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