- from the eyes, skin lesions, synovial fluid, and, when clinically war-
rologic (i.e., meningoencephalitis, behavioral abnormalities, and ranted, CSF may be useful in the initial evaluation. Identification of
mental retardation) abnormalities. Neonatal manifestations of con- gram-negative intracellular diplococci in these smears can be helpful,
genital rubella syndrome include growth retardation, interstitial in particular if the organism is not recovered in culture. N. gonorrhoeae
pneumonia, radiolucent bone disease, hepatosplenomegaly, thrombo- can be cultured from normally sterile sites such as blood, CSF, and
cytopenia, and dermal erythropoiesis, also called blueberry muffin synovial fluid.
lesions. The occurrence of congenital defects varies with timing of the For routine ophthalmia neonatorum prophylaxis of infants imme-
maternal infection. diately after birth, a 1% silver nitrate solution, 1% tetracycline, or 0.5%
Detection of rubella-specific IgM antibody usually indicates recent erythromycin ophthalmic ointment is instilled into each eye. Prophy-
postnatal infection or congenital infection in a newborn infant, but laxis may be delayed for as long as 1 hour after birth to facilitate
false-positive and false-negative results occur. Congenital infection can parent-infant bonding. Topical antimicrobial agents cause less chemi-
be confirmed by stable or increasing rubella-specific IgG over several cal irritation than silver nitrate. None of the topical agents is effective
months. Rubella virus can be isolated most consistently from throat against C. trachomatis.343
or nasal swabs by inoculation of appropriate cell culture. Blood, urine, When prophylaxis is administered, infants born to mothers with
CSF, and pharyngeal swab specimens can also yield virus in congeni- known gonococcal infection rarely develop gonococcal ophthalmia.
tally infected infants. However, because gonococcal ophthalmia or disseminated disease
Infants with congenital rubella should be considered contagious occasionally can occur in this situation, infants born to mothers known
until at least 1 year old, unless nasopharyngeal and urine cultures are to have gonorrhea should receive a single dose of ceftriaxone (125 mg)
repeatedly negative for rubella virus. Infectious precautions should be given intravenously or intramuscularly. Preterm and low-birth-weight
considered for children up to 3 years old who are hospitalized for infants are given 25 to 50 mg/kg of ceftriaxone to a maximum dose of
congenital cataract extraction. Caregivers of these infants and children 125 mg.
should be made aware of the potential hazard to susceptible pregnant Infants with clinical evidence of ophthalmia neonatorum, scalp
contacts. abscess, or disseminated disease should be hospitalized. Cultures of the
blood, eye discharge, or other sites of infection such as CSF should be
performed to confirm the diagnosis and determine antimicrobial sus-
Sexually Transmitted Infections ceptibility. Tests for concomitant infection with C. trachomatis, syphi-
lis, and HIV infection should be performed. Recommended treatment,
Chlamydia including for ophthalmia neonatorum, is ceftriaxone (25 to 50 mg/kg,
In the newborn period, Chlamydia trachomatis is associated with con- given intravenously or intramuscularly, not to exceed 125 mg) given
junctivitis and pneumonia. Acquisition of C. trachomatis occurs in once. Infants with gonococcal ophthalmia should receive eye irriga-
approximately 50% of infants born vaginally to infected mothers and tions with saline solution immediately and at frequent intervals until
in some infants delivered by cesarean section with intact membranes.342 the discharge is eliminated. Topical antimicrobial treatment alone is
Neonatal chlamydial conjunctivitis is characterized by ocular conges- inadequate and is unnecessary when recommended systemic antimi-
tion, edema, and discharge developing a few days to several weeks after crobial treatment is provided. Infants with gonococcal ophthalmia
birth and usually lasting 1 to 2 weeks. Pneumonia in infants is usually should be hospitalized and evaluated for disseminated infection. Rec-
an insidious afebrile illness occurring between 2 and 20 weeks after ommended therapy for arthritis and septicemia is ceftriaxone or cefo-

24. 1220 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin
taxime for 7 days. If meningitis is documented, treatment should present. When circumstances warrant evaluation of an infant for syph-
continue for a total of 10 to 14 days. ilis, the infant should be treated if test results cannot exclude infection,
if the infant cannot be adequately evaluated, or if adequate follow-up
Syphilis cannot be ensured.
Congenital syphilis is contracted from an infected mother through Infants with proven congenital syphilis should be treated with
transplacental transmission of Treponema pallidum at any time during aqueous crystalline penicillin G. The dosage should be based on chron-
the pregnancy or birth. Intrauterine syphilis can result in stillbirth, ologic age, not gestational age. The dose of penicillin G is 100,000 to
hydrops fetalis, or preterm birth. The infant can present with edema, 150,000 U/kg per day, administered as 50,000 U/kg per dose intrave-
hepatosplenomegaly, lymphadenopathy, mucocutaneous lesions, nously every 12 hours during the first 7 days of life and then every 8
osteochondritis, pseudoparalysis, rash, or snuffles at birth or within hours thereafter for a total of 10 days. Alternatively, penicillin G pro-
the first 2 months of life. Hemolytic anemia or thrombocytopenia may caine (50, 000 U/kg/day) given intramuscularly for 10 days may be
be identified on laboratory evaluation. Untreated infants, regardless of considered, but adequate CSF concentrations may not be achieved
whether they have manifestations in infancy, may develop late mani- with this regimen.
festations, usually after 2 years of age and involving the bones, central
nervous system, eyes, joints, and teeth. Some consequences of intra-
uterine infection may not become apparent until many years after
birth.
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