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Obstetric and Postnatal Management DecisionsThe nature of obstetric clinical practice requires consideration of two patients: mother and fetus. The intrinsic biologic interdependence of one with the other creates challenges not typically encountered in other realms of medical practice. Often, there is a paucity of objective data to support the evaluation of risks and benefi ts associated with a given clinical situation, forcing obstetricians to rely on their clinical acumen and experience. Family perspectives must be integrated in clinical decision making, along with the advice and counsel of other clinical providers. In this chapter, we review how to best use neonato-logic expertise in the obstetric decision-making process.

Optimal perinatal care often derives from collaboration between the obstetrician and neonatologist during pregnancy and especially around the time of labor to eliminate ambiguity and confusion in the delivery room and to ensure that patients and families understand the rationale for obstetric and postnatal management decisions. The neo-natologist can provide information regarding risks to the fetus associ-ated with delaying or initiating preterm delivery and can identify the optimal location for delivery to ensure that skilled personnel are present to support the newborn infant.

In addition to contributing information about gestational age–specifi c outcomes, the neonatologist can anticipate neonatal com-plications related to maternal disorders such as diabetes mellitus, hypertension, and multiple gestations or to prenatally detected fetal conditions such as congenital infections, alloimmunization, or devel-opmental anomalies. When a lethal condition or high risk of death in the delivery room is anticipated, the neonatologist can assist with the formulation of a birth plan and develop parameters for delivery room intervention.

Preparing parents by describing delivery room management and resuscitation of a high-risk infant can demystify the process and reduce some of the fear anticipated by the expectant family. Premature infants are susceptible to thermal instability and are moved rapidly after birth to a warming bed to prevent hypothermia while assessing the infant’s cardiorespiratory status and vigor. The need for resuscitation is deter-mined by careful evaluation of cardiorespiratory parameters and appropriate response according to published Neonatal Resuscitation Program guidelines.1

Common Morbidities of Pregnancy and Neonatal OutcomesComplications of pregnancy that affect infant well-being may be immediately evident after birth, such as hypotension related to mater-nal hemorrhage, or may manifest hours later, such as hypoglycemia related to maternal diabetes or thrombocytopenia related to maternal preeclampsia. Anemia and thyroid disorders related to transplacental passage of maternal IgG antibodies to platelets or thyroid, respectively, may manifest days after delivery.

Diabetes during pregnancy serves as an example. Infants born to women with diabetes are often macrosomic, increasing the risk of shoulder dystocia and birth injury. After delivery, these infants may have signifi cant hypoglycemia, polycythemia, and electrolyte distur-bances, which require close surveillance and treatment. Lung matura-tion is delayed in the infants born to women with diabetes, increasing the incidence of respiratory distress syndrome (RDS) at a given gesta-tional age. Infants of diabetic mothers may also have delayed neuro-logic maturation, with decreased tone typically leading to delayed feeding competence. Less common complications include an increased incidence of congenital heart disease and skeletal malformations. These neonatal complications are typically managed without long-term sequelae, but they are not without consequences, such as pro-longed hospital stay. Neonatal complications for the infant of a woman with diabetes are a function of maternal glycemic control. Careful antenatal attention to optimal control of blood glucose can reduce neonatal morbidity due to maternal diabetes.

Table 58-1 summarizes other morbidities of pregnancy and their effects on neonatal outcome. The list is not exhaustive and does not take into account how multiple morbidities may interact to create additional complications. All of these problems may contribute to increased length of hospital stay after delivery and to long-term morbidity.

Chorioamnionitis has diverse effects on the fetus and neonatal outcome. It is associated with premature rupture of membranes and preterm delivery. Elevated levels of proinfl ammatory cytokines may predispose neonates to cerebral injury.2 Although suspected or proven neonatal sepsis is more common in the setting of chorioamnio-

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

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1198 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin

nitis, many neonates born to mothers with histologically proven chorioamnionitis are asymptomatic and appear uninfected. Animal models and associated epidemiologic data suggest that chorioamnio-nitis can accelerate fetal lung maturation, as measured by surfactant production and function. However, preterm infants born to mothers with chorioamnionitis are more likely to develop bronchopulmonary dysplasia (BPD).3-5 The neonatal consequences of chorioamnionitis are likely related to the timing, severity, and extent of the infection and the associated infl ammatory response.

The effects of preeclampsia on the neonate include intrauterine growth retardation, hypoglycemia, neutropenia, thrombocytopenia, polycythemia, and electrolyte abnormalities such as hypocalcemia. Most of these problems appear related to placental insuffi ciency, with diminished oxygen and nutrient delivery to the fetus. With delivery and supportive care, most of these problems will resolve with time, although some patients will require treatment with intravenous calcium or glucose, or both, in the early neonatal period. Similarly, severe thrombocytopenia may require platelet transfusion therapy. Preeclampsia may protect against intraventricular hemorrhage (IVH) in preterm infants, perhaps because of maternal treatment or other unknown factors.6 Unlike intrauterine infl ammation, preeclampsia does not appear to accelerate lung maturation.7

Maternal autoimmune disease may affect the neonate through transplacental transfer of autoantibodies. Symptoms are a function of the extent of antibody transfer. Treatment is supportive and based on the affected neonatal organ systems. For example, maternal Graves disease may cause neonatal thyrotoxicosis requiring treatment with propylthiouracil or β-blockers. Maternal lupus or connective tissue disease is linked to congenital heart block that may require long-term pacing after delivery. Myasthenia gravis during pregnancy occasionally results in a transient form of the disease in the neonate. Supportive therapy during the early neonatal period addresses most issues associ-ated with maternal autoimmune disorders. Passively transferred auto-antibodies gradually clear from the neonatal circulation with a half-life of 2 to 3 weeks.

Neonatal outcome associated with maternal nutritional status during pregnancy is of growing interest. The Dutch famine of 1944 to 1945 created a unique circumstance for studying the consequences of severe undernutrition during pregnancy (i.e., caloric intake <1000 kcal/

day). Mothers experienced signifi cant third-trimester weight loss, and offspring were underweight.8 There is growing evidence that infants undernourished during fetal life are at higher risk for “adult” diseases such as atherosclerosis and hypertension. Poor maternal nutrition during intrauterine life may signal the fetus to modify metabolic path-ways and blood pressure regulatory systems, with health consequences lasting into late childhood and beyond.9 Conversely, maternal overnu-trition (i.e., excessive caloric intake) predisposes mothers to insulin resistance and large-for-gestational-age infants.10,11

Neonatal anemia may be a consequence of perinatal events such as placental abruption, ruptured vasa previa, or fetal-maternal transfu-sion. At delivery, the neonate may be asymptomatic or display pro-found effects of blood loss, including high-output heart failure or hypovolemic shock. The duration and extent of blood loss along with any fetal compensation typically determine neonatal clinical status at delivery and subsequent management. In the delivery room, prompt recognition of acute blood loss and transfusion with type O, Rh-negative blood can be a lifesaving intervention.

Neonates from a multifetal gestation are, on average, smaller at a given gestational age than their singleton counterparts. They are also more likely to deliver before term and therefore are more likely to experience the complications associated with low birth weight and prematurity described in this chapter. Monochorionic twins may expe-rience twin-twin transfusion syndrome. The associated discordant growth and additional problems of anemia, polycythemia, congestive heart failure, and hydrops may further complicate the clinical course after delivery, even after amnioreduction or fetoscopic laser occlusion. Cerebral lesions such as periventricular white matter injury and ven-tricular enlargement may occur more frequently in the setting of twin-twin transfusion syndrome.12 Additional epidemiologic studies and long-term follow-up are needed to further address this issue.

Congenital malformations present signifi cant challenges for care-givers and families, and prenatal diagnosis is an opportunity to provide anticipatory guidance. The neonatologist can facilitate delivery cover-age and ensure availability of appropriate equipment, medications, and personnel. Table 58-1 summarizes some of the important consider-ations associated with management of congenital malformations and refl ects the importance of multidisciplinary input. Typically, these patients are best delivered in a setting where experienced delivery

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 profi le available for immediate evaluationNeural tube defects Dressings to cover defect, IV fl uids, neurosurgery, urologic evaluation, orthopedics evaluation

and managementAbdominal wall defects Saline-fi lled sterile bag to contain exposed abdominal contents, IV fl uids, pediatric surgery,

genetics evaluation and managementCyanotic congenital heart disease IV access, prostaglandin E1, immediate availability of mechanical ventilation

ECMO, extracorporeal membrane oxygenation; IV, intravenous.

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1199CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin

room attendance is available. If the needed consultative services and equipment are not readily available, arrangement should be made for prompt transfer to a tertiary center. Successful transports depend on clear communication between centers, for example, regarding delivery of an infant with gastroschisis, so that the delivering hospital provides adequate intravenous hydration and protection of exposed abdominal organs, and the referral center can mobilize pediatric surgical intervention immediately on arrival of the infant.

In settings of premature, preterm, or prolonged rupture of mem-branes and premature labor, mothers are frequently treated with anti-biotics and tocolytic agents. Maternal medications administered during pregnancy for non-obstetric diseases can have a signifi cant impact on the neonate. A common challenge in many centers is the treatment of opiate-addicted mothers on methadone. The symptoms of neonatal abstinence syndrome vary as a function of the degree of prenatal opiate exposure and age after delivery. Many infants appear neurologically normal at delivery, only to exhibit symptoms later on the fi rst or second day or extrauterine life. Infants with neonatal abstinence syn-drome typically demonstrate irritability, poor feeding, loose and fre-quent stools, and in severe cases, seizures. Treatment options include nonpharmacologic intervention (e.g., swaddling, minimal stimula-tion), methadone, or non-narcotic drugs such as phenobarbital. These infants often require hospitalization for many days or weeks until their irritability is under suffi cient control to allow for care in a home setting. There is clinical evidence that neonates may also exhibit similar symptoms after withdrawal from antenatal nicotine exposure.13,14 The consequences of other illicit drug use during pregnancy have been widely studied but are diffi cult to assess because of diffi culties with diagnosis and confounding variables. Maternal cocaine abuse has been associated with obstetric complications such as placental abruption. Vascular compromise may predispose neonates to cerebral infarcts and bowel injury. Developmental delay and behavioral problems are observed, although associated factors such as poverty, lack of prenatal care, and low socioeconomic status also contribute.

Alloimmune hemolytic disorders such as Rh hemolytic disease and ABO incompatibility can cause neonatal morbidity ranging from uncomplicated hyperbilirubinemia to severe anemia, hydrops, and high-output congestive heart failure. Although it is uncommon, Rh hemolytic disease must be considered as a cause of unexplained hydrops, anemia, or heart failure in infants born to Rh-negative mothers, especially if there is a possibility of maternal sensitization. ABO incompatibility is common, with up to 20% of all pregnancies potentially at risk. The responsible isohemagglutinins have weak affi nity for blood group antigens, and the degree of hemolysis and subsequent jaundice varies among patients. Indirect immunoglobulin (Coombs) testing has limited value in predicting clinically signifi cant jaundice. Neonatal morbidity is typically restricted to hyperbilirubine-mia requiring treatment with phototherapy.

PrematurityThe mean duration of a spontaneous singleton pregnancy is 280 days or 40 menstrual weeks, 38 weeks after conception. An infant delivered before completion of 37 weeks’ gestation is considered to be preterm according to the World Health Organization (WHO) defi nition. Infant morbidity and mortality increase with decreasing gestational age at birth. The risk of poor outcome, defi ned as death or lifelong handicap, increases dramatically as gestational age decreases, especially for very low birth weight (VLBW) infants (Fig. 58-1).

Complications of PrematurityBesides increased mortality risk, prematurity is associated with an increased risk for morbidity in almost every major organ system. BPD, retinopathy of prematurity, necrotizing enterocolitis, and IVH are par-ticularly linked to preterm births. Intrauterine growth restriction and increased susceptibility to infection are not restricted to the preterm infant but are complicated in the immature infant. Table 58-2 sum-marizes common complications of prematurity by organ system.

The rate of preterm birth increased by 30% between 1983 and 2004, from 9.6% to 12.5%. Three major causes have been identifi ed to explain the rise (see Chapter 29): improved gestational dating asso-ciated with increased use of early ultrasound,16 the substantial rise in multifetal gestation associated with assisted reproductive technology, and an increase in “indicated” preterm births.17 The latter category is important because decisions affecting the timing and management of preterm delivery can have a profound effect on neonatal outcome. The risk of death before birth hospital discharge doubles when the gestational age decreases from 27.5 weeks (10%) to 26 weeks (20%). Delaying delivery even for a few days may substantially improve outcome, especially before 32 weeks, assuming that the intrauterine environment is safe to support the fetus. However, in some clinical situations with a high potential for preterm delivery, it is diffi cult to assess the quality of the intrauterine environment. Three common examples are preterm, premature rupture of membranes (see Chapter 31), placental abruption (see Chapter 37), and preeclampsia (see Chapter 35). In each case, prolonging gestation to allow continued fetal growth and maturation in utero is accompanied by an uncertain risk of rapid change in maternal status with a corresponding increased risk of fetal compromise. Tests of fetal well-being are discussed in Chapter 21, and clinical decision making in obstetrics is addressed in Chapters 28 and 29.

Obstetric decisions about the timing of delivery in the setting of uncertain in utero risk are a signifi cant contributing factor to the increase in late preterm births, after 32 to 34 weeks. The contribution of elective delivery must also be considered. Although perinatal mor-

TABLE 58-2 COMMON COMPLICATIONS OF PREMATURITY BY ORGAN SYSTEM

Organ System Morbidity

Pulmonary Respiratory distress syndromeBronchopulmonary dysplasiaPulmonary hypoplasiaApnea of prematurity

Cardiovascular Patent ductus arteriosusApnea and bradycardiaHypotension

Gastrointestinal, hepatic Necrotizing enterocolitisDysmotility or refl uxFeeding diffi cultiesHypoglycemia

Central nervous system Intraventricular hemorrhagePeriventricular leukomalacia

Visual Retinopathy of prematuritySkin Excess insensible water loss

HypothermiaImmunologic, hematologic Increased incidence of sepsis and

meningitisAnemia of prematurity

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tality continues to decrease, in part due to a decline in stillbirths,17 interest in understanding the extent of morbidity associated with late preterm deliveries has intensifi ed because of the large number of these late preterm infants and the potential to avoid morbidities, such as temperature instability, feeding problems, hyperbilirubinemia requir-ing treatment, suspected sepsis, and respiratory distress. Infants born at 35 weeks’ gestation are nine times more likely to require mechanical ventilation than those born at term.18

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 development proceed rapidly during the third trimester and continue for the fi rst several years of life. An infant born at 35 weeks’ gestation has approximately one-half the brain volume of a term infant. Although IVH is unusual after 32 weeks’ gestation, regions including the periventricular white matter continue to undergo rapid myelination during this period. Studies by Stein and colleagues19 and Kirkegaard and coworkers20 demonstrate an association between late preterm delivery and long-term neurodevelopmental problems, including learning disabilities and attention defi cit disorders. Careful neurologic and epidemiologic studies will be required to defi ne any mechanistic connection between late preterm delivery and these long-term outcomes.

Our growing recognition of the morbidity and mortality risks asso-ciated with preterm delivery clearly deserve close scrutiny and further study. Table 58-3 compares estimates of complication rates between preterm and late preterm infants.

Classic preterm infants, typically defi ned as those born before 32 weeks’ gestation or weighing less than 1500 g, or both, comprise only 1.5% of all deliveries, whereas the late preterm population accounts for 8% to 9% of all births. Even uncommon complications in the later preterm population may represent a signifi cant health care burden. As the number of late preterm infants continues to increase, clinicians and policymakers will likely focus additional attention on the causes and prevention of such deliveries (Fig. 58-2).

Decisions at the Threshold of ViabilityDecisions regarding treatment of infants at the “limit of viability” are often the most diffi cult for families and health care professionals. The diffi culty stems in part from the lack of clarity in defi ning what that limit is, which has fallen by approximately 1 week every decade over the past 40 years. Among developed countries, most identify the limit of viability at 22 to 25 weeks’ gestation.29-31 Making decisions at this early gestation requires accurate information about mortality and morbidity for this population. At 22 weeks (22 0/7days to 22 6/7 days), survival is rare and typically not included in studies of survival or long-term outcome. Rates of survival to hospital discharge for infants born at 23 weeks’ gestation (23 0/7 to 23 6/7 days) range from 15% to 30%. Survival increases to between 30 and 55% for infants born at 24 weeks’ gestation.15,23,30,32-35 The Vermont-Oxford Network reported weight-based survival for more than 4000 infants born between 401 and 500 g (mean gestational age of 23.3 ± 2.1 weeks) from 1996 to 2000. Survival to hospital discharge was 17%.36 Although mortality

50022 23 24 25 26

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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-specifi c 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.)

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rates decline for each 1-week increase in gestational age at delivery, long-term neurodevelopmental outcomes do not improve proportion-ately. Of infants born at less than 25 weeks’ gestation, 30% to 50% will have moderate to severe disability, including blindness, deafness, devel-opmental delays and cerebral palsy.23,30,32 The National Institute of Child Health and Human Development reported neurodevelopmental outcomes for more than 5000 infants born between 22 and 26 weeks’ gestation from 1993 to 1998. Bayley mental development index (MDI) and nonverbal development index (NDI) scores improved and blind-ness was reduced, but rates of severe cerebral palsy, hearing loss, shunted hydrocephalus, and seizures were unchanged.37

Birth weight and gender also affect survival rates. Higher weights within gestational age categories and female sex consistently show a survival advantage and better neurodevelopmental outcomes.15,37 Sur-vival and long-term outcomes of very preterm infants are improved

with delivery at a tertiary center, rather than neonatal transfer from an outlying facility.38-40 When families desire resuscitation or dating is uncertain, every attempt should be made to transfer to a tertiary center for delivery. Maternal transfer to a tertiary center and administration of corticosteroids (see Chapter 23) are the only antenatal interventions that have been signifi cantly and consistently related to improved neo-natal neurodevelopmental outcomes.37 Other attempted strategies are discussed in Chapter 29.

Planning for Delivery at the Limits of ViabilityIdeally, discussion between physicians and parents should begin before birth in a nonemergent situation, and include both obstetric and neo-natal care providers. Even during active labor, communication with the family should be initiated as a foundation for postnatal discussions. The family should understand that plans made before delivery are

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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 infl uences 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.)

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 g80% < 27 wk21

5%

Bronchopulmonary dysplasia 23% < 1500 g15 UncommonRetinopathy of prematurity Approx 40% < 1500 g22-24

Intraventricular hemorrhage with ventricular dilation or parenchymal involvement

11% < 1500 g15 Rare

Necrotizing enterocolitis 5-7% < 1500 g15 UncommonPatent ductus arteriosus 30% < 1500 g15 UncommonFeeding diffi culty >90% 10-15%25

Hypoglycemia NA 10-15%25

*Defi ned as <32 weeks and/or <1500 g.†Defi ned as 32-37 weeks and/or 1500-2500 g.

NA, not available; surf Rx, surfactant treatment.

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infl uenced 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 fi ndings, may change the infant’s prognosis.30

Neonatal Resuscitation at the Limits

of ViabilityIf time allows before delivery of an infant whose gestational age is near the threshold of viability, a thoughtful birth plan developed by the parents in consultation with maternal-fetal medicine specialists and the neonatologist should be established. The neonatologist can assist families in making decisions regarding a birth plan for their infant by providing general information about the prognosis, the hos-pital course, potential complications, survival information, and general health and well-being of infants delivered at the similar gestational age. When time does not permit such discussions, careful evaluation of gestational age and response to resuscitation are instrumental in 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 age and fetal status, and to provide medical leadership in decisions to be made jointly with families.29,31 In cases of precipitous deliveries when communication with families has not occurred, physicians should use their best judgment on behalf of the infant to initiate resus-citation until families can be brought into the discussion, erring on the side of resuscitation if the appropriate course is uncertain.29,41

Under ideal circumstances, the health care team and the infant’s family should make shared management decisions regarding these infants. The American Medical Association and American Academy of Pediatrics endorse the concept that “the primary consideration for decisions regarding life-sustaining treatment for seriously ill newborns should be what is best for the newborn,” and they recognize parents as having the primary role in determining the goals of care for their infant.1,29,42 Discussions with the family should include local and national information on mortality as well as long-term outcomes. Parental participation should be encouraged with open communica-tion regarding their personal values and goals.

Decisions about resuscitation should be individualized to the case and the family but should begin with parameters for care that are based on global reviews of the medical and ethical literature and expertise. The Nuffi eld Council on Bioethics in the United Kingdom has pro-posed parameters for treating extremely premature infants that parallel guidance from the American Academy of Pediatrics.1,29 When gestation or birth weight are associated with almost certain early death and anticipated morbidity is unacceptably high, resuscitation is not indi-cated. Exceptions to comply with parental requests may be appropriate in specifi c cases, such as for infants born at less than 23 weeks’ gestation or with a birth weight of 400 g. When the prognosis is more uncertain, survival is borderline with a high rate of morbidity, such as at 23 to 24 weeks’ gestation, parental views should be supported.

Decisions regarding care of extremely preterm infants is always diffi cult for all involved. Parental involvement, active listening, and accurate information are critical to an optimal outcome for infants and their families. Although parents are considered the best surrogate for their infant, health care professionals have a legal and ethical obligation to provide appropriate care for the infant based on medical informa-tion. If agreement with the family cannot be reached, it may be appro-priate to consult the hospital ethics committee or legal council. If the situation is emergent and the responsible physician concludes the parents wishes are not in the best interest of the infant, it is appropriate to resuscitate against parental objection.35

Respiratory Problems in the Neonatal PeriodNo aspect of the transition from fetal to neonatal life is more dramatic than the process of pulmonary adaptation. In a normal term infant, the lungs expand with air, pulmonary vascular resistance rapidly decreases, and vigorous, consistent respiratory effort ensues within a minute of separation from the placenta. The process depends on crucial physio-logic mechanisms, including production of functional surfactant, dila-tion of resistance pulmonary arterioles, bulk transfer of fl uid from air spaces, and physiologic closure of the ductus arteriosus, foramen ovale. Complications such as prematurity, infection, neuromuscular disor-ders, developmental defects, or complications of labor may interfere with neonatal respiratory function. Common respiratory problems of neonates are reviewed in the following sections.

Transient Tachypnea of the Newborn

Defi nitionTransient tachypnea of the newborn (TTN), commonly known as wet lungs, is a mild condition affecting term and late preterm infants. This is the most common respiratory cause of admission to the special care nursery. Transient tachypnea is self-limiting, with no risk of recurrence or residual pulmonary dysfunction. It rarely causes hypoxic respiratory failure.43

PathophysiologyDuring the last trimester, a series of physiologic events led to changes in the hormonal milieu of the fetus and its mother to facilitate neonatal transition.44 Rapid clearance of fetal lung fl uid is essential for successful transition to air breathing. The bulk of this fl uid clearance is mediated by transepithelial sodium re-absorption through amiloride sensitive sodium channels in the respiratory epithelial cells.45 The mechanisms for such an effective “self-resuscitation” soon after birth are not com-pletely understood. Traditional explanations based on Starling forces and vaginal squeeze for fl uid clearance account only for a fraction of the fl uid absorbed.

Risk FactorsTransient tachypnea is classically seen in infants delivered near term, especially after cesarean birth before the onset of spontaneous labor.46,47 Absence of labor is accompanied by impaired surge of endogenous steroids and catecholamines necessary for a successful transition.48 Additional risk factors such as multiple gestations, excessive maternal sedation, prolonged labor, and complications resulting from excessive maternal fl uid administration have been less consistently observed.

Clinical PresentationThe clinical features of TTN include a combination of grunting, tachy-pnea, nasal fl aring, and mild intercostal and subcostal retractions along with mild central cyanosis. The grunting can be fairly signifi cant and sometimes misdiagnosed as RDS resulting from surfactant defi ciency. The chest radiograph usually shows prominent perihilar streaks that represent engorged pulmonary lymphatics and blood vessels. The radiographic appearance and clinical symptoms rapidly improve within the fi rst 24 to 48 hours. The presence of fl uid in the fi ssures is a common nonspecifi c fi nding. TTN is a diagnosis of exclusion and it is important that other potential causes of respiratory distress in the

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newborn are excluded. The differential diagnosis of TTN includes pneumonia or sepsis, air leaks, surfactant defi ciency, and congenital heart disease. Other rare diagnoses are pulmonary hypertension, meconium aspiration, and polycythemia.

DiagnosisTTN is primarily a clinical diagnosis. Chest radiographs typically dem-onstrate mild pulmonary congestion with hazy lung fi elds. The pul-monary vasculature may be prominent. Small accumulations of extrapleural fl uid, especially in the minor fi ssure on the right side, may be seen.

ManagementManagement is mainly supportive. Supplemental oxygen is provided to keep the oxygen saturation level greater than 90%. Infants are usually given intravenous fl uids and not fed orally until their tachy-pnea resolves. Rarely, infants may need continuous positive airway pressure to relieve symptoms. Diuretic therapy has been shown to be ineffective.49

Neonatal ImplicationsTTN can lead to signifi cant morbidity related to delayed initiation of oral feeding, which may interfere with parental bonding and establish-ment of successful breastfeeding. The hospital stay is prolonged for mother and infant. The existing perinatal guidelines50 recommend scheduling elective cesarean births only after 39 completed weeks’ ges-tation to reduce the incidence of TTN (Fig. 58-3).

Pulmonary HypoplasiaLung development begins during the fi rst trimester when the ventral foregut endoderm projects into adjacent splanchnic mesoderm (see Chapter 15). Branching morphogenesis, epithelial differentiation, and acquisition of a functional interface for gas exchange ensue through the remainder of gestation and are not completed until the second or

third year of postnatal life. Clinical conditions associated with pulmo-nary hypoplasia and approaches to prevention and treatment are dis-cussed here.

Perturbation of lung development at anytime during gestation may lead to clinically signifi cant pulmonary hypoplasia. Two general patho-physiologic mechanisms contribute to pulmonary hypoplasia: extrinsic compression and neuromuscular dysfunction. Infants with aneuploidy such as trisomy 21 and those with multiple congenital anomalies or hydrops fetalis have a high incidence of pulmonary hypoplasia.

Oligohydramnios, whether caused by premature rupture of mem-branes or diminished fetal urine production, can lead to pulmonary hypoplasia. The reduction in branching morphogenesis and surface area for gas exchange may be lethal or clinically imperceptible. Clinical studies link the degree of pulmonary hypoplasia to the duration and severity of the oligohydramnios. Similarly, pulmonary hypoplasia is a hallmark of congenital diaphragmatic hernia (CDH), caused by extrin-sic compression of the developing fetal lung by the herniated abdomi-nal contents. The degree of pulmonary hypoplasia in CDH is directly related to the extent of herniation. Large hernias occur earlier in gesta-tion. In most cases, the contralateral lung is also hypoplastic.

Lindner and associates51 report a signifi cant mortality risk for infants born to women with premature rupture of membranes and oligohydramnios before 20 weeks’ gestation. Their retrospective analy-sis demonstrated 69% short-term mortality risk. However, the remain-ing infants fared well and were discharged with apparently normal pulmonary function. Prediction of clinical outcome is diffi cult for these infants.

Prenatal diagnosis and treatment of pulmonary hypoplasia are discussed in Chapters 18 and 24. Postnatal treatment for pulmonary hypoplasia is largely supportive. A subset of infants with profound hypoplasia have insuffi cient surface area for effective gas exchange. These patients typically display profound hypoxemia, respiratory aci-dosis, pneumothorax, and pulmonary interstitial emphysema. At the other end of the spectrum, some infants have no clinical evidence of pulmonary insuffi ciency 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 hyperinfl ation. In contrast, neonates with RDS have diminished lung volumes on chest radiographs refl ecting atelectasis associated with surfactant defi ciency. Diffuse “ground-glass” infi ltrates along with air bronchograms make the cardiothymic silhouette indistinct.

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when stressed. In between is a cohort of patients with respiratory insuffi ciency responsive to mechanical ventilation and pharmacologic support. Typically, these patients have adequate oxygenation and ven-tilation, suggesting adequate gas exchange capacity. However, many develop pulmonary hypertension. The pathophysiologic sequence begins with limited cross-sectional area of resistance arterioles, fol-lowed by smooth muscle hyperplasia in these same vessels. Early use of pulmonary vasodilators such as nitric oxide is the mainstay of man-agement for increased pulmonary vasoreactivity. Optimizing pulmo-nary blood fl ow reduces the potential for hypoxemia thought to stimulate pathologic medial hyperplasia. If oxygenation, ventilation, and acid-base balance are maintained, nutritional support and time can allow suffi cient lung growth to support the infant’s metabolic demands. In many cases, the process is lengthy, requiring mechanical ventilation and treatment with pulmonary vasodilators such as silde-nafi l, bosentan, or prostacyclin for weeks to months. Just as prenatal prognosis is diffi cult to assess, predicting outcome for patients with pulmonary hypoplasia managed in the neonatal intensive care unit is hampered by limited data.

Respiratory Distress SyndromeRDS is a signifi cant cause of early neonatal mortality and long-term morbidity. However, in the past 3 decades, signifi cant advances have been made in the management of RDS, with consequent decreases in associated morbidity and mortality.

Perinatal Risk FactorsThe classic risk factors for RDS are prematurity and low birth weight. Factors that negatively affect surfactant synthesis include maternal diabetes, perinatal asphyxia, cesarean delivery without labor, and genetic factors (i.e., white race, history of RDS in siblings, male sex, and surfactant protein B defi ciency).52 Congenital malformations that lead to lung hypoplasia such as diaphragmatic hernia are also associ-ated with signifi cant surfactant defi ciency. Prenatal assessment of fetal lung maturity and treatment to induce fetal lung maturity are dis-cussed in detail in Chapter 23.

Clinical PresentationSymptoms are typically evident in the delivery room, including tachy-pnea, nasal fl aring, subcostal and intercostal retractions, cyanosis, and expiratory grunting. The characteristic expiratory grunt results from expiration through a partially closed glottis, providing continuous distending airway pressure to maintain functional residual capacity and thereby prevent alveolar collapse. These signs of respiratory diffi -culty are not specifi c to RDS and have a variety of pulmonary and nonpulmonary causes, such as transient tachypnea, air leaks, congeni-tal malformations, hypothermia, hypoglycemia, anemia, polycythe-mia, and metabolic acidosis. Progressive worsening of symptoms in the fi rst 2 to 3 days, followed by recovery, characterizes the typical clinical course. This timeline (curve) is modifi ed by administration of exogenous surfactant with a more rapid recovery. Classic radiographic fi ndings include low-volume lungs with a diffuse reticulogranular pattern and air bronchograms. The diagnosis can be established chem-ically by measuring surfactant activity in tracheal or gastric aspirates, but this is not routinely done.53

ManagementInfants are managed in an incubator or under a radiant warmer in a neutral thermal environment to minimize oxygen requirement and consumption. Arterial oxygen tension (PaO2) is maintained between

50 and 80 mm Hg, with saturations between 88% and 96%. Hypercar-bia and hyperoxia are avoided. Heart rate, blood pressure, respiratory rate, and peripheral perfusion are monitored closely. Because sepsis cannot be excluded, screening blood culture and complete blood cell counts with differential counts are performed, and infants are started on broad-spectrum antibiotics for at least 48 hours.

SURFACTANT THERAPYSurfactant replacement is one of the safest and most effective inter-

ventions in neonatology. The fi rst successful clinical trial of surfactant use was reported in 1980 using surfactant prepared from an organic solvent extract of bovine lung to treat 10 infants with RDS.54 By the early 1990s, widespread use of surfactant leads to a progressive decrease in RDS-associated mortality. Two strategies for treatment are com-monly used: prophylactic surfactant, in which surfactant is adminis-tered before the fi rst breath to all infants at risk for developing RDS, and rescue therapy, in which surfactant is given after the onset of respiratory signs. The advantages of prophylactic administration include a better distribution of surfactant when instilled into a partially fl uid fi lled lung along with the potential to decrease trauma related to resuscitation. Avoiding treatment of unaffected infants and related cost savings are the advantages of rescue therapy. Biologically active surfactant can be prepared from bovine, porcine, human, or synthetic sources. When administered to patients with surfactant defi ciency and RDS, all these preparations show improvement in oxygenation and a decreased need for ventilatory support, along with decreased air leaks and death.55 The combined use of antenatal corticosteroids and post-natal surfactant improves neonatal outcome more than postnatal sur-factant therapy alone.

CONTINUOUS POSITIVE AIRWAY PRESSUREIn infants with acute RDS, continuous positive airway pressure

(CPAP) appears to prevent atelectasis, minimize lung injury, and pre-serve surfactant function, allowing infants to be managed without endotracheal intubation and mechanical ventilation. Early delivery room CPAP therapy decreases the need for mechanical ventilation and the incidence of long-term pulmonary morbidity.56,57 Increasing use of CPAP has led to decreased use of surfactant and decreased incidence of BPD.58 Common complications of CPAP include pneumothorax and pneumomediastinum. Rarely, the increased transthoracic pressure leads to progressive decrease in venous return and decreased cardiac output. Brief intubation and administration of surfactant followed by extubation to CPAP is an additional RDS treatment strategy increas-ingly used in Europe and Australia.59 Prospective, randomized trials enrolling extremely low birth weight (ELBW) infants and comparing early delivery room CPAP with early prophylactic surfactant therapy are being conducted in the National Institute of Child Health and Human Development (NICHD) Neonatal Network (i.e., SUPPORT trial).

MECHANICAL VENTILATIONThe goal of mechanical ventilation is to limit volutrauma and baro-

trauma without causing progressive atelectasis while maintaining adequate gas exchange. Complications associated with mechanical ventilation include pulmonary air leaks, endotracheal tube displace-ment or dislodgement, obstruction, infection, and long-term compli-cations such as BPD and subglottic stenosis.

ComplicationsAcute complications include air leaks such as pneumothorax, pneu-momediastinum, pneumopericardium, and pulmonary interstitial

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emphysema. The incidence of these complications has decreased sig-nifi cantly with surfactant treatment. Infection, intracranial hemor-rhage, and patent ductus arteriosus occur more frequently in VLBW infants with RDS. Long-term complications and comorbidities include BPD, poor neurodevelopmental outcomes, and retinopathy of prema-turity. Incidence of these complications is inversely related to decreas-ing birth weight and gestation.

Promising new therapies for the treatment of RDS include early inhaled nitric oxide and supplementary inositol for prevention of long-term pulmonary morbidity (e.g., BPD).60-62 Noninvasive respira-tory support techniques such as synchronized nasal intermittent posi-tive ventilation (SNIPPV) and high-fl ow nasal cannulas are being studied to decrease ventilator-associated lung injury.63,64

Bronchopulmonary DysplasiaThe classic form of BPD was fi rst described65 in a group of preterm infants who were mechanically ventilated at birth and who later developed chronic respiratory failure with characteristic radiological fi ndings. These infants were larger, late preterm infants with lung changes attributed to mechanical trauma and oxygen toxicity. Smaller, extremely preterm infants with lung immaturity who have received antenatal glucocorticoids have developed a milder form, called new BPD.66 This disease primarily occurs in infants weighing less than 1000 g who have very mild or no initial respiratory distress. The clini-cal diagnosis is based on the need for supplemental oxygen at 36 weeks’ corrected gestational age.67 A physiologic defi nition of BPD based on the need for oxygen at the time of diagnosis has been developed.68

Clinically, the transition from RDS to BPD is subtle and gradual. Radiologically, classic BPD is marked by areas of shifting focal atelec-tasis and hyperinfl ation with or without parenchymal cyst formation. Chest radiographs of infants with the new BPD show bilateral haziness, refl ecting diffuse microatelectasis without multiple cystic changes. These changes lead to ventilation-perfusion mismatching and increased work of breathing. Preterm infants with BPD gradually wean off respiratory support and oxygen or continue to worsen with progres-sively severe respiratory failure, pulmonary hypertension, and a high mortality risk.

PathophysiologyRisk factors predisposing preterm infants to BPD include extreme pre-maturity, oxygen toxicity, mechanical ventilation, and infl ammation.69 The pathologic fi ndings characterized by severe airway injury and fi brosis in the old BPD have been replaced in the new BPD with large, simplifi ed alveolar structures, impaired capillary confi guration, and various degrees of interstitial cellularity or fi broproliferation.70 Airway and vascular lesions tend to be associated with more severe disease.

Oxygen-induced lung injury is an important contributing factor. Exposure to oxygen in the fi rst 2 weeks of life and as chronic therapy has been associated in clinical studies with the severity of BPD.71,72 In animal models, hyperoxia has been shown to mimic many of the pathologic fi ndings of BPD. Two large, randomized trials in preterm infants suggested that the use of supplemental oxygen to maintain higher saturations resulted in worsening pulmonary outcomes.73,74 Barotrauma and volutrauma associated with mechanical ventilation have been identifi ed as major factors causing lung injury in preterm infants.75,76 Surfactant replacement therapy is benefi cial in decreasing symptoms of RDS and improving survival. The effi cacy of surfactant to decrease the incidence of subsequent BPD is less well established. Chronic infl ammation and edema associated with positive-pressure ventilation cause surfactant protein inactivation.

Because intrauterine infl ammation is increasingly recognized as a cause of preterm parturition, antenatal infl ammation is gaining more attention in the pathogenesis of BPD and other morbidities of prematurity.77 Chorioamnionitis has been strongly associated with impaired pulmonary and vascular growth, a typical fi nding in the new BPD.

Most deliveries before 30 weeks’ gestation are associated with his-tologic chorioamnionitis, which except for preterm initiation of labor is otherwise clinically silent. The more preterm the delivery, the more often histologic chorioamnionitis is detected. Increased levels of pro-infl ammatory mediators in amniotic fl uid, placental tissues, tracheal aspirates, lung, and serum of ELBW preterm infants support an impor-tant role for both intrauterine and extrauterine infl ammation in the development and severity of BPD. The proposed interaction between the proinfl ammatory and anti-infl ammatory infl uences on the devel-oping fetal and preterm lung is detailed in Figure 58-4. Several animal models and preterm studies demonstrate that mediators of infl am-mation, including endotoxins, tumor necrosis factor, IL-1, IL-6, IL-8, and transforming growth factor α can enhance lung maturation but concurrently impede alveolar septation and vasculogenesis, contribut-ing to the development of BPD.78-81 Chorioamnionitis alone is associ-ated with BPD, but the probability is increased when these infants receive a second insult such as mechanical ventilation or postnatal infection.82-84

Maternal genital mycoplasmal infection, particularly with Myco-plasma hominis and Ureaplasma urealyticum, is associated with preterm delivery.85 Numerous studies have isolated these organisms from amniotic fl uid and placentas in women with spontaneous preterm birth (i.e., preterm birth due to preterm labor or preterm rupture of membranes). After birth, these organisms are known to colonize and elicit a proinfl ammatory response in the respiratory tract, leading to BPD.

The unpredictable variation in the incidence of BPD, despite adjusting for low birth weight and prematurity, suggests a genetic predisposition to the occurrence and the severity of BPD. Expression of genes critical to surfactant synthesis, vascular development, and infl ammatory regulation are likely to play a role in the pathogenesis of BPD. Twin studies have shown that the BPD status of one twin, even after correcting for contributing factors, is a highly signifi cant predic-tor of BPD in the second twin. In this particular cohort, after control-ling for covariates, genetic factors accounted for 53% of the variance in the liability for BPD.86 Genetic polymorphisms in the infl ammatory response are increasingly recognized as important in the pathogenesis of preterm parturition (see Chapter 28), and may be similarly impor-tant in the genesis of infl ammatory morbidities in the preterm neonate as well.

Long-Term ComplicationsInfants with BPD have signifi cant pulmonary sequelae during child-hood and adolescence. Reactive airway disease occurs more frequently, with increased risk of bronchiolitis and pneumonia. Up to 50% of infants with BPD require readmission to hospital for lower respiratory tract illness in the fi rst year of life.87

BPD is an independent predictor of adverse neurologic outcomes. Infants with BPD exhibit lower average IQs, academic diffi culties, delayed speech and language development, impaired visual-motor integration, and behavior problems.88 Sparse data also suggest an increased risk for attention defi cit disorders, memory and learning defi cits. Delayed growth occurs in 30% to 60% of infants with BPD at 2 years. The degree of long-term growth delay is inversely proportional to birth weight and directly proportional to the severity of BPD.

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Prevention StrategiesSeveral strategies to decrease the incidence of BPD have been tried, including administration of surfactant in the delivery room, antioxi-dant superoxide dismutase and vitamin A supplementation, optimiz-ing fl uid and parenteral nutrition, aggressive treatment of patent ductus arteriosus, minimizing mechanical ventilation, limiting expo-sure to high levels of oxygen, and infection prevention. Table 58-4 enumerates current strategies and their relative effectiveness in pre-venting BPD.89 Large, controlled clinical trials and meta-analysis have not demonstrated a signifi cant impact of these pharmacologic and nutritional interventions.90 The multifactorial nature of BPD suggests that targeting individual pathways is unlikely to have a signifi cant effect on outcome. Strategies to address several pathways simultaneously are more promising (Fig. 58-4).

Meconium-Stained Amniotic Fluid and Meconium Aspiration SyndromeThe signifi cance and management of meconium-stained amniotic fl uid has evolved with time. Meconium is present in the fetal intestine by the second trimester. Maturation of intestinal smooth muscle and

the myenteric plexus progresses through the third trimester. Intrauter-ine passage of meconium is unusual before 36 weeks and does not typically occur for several days after preterm delivery. The potential for intrauterine meconium passage increases with each week of gestation thereafter.91 The physiologic stimuli for passage of meconium are still incompletely understood. Clinical experience and epidemiologic data suggest that a stressed fetus may pass meconium before birth. Infants born through meconium-stained amniotic fl uid have a lower pH and are likely to have nonreassuring fetal heart tracings.92 Meconium-stained amniotic fl uid at delivery occurs in 12% to 15% of all deliveries and occurs more frequently in post-term gestation and in African Americans.93

In contrast to meconium-stained amniotic fl uid, meconium aspira-tion syndrome is unusual. Meconium aspiration syndrome is a clinical diagnosis that includes delivery through meconium-stained amniotic fl uid along with respiratory distress and a characteristic appearance on chest radiographs. Approximately 2% of deliveries with meconium-stained amniotic fl uid are complicated by meconium aspiration syn-drome, but the reported incidence varies widely.94,95 The severity of the syndrome varies. The hallmarks of severe disease are the need for posi-tive-pressure ventilation and the presence of pulmonary hypertension. Severe meconium aspiration is associated with signifi cant mortality and morbidity risk, including air leak, chronic lung disease, and devel-opmental delay.

A relationship between meconium-stained amniotic fl uid and meconium aspiration syndrome has been presumed since the 1960s, when the strategy of tracheal suctioning in the delivery room to prevent meconium aspiration was proposed.96 By the 1970s, this practice was clinically established and affi rmed by retrospective reviews. Oropha-ryngeal suctioning on the perineum before delivery of the chest to complement tracheal suctioning was also recommended. However, additional studies did not verify the benefi t of tracheal suctioning. Tracheal suctioning did not affect the incidence of meconium aspira-tion syndrome in vigorous infants in large, prospective, randomized trial.97 Another prospective, randomized, controlled study in 2514 infants to determine the effi cacy of oropharyngeal suctioning before delivery of the fetal shoulders in infants born through meconium-stained amniotic fl uid also found no reduction in meconium aspiration syndrome.98 Amnioinfusion during labor to dilute the con-centration of meconium has also been studied to prevent meconium aspiration, but a randomized trial found no reduction in the incidence or severity of meconium aspiration.99 These well-designed clinical trials support the notion that meconium-stained amniotic fl uid may

TABLE 58-4 BRONCHOPULMONARY DYSPLASIA PREVENTION STRATEGIES

Intervention

Relative

Effectiveness

Evidence or

Quality of

Data

Antenatal steroids + StrongEarly surfactant ++ StrongPostnatal systemic steroid ++ ModerateVitamin A + HighAntioxidants − ModeratePermissive hypercapnia +++ MinimalFluid restriction ++ ModerateHigh-frequency ventilation ± ModerateDelivery room management ++++ Animal dataInhaled nitric oxide + MinimalContinuous positive airway

pressure used early+++ Moderate

Chorioamnionitis

Antenatal corticosteroids Indomethacin

Anti-infammatory

Pro-infammatory

Postnatal corticosteroids

Preterm fetallung

Transitionallung

Pretermpostnatal lung

Altered lungdevelopment

and BPD

Resuscitation Mechanicalventilation

Oxygen Sepsispneumonia

FIGURE 58-4 Role of infl ammation in the pathogenesis of bronchopulmonary dysplasia (BPD).

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not have a true mechanistic, pathophysiologic connection with meco-nium aspiration syndrome.

In 2001, Ghidini and Spong100 questioned the connection between meconium-stained amniotic fl uid and meconium aspiration syndrome. Reports describe infants born through clear amniotic fl uid with respi-ratory distress with pulmonary hypertension and other clinical char-acteristics of meconium aspiration syndrome.101 Experimental data suggest that factors promoting fetal acidosis and hypoxemia promote remodeling of resistance pulmonary arteries. These same factors can promote intrauterine meconium passage. However, the remodeling, perhaps exacerbated by infl ammation from infection or by meconium, produces a clinical syndrome called meconium aspiration syndrome.102,103 The incidence of meconium aspiration syndrome has decreased in several centers over the past several years, perhaps a consequence of improvements in obstetric assessment and management,104,105 including a reduction in the incidence of post-term deliveries. Our center has experienced a decline in meconium aspiration syn-drome while concurrently pursuing a policy of no routine tracheal suctioning for infants born through meconium-stained amniotic fl uid.

Treatment of severe meconium aspiration syndrome has dramati-cally improved in recent years, leading to decreases in morbidity and mortality. Signifi cant advances have come from treatment of pulmo-nary hypertension with selective pulmonary vasodilators, including inhaled nitric oxide, sildenafi l, 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. Although the mechanism is unclear, this intervention reduces ventila-tion-perfusion mismatch and probably reduces the risk of ventilator-associated lung injury.106

The current state of knowledge regarding meconium-stained amni-otic fl uid and meconium aspiration syndrome presents challenges for obstetricians and neonatologists. The incidence of meconium aspira-tion syndrome has decreased, but the reasons for the decline are not readily apparent. The Neonatal Resuscitation Program35 protocol for delivery room management no longer recommends tracheal suction-ing for vigorous infants, implying that airway management leading to establishment of ventilation should take precedence. Meconium or other material obstructing the airway should be cleared, but suctioning an unobstructed airway at the expense of delaying initiation of effec-tive ventilation may be deleterious. A collaborative approach between obstetrician and neonatologist is paramount. Personnel skilled in establishment of ventilation and airway patency should attend any infant expected to be depressed at delivery.

Pulmonary HypertensionAt delivery the normal transition from fetal to neonatal pulmonary circulation is mediated by a rapid, dramatic decrease in pulmonary vascular resistance. Endothelial cell shape change, relaxation of pulmo-nary arteriolar smooth muscle, and alveolar gaseous distention all contribute to this process. Several pathologic processes, including con-genital malformations, sepsis, and pneumonia, can alter this sequence to produce neonatal pulmonary hypertension. It typically accompanies pulmonary hypoplasia when diminished surface area for gas exchange and inadequate pulmonary blood fl ow lead to hypoxia and remodeling of the resistance pulmonary arterioles. These vessels are more prone to constriction under conditions of acidosis and hypoxemia, resulting in the right to left shunting of deoxygenated blood characteristic of neonatal persistent pulmonary hypertension. In neonates, pulmonary

hypertension tends to mimic prenatal physiology when pulmonary vascular resistance is necessarily high.

First principles of management include optimal oxygenation and ventilation through elimination of ventilation-perfusion mismatch. When positive-pressure ventilation is employed, overdistention must be avoided to minimize the risk of lung injury and BPD. Treatment of pulmonary hypertension has been revolutionized by pharmaco-logic interventions that specifi cally reduce pulmonary vascular resis-tance. Of these, nitric oxide is the best studied, with clear evidence of effi cacy for treatment of pulmonary hypertension in the setting of meconium aspiration syndrome or sepsis.107 Clinical experience with other pulmonary vasodilators, including sildenafi l, bosentan, and prostacyclin, is increasing and has proved useful in certain clini-cal situations.108

Excessive proliferation of medial smooth muscle or its presence in vessels ordinarily devoid of smooth muscle complicates the treatment of pulmonary hypertension. This pathologic remodeling can occur in utero or during postnatal life. The stimuli for this process are not understood, but typically include hypoxic stress of extended duration and volutrauma associated with mechanical ventilation. Pulmonary vasodilators become less effective as remodeling progresses, prompting clinicians to pursue “gentle” ventilation strategies.109 By focusing on preductal rather than postductal oxygen saturations, lower ventilator settings can be achieved, reducing the risk of remodeling.

Gastrointestinal Problems in Neonatal PeriodNecrotizing enterocolitis (NEC) is a devastating complication of pre-maturity and the most common gastrointestinal emergency in the neonatal period. It affects 1% to 5% of infants admitted to neonatal intensive care units.110 The reported incidence is 4% to 13%111 in VLBW infants (<1500 g). NEC is characterized by an infl ammation of the intestines, which can progress to transmural necrosis and per-foration. The onset typically occurs within the fi rst 2 to 3 weeks of life, but it can occur well beyond the fi rst month. The mortality rate related to NEC ranges from 10% to 30% for all cases and up to 50% for infants requiring surgery.111-114 As more preterm and low-birth-weight infants survive the initial days of life, the number of infants at risk for NEC has increased. From 1982 to 1992, although overall U.S. neonatal mortality rates declined, the mortality rates for NEC increased.26

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, indomethacin tocolysis has been most often reported. Some studies report reduced incidence of NEC in infants treated with antenatal steroids.116-118

Initial trials on use of indomethacin as a tocolytic showed no adverse neonatal affects although sample sizes were small.119,120 Although some subsequent case reports and retrospective reviews suggested indomethacin might be associated with adverse neonatal outcomes, including NEC,121,122 others found no association123,124 of indomethacin tocolysis with NEC when used as a single agent but did fi nd an increased risk when used as part of double-agent tocolytic therapy, even after controlling for neonatal sepsis. A meta-analysis of randomized, controlled trials and observational studies from 1966 though 2004 found no signifi cant association between indomethacin tocolysis and NEC in either study type, although the pooled sample

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size of the published randomized, controlled trials limited statistical power.125 There is insuffi cient evidence to alter use of antenatal indo-methacin in relationship to NEC (see Chapter 29).

Postnatal interventions to prevent the development of NEC include alterations in feeding type and advancements, oral antibiot-ics, immune globulin use and vitamin supplementation. Decreased 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] = 0.25; 95% confi dence interval [CI], 0.06 to 0.98) with the use of human milk.126 Mothers of infants at risk, particularly those less than 32 weeks’ gestation, should be encouraged to supply breast milk for their infant. Providing early prenatal and postnatal counseling on use of human milk increases the initiation of lactation and neonatal intake of mother’s milk without increasing maternal stress or anxiety.127 Newer preventive interventions being explored include the use of probiotics and growth factors aimed at protecting the gut epithelium.128

NEC may present slowly or as a sudden catastrophic event. Abdom-inal distention occurs early, with bloody stools present in 25% of cases.110 The radiographic hallmark is the presence of pneumatosis intestinalis or portal venous gas (see Fig. 58-2). Progression may be rapid, resulting in bowel perforation with evidence of free air on the radiograph. Early management consists of bowel decompression, intravenous antibiotics, and respiratory and cardiovascular support as indicated. The single absolute indication for surgical intervention is pneumoperitoneum (Fig. 58-5).

For infants who survive NEC, morbidity is high, including high rates of growth failure, chronic lung disease, and nosocomial infec-tions.129-131 Lengths of stay and hospital costs are signifi cantly length-ened, particularly in surgical NEC.131 Long-term neurologic outcomes

are adversely affected. NEC is an independent risk factor for develop-ment of cerebral palsy and developmental delay.129,130,132 For infants with surgical NEC, depending on the amount of bowel lost, there is risk of short gut syndrome requiring parenteral nutrition and, ulti-mately, small bowel or liver transplantation. NEC is the single most common cause of the short gut syndrome in children.27-29

HyperbilirubinemiaHyperbilirubinemia is common; 60% of term infants and 80% of preterm infants develop jaundice in the fi rst week of life.133 Bilirubin levels are elevated in neonates due to increased production coupled with decreased excretion. Increased production is related to higher rates of red cell turnover and shorter red cell life span.134 Rates of excretion are lower because of diminished activity of glucoronosyl-transferase, limiting bilirubin conjugation, and increased enterohe-patic circulation. In most cases, jaundice has no clinical signifi cance because bilirubin levels remain low, and it is transient. Less than 3% develop levels greater than 15 mg/dL.133 Risk factors for development of severe jaundice are outlined in Table 58-5.

Several important risk factors have their origin in the prenatal and perinatal environment. Hyperbilirubinemia is seen more frequently in infants of mothers who are diabetic (IDM). The pathogenesis of increased bilirubin in IDM infants is uncertain but has been attributed to polycythemia as well as increased red cell turnover.136,137 Prenatally, maternal blood group immunization may result from blood transfu-sion or fetal maternal hemorrhage. Although the prevalence of Rh(D) immunization has signifi cantly decreased with the advent of preven-tion programs, including use of Rh immune globulin, antibodies to other blood group antigens may still occur. ABO hemolytic disease, a common cause of severe jaundice in the newborn, rarely 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.

Ch058-X4224.indd 1208 8/26/2008 4:15:08 PM


lytic disease in the fetus. Other antibodies associated with hemolytic disease in the fetus and newborn are discussed in Chapter 26. A fetus who is apparently unaffected in utero may have continued hemolysis postnatally; physicians caring for the newborn should be notifi ed of any maternal sensitization.

Other perinatal factors associated with severe hyperbilirubinemia include delivery before 38 weeks. Infants born at 36 to 37 weeks’ gesta-tion have an almost sixfold increase of signifi cant hyperbilirubine-mia138 and require close surveillance and monitoring, especially if breastfed.139 Feeding diffi culties, also common for the near term infant, increase this risk still further and may result in delayed hospital dis-charge or readmission for the infant. The presence of bruising or a cephalohematoma, more common after instrumented or diffi cult deliveries, will also increase risk. Polymorphisms of genes coding for enzymes mediating bilirubin catabolism may also contribute to the development of severe hyperbilirubinemia.140

The primary consequence of severe hyperbilirubinemia is poten-tial neurotoxicity. Kernicterus is a neurologic syndrome resulting from deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei, and neuronal necrosis.141 Clinical features may be acute or chronic, resulting in tone and movement disorders such as choreoathetosis and spastic quadriplegia, mental retardation, and sen-sorineural hearing loss.142 A number of factors infl uence the neuro-toxic effects of bilirubin, making prediction of outcome diffi cult. Bilirubin more easily enters the brain if it is not bound to albumin, is unconjugated, or there is increased permeability of the blood brain barrier.142 Conditions such as prematurity that alter albumin levels or that alter the blood brain barrier such as infection, acidosis, and pre-maturity affect bilirubin entry into the brain. As a result, there is no serum level of bilirubin that predicts outcome. In early studies of infants with Rh hemolytic disease, kernicterus developed in 8% of infants with serum bilirubin concentrations of 19 to 24 mg/dL, 33% with levels of 25 to 29 mg/dL, and 73% of infants with levels of 30 to 40 mg/dL.141

Levels of indirect bilirubin below 25 mg/dL in otherwise term healthy infants without hemolytic disease are unlikely to result in ker-nicterus without other risk factors, as indicated in a study of 140 term and near-term infants with levels above 25 mg/dL, in which no cases of kernicterus occurred.143 Kernicterus has however been reported in otherwise healthy breastfed term newborns at levels above 30 mg/dL.144 One of the most important of these risk factors is prematurity. The less mature the infant the greater the susceptibility of the neonatal

brain.141 At what level more subtle neurologic abnormalities appear remains unclear.139

Management of hyperbilirubinemia is aimed at the prevention of bilirubin encephalopathy while minimizing interference with breast-feeding and unnecessary parental anxiety. Key elements in prevention include systematic evaluation of newborns before discharge for the presence of jaundice and its risk factors, promotion and support of successful breastfeeding, interpretation of jaundice levels based on the hour of life, parental education, and appropriate neonatal follow-up based on time of discharge.139 Treatment of severe hyperbilirubinemia should be initiated promptly when identifi ed. Guidelines for treatment with phototherapy and exchange transfusion vary with gestational age, the presence or absence of risk factors, and the hour of life. Nomo-grams to guide patient management are available from the American Academy of Pediatrics.139 Kernicterus is largely preventable. It requires close collaboration between prenatal and postnatal caretakers for accu-rate dissemination of information regarding risk factors for parents and caregivers.

Feeding ProblemsFeeding problems related to complications of prematurity, congenital anomalies, or gastrointestinal disorders contribute signifi cantly to length of stay for hospitalized newborns. In a study of children referred to an interdisciplinary feeding team, 38% were born preterm.145 Pre-mature infants with a history of neonatal chronic lung disease or neu-rologic injury such as IVH or periventricular leukomalacia (PVL) and those with a history of NEC are at the highest risk for long-term feeding problems. These medically complex infants often have other comorbidities, such as tracheomalacia, chronic aspiration, and gastro-esophageal refl ux (GER), that interfere with normal maturational pat-terns of feeding. Premature infants with complex medical problems often require prolonged intubation and mechanical ventilation with delayed initiation of enteral feeding, all of which have been associated with subsequent feeding diffi culties. These infants often have diffi culty integrating sensory input because of medical interventions and neuro-logic immaturity. All of these factors combine to increase the risk of developing oral aversion.

Infants with congenital anomalies are also at high risk for feeding disorders. Infants with tracheoesophageal fi stula with esophageal atresia often have diffi culty feeding due to tracheomalacia, recurrent esophageal stricture, and GER, which are known associates of this disorder. Infants with CDH have an extremely high incidence of oral aversion and growth problems in addition to the pulmonary complica-tions. Surviving infants and children with CDH have a 60% to 80% incidence of associated GER which has been shown to persist into adulthood.146-151 Often, GER is severe, refractory to medical therapy, and requires a surgical antirefl ux procedure. Infants with CDH often have inadequate caloric intake due to fatigue or oral aversion and increased energy requirements leading to poor growth. Often these infants require supplemental tube feedings by nasogastric, nasojejunal, or gastrostomy feeding tube. These feeding diffi culties may last several years and are often accompanied by a behavioral-based feeding component.

Infants with congenital or acquired gastrointestinal abnormalities often have associated feeding diffi culties. Infants with conditions such as gastroschisis with or without associated intestinal atresias often require prolonged hospitalization because of a slow tolerance of enteral feedings and a higher risk for NEC after gastroschisis repair.152,153 They often have dysmotility and severe GER with oral aversion.154 A small percentage of patients have long-term intolerance of enteral feedings

TABLE 58-5 COMMON CLINICAL RISK FACTORS FOR SEVERE HYPERBILIRUBINEMIA

Jaundice in the fi rst 24 hoursVisible jaundice before dischargePrevious jaundiced siblingExclusive breastfeedingBruising, cephalohematomaEast Asian, Mediterranean, or Native American origin or ethnicityMaternal age >25 yearsMale sexUnrecognized hemolysis (i.e., ABO, Rh, c, C, E, Kell, and other

minor blood group antigens)Glucose–6-phosphate dehydrogenase defi ciencyInfant of a diabetic mother

Adapted from Centers for Disease Control and Prevention: Kernicterus

in full-term infants; United States, 1994-1998. Report No.: 50(23), 2001.

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and require prolonged total parenteral nutrition (TPN). Patients requiring long-term TPN may develop liver injury or cholestasis and ultimately may require liver or small bowel transplantation. Infants who develop short bowel syndrome resulting from NEC also have diffi culties tolerating enteral feeds, depending on the length and func-tion of the remaining bowel. Like patients with gastroschisis, infants with severe short bowel syndrome may require prolonged TPN and go on to develop liver or intestinal failure requiring transplantation.

In summary, premature infants and infants with congenital anom-alies or acquired gastrointestinal abnormalities are at high risk for long-term feeding problems. It is important to counsel families regard-ing this risk. Minimizing iatrogenic oral aversion is crucial. Involving a feeding specialist early in a medically complex infant’s course may help reduce these problems.

Neurologic Problems in the Neonatal PeriodHypoxic-Ischemic EncephalopathyInjury to the brain sustained during the perinatal period was once thought to be one of the most common causes of death or severe, long-term neurologic defi cits in children.155 However, data show that only 10% of brain injury is related to perinatal or intrapartum events.156,157 There is increasing recognition that events occurring well before labor contribute signifi cantly to the cause of brain injury. Despite improvements in perinatal practice, the incidence of hypoxic-ischemic encephalopathy has remained stable at 1 or 2 cases per 1000 term births.158,159 Strategies for prevention of brain injury have been mainly supportive because prevention has been diffi cult because of the lack of clinically reliable indicators and the occurrence of the initiating event well before the onset of labor. However, because brain injury initiated by a hypoxic-ischemic event is also affected by a “reperfusion phase” of injury, strategies targeting this process of ongoing injury are being developed for neuroprotection.160,161

Defi nition of AsphyxiaThe brain injury referred to as hypoxic-ischemic encephalopathy occurs due to impaired cerebral blood fl ow likely as a consequence of interrupted placental blood fl ow leading to impaired gas exchange.162 If gas exchange is persistently impaired, hypoxemia and hypercapnia develop with resultant fetal acidosis or what has been referred to as asphyxia. Severe fetal acidemia, defi ned as an umbilical arterial pH of less than 7.00, is associated with an increased risk of adverse neurologic outcome.163,164 However, even with this degree of acidemia, only a small portion of infants develop signifi cant encephalopathy and sub-sequent sustained neurologic injury.165-167 Fetal scalp blood sampling and umbilical cord gas data do not have great sensitivity to predict long-term neurologic impairment.

Clinical MarkersOther clinical measures to identify fetal stress (such as fetal heart rate abnormalities, meconium-stained amniotic fl uid, low Apgar scores, and need for cardiopulmonary resuscitation CPR) in the delivery room do not reliably identify infants at high risk for brain injury when used in isolation. Despite the widespread use of electronic fetal heart rate monitoring (EFM) which detects changes in fetal heart rate related to fetal oxygenation, there has been no reduction in the incidence of cerebral palsy.163 In 2005, an American College of Obstetricians and

Gynecologists (ACOG) practice bulletin called “Clinical Management Guidelines for Obstetrician-Gynecologists”164 concluded that EFM has a high false-positive rate to predict adverse outcomes and is associated with an increase in operative deliveries without any reduction in cere-bral palsy. Meconium-stained amniotic fl uid is commonly seen during labor, but no data exist to associate it with adverse neurologic outcome. Apgar scores were originally introduced to identify infants in need of resuscitation, not to predict neurologic outcome. Apgar scores are not specifi c to an infant’s acid-base status but can refl ect drug use, meta-bolic disorder, trauma, hypovolemia, infection, neuromuscular disor-der, and congenital anomalies. However, a persistently low Apgar score after 5 minutes despite intensive CPR has been associated with increased morbidity and mortality.162,168-170 The combination of a low 5-minute Apgar score with other markers such as fetal acidemia and the need for CPR in the delivery room, predicts a signifi cantly increased risk of brain injury.171,172 Perlman and Risser172 found a 340-fold increased risk of seizures and associated moderate to severe encepha-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 EncephalopathyNeonatal encephalopathy is clinically characterized by depressed level of consciousness, abnormal muscle tone and refl exes, abnormal respi-ratory pattern, and seizures.155 These fi ndings may result from a hypoxic-ischemic event but can also be due to other conditions such as metabolic disorders, neuromuscular disorders, toxin exposure, and chromosomal abnormalities or syndromes. Not all infants with neo-natal encephalopathy go on to develop permanent neurologic impair-ment. The Sarnat staging system is frequently used to classify the degree of encephalopathy and predict neurologic outcome.166 Infants with mild encephalopathy (Sarnat stage 1) generally have a favorable outcome. Infants with moderate encephalopathy (Sarnat stage 2) develop long-term neurologic compromise in 20% to 25% of cases, and infants with severe encephalopathy (Sarnat stage 3) have a greater than 80% risk of death or long-term neurologic sequelae.155

Multiorgan InjuryIn addition to neurologic compromise, the interruption of placental blood fl ow can result in systemic organ injury. Animal models and clinical studies have demonstrated that the kidney is exquisitely sensi-tive to reductions in renal blood fl ow.173,174 The result of decreased renal perfusion is acute tubular necrosis with varying degrees of oligu-ria and azotemia. Other organ systems are also sensitive to reduced blood fl ow. Decreased blood fl ow to the gastrointestinal tract can lead to luminal ischemia and increased risk for NEC. Decreased pulmonary blood fl ow can result in persistent pulmonary hypertension of the newborn. Lack of blood fl ow to the liver can result in hepatocellular injury and impaired synthetic function, leading to hypoglycemia and disseminated intravascular coagulation. Fluid retention and hypona-tremia can develop due to the combination of impaired renal function and the release of antidiuretic hormone. Suppression of parathyroid hormone release can lead to hypocalcemia and hypomagnesemia. These electrolyte abnormalities can further affect myocardial function. Muscle can be affected by electrolyte abnormalities and direct cellular injury, leading to rhabdomyolysis.162

NeuropathologyThe reduction in cerebral blood fl ow associated with a hypoxic-isch-emic event sets off a complex cascade of regional circulatory factors and biochemical changes at the cellular level. Hypoxia induces a switch from normal oxidative phosphorylation to anaerobic metabolism,

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leading to depletion of high-energy phosphate reserves, accumulation of lactic acid, and inability to maintain cellular functions.161,175 The end result is cellular energy failure, metabolic acidosis, release of glutamate and intracellular calcium, lipid peroxidation, build-up of nitric oxide, and eventual cell death.155,161,176 It is this process of cellular injury that is being targeted for neuroprotection strategies.

NeuroimagingDiffusion-weighted magnetic resonance imaging (MRI) has become the gold standard to defi ne the extent and potentially the timing of the brain injury. Diffusion-weighted techniques can detect signal changes due to reduced brain water diffusivity within the fi rst 24 to 48 hours of the insult.162,177-179 Magnetic resonance spectroscopy can also detect alterations in metabolites such as lactate, N-acetyl aspartate, choline, and creatinine in specifi c regions of the brain indicating injury.177,180 However, MRI is diffi cult to perform in an unstable patient, and com-puted tomography (CT) may be preferable as the initial study for term infants and ultrasound for preterm infants.

Neuroprotection StrategiesBrain cooling by selective cooling of the head or systemic hypothermia has been studied as a potential therapy for neonates with hypoxic-ischemic encephalopathy. The Cool Cap Study Group found no sig-nifi cant improvement in survival or severe neurodevelopmental disability in 234 term infants with moderate to severe neonatal enceph-alopathy and abnormal amplitude integrated electroencephalography (aEEG) in a multicenter, randomized trial of selective head cooling.165 However, there was improvement in infants with less severe aEEG changes in a subgroup analysis.165 A large, multicenter, randomized trial of brain cooling using whole-body hypothermia for infants of 36 weeks’ gestation with moderate or severe encephalopathy found that systemic hypothermia resulted in an 18% reduction of death or mod-erate or severe disability at 18 to 22 months of age.181 Proposed reasons for the greater benefi t in the latter study from the NICHD Neonatal Research Network are earlier initiation of cooling and possible differ-ences in the severity of brain injury (Cool Cap study required the additional evidence of an abnormal aEEG).165 There are insuffi cient data to suggest that one method of brain cooling is superior to the other. Until more data are available, treatment with brain cooling is best considered an experimental technique.167

Because the therapeutic window for effective treatment may be limited to within 6 hours of delivery, future efforts are being focused on early identifi cation of infants at the greatest risk for hypoxic-ischemic injury. Infants at highest risk are those with evidence of a sentinel event during labor, pronounced respiratory and neuromuscu-lar depression at delivery with persistently low Apgar scores, the need for delivery room resuscitation, severe fetal acidemia (umbilical artery pH less than7.00 or base defi cit of 16 mEq/L), and evidence of an early abnormal neurologic examination, seizures, or an abnormal aEEG.161,172,182-184

Summary of Hypoxic-Ischemic Brain InjuryHypoxic-ischemic brain injury due to intrapartum asphyxia is a rare but serious cause of long-term neurodevelopmental disability. It is often diffi cult to defi ne a specifi c intrapartum event because the initiat-ing event may occur before the onset of labor. Early identifi cation of at-risk newborns by neuroimaging techniques, aEEG fi ndings, history, and clinical examination may provide an opportunity to ameliorate the effects of ongoing brain injury using neuroprotective strategies. The goal of these therapeutic interventions is the reduction of long-term neurodevelopmental disabilities, including cerebral palsy.

Intraventricular HemorrhageIVH (i.e., germinal matrix hemorrhage) occurs most commonly in preterm infants and is a major cause of mortality and long-term dis-ability. Bleeding originates in the subependymal germinal matrix but may rupture through the ependyma into the ventricular system. IVH is graded into four categories:

Grade I: Bleeding is localized to the germinal matrixGrade II: Bleeding into the ventricle but the clot does not distend

the ventricleGrade III: Bleeding into the ventricle with ventricular dilationGrade IV: Intraparenchymal extension

IncidenceDiagnosis is made most commonly by cranial ultrasound, with most hemorrhages occurring within 6 hours of birth and 90% within the fi rst 5 days of life.185 The incidence of IVH has decreased signifi cantly with improvements in perinatal care such as maternal transfer and antenatal steroids. From 1990 to 1999, the incidence of IVH reported for infants with birth weights of less than 1000 g was 43%, and 13% were grade III or grade IV. In 2000 and 2002, the overall incidence of IVH decreased to 22%; only 3% were severe despite improvements in survival.186 Lower gestational age is associated with an increased risk of severe IVH.168

PathogenesisAnatomic and physiologic factors have been implicated in the patho-genesis of IVH. The germinal matrix is composed of thin-walled blood vessels that lack supportive tissue. These fragile vessels have a tendency to rupture spontaneously or in response to stress, such as hypoxia-ischemia, changes in blood pressure or cerebral perfusion, and pneu-mothoraces. In addition to these structural factors, premature infants have an immature cerebrovascular autoregulation system (so-called pressure-passive circulation) in response to systemic hypotension, which makes them more susceptible to hemorrhage.174,185,187 Immatu-rities in the coagulation system and increased fi brinolytic activity of premature infants may also play a role.169,188-190

OutcomesAlthough it has been generally thought that infants with grade I or II IVH have similar outcomes to those without cranial ultrasound abnor-malities, extremely-low-birth-weight infants with grade I or II IVH had worse neurodevelopmental outcomes at 20 months corrected age compared with those with normal cranial ultrasound scans in a 2006 report.191 About 35% of infants with grade III IVH have adverse neurologic outcomes. In those who develop post-hemorrhagic hydrocephalus requiring surgical intervention, the disability rate increases to about 60%.169 Grade IV IVH is associated with the highest mortality rates, and 80% to 90% are associated with poor neurologic outcomes.170

Antenatal PreventionThe only therapies shown to decrease the incidence of IVH in prema-ture infants are antenatal corticosteroid administration and maternal transfer to a tertiary care center for delivery. Multiple studies have shown that the administration of corticosteroids before preterm deliv-ery to induce lung maturity has signifi cantly reduced the incidence of RDS, mortality, and severe IVH. According to a meta-analysis of four trials that included 596 infants of 24 to 33 weeks’ gestation, prenatal corticosteroid therapy was associated with a relative risk reduction for

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IVH of 0.57 (95% CI, 0.41 to 0.78).171 Maternal transfer to a tertiary care center for gestational age less than 32 weeks decreased the inci-dence of death or major morbidity, including IVH.39 Antenatal pheno-barbital, vitamin K, and magnesium sulfate have failed to demonstrate a consistent decrease in overall IVH, severe IVH, or death.192-194

Postnatal PreventionThe goal of postnatal prevention has been blood pressure stabilization to prevent fl uctuations in cerebral perfusion, correction of coagulation disturbances, and stabilization of germinal matrix vasculature.185 Post-natal administration of phenobarbital and muscle paralysis have been shown to stabilize blood pressure, but neither has been found to decrease the incidence of IVH or neurologic impairment.195,196 Fresh-frozen plasma and ethamsylate to promote platelet adhesiveness and correct coagulation disorders also do not reduce the incidence of IVH.194,197-199 Indomethacin remains the most promising preventive therapy for IVH because of its ability to constrict the cerebral vascu-lature, inhibit prostaglandin and free radical production, and mature the germinal matrix vasculature.197,200-202 Prophylactic indomethacin decreases the incidence of severe IVH. Follow-up studies have shown slight improvement in cognitive function in infants who received pro-phylactic indomethacin but no difference in the incidence of cerebral palsy.203-205 Prophylactic indomethacin is reserved for preterm infants at high risk for IVH until further studies clarify the appropriate can-didates for prophylaxis.

Post-hemorrhagic HydrocephalusThe most serious complication of IVH is post-hemorrhagic hydro-cephalus due to obstruction of cerebrospinal fl uid (CSF) fl ow. This occurs when multiple blood clots obstruct CSF reabsorption channels, leading to transforming growth factor β1 (TGF-β1)–stimulated pro-duction of extracellular matrix proteins such as fi bronectin and laminin, which ultimately lead to scar formation.206 Progressive ven-tricular dilatation can worsen brain injury because of damage to peri-ventricular white matter resulting from increased intracranial pressure and edema.172 Therapies such as serial lumbar punctures, diuretics, and intraventricular fi brinolytic therapy are ineffective and may even be harmful.207 Although surgical shunt placement carries signifi cant risk of shunt complications and infection, it remains the defi nitive therapy for progressive post-hemorrhagic hydrocephalus.

Summary of Intraventricular HemorrhageIVH due to a fragile germinal matrix and an unstable cerebrovascular autoregulatory system remains a signifi cant cause of neurologic mor-bidity in preterm infants. Infants with cardiorespiratory complications are at highest risk. Antenatal corticosteroids are the most effective preventive therapy available. Despite signifi cant reduction in the incidence of severe IVH, new prevention and treatment therapies for hydrocephalus are needed.

Periventricular LeukomalaciaPVL refers to injury to the deep cerebral white matter in two charac-teristic patterns, described as focal periventricular necrosis and diffuse cerebral white matter injury. This type of brain injury typically affects premature infants and is a common cause of cerebral palsy. Preterm infants who have suffered an IVH or have cardiopulmonary instability are at the highest risk. Other intrauterine factors, such as infection, premature prolonged rupture of membranes, fi rst-trimester hemor-rhage, placental abruption, and prolonged tocolysis, have been associ-ated with increased risk of PVL.174,208-211 The reported incidence of PVL

detected by ultrasound examination in VLBW infants is 5% to 15%.212 However, ultrasound often fails to identify the more subtle evidence of diffuse white matter injury. The incidence of PVL diagnosed at autopsy is much higher, indicating that the true incidence of PVL is likely underestimated.

NeuropathologyFocal necrosis most commonly occurs in the cerebral white matter at the level of the trigone of the lateral ventricles and around the foramen of Monro.212 These sites make up the border zones of the long penetrating arteries. Classically, these lesions undergo a coagula-tive necrosis that results in cyst formation or focal glial scars.174 The more diffuse type of injury may also occur in conjunction with focal necrosis but is more frequently recognized as an independent entity. Diffuse white matter injury seems to affect premyelinating oligoden-drocytes and leads to global loss of these cells and an increase in hypertrophic astrocytes in response to the diffuse injury.174,212-214 This loss of oligodendrocytes leads to white matter volume loss and ventriculomegaly.

PathogenesisThe pathogenesis of PVL primarily occurs by hypoxia-ischemia leading to neuronal injury due to free radical exposure, cytokine toxicity, and exposure to excessive excitatory neurotransmitters such as gluta-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 supply is composed of long penetrating arteries that terminate deep in the periventricular white matter, basal penetrating arteries, which supply the immediate periventricular area, and short penetrating arter-ies, which supply the subcortical white matter. Focal necrosis occurs most commonly in the anterior and posterior periventricular border zones because in premature infants these vessels are immature. Diffuse white matter injury may also occur due to vascular immaturity. At early gestations (24 to 28 weeks), there are few anastomoses between the long and short penetrators. Arterial border zones may occur in the subcortical and remote periventricular areas, resulting in a more diffuse type of injury.212

The preterm brain is vulnerable to ischemia because of impaired cerebrovascular regulation. Preterm infants exhibit a pressure-passive circulation; a decrease in systemic blood pressure is associated with a decrease in cerebral perfusion, leading to ischemia.212,216,217 Immature oligodendrocytes seem to be more sensitive to free radical injury, cyto-kine effects, and the presence of glutamate.

Clinical OutcomesThe most common long-term sequela of PVL is spastic diplegia, a form of cerebral palsy in which the lower extremities are more affected than the upper extremities. The descending fi bers of the motor cortex, 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 manifestations such as cognitive, visual, or auditory impairments.

Summary of Periventricular LeukomalaciaPVL is a major cause of neurologic morbidity in premature infants, especially those who weigh less than 1000 g at birth. Prevention is the only strategy to treat PVL. Avoidance of fl uctuations in blood pressure and cerebral vasoconstrictors, such as extreme hypocarbia, is impor-tant because of the known immaturity in cerebrovascular autoregula-tion of preterm infants. Investigational strategies targeting the cascade of oligodendroglial death may be promising.

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Perinatal StrokeArterial ischemic stroke (AIS) in neonates is defi ned as a cerebrovas-cular event around the time of birth with resultant clinical or radio-graphic evidence of focal cerebral arterial infarction. Most occur in the distribution of the middle cerebral artery.176,218-220 AIS accounts for most perinatal ischemic strokes. When the diagnosis is based on symp-toms in the neonatal period, the reported incidence is 1 case in 4000 live births.176,221,222 The incidence of perinatal ischemic strokes that were asymptomatic in the neonatal period and diagnosed at a later time is unknown.

Clinical PresentationNeonatal seizures are the most common clinical presentation and usually are focal in origin without other signs of neonatal encepha-lopathy.176,223 However, some infants are systemically ill, and the diag-nosis is made with neuroimaging to rule out evidence of hypoxic-ischemic injury or bleeding. Neonates with focal neurologic signs account for less than 25% of cases.218,222,224,225

Perinatal stroke may also be identifi ed retrospectively in initially well-appearing infants who present in later months with signs of hemi-paresis, developmental delay, or seizures.176,226 In these cases, neuroim-aging reveals a remote injury, often occurring in the middle cerebral artery territory.

Pathophysiology and Risk FactorsThe mechanisms of perinatal stroke are thought to be multifactorial. Regional ischemia with subsequent hypoxia and infarction plays a role. A relative hypercoagulable state in newborns due to the presence of fetal hemoglobin, polycythemia, and activation of coagulation factors in the fetus and mother around the time of birth seems to increase the risk of a thromboembolic event leading to stoke.176,227 Risk factors for perinatal stroke include maternal and placental disorders, neonatal hypoxic-ischemic injury, hematologic disorders, infection, cardiac dis-orders, trauma, and drugs. Often, a combination of risk factors is identifi ed.

Neuroimaging and Electroencephalographic

AssessmentAlthough cranial ultrasound is the easiest to perform, it is not a sensi-tive indicator of perinatal stroke.175 Little information exists on prena-tal cranial ultrasound, but prenatal ultrasound scans may show areas of unilateral echolucencies, which may represent areas later identifi ed as prenatal stroke. CT imaging can usually be performed readily in neonates and usually does not require sedation. CT evidence of peri-natal ischemic stroke includes focal hypodensity with or without intraparenchymal hemorrhage, abnormal gray-white differentiation, and evidence of volume loss or porencephaly if the injury is remote 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.

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MRI with diffusion-weighted imaging is the most sensitive, espe-cially in the setting of early infarction. MRI may be able to demonstrate restricted diffusion within a vascular distribution for acute stroke as well as chronic changes such as encephalomalacia, gliosis, and ven-triculomegaly for remote events (see Fig. 58-6). MR angiography may be useful in some cases to confi rm arterial occlusion although it is not commonly used unless a vascular malformation is suspected. Func-tional MRI may be valuable in the future to understand how the brain reorganizes after perinatal stroke.218,228,229 EEG may be useful to detect subclinical seizures that may cause secondary brain injury.218

Further diagnostic studies focused on risk factors for perinatal ische-mic stroke should include blood tests for coagulation disturbances and genetic predispositions, urine toxicology for metabolic disorders and toxins such as cocaine, echocardiography, infectious workup including lumbar puncture, maternal testing for acquired coagulation disorders such as antiphospholipid antibodies, and an assessment of the placenta.176

OutcomesPerinatal ischemic stroke is the most common cause of hemiplegic cerebral palsy (CP).176 Although not all survivors of perinatal stroke suffer long-term disabilities, 50% to 75% of infants who suffered a perinatal stroke will have a neurologic defi cit or seizures.215,218,230-232 Lee and colleagues215 reported a population-based study of neonatal AIS showing that 32% of infants with AIS who presented with symptoms in the neonatal period went on to develop CP, whereas 82% of infants diagnosed retrospectively developed CP. Because patients identifi ed retrospectively presented because of hemiparesis, they were more likely to be classifi ed as having CP.

Summary of Perinatal StrokePerinatal 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-tures. Neuroprotective strategies and approaches to prevention are needed. Advanced neuroimaging techniques to better understand how the brain reorganizes after this type of injury are being used as research tools.

Cerebral PalsyCerebral palsy (CP) is a clinical diagnosis that refers to a group of nonprogressive motor impairments. As early as 1862, William John Little described the relationship between children with motor abnor-malities and pregnancy complications such as diffi cult labor, neonatal asphyxia, and premature birth.177 In 2005, the International Commit-tee on Cerebral Palsy Classifi cation defi ned CP as “a group of devel-opmental disorders of movement and posture, which cause activity limitations that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, cognition, communication, perception, and behavior and by a seizure disorder.”178 Despite improvements in perinatal care, the prevalence of CP has remained relatively unchanged over the past 50 years, with an incidence of 1.5 to 2.5 cases per 1000 live births.155,233,234

Classifi cationTraditionally, CP has been classifi ed by topography based on the affected limb involvement (i.e., monoplegia, hemiplegia, diplegia, tri-plegia, and quadriplegia) and a description of the predominant type of tone or movement abnormality (i.e., spastic, dyskinetic, ataxic,

hypotonic, or mixed). The International Committee on Cerebral Palsy Classifi cation proposed a new classifi cation system that takes into account the presence or absence of associated impairments, other ana-tomic involvement besides limbs, radiologic fi ndings, and causation (Table 58-6).

EtiologyCerebral palsy is a result of injury to the developing brain that occurs prenatally, perinatally, or postnatally. Between 75% and 80% of cases of CP have been attributed to events during pregnancy. Ten percent are attributable to intrapartum events such as birth asphyxia,156,235,236 and 10% follow postnatal causes such as head injury or central nervous system infection.179,180 Risk factors for cerebral palsy include prematu-rity, multiple gestation, growth restriction, intracranial hemorrhage, PVL, infections, placental pathology, genetic syndromes, structural brain abnormalities, birth asphyxia or trauma, and kernicterus. The origins of CP tend to be multifactorial, but in some cases, no cause is identifi ed. Some of the more common risk factors will be discussed in detail. The roles of intracranial hemorrhage, PVL, and birth asphyxia contributing to CP have been discussed in a previous section of this chapter.

PrematurityPrematurity and low birth weight seem to be the most important risk factors for CP, with an increased prevalence of CP associated with decreasing gestational age and decreasing birth weight as compared with term infants. It is important fi rst to consider the rates of CP and neurosensory impairments in term infants. Msall and coworkers237

TABLE 58-6 COMPONENTS OF CEREBRAL PALSY CLASSIFICATION

1. Motor abnormalities A. Nature and typology of the motor disorder: the observed

tonal abnormalities assessed on examination (e.g., hypertonia, hypotonia) and the diagnosed movement disorders, such as spasticity, ataxia, dystonia, or athetosis

B. Functional motor abilities: the extent to which the individual is limited in his or her motor function in all body areas, including oromotor and speech function

2. Associated impairments A. Presence of absence of associated nonmotor

neurodevelopmental or sensory problems, such as seizures, hearing or vision impairments, and attentional, behavioral, communicative, or cognitive defi cits

B. Extent to which impairments interact in individuals with cerebral palsy

3. Anatomic and radiologic fi ndings A. Anatomic distribution: parts of the body (e.g., limbs, trunk,

bulbar region) affected by motor impairments or limitations B. Radiologic fi ndings: neuroanatomic fi ndings on computed

tomography or magnetic resonance imaging, such as ventricular enlargement, white matter loss, or brain anomaly

4. Causation and timing A. Whether there is a clearly identifi ed cause, as is usually the

case with postnatal cerebral palsy (e.g., meningitis, head injury), or when brain malformations are present

B. Presumed time frame during which the injury occurred, if known

Adapted from Bax M, Goldstein M, Rosenbaum P, et al: Proposed

defi nition and classifi cation of cerebral palsy, April 2005. Dev Med

Child Neurol 47:571-576, 2005.

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reported rates of disability in term infants as follows: 0.2% for CP, 2% to 3% for cognitive impairment, 0.1% to 0.3% for hearing loss, and 0.1% for visual impairment.237 With improvements in survival for ELBW infants, defi ned as less than 1000 g, there are concerns that dis-ability rates will increase as well. Several investigators have reported neurodevelopmental disability rates among ELBW infants born in the 1990s. Reported rates range from 8% to 19% with CP, 19% to 49% with developmental disability, 1% to 4% with hearing impairment, and 1% to 4% with visual impairment.23,32,132,238-240 When extreme prema-turity is considered, Shankaran and associates181 showed that surviving 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-ability rates of 60%, with almost one third of infants having CP. The increase in disability rates may be related to heavy use of postnatal steroids to treat neonatal chronic lung disease and high rates of sepsis during this period. Poor neurodevelopmental outcomes have been associated with widespread use of postnatal steroids in the 1990s, and routine use of this therapy to treat chronic lung disease is now discour-aged.31,241-243 The association between sepsis and cerebral palsy has also been identifi ed in many studies and is discussed in a later section.

Because further reduction in mortality of ELBW infants is unlikely, strategies to reduce neonatal morbidity are increasingly important. Decreased rates of CP have been reported in ELBW infants born between 2000 and 2002, a period associated with increased use of antenatal steroids, decreased use of postnatal steroids, and decreased incidence of nosocomial sepsis.186 Chronic lung disease is an indepen-dent risk factor for neurodevelopmental disability for which improved strategies are needed. Inhaled nitric oxide for preterm infants with respiratory failure has been studied, and improved cognitive outcome in infants treated with inhaled nitric oxide has been reported,244,245 but this effect has not been consistently observed in ELBW infants.246,247

Multiple BirthsThe risk of developing CP is signifi cantly higher in multiple gestations compared with singleton births. Data from CP registries show that the risk for developing CP in twins is four or fi ve times greater than single-tons. For triplets the risk is 12 to 13 times greater.183,248-250 Although twins comprise only 1.6% of the population, they have a 5% to 10% incidence of CP.251 The higher rate of CP in multiple births may relate to preterm birth and to other complications associated with multiple gestation such as placental and cord abnormalities, intra-placental shunting, structural anomalies, and diffi culties at delivery.

The incidence of CP increases as birth weight decreases. Only 0.9% of singletons weigh less than 1500 g at birth, compared with 9.4% of twins, 32.2% of triplets, and 73.3% of quadruplets.183,252 Population-based registries have also broken down the risks of CP related to birth weight groups as follows: 66.5 per 1000 surviving infants born weigh-ing less than 1000 g, 57.4 per 1000 surviving infants with birth weights between 1000 and 1499 g, and 8.9 per 1000 surviving infants with birth weights between 1500 and 2499 g.182 However, twins with birth weight above 2500 g still have a threefold to fourfold increased risk of devel-oping CP compared with singletons.183 It is unclear why this risk remains increased near term, but it may be linked to an increased risk of asphyxia or fetal growth restriction, which occurs more commonly in multiples.

The risk of CP is increased with the fetal death of a co-twin and is 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 greater than if one twin died in utero, with same-sex twins having a greater risk than different-sex twins.183 These data suggest that mono-

chorionic placentation has a signifi cant role in the pathogenesis of CP, likely because of placental vascular anastomoses.

Multiple gestations have signifi cantly increased because of assisted reproductive technology (ART). The increased risk of CP associated with ART is likely because of the higher rate of preterm births because ART is typically not associated with monochorionicity unless mono-zygotic division occurs. However, the increased risk of CP associated with ART requires further study. A Danish study suggests that IVF pregnancies may carry an increased risk of CP not attributable to birth weight or gestation184 (see Chapter 29).

Growth RestrictionThere is much debate in the literature about whether infants with fetal growth restriction have an increased incidence of CP. Many investiga-tors have reported an increased risk of CP for infants who are small for gestational age (SGA).257-262 However, fetal growth restriction is a separate entity from SGA (see Chapter 34). Fetal growth restriction refers to failure of a fetus to grow at an optimal predicted rate, using fetal growth standards derived from ultrasound measurements of healthy fetuses in utero at each gestational age. Fetal growth curves can account for variables, including fetal sex, ethnicity, parity, and maternal height and weight.263-265 SGA refers to infants who weigh less than a given percentile (usually the 10th) for gestational age and does not take into account potential etiologies of SGA such as constitutional small stature, chromosomal anomalies, congenital infections, or structural malformations. Studies of risk of cerebral palsy often use birth weight alone to defi ne their population of interest, which may explain the observed increased risk of CP associated with low birth weight. This increased risk of CP may result from the effects of intrauterine growth restriction, because these cohort studies include more mature SGA term infants and preterm infants with equivalent birth weights.266,267 The terminology used affects how the data may be interpreted.

Many studies have demonstrated that SGA term or preterm infants beyond 33 weeks’ gestation have the highest risk of developing CP.259-261 The Surveillance of Cerebral Palsy in Europe (SCPE) Col-laborative Group reported that infants born between 32 and 42 weeks’ gestation with a birth weight below the 10th percentile were four to six times more likely to develop CP than infants with a birth weight between the 25th and 75th percentile.267,268 For infants born before 33 weeks’ gestation with fetal growth restriction, the association is less clear, because this population has the highest risk of adverse neurode-velopmental outcome. It is therefore diffi cult to separate the risk purely due to growth restriction from the effect of prematurity in general. Other factors that increase the risk of CP are the severity of SGA, male sex, and perinatal asphyxia.269

Growth-restricted infants may be more susceptible to intrapartum hypoxia, which leads to adverse neurologic outcome. Data from the Collaborative Perinatal Project showed that infants with intrauterine growth restriction (IUGR) had similar incidences of CP compared with non-IUGR infants when examined at 7 years of age in the absence of intrapartum hypoxia. However, when intrapartum hypoxia was identifi ed, children with IUGR had an increased incidence of neuro-developmental disability compared with those without IUGR.197 The relative risk of CP due to intrapartum hypoxia was actually lower in a study of infants who were SGA compared with appropriate for gesta-tional age (AGA) infants.262 Based on confl icting results it seems clear that other factors may be involved.

Perinatal InfectionsMaternal, intrauterine, and neonatal infections have all been associ-ated with cerebral palsy. Congenital viral infections such as toxoplas-

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mosis, rubella, cytomegalovirus (CMV), herpes simplex virus, and syphilis may account for 5% to 10% of CP cases.270 Maternal infection and infl ammation has been associated with an increased incidence of preterm birth and are risk factors for the development of CP. Intra-amniotic infection, also referred to as clinical chorioamnionitis, has been associated with preterm labor, preterm premature rupture of the fetal membranes, and subsequent preterm birth.271,272 Chorioamnio-nitis also has been associated with an increased risk for developing CP through several likely mechanisms. An increased risk of IVH and PVL has been associated with maternal chorioamnionitis and premature rupture of membranes in numerous studies.210,211,273-275 Histologic cho-rioamnionitis without clinical signs of intra-amniotic infection has also been linked to increased risk of IVH, PVL, and CP.276-280

Laboratory and clinical evidence has emerged that supports the hypothesis that intrauterine infection and infl ammation leads to the production of proinfl ammatory cytokines, which are responsible for white matter brain injury and ultimately for CP. These cytokines are potentially toxic to developing oligodendrocytes in fetal white matter and cause reduced myelination and subsequent white matter injury.270,273,281,282 Various cytokines may have a direct toxic effect on cerebral white matter by increasing the production of nitric oxide synthase, cyclooxygenase, other associated free radicals, and excitatory amino acids.270,282-285 This relationship between elevated cytokine levels and the development of white matter injury has been seen in both preterm and term infants. A fourfold to sixfold increased risk for white matter injury has been associated with elevated levels of interleukin (IL) 1β from amniotic fl uid and from umbilical cord blood in preterm infants.2,286 In a study of term infants who went on to develop CP, stored blood samples had signifi cantly increased levels of the cytokines IL-1, IL-8, IL-9, tumor necrosis factor β, and RANTES.287 The combination of intrauterine infection and intrapartum hypoxia has been correlated with a dramatic increase in the incidence of CP.288

Neonatal infection has been associated with the development of CP due to direct central nervous system damage, e.g., in meningitis, or to a systemic infl ammatory response syndrome (SIRS) that leads to sepsis, shock, and multiorgan system failure.270 Preterm infants who develop infection seem to be at higher risk.289,290 A study of 6093 ELBW survivors born between 1993 and 2001 found an 8% incidence of CP among infants who did not develop a postnatal infection and a 20% incidence of CP in infants whose hospital course was complicated by sepsis, NEC, or meningitis.240 The infected infants also had an extremely high risk of cognitive impairment, defi ned as a Bayley MDI score less than 70 at 18 months compared with noninfected infants (33% to 42% versus 22%).240 Another study of ELBW survivors found that NEC requiring surgical intervention was associated with a signifi cant increase in both the incidence of CP and developmental disabilities compared with those without NEC.129

Placental AbnormalitiesBecause the placenta supplies nutrients to the developing fetus and serves as a barrier that protects the fetus from infl uences such as infec-tious organisms, toxins, trauma, and immune mediators, placental abnormalities can predispose fetuses to adverse outcomes. Placental abnormalities associated with CP can fall into three categories. The fi rst encompasses events that occur during or before labor, also known as sentinel lesions, that can cause fetal hypoxia. These lesions include uteroplacental separation, fetal hemorrhage, and umbilical cord occlusion.291 The next category is made up of thromboinfl ammatory processes that affect fetal circulation and include fetal thrombotic vasculopathy, chronic villitis, meconium-associated fetal vascular necrosis, and fetal vasculitis related to chorioamnionitis.291,292 The third

category includes processes that cause decreased placental reserve, such as chronic placental insuffi ciency, chronic villitis, chronic abrup-tion, chronic vascular obstruction, and perivillous fi brin deposition.293 Evaluation of the placenta in the cause of neonatal encephalopathy may provide some insight into the fetal intrauterine environment and its contribution to the neurologic impairment.

Coexisting ImpairmentsHistorically, CP has been defi ned strictly by the location and degree of motor impairment. However, associated coimpairments such as dis-turbances in sensation, cognition, communication, perception, and behavior are common, as are seizures. A new defi nition that includes coimpairments has been proposed.178,234 A Dutch population study of children with CP reported that 40% had seizures, 65% had cognitive defi cits (IQ < 85), and 34% had visual impairments.294 Hearing impair-ments and feeding diffi culties are also common.

Strategies to Reduce Cerebral PalsyStrategies to reduce CP have focused on asphyxia and premature birth because these factors seem to be the most amenable to intervention to prevent CP. Strategies commonly used to reduce intrapartum hypoxia such as fetal heart monitoring, maternal oxygen administration, repo-sitioning, and strict guidelines for oxytocin use have not affected the rate of CP. Fetal heart rate monitoring increases the rate of operative interventions without reducing the rate of CP164 and may theoretically increase the prevalence of CP by increasing the risk of chorioamnio-nitis.295,296 Reduction of perinatal intracranial injuries associated with the decreased use of forceps and vacuum extraction in the past 20 years is a positive trend that may contribute to a reduction in the incidence of CP.155,297

Preterm birth accounts for approximately 35% of cerebral palsy cases.298 Strategies to reduce the incidence of preterm birth have been sought to reduce the incidence of CP, provided the risk of an in utero insult is not increased by prolonging pregnancy. Prevention of preterm birth has proved elusive, making strategies to reduce morbidity more immediately promising. Antenatal steroids decrease the incidence of several morbidities strongly associated with cerebral palsy, including IVH, PVL,171,299 RDS, and chronic lung disease. Postnatal steroids used to treat neonatal chronic lung disease, however, are associated with a signifi cantly increased risk of CP.241,300-302

Another strategy under study to reduce CP in preterm infants is the administration of magnesium sulfate before delivery. The pro-posed benefi cial mechanism is the ability of magnesium sulfate to sta-bilize vascular tone, reduce reperfusion injury, and reduce cytokine mediated injury.303,304 Several observational studies have found an association between maternal administration of magnesium sulfate (given for preeclampsia or preterm labor) and a reduced risk of CP.305-308 However, other investigators have reported no protective effect of magnesium.309-314 The Australasian Collaborative Trial of Magnesium Sulphate examined the effi cacy of magnesium sulfate given to women at risk for preterm birth less than 30 weeks’ gestation solely for neuroprotection. This study was a much larger, randomized, controlled trial (N = 1062), and the investigators reported a lower incidence of CP, although the difference was not statistically signifi cant (6.8% versus 8.2%), and no serious harmful effects to women or their children.194 Although the use of prenatal magnesium sulfate cannot be recommended based on this study alone, this intervention is being further investigated (see Chapter 29). A large, 10-year NIH trial of intrapartum administration of magnesium sulfate as neuroprotective agent found a reduced rate of moderate to severe cerebral palsy among survivors at 2 years of age who received antenatal magnesium.315

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Summary of Cerebral PalsyCerebral palsy is a signifi cant adverse event with origins in pregnancy. Many risk factors have been identifi ed, although sometimes no etio-logic factor is found. Strategies to reduce asphyxia and prevent preterm birth have not shown a signifi cant decrease in rates of CP. Because most CP is related to extremely preterm birth and the survival rates of these ELBW infants is improving, strategies to reduce neonatal brain injury, such as the use of antenatal steroids, are the most promising. Future trials of antenatal neuroprotection for preterm infants may prove ben-efi cial to combat infl ammation- or cytokine-mediated brain injury.

Infectious Disease Problems in the Neonatal PeriodNeonatal infection is a signifi cant cause of neonatal morbidity and mortality in preterm and term infants. The risk of infection is inversely related to gestational age. The clinical manifestations of neonatal infec-tion vary by pathogen and age of acquisition. The spectrum of patho-gens causing neonatal infection is broad and has changed over the decades.316 However, the cornerstones of management remain preven-tion when possible, early detection, and focused treatment.

Compared with older children and adults, neonatal host defense is blunted by incomplete development and experience with self versus non-self discrimination.317 All components of the immune system are defi cient. Nonspecifi c immunity is defective at several levels. Skin and mucosal barriers are immature, especially in preterm infants. Levels of nonspecifi c antibacterial proteins such as lysozyme and lactoferrin are low. Neutrophil numbers are low, with limited storage pools available to clear bacteria. Key neutrophil functions, including chemotaxis, phagocytosis, and intracellular killing, are limited. The neonate is poorly equipped to clear transient bacteremia and localize bacterial infection. Specifi c humoral and cell-mediated immune functions are also limited. Circulating immunoglobulin levels are very low compared with adult levels. The neonate acquires virtually all of its circulating IgG from the mother through transplacental transport. The bulk of this antibody is transferred during the third trimester, making the preterm infant profoundly defi cient. 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 function is almost undetectable by standard functional assays.

The nature of neonatal immune function accounts for the clinical manifestations of most early-onset infections. Nonspecifi c signs such as lethargy, poor feeding, temperature instability, decreased tone, apnea, and altered perfusion may or may not be present. Fever is uncommon, as are localized processes such as cellulitis, abscesses, or osteomyelitis. When present, they are usually accompanied by bacte-remia. Similarly, bacteremia must always be suspected in neonates with meningitis or urinary tract infections.

ChorioamnionitisThe relationship between chorioamnionitis and neonatal infection is complex and remains incompletely understood. Some studies demon-strate a direct correlation between chorioamnionitis and neonatal infection. Other poor neonatal outcomes, including RDS and BPD, are associated with chorioamnionitis.84,318 However, other clinical series and studies using animal model systems reach essentially the opposite conclusion—that chorioamnionitis protects against these same out-comes.319,320 Some of the confusion is grounded in defi nitions of cho-

rioamnionitis. Clinical chorioamnionitis, as characterized by maternal fever and uterine tenderness, is probably a very different disease from clinically silent histologic chorioamnionitis commonly seen in preterm deliveries. Whether these represent different disease entities or differ-ent manifestations of the same disease spectrum is not evident. The fetal response to infection has important consequences for neonatal outcome. Studies using proteomic analysis of amniotic fl uid show promise for relating the diagnosis of chorioamnionitis to the neonatal clinical course.321,322

Group B b-Hemolytic StreptococciInfection with group B β-hemolytic streptococci (GBS) was fi rst rec-ognized as a cause of early-onset neonatal sepsis in the 1970s. By the 1990s, GBS was a leading cause of serious neonatal infections. The organism is a common colonizing constituent of the vagina and rectum in 10% to 30% of pregnant women. GBS colonization is more common in African-American women and those with a previous history of a neonate with GBS disease or a history of a GBS urinary tract infection. Epidemiologic studies demonstrate that most invasive, early-onset neonatal GBS disease involves vertical transmission from the mother to the fetus during labor. This observation led to studies of intrapar-tum antibiotic prophylaxis with penicillin G or ampicillin. The success of this strategy prompted the publication of guidelines for intrapartum antibiotic prophylaxis by the Centers for Disease Control and Preven-tion.323 A follow-up study completed in 2005 confi rmed the success of this strategy.324 Most infants with invasive, serious GBS now seen are born to mothers with negative GBS screening cultures who have pre-sumably converted to GBS-positive carrier status in the interval between screening and delivery.325 In the future, rapid GBS screening technology may allow for identifi cation of these women when they present in labor.326 There is some concern that intrapartum antibiotic prophylaxis may be associated with a higher incidence of serious bacte-rial infections later in infancy. This was most pronounced when broad-spectrum antibiotics were used for intrapartum prophylaxis rather than penicillin G.327 The advantages of intrapartum antibiotic prophy-laxis to reduce the risk of invasive neonatal GBS disease clearly out-weigh any risks, especially if penicillin is employed.

Viral Infections

CytomegalovirusHuman cytomegalovirus (CMV) is transmitted horizontally (i.e., direct person-to-person contact with virus-containing secretions) and vertically (i.e., from mother to infant before, during, or after birth) and through transfusion of blood products or organ transplantation from previously infected donors. Vertical transmission of CMV to infants occurs by one of the following routes of transmission: in utero by transplacental passage of maternal blood borne virus, through an infected maternal genital tract, and postnatally by ingestion of CMV-positive human milk.328,329

Approximately 1% of all liveborn infants are infected in utero and excrete CMV at birth. Risk to the fetus is greatest in the fi rst half of gestation. Although fetal infection can occur after maternal primary infection or after reactivation of infection during pregnancy, sequelae are far more common in infants exposed to maternal primary infec-tion, with 10% to 20% of infants manifesting neurodevelopmental impairment or sensorineural hearing loss in childhood.330

Congenital CMV infection is usually clinically silent. Some infected infants who appear healthy at birth are subsequently found to develop

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hearing loss or learning disabilities. Approximately 10% of infants with congenital CMV infection exhibit evidence of profound involvement at birth, including intrauterine growth restriction, jaundice, purpura, hepatosplenomegaly, microcephaly, intracerebral calcifi cations, and retinitis.331 Although ganciclovir has been used to treat some infants with congenital CMV infection, it is not recommended routinely because of insuffi cient effi cacy data. One study of ganciclovir treat-ment provided to infants with congenital CMV with central nervous system involvement suggested that treatment decreased progression of hearing impairment.332 Because of the potential toxicity of long-term ganciclovir therapy, additional investigation is required before a rec-ommendation can be made.

Infection acquired during pregnancy from maternal cervical secre-tions or after delivery from human milk usually is not associated with clinical illness. Infections resulting from transfusion of blood products with CMV-seropositive donors and from human milk to preterm infants have been associated with serious systemic infections, includ-ing lower respiratory tract infection. Transmission of CMV by transfu-sion to newborn infants has been reduced by using CMV-antibody negative donors, by freezing erythrocytes in glycerol, or by removal of leukocytes by fi ltration before administration.333 CMV transmission by human milk can be decreased by pasteurization.334 However, freeze-thawing is probably not effective.335 If fresh donor milk is needed for infants born to CMV-antibody negative mothers, provision of these infants with milk from only CMV-antibody negative women should be considered.

Hepatitis BHBV is a DNA virus whose important components include an outer lipoprotein envelope containing antibody to hepatitis B surface antigen (HBsAg) and an inner nucleocapsid containing the hepatitis B core antigen. Only antibody to HBsAg (anti-HBs) provides protection from HBV infection. Perinatal transmission of HBV is highly effi cient and usually occurs from blood exposure during labor and delivery. In utero transmission of HBV is rare, accounting for less than 2% of perinatal infections in most studies. The risk of an infant acquiring HBV from an infected mother as a result of perinatal exposure is 70% to 90% for infants born to mothers who are HBsAg and HBeAg positive. The risk is 5% to 20% for infants born to mothers who are HBeAg negative. Age at the time of acute infection is the primary determinant of risk of progression to chronic HBV infection. More than 90% of infants with perinatal infection will develop chronic HBV infection. Between 25% and 50% of children infected between 1 to 5 years of age become chronically infected, whereas only 2% to 6% of older children or adults develop chronic HBV infection.336

The goals of HBV prevention programs are to prevent the acute HBV infection and to decrease the rates of chronic HBV infection and HBV-related chronic liver disease. Over the past 2 decades a strategy has been progressively implemented in the United States to prevent HBV transmission. This includes the following components: universal immunization of infants beginning at birth, prevention of perinatal HBV infection by routine screening of all pregnant women and appro-priate immunoprophylaxis of infants born to HBsAg-positive women and infants born to women with unknown HBsAg status, routine immunization of children and adolescents who have previously not been immunized, and immunization of previously nonimmunized adults at increased risk of infection.

Two types of products are available for hepatitis B immunoprophy-laxis. Hepatitis B immune globulin (HBIG) provides short-term pro-tection (3 to 6 months) and is indicated only in postexposure circumstances. Hepatitis B vaccine is used for pre-exposure and post-

exposure protection and provides long-term protection. Pre-exposure immunization with hepatitis B vaccine is the most effective means to prevent HBV transmission. To decrease the HBV transmission rate universal immunization is necessary. Postexposure prophylaxis with hepatitis B vaccine and HBIG or hepatitis B vaccine alone effec-tively prevents infection after exposure to HBV. The effectiveness of postexposure immunoprophylaxis is related to the time elapsed between exposure and administration. Immunoprophylaxis is most effective if given within 12 to 24 hours of exposure. Serologic testing of all pregnant women for HBsAg is essential for identifying women whose infants will require postexposure prophylaxis beginning at birth.

Hepatitis B vaccines are highly effective and safe. These vaccines are 90% to 95% effi cacious for preventing HBV infection. Studies in preterm infants and low-birth-weight infants (<2000 g) have demon-strated decreased seroconversion rates after administration of hepatitis B vaccination. However, by 1 month chronological age medically stable preterm infants should be immunized, regardless of initial birth weight or gestational age. Routine postimmunization testing for anti-HBs is not necessary for most infants. However, postimmunization testing for HBsAg and anti-HBs at 9 to 18 months is recommended for infants born to HBsAg-positive mothers.

Immunization of pregnant women with hepatitis B vaccine has not been associated with adverse effects on the developing fetus. Because HBV infection may result in severe disease in the mother and chronic infection in the newborn infant, pregnancy is not considered a contra-indication to immunization. Lactation is also not a contraindication to immunization.

Herpes Simplex VirusNeonatal herpes simplex virus infections range from localized skin lesions to overwhelming disseminated disease. The latter has a case-fatality rate in excess of 50%, even with prompt initiation of antiviral therapy. Vertical transmission is the likely mode of transmission for most cases. Mothers with a history of previous disease appear to convey at least some type-specifi c immunity to the neonate. Most mothers of severely infected infants have no recognized history of HSV and no evidence of active disease on physical examination. No screening protocols for HSV are available, and there is no vaccine.337,338

Human Immunodefi ciency VirusLandmark studies339,340 in the 1990s demonstrated the value of intra-partum antiretroviral therapy to reduce the risk of maternal to fetal transmission of human immunodefi ciency virus (HIV). Improve-ments in the quality and availability of rapid HIV testing holds promise for timely and accurate identifi cation of infected women and their newborn infants. The risk of congenital HIV is reduced to approxi-mately 1% when HIV-positive mothers receive antiretroviral therapy during labor and treatment is continued for the neonate within 12 hours of delivery, Breastfeeding is contraindicated, unless there is no access to clean water and infant formula.

Laboratory diagnosis of HIV infection during infancy depends on detection of virus or viral nucleic acid. Cord blood should not be used for this early test because of possible contamination by maternal blood. A positive result identifi es infants who have been infected in utero. Approximately 93% of infected infants have detectable HIV DNA at 2 weeks, and almost all HIV-infected infants have positive HIV DNA PCR assay results by 1 month of age. A test within the fi rst 14 days of age can facilitate decisions regarding initiation of antiretroviral therapy. Transplacental passage of antibodies complicates use of antibody-

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based assays for diagnosis of infection in infants because all infants born to HIV-seropositive mothers have passively acquired maternal antibodies.

Antiretroviral therapy is indicated for most HIV-infected children. Initiation of therapy depends on virologic, immunologic, and clinical criteria. Because HIV infection is a rapidly changing area, consultation with an expert in pediatric HIV is recommended.

RubellaHumans are the only source of infection. Peak incidence of infection is in late winter and early spring. Before widespread use of rubella vaccine, rubella was an epidemic disease with most cases occurring in children. The incidence of rubella has decreased 99% from the prevac-cine era. Although the number of susceptible people has decreased since introduction and widespread use of rubella vaccine, serologic surveys indicate that approximately 10% of the U.S. population older than 5 years is susceptible. The percentage of susceptible people who are foreign born or from areas with poor vaccine coverage is higher. The risk of congenital rubella syndrome is highest among infants of women born outside the United States. Epidemiologic data suggests that rubella is no longer endemic in the United States.341

Congenital rubella syndrome is characterized by a constellation of anomalies, which may include ophthalmologic (i.e., cataracts, microphthalmos, pigmentary retinopathy, and congenital glaucoma), cardiac (i.e., patent ductus arteriosus and peripheral pulmonary artery stenosis), auditory (i.e., sensorineural hearing impairment), and neu-rologic (i.e., meningoencephalitis, behavioral abnormalities, and mental retardation) abnormalities. Neonatal manifestations of con-genital rubella syndrome include growth retardation, interstitial pneumonia, radiolucent bone disease, hepatosplenomegaly, thrombo-cytopenia, and dermal erythropoiesis, also called blueberry muffi n lesions. The occurrence of congenital defects varies with timing of the maternal infection.

Detection of rubella-specifi c IgM antibody usually indicates recent postnatal infection or congenital infection in a newborn infant, but false-positive and false-negative results occur. Congenital infection can be confi rmed by stable or increasing rubella-specifi c IgG over several months. Rubella virus can be isolated most consistently from throat or nasal swabs by inoculation of appropriate cell culture. Blood, urine, CSF, and pharyngeal swab specimens can also yield virus in congeni-tally infected infants.

Infants with congenital rubella should be considered contagious until at least 1 year old, unless nasopharyngeal and urine cultures are repeatedly negative for rubella virus. Infectious precautions should be considered for children up to 3 years old who are hospitalized for congenital cataract extraction. Caregivers of these infants and children should be made aware of the potential hazard to susceptible pregnant contacts.

Sexually Transmitted Infections

ChlamydiaIn the newborn period, Chlamydia trachomatis is associated with con-junctivitis and pneumonia. Acquisition of C. trachomatis occurs in approximately 50% of infants born vaginally to infected mothers and in some infants delivered by cesarean section with intact membranes.342 Neonatal chlamydial conjunctivitis is characterized by ocular conges-tion, edema, and discharge developing a few days to several weeks after birth and usually lasting 1 to 2 weeks. Pneumonia in infants is usually an insidious afebrile illness occurring between 2 and 20 weeks after

birth. It is characterized by a staccato cough, tachypnea, and rales on physical examination. Pulmonary hyperinfl ation and infi ltrates are demonstrated on the chest radiograph.

Topical prophylaxis with silver nitrate, erythromycin, or tetracy-cline for all newborn infants to avert gonococcal ophthalmia does not prevent chlamydial conjunctivitis or extraocular infections.343 Infants with chlamydial conjunctivitis are treated with oral erythromycin base or ethylsuccinate (50 mg/kg per day in four divided doses) for 14 days. Alternatively, oral sulfonamides may be used after the immediate neo-natal period for infants who do not tolerate erythromycin. Because the effi cacy of treatment is about 80%, follow-up of infants is recom-mended. In some instances, a second course of therapy may be required.

Chlamydial pneumonia is treated with oral azithromycin (20 mg/kg/day) for 3 days or erythromycin base or ethylsuccinate (50 mg/kg per day in four divided doses) for 14 days. Detection and treatment of C. trachomatis infections before delivery is the most effective way to reduce the risk of neonatal conjunctivitis and pneumonia.

Gonococcal InfectionsInfection with Neisseria gonorrhoeae in the newborn infant usually involves the eyes. Other types of gonococcal infections include arthri-tis, disseminated disease with bacteremia, meningitis, scalp abscess, or vaginitis.

Microscopic examination of Gram-stained smears of exudates from the eyes, skin lesions, synovial fl uid, and, when clinically war-ranted, CSF may be useful in the initial evaluation. Identifi cation of gram-negative intracellular diplococci in these smears can be helpful, in particular if the organism is not recovered in culture. N. gonorrhoeae can be cultured from normally sterile sites such as blood, CSF, and synovial fl uid.

For routine ophthalmia neonatorum prophylaxis of infants imme-diately after birth, a 1% silver nitrate solution, 1% tetracycline, or 0.5% erythromycin ophthalmic ointment is instilled into each eye. Prophy-laxis may be delayed for as long as 1 hour after birth to facilitate parent-infant bonding. Topical antimicrobial agents cause less chemi-cal irritation than silver nitrate. None of the topical agents is effective against C. trachomatis.343

When prophylaxis is administered, infants born to mothers with known gonococcal infection rarely develop gonococcal ophthalmia. However, because gonococcal ophthalmia or disseminated disease occasionally can occur in this situation, infants born to mothers known to have gonorrhea should receive a single dose of ceftriaxone (125 mg) given intravenously or intramuscularly. Preterm and low-birth-weight infants are given 25 to 50 mg/kg of ceftriaxone to a maximum dose of 125 mg.

Infants with clinical evidence of ophthalmia neonatorum, scalp 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 confi rm the diagnosis and determine antimicrobial sus-ceptibility. Tests for concomitant infection with C. trachomatis, syphi-lis, and HIV infection should be performed. Recommended treatment, including for ophthalmia neonatorum, is ceftriaxone (25 to 50 mg/kg, given intravenously or intramuscularly, not to exceed 125 mg) given once. Infants with gonococcal ophthalmia should receive eye irriga-tions with saline solution immediately and at frequent intervals until the discharge is eliminated. Topical antimicrobial treatment alone is inadequate and is unnecessary when recommended systemic antimi-crobial treatment is provided. Infants with gonococcal ophthalmia should be hospitalized and evaluated for disseminated infection. Rec-ommended therapy for arthritis and septicemia is ceftriaxone or cefo-

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taxime for 7 days. If meningitis is documented, treatment should continue for a total of 10 to 14 days.

SyphilisCongenital syphilis is contracted from an infected mother through transplacental transmission of Treponema pallidum at any time during the pregnancy or birth. Intrauterine syphilis can result in stillbirth, hydrops fetalis, or preterm birth. The infant can present with edema, hepatosplenomegaly, lymphadenopathy, mucocutaneous lesions, osteochondritis, pseudoparalysis, rash, or snuffl es at birth or within the fi rst 2 months of life. Hemolytic anemia or thrombocytopenia may be identifi ed on laboratory evaluation. Untreated infants, regardless of whether they have manifestations in infancy, may develop late mani-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.

Defi nitive diagnosis is established by identifi cation of spirochetes by microscopic dark fi eld examination or by direct fl uorescent anti-body tests of lesion exudates or tissue such as the placenta or umbilical cord. Presumptive diagnosis is possible using nontreponemal and treponemal tests. The use of only one type of test is insuffi cient for diagnosis, because false-positive nontreponemal test results occur with various medical conditions and false-positive treponemal test results can occur with other spirochetal diseases.

No newborn infant should be discharged from the hospital without determination of the mother’s serologic status for syphilis.344 All infants born to seropositive mothers require a careful examination and a quantitative nontreponemal syphilis test. The test performed in the infant should be the same as that performed on the mother so that comparison of titer results is facilitated. An infant should be evaluated for congenital syphilis if the maternal titer has increased fourfold, if the infant titer is fourfold greater than the mother’s titer, or if the infant has clinical manifestations of syphilis. The infant should be evaluated if born to a mother with positive nontreponemal and trepo-nemal test results if the mother has any of the following conditions. First, the syphilis has not been treated or treatment has not been docu-mented. Second, syphilis during pregnancy was treated with a non-penicillin regimen. Third, syphilis was treated less than 1 month before delivery because treatment failures occur and effi cacy cannot be assumed. Fourth, syphilis was treated before pregnancy but with insuf-fi cient follow-up to assess the response to treatment and current infec-tion status.

Evaluation for syphilis in an infant should include a physical exam-ination, quantitative nontreponemal syphilis test of serum from the infant, VDRL test of the CSF and analysis of the CSF for cells and protein concentration, long bone radiographs, and a complete blood cell and platelet counts. Other clinically indicated tests may include a chest radiograph, liver function tests, ultrasonography, ophthalmo-logic examination, and an auditory brainstem response test. Pathologic examination of the placenta or umbilical cord using specifi c anti-treponemal antibody staining is also recommended.

Infants should be treated for congenital syphilis if they have proven or probable disease demonstrated by one or more of the following: physical, laboratory, or radiographic evidence of active disease; posi-tive placenta or umbilical cord test results for treponemes using direct fl uorescent antibody T. pallidum staining or dark-fi eld test; a reactive result on VDRL on testing of CSF; or 4a serum quantitative nontrepo-nemal titer is at least fourfold higher than the mother’s titer using the same test and preferably the same laboratory. If the infant’s titer is less than four times that of the mother, congenital syphilis still can be

present. When circumstances warrant evaluation of an infant for syph-ilis, the infant should be treated if test results cannot exclude infection, if the infant cannot be adequately evaluated, or if adequate follow-up cannot be ensured.

Infants with proven congenital syphilis should be treated with aqueous crystalline penicillin G. The dosage should be based on chron-ologic age, not gestational age. The dose of penicillin G is 100,000 to 150,000 U/kg per day, administered as 50,000 U/kg per dose intrave-nously every 12 hours during the fi rst 7 days of life and then every 8 hours thereafter for a total of 10 days. Alternatively, penicillin G pro-caine (50, 000 U/kg/day) given intramuscularly for 10 days may be considered, but adequate CSF concentrations may not be achieved with this regimen.

References 1. American Academy of Pediatrics, American Heart Association: Ethics and

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