73 - neonatal morbidities of prenatal and perinatal origin

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Neonatal Morbidities of Prenatal and Perinatal OriginJAMES M. GREENBERG, MD | BETH HABERMAN, MD | VIVEK NARENDRAN, MD | AMY T. NATHAN, MD | KURT SCHIBLER, MD

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Obstetric Decisions and Neonatal OutcomesThe nature of obstetrics clinical practice requires consideration of two patients: mother and fetus. The intrinsic biological inter-dependence of one with the other creates unique challenges not typically encountered in other realms of medical practice. Often there is a paucity of objective data to support the evaluation of risks and benefits associated with a given clinical situation, forcing obstetricians to rely on their clinical acumen and expe-rience. Family perspectives must be integrated in clinical deci-sion making, along with the advice and counsel of other clinical providers. This chapter reviews how to best utilize neonatology expertise in the obstetric decision-making process.

THE PERINATAL CONSULTATION AND THE ROLE OF THE NEONATOLOGIST

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

In addition to contributing information about gestational age–specific outcomes, the neonatologist can also anticipate neonatal complications related to maternal disorders such as diabetes mellitus, hypertension, and multiple gestation, or pre-natally detect fetal conditions such as congenital infections, alloimmunization, or anomalies. When a lethal condition or high risk of death in the delivery room is anticipated, the neo-natologist can assist with the formulation of a birth plan and develop parameters for delivery room intervention.

Preparing parents by description of delivery room man-agement and resuscitation of a high-risk infant can demystify the process and reduce some of the fear anticipated by the expectant family. Making parents aware that premature infants are susceptible to thermal instability will reduce their anxiety when the newborn is rapidly moved to a warming bed after birth. The need for resuscitation is determined by careful evaluation of cardiorespiratory parameters and appropri-ate response according to published Neonatal Resuscitation Program guidelines.1

COMMON MORBIDITIES OF PREGNANCY AND NEONATAL OUTCOME

Complications of pregnancy that affect infant well-being may be immediately evident after birth, such as hypotension related to maternal hemorrhage, or may present hours later, such as hypoglycemia related to maternal diabetes, or thrombocyto-penia related to maternal preeclampsia. Anemia and thyroid disorders related to transplacental passage of maternal immu-noglobulin G (IgG) antibodies to fetal red blood cell anti-gens or to thyroid, respectively, may even present days after delivery.

Diabetes during pregnancy can serve as a prototypic example. Infants born to women with diabetes are often macro-somic, increasing the risk of shoulder dystocia and birth injury. After delivery, these infants may have significant hypoglycemia, polycythemia, and electrolyte disturbances, which require close surveillance and treatment. Lung maturation is delayed in the infant of a diabetic mother (IDM), increasing the incidence of respiratory distress syndrome (RDS) at a given gestational age. The IDM also has delayed neurologic maturation, with decreased tone typically leading to delayed onset of feeding competence. Less common complications include an increased incidence of congenital heart disease and skeletal malforma-tions. Most neonatal complications of maternal diabetes are managed without long-term sequelae, but may prolong length of hospital stay. Anticipatory guidance for parents can decrease anxiety and improve readiness for hospital discharge. Neonatal complications for the IDM are a function of maternal glyce-mic control; thus careful screening by physicians and attention by patients will reduce neonatal morbidity due to maternal diabetes.

Other morbidities of pregnancy and their effects on neonatal outcome are summarized in Table 73.1. The list is not exhaus-tive, and does not take into account how multiple morbidities may interact to create additional complications. Any of these problems may contribute to increased length of hospital stay after delivery as well as long-term morbidity.

Chorioamnionitis has diverse effects on the fetus and on neonatal outcome. It is associated with premature rupture of membranes and therefore preterm birth. Elevated levels of pro-inflammatory cytokines may predispose neonates to cerebral injury.2 While suspected or proven neonatal sepsis is more common in the setting of chorioamnionitis, many neonates born to mothers with histologically proven chorioamnionitis are asymptomatic and appear unaffected, with normal preg-nancy outcomes. Animal models and associated epidemiologic

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1310 PART 6 The Neonate

(caloric intake <1000 kcal/d). Mothers experienced significant third-trimester weight loss and offspring were underweight.9 Low maternal body mass index (BMI) is associated with increased risk of preterm birth.10 There is now growing evi-dence that infants undernourished during fetal life have higher risk for development of “adult” diseases such as atherosclero-sis and hypertension. Poor maternal nutrition during intra-uterine life may signal the fetus to modify metabolic pathways and blood pressure regulatory systems with long-term health consequences lasting into late childhood and beyond.11 Con-versely, maternal overnutrition as defined by excessive caloric intake predisposes mothers to insulin resistance and large-for-gestational-age infants. In general, maternal BMI and birth weight have increased over time even though mean gestational age at delivery has declined.12–15 Elevated maternal BMI is asso-ciated with excess stillbirth and neonatal mortality, and may increase the risk for preterm birth.16 Maternal obesity (BMI >30) is a risk factor for developmental delay within a cohort of extremely preterm infants and for cerebral palsy (CP) among a term population.17,18

Neonatal anemia may be a consequence of perinatal events such as placental abruption, ruptured vasa previa, or fetal-maternal transfusion. At delivery, the neonate may be asymp-tomatic or display profound effects of blood loss, including high-output heart failure or hypovolemic shock. The duration and extent of blood loss along with any fetal compensation determines neonatal clinical status at delivery and subsequent management. In the delivery room, prompt recognition of acute blood loss and transfusion with O-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 complications associated with low birth weight and prematurity described elsewhere in this chapter. Identical twins may also experience twin-twin trans-fusion syndrome. The associated discordant growth and addi-tional problems of anemia, polycythemia, congestive heart failure, and hydrops may further complicate the clinical course following delivery, even after amnioreduction or selective feto-scopic laser photocoagulation. Of additional concern are cere-bral lesions such as periventricular white matter injury and

data suggest that chorioamnionitis can accelerate fetal lung maturation as measured by surfactant production and function. However, preterm infants born to mothers with chorioamnio-nitis 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 associated inflammatory response.

The effects of preeclampsia on the neonate are well known and include intrauterine growth restriction (IUGR), hypo-glycemia, neutropenia, thrombocytopenia, polycythemia, and electrolyte abnormalities such as hypocalcemia. Most of these problems relate to placental insufficiency with diminished oxygen and nutrient delivery to the fetus. With delivery and supportive care, most of these problems will resolve with time, although some patients will require treatment with intravenous calcium and/or glucose in the early neonatal period. Similarly, severe thrombocytopenia may require platelet transfusion therapy. Some studies suggest preeclampsia may protect against intraventricular hemorrhage (IVH) in preterm infants, perhaps because of maternal treatment or other unknown factors.6 In contrast to intrauterine inflammation, preeclampsia does not appear to accelerate lung maturation.7 Predicting the conse-quences of maternal preeclampsia on neonatal outcome remains difficult.8

Maternal autoimmune disease may affect the neonate through transplacental transfer of autoantibodies. The extent of antibody transfer drives severity of symptoms. Treatment is supportive and based on the affected neonatal organ system. For example, maternal Graves disease may cause neonatal thy-rotoxicosis requiring treatment with propylthiouracil or β-blockers. Maternal lupus or connective tissue disease is linked to congenital heart block that may require long-term atrial pacing after delivery. Myasthenia gravis during pregnancy can promote a transient form of the disease in the neonate. Sup-portive therapy during the early neonatal period will address most issues associated with maternal autoimmune disorders. Passively transferred autoantibodies gradually clear from the neonatal circulation with a half-life of 2–3 weeks.

Neonatal outcome associated with maternal nutritional status during pregnancy is of growing interest. The Dutch famine of 1944–1945 created a unique circumstance for study-ing the consequences of severe undernutrition during pregnancy

Malformation Management Considerations

Clefts Alternative feeding devices (e.g., Haberman Feedera), genetics evaluation, occupational/physical therapy

Congenital diaphragmatic hernia Skilled airway management, pediatric surgery, immediate availability of mechanical ventilation, nitric oxide (ECMO)

Upper airway obstruction/micrognathia Skilled airway management, otolaryngology, genetics evaluation/management, immediate availability of mechanical ventilation, tracheostomy tube placement

Hydrops/hydrothorax/peritoneal effusion Skilled airway management, nitric oxide, ECMO, chest tube placement, paracentesis, immediate availability of mechanical ventilation

Ambiguous genitalia Endocrinology, urology, genetic consults available for immediate evaluation; assessment of electrolytes

Neural tube defects Sterile, moist dressing to cover defect and prevent desiccation; IV fluids; neurosurgery, urology, orthopedics evaluation/management

Abdominal wall defects Saline-filled sterile bag to contain exposed abdominal contents and prevent desiccation, IV fluids, pediatric surgery, genetics evaluation/management

Cyanotic congenital heart disease IV access, prostaglandin E1, immediate availability of mechanical ventilation

aAthrodax Healthcare Limited, Gloustershire, United Kingdom.ECMO, Extracorporeal membrane oxygenation; IV, intravenous.

TABLE

73.1 Other Morbidities of Pregnancy and Their Effects on Neonatal Outcome


73 Neonatal Morbidities of Prenatal and Perinatal Origin 1311

anemia, hydrops, and high-output congestive heart failure. Rh hemolytic disease is now uncommon, but it still must be con-sidered as a cause of unexplained hydrops, anemia, and/or heart failure in infants born to Rh-negative mothers, especially if there is a possibility of maternal sensitization. ABO incompat-ibility is common, with up to 20% of all pregnancies potentially at risk. The responsible isohemagglutinins have weak affinity for blood group antigens. Therefore the degree of hemolysis and subsequent jaundice varies from patient to patient. Indirect immunoglobulin (Coombs) testing has limited value in pre-dicting clinically significant jaundice. The neonatal morbidity is typically restricted to hyperbilirubinemia requiring treatment with phototherapy.

PrematurityThe mean duration of a spontaneous singleton pregnancy is 282 days, or 40 menstrual weeks (38 postconceptional weeks). An infant delivered prior to completion of the 37th week of gestation is considered preterm (World Health Organization definition). Infant morbidity and mortality increase with decreasing gestational age at birth. The risk of poor outcome, defined as death or lifelong handicap, increases dramatically as gestational age decreases, especially for very-low-birth-weight infants.25,26 The interplay between birth weight and gestational age, first documented by Lemons and colleagues,27 remains valid (Fig. 73.1).

COMPLICATIONS OF PREMATURITY

Beyond increased mortality risk, prematurity is also associated with increased risk of morbidity in nearly every major organ system. Retinopathy of prematurity, BPD, necrotizing enteroco-litis (NEC), and IVH are particularly linked to the preterm state. IUGR and increased susceptibility to infection are not restricted to the preterm infant but are complicated in the immature infant. Table 73.2 summarizes common complications of pre-maturity by organ system.

ventricular enlargement that may occur more frequently in the setting of twin-twin transfusion syndrome.19 Additional epide-miologic studies and long-term follow-up are needed to further address this issue.

Congenital malformations present significant challenges for caregivers and families. Prenatal diagnosis offers opportunity to plan for delivery room management and provide anticipatory guidance. Choosing the site of delivery should be based on opti-mizing availability of appropriate expertise. The neonatologist can facilitate appropriate delivery coverage and ensure avail-ability of appropriate equipment, medications, and personnel. Table 73.1 summarizes some of the important considerations associated with neonatal management of congenital malforma-tions. Management considerations include availability of exper-tise and equipment needed for optimal management.

Table 73.1 reflects the importance of multidisciplinary input for optimal management of patients with congenital malforma-tions. Typically, such patients are best delivered in a setting with experienced delivery room attendants. If needed consultative services or equipment is not readily available, arrangements should be made for prompt transfer to a tertiary care center. Successful transports depend on clear communication between centers. For example, prompt notification of the delivery of an infant with gastroschisis ensures that the delivering hospi-tal will provide adequate intravenous hydration and protec-tion of exposed viscera, while alerting the referral center to organize availability of pediatric surgery expertise immediately on arrival.

In settings of premature, preterm, or prolonged rupture of membranes and premature labor, mothers are frequently treated with antibiotics and tocolytic agents. Maternal medications administered during pregnancy for nonobstetric diseases can have a significant impact on the neonate. A common challenge in many centers evolved from the treatment of opiate-addicted mothers with methadone or buprenorphine.20,21 The symptoms of neonatal abstinence syndrome vary as a function of the degree of prenatal opiate exposure and age after delivery. Many infants will appear neurologically normal at delivery, only to exhibit symptoms later, on the first, second, or even third day of postnatal life. Infants with neonatal abstinence syndrome typically demonstrate irritability, poor feeding, loose and fre-quent stools, and, in severe cases, seizures. Treatment options include nonpharmacologic intervention (swaddling, minimal stimulation); methadone, morphine, or buprenorphine; or nonnarcotic drugs such as phenobarbital. Often these infants require hospitalization for many days or weeks until their irri-tability is under sufficient control to allow for care in a home setting. There is clinical evidence that neonates may also exhibit similar symptoms following withdrawal from antenatal nico-tine exposure.22–24 The consequences of other illicit drug use during pregnancy have been widely studied, but are more dif-ficult to assess due to difficulties with diagnosis and confound-ing variables. Maternal cocaine abuse has been associated with obstetric complications such as placental abruption. In the neonate, vascular compromise is suspected to predispose these patients to cerebral infarcts and bowel injury. Developmental delay and behavioral problems are also noted, although associ-ated factors such as poverty, lack of prenatal care, and low socioeconomic status clearly contribute as well.

Alloimmune hemolytic disorders such as Rh hemolytic disease and ABO incompatibility can cause neonatal morbidity ranging from uncomplicated hyperbilirubinemia to severe

Organ System Morbidity

Pulmonary Respiratory distress syndromeBronchopulmonary dysplasiaPulmonary hypoplasiaApnea of prematurity

Cardiovascular Patent ductus arteriosusApnea and bradycardiaHypotension

Gastrointestinal/Liver Necrotizing enterocolitisDysmotility/refluxFeeding difficultiesHypoglycemia

Central nervous system

Intraventricular hemorrhagePeriventricular leukomalaciaCerebral palsyAttention deficit disorders

Visual Retinopathy of prematuritySkin Excess insensible water loss

HypothermiaImmune/Hematologic Increased incidence of sepsis/meningitis

Anemia of prematurity

TABLE

73.2 Common Complications of Prematurity by Organ System



potential to avoid morbidities such as temperature instability, feeding problems, hyperbilirubinemia requiring treatment, sus-pected sepsis, and respiratory distress. Infants born at 35 weeks’ gestation are nine times more likely to require mechanical ven-tilation than those born at term.31

Most complications of late preterm birth are easily treated, but their economic and social impacts are substantial, and long-term sequelae are not well understood. For example, brain growth and development proceeds rapidly during the third tri-mester and continues for the first 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 of the fetal brain, including the periventricular white matter, continue to undergo rapid myelin-ation during this period. Studies demonstrate an association between late preterm birth and long-term neurodevelopmental problems, including learning disabilities and attention deficit disorders.32–36 Additional neurologic and epidemiologic studies will be required to define mechanistic connections between late preterm birth and these long-term outcomes. It is also impor-tant to recognize that infants born late preterm experience excess infant mortality (death before 12 months) compared to their full-term counterparts. The infant mortality rate for 34–36 weeks’ gestation is three times higher than that for infants deliv-ered at 40 weeks.37 Recent efforts to decrease late preterm births through reductions in elective delivery before 39 weeks demon-strate meaningful progress.38

Our growing recognition of the morbidity and mortality risks associated with preterm birth clearly deserves further study. Table 73.3 compares estimates of complication rates between preterm and late preterm infants.

The preterm birth rate increased by 30% between 1983 and 2004, from 9.6% to 12.5%, before declining modestly. Major causes posited for this increase included a substantial rise in mul-tifetal gestation associated with assisted reproductive technology (ART) and an increase in “indicated” preterm births (see Chapter 29).28,29 This last category has major import because decisions affecting the timing and management of preterm birth can have a profound effect on neonatal outcome. The risk of death prior to 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, espe-cially before 32 weeks, if the intrauterine environment is safe to support the fetus. However, in some clinical situations with a high potential for preterm birth, it is difficult to assess the quality of the intrauterine environment. Three common examples are preterm premature rupture of the fetal membranes (Chapter 42), placental abruption (Chapter 46), and preeclampsia (Chapter 48). 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 34, and clinical decision making in obstet-rics is addressed in Chapters 28 and 29.

Obstetric decisions about timing of delivery in the setting of uncertain in utero risk are a contributing factor to the increase in late preterm births (after 32–34 weeks’ gestation). The con-tribution of truly elective preterm birth must also be consid-ered. While perinatal mortality continues to decrease, in part due to a decline in stillbirths,30 interest in understanding mor-bidity associated with late preterm birth has intensified because of the large number of these late preterm infants and the

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Figure 73.1 Estimated mortality risk by birth weight and gestational age. Data are based on singleton infants born in National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1995 and December 31, 1996. Numeric values represent age- and weight-specific mortality rates. (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. 2001;107[1]:E1, with permission of the American Academy of Pediatrics.)



professionals. The difficulty stems in part from the lack of clarity in defining what that limit is. Indeed, it has fallen by approximately 1 week every decade over the past 40 years. Among developed countries, most identify the limit of extra-uterine viability at 22–25 weeks’ gestation.45–50 Making decisions at this early gestational age requires accurate information regarding mortality and morbidity. At 22 weeks (22 0/7days to 22 6/7 days) survival is very rare.49 Rates of survival to hospital discharge range from 15% to 30% for infants born at 23 weeks’ gestation (23 0/7 to 23 6/7 days). Survival increases to between 30% and 55% for infants born at 24 weeks’ gestation.25,41,46,48,51–53 The Vermont–Oxford Network reported weight-based survival for over 4000 infants born between 401 and 500 g (mean ges-tational age, 23.3 ± 2.1 weeks) from 1996 to 2000. Survival to hospital discharge was 17%.54

While mortality rates fell for each 1-week increase in gesta-tional age at delivery, long-term neurodevelopmental outcomes did not improve proportionately. Of infants born at less than 25 weeks’ gestation, 30%–50% will have moderate to severe disability, including blindness, deafness, developmental delays’ and CP.46,48,51 A study from The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network reported mortality and neurodevelopmental outcomes for 4274 infants born between 22 and 24 weeks’ gestation from 2000 to 2011.55 Survival rates with and without neurodevelop-mental impairment increased over the study period, especially at 23 and 24 weeks’ gestation, but intact survival before 23 weeks remained rare and did not improve over time.

Birth weight and gender also affect survival rates. Higher weights within gestational age categories and female gender consistently show a survival advantage and better neurodevel-opmental outcomes.25,55 Survival and long-term outcomes of very preterm infants are improved with delivery at a tertiary care center, rather than neonatal transfer from an outlying facility.56–58 When families desire resuscitation, or dating is uncertain, every attempt should be made to transfer to a tertiary care center for delivery. Maternal transfer to a tertiary care center and administration of corticosteroids (see Chapter 36) are the only antenatal interventions that have been significantly

Figure 73.2 Peak gestational age and risk of intrauterine fetal demise. (A) The transition 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. (Data modified from Davidoff and coworkers42.) (B) The risk of intrauterine fetal demise increases with increasing gestational age, especially beyond 40 weeks. (Data modified from Yudkin and colleagues43 and Smith44). The risk of intrauterine fetal demise likely influences obstetric decision making regarding timing of delivery in pregnancies approaching 40 weeks’ gestation.

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Complication of Prematurity

Incidence in Preterma

Incidence in Late Pretermb

Respiratory distress syndrome

65% surf RX <1500 g80% <27 weeks39

5%

Bronchopulmonary dysplasia

23% <1500 g25,40 Uncommon

Retinopathy of prematurity

≈40% <1500 g41,42

Intraventricular hemorrhage with ventricular dilation or parenchymal involvement

11% <1500 g25 Rare

Necrotizing enterocolitis

5%–7% <1500 g25 Uncommon

Patent ductus arteriosus

30% <1500 g25 Uncommon

Feeding difficulty >90% 10%–15%41

Hypoglycemia NA 10%–15%41

aDefined as less than 32 weeks and/or less than 1500 g.bDefined as 32–38 weeks and/or 1500–2500 g.NA, Not available; surf RX, surfactant treatment.

TABLE

73.3 Estimates of Complication Rates Between Preterm and Late Preterm Infants

Note that extremely preterm infants, typically defined as those born prior to 32 weeks’ gestation and/or weighing less than 1500 g, comprise only 1.5%–2% of all deliveries, while the late preterm population accounts for 8%–9% of all births. Thus even uncommon complications in the later preterm population may represent a significant health care burden. Recent efforts focused on elimination of elective deliveries before 39 weeks have seen genuine, sustainable reductions.38 Additional atten-tion to the causes and prevention of late preterm deliveries is also warranted (Fig. 73.2).

DECISIONS AT THE THRESHOLD OF VIABILITY

Decisions regarding treatment of infants at the “limit of viabil-ity” are often the most difficult for families and health care



indicated. Exceptions to comply with parental requests may be considered in specific cases. Where prognosis is more uncertain, with borderline survival and high morbidity rates (e.g., 23–24 weeks’ gestation), parental views should be supported.

Decisions regarding care of extremely preterm infants are always difficult. Parental involvement, active listening, and accurate information are critical to an optimal outcome for infants and their families. While 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 current medical information. If agreement with the family cannot be reached, it may be appropriate to consult the hospital ethics committee or legal counsel. If the situation is emergent and the responsible physician concludes that the parents’ wishes are not in the best interest of the infant, it can be appropriate to resuscitate over parental objection.63,64

Prenatal and Perinatal MorbiditiesRESPIRATORY PROBLEMS IN THE NEONATAL PERIOD

No aspect of the transition from fetal to neonatal life is more dramatic than the process of pulmonary adaptation. In a normal term infant, lungs expand with air, pulmonary vascular resis-tance rapidly decreases, and vigorous, consistent respiratory effort ensues within a minute of separation from the placenta. The process is dependent on crucial physiologic mechanisms, including production of functional surfactant, dilation of high-resistance pulmonary arterioles, bulk transfer of fluid from air-spaces, and physiologic closure of the ductus arteriosus and foramen ovale. Complications such as prematurity, infection, neuromuscular disorders, developmental defects, or complica-tions of labor may interfere with the transition to normal neo-natal respiratory function. Common respiratory problems of neonates are reviewed in the following sections.

Transient Tachypnea of the NewbornDefinition. Transient tachypnea of the newborn (TTN), com-monly 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. TTN is self-limiting, with no risk of recurrence or residual pulmonary dys-function. It rarely causes hypoxic respiratory failure.65

Pathophysiology. During the last trimester, a series of physi-ologic events leads to changes in the hormonal milieu of the fetus and its mother to facilitate neonatal transition.60 Rapid clearance of fetal lung fluid is essential for successful transition to air breathing. The bulk of this fluid clearance is mediated by transepithelial sodium reabsorption through amiloride-sensitive sodium channels in the respiratory epithelial cells.66 The mechanisms for such an effective “self-resuscitation” soon after birth are not completely understood. Traditional explana-tions based on Starling forces and vaginal squeeze for fluid clearance account only for a fraction of the fluid absorbed.

Risk Factors. This condition is classically seen in infants deliv-ered late preterm or early term, especially after cesarean birth before the onset of spontaneous labor.67,68 Absence of labor is accompanied by an impaired surge of the endogenous steroids and catecholamines necessary for a successful transition.69

and consistently related to improved neonatal neurodevelop-mental outcomes.55 Other attempted strategies are discussed in Chapter 29.

Planning for Delivery at the Limits of ViabilityIdeally, discussion between physicians and parents should begin prior to birth in a nonemergent situation, and include both obstetrics and neonatal care providers. Even during active labor, communication with the family should be initiated as a founda-tion for postnatal discussions. The family should understand that plans made before delivery are influenced by maternal and fetal considerations, and based on limited information. It should be emphasized that information available only after delivery, such as birth weight and neonatal physical findings, may change the infant’s prognosis.46

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 devel-oped by the parents in consultation with maternal-fetal medi-cine 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 prognosis, likely hospital course, potential complications, survival information, and general health and well-being of infants delivered at a 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 nonviability of an extremely premature infant. The presence of an experi-enced pediatrician at delivery is recommended to assess weight, gestational age, and fetal status and to provide medical leader-ship in decisions to be made jointly with families.53,55 In cases of precipitous deliveries wherein communication with families has not occurred, the physician should use his/her best judg-ment on behalf of the infant to initiate resuscitation until fami-lies can be brought into the discussion, erring on the side of resuscitation if the appropriate course is uncertain.59,60

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 recognize parents as having the primary role in determining the goals of care for their infant.1,48,61 Discus-sions with the family should include local and national infor-mation on mortality as well as long-term outcomes. Every effort should be made to utilize up-to-date data. Health care providers tend to be more pessimistic when considering outcomes based solely on experience and subjective reasoning.62 Parental par-ticipation should be encouraged, with open communication regarding their personal values and goals.

Decisions regarding 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 Nuffield Council on Bioethics, in the United Kingdom, has proposed parameters for treating extremely premature infants that parallel guidance from the American Academy of Pediatrics.1,45 Where gestation or birth weight are associated with almost certain early death, and antic-ipated morbidity is unacceptably high, resuscitation is not



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 sever-ity of the oligohydramnios. Similarly, pulmonary hypoplasia is a hallmark of congenital diaphragmatic hernia (CDH), due to extrinsic compression of the developing fetal lung by the herni-ated abdominal contents. The degree of pulmonary hypoplasia in CDH is directly related to the extent of herniation. Large hernias occur earlier in gestation. In most cases, the contra-lateral lung is also hypoplastic.73 Recent studies document some degree of catch-up lung growth following delivery.

Lindner and colleagues74 report significant mortality risk in infants born to women with premature rupture of membranes and oligohydramnios prior to 20 weeks’ gestation. The retro-spective analysis demonstrated 69% short-term mortality risk. However, the remainder of the infants did well and were dis-charged with apparently normal pulmonary function. Predic-tion of clinical outcome is difficult in these infants.74,75 (Prenatal diagnosis and treatment of pulmonary hypoplasia is discussed in Chapters 18 and 24.)

Postnatal treatment for pulmonary hypoplasia is largely sup-portive. A subset of infants with profound hypoplasia will have insufficient 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 will have no clinical evidence of pulmonary insufficiency at birth, but have diminished reserves when stressed. In between is a cohort of patients with respiratory insufficiency responsive to mechanical ventilation and pharmacologic support. Typically, these patients have adequate oxygenation and ventilation, suggesting adequate gas exchange capacity. However, many develop PHT. The patho-physiologic sequence begins with limited cross-sectional area of resistance arterioles, followed by smooth muscle hyperplasia in these same vessels. Early use of pulmonary vasodilators such as nitric oxide is the mainstay of management for increased pulmonary vasoreactivity. Optimizing pulmonary blood flow reduces the potential for hypoxemia thought to stimulate pathologic medial hyperplasia. If oxygenation, ventilation, and acid-base balance are maintained, nutritional support over time can allow sufficient lung growth to support the infant’s meta-bolic demands. In many cases the process is lengthy, requiring mechanical ventilation and treatment with pulmonary vasodi-lators such as sildenafil, bosentan, or prostacyclin for weeks to months. Prognostic indicators for CDH such as percent pre-dicted lung volume and lung area–to–head circumference ratio measurements are useful for guiding management and parental counseling.76 Otherwise, defining risk and predicting outcome for patients with pulmonary hypoplasia managed in the neona-tal intensive care unit is hampered by limited data.

Respiratory Distress SyndromeRDS is a significant cause of early neonatal mortality and long-term morbidity. However, in the last three decades, significant advances have been made in the management of RDS with a consequent decrease in associated morbidity and mortality.

Perinatal Risk Factors. The classic risk factors for RDS are prematurity and low birth weight. Factors that negatively affect surfactant synthesis include maternal diabetes, perinatal asphyxia, cesarean birth without labor, and genetic factors (Caucasian race, history of RDS in siblings, male sex, and

Additional risk factors such as multiple gestations, excessive maternal sedation, prolonged labor, and complications result-ing from excessive maternal fluid administration have been less consistently observed.

Clinical Presentation. The clinical features of TTN include a combination of grunting, tachypnea, nasal flaring, and mild intercostal and subcostal retractions along with mild central cyanosis. The grunting can be prominent and is sometimes misdiagnosed as RDS secondary to surfactant deficiency. The chest radiograph usually shows prominent perihilar streaking that represents engorged pulmonary lymphatics and blood vessels. The presence of fluid in the fissures is a common, non-specific finding. Clinical symptoms rapidly improve in the first 24–48 hours after birth. TTN is a diagnosis of exclusion, and it is important that other potential causes of respiratory dis-tress in the newborn are excluded. The differential diagnosis of TTN includes pneumonia/sepsis, air leaks, surfactant defi-ciency, and congenital heart disease. Other rare diagnoses are pulmonary hypertension (PHT), meconium aspiration, and polycythemia.70

Diagnosis. This is primarily a clinical diagnosis. As noted, chest radiographs typically demonstrate mild pulmonary con-gestion, with hazy lung fields. The pulmonary vasculature may be prominent. Small accumulations of extrapleural fluid may be seen, especially in the minor fissure on the right side.

Management. Management is mainly supportive. Supplemen-tal oxygen is provided to keep the O2 saturations greater than 90%. Infants are usually given intravenous fluids and not fed orally until their tachypnea resolves. Rarely, infants may need continuous positive airway pressure (CPAP) to relieve symp-toms. Diuretic therapy is not effective.71

Neonatal Implications. TTN can lead to morbidity related to delayed initiation of oral feeding, which may, in turn, interfere with parental bonding and establishment of successful breast-feeding. The hospital stay is prolonged for mother and infant. Current perinatal guidelines72 recommending scheduling of elective cesarean births after 39 completed weeks of gestation should reduce the incidence of TTN.

Pulmonary HypoplasiaLung development begins during the first trimester when the ventral foregut endoderm projects into adjacent splanchnic mesoderm (see Chapter 16). Branching morphogenesis, epithe-lial differentiation, and acquisition of a functional interface for gas exchange ensue through the remainder of gestation and are not completed until the second or third year of postnatal life. Clinical conditions associated with pulmonary hypoplasia and approaches to prevention and treatment are discussed here.

Perturbation of lung development at any time during gesta-tion may lead to clinically significant pulmonary hypoplasia. Two general pathophysiologic mechanisms contribute to pul-monary 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 due to very preterm premature rupture of the membranes or diminished fetal urine produc-tion, can lead to pulmonary hypoplasia. The reduction in



screening blood culture and complete blood counts with dif-ferential counts are performed and infants are started on broad-spectrum antibiotics for 48 hours, until culture results are available.

Surfactant Therapy. Surfactant replacement is one of the safest and most effective interventions in neonatology. The first 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.80 By the early 1990s, widespread use of surfactant led to a progressive decrease in RDS-associated mortality. Three strategies for treatment are commonly used: (1) prophylactic surfactant, in which surfac-tant is administered via endotracheal tube before the first breath to all infants at risk of developing RDS; (2) rescue therapy, wherein surfactant is given via endotracheal tube after the onset of respiratory signs; and (3) minimally invasive methods of surfactant administration for infants on noninvasive ventila-tion.81 The advantages of prophylactic administration include a better distribution of surfactant when instilled into a partially fluid-filled lung along with the potential to decrease trauma related to resuscitation. Avoiding treatment of unaffected infants and related cost savings are the advantages of rescue therapy. Less invasive methods of surfactant administration include nebulization, instillation into the pharynx before the first breath, and administration via laryngeal mask or thin cath-eter. The thin catheter method allows the instillation of surfac-tant into a spontaneously breathing infant (better surfactant distribution), without the disruption of nasal CPAP, and poten-tially avoids positive pressure–induced lung injury.

Biologically active surfactant can be prepared from bovine, porcine, human, or synthetic sources. When administered to patients with surfactant deficiency and RDS, all these prepara-tions show improvement in oxygenation and a decreased need for ventilator support, along with decreased air leaks and death.82 The combined use of antenatal corticosteroids and postnatal surfactant improves neonatal outcome more than postnatal surfactant therapy alone.

surfactant protein-B deficiency).77 Congenital malformations that lead to lung hypoplasia, such as diaphragmatic hernia or giant omphalocele, are also associated with significant surfac-tant deficiency.78 (Prenatal assessment of fetal lung maturity and treatment to induce fetal lung maturity are discussed in detail in Chapter 36.)

Clinical Presentation and Diagnosis. Symptoms are typically evident in the delivery room or shortly thereafter, including tachypnea, nasal flaring, subcostal and intercostal retractions, cyanosis, and expiratory grunting. The characteristic expiratory grunt is secondary to expiration through a partially closed glottis, providing continuous distending airway pressure to maintain functional residual capacity (thereby preventing alve-olar collapse). These signs of respiratory difficulty are not spe-cific to RDS and can occur from a variety of pulmonary and nonpulmonary causes such as transient tachypnea, air leaks, congenital malformations, hypothermia, hypoglycemia, anemia, polycythemia, and metabolic acidosis. Progressive worsening of symptoms in the first 2–3 days followed by recovery character-izes the typical clinical course. This time line (curve) is modified by administration of exogenous surfactant with a resultant more rapid recovery. Classic radiographic findings include low-volume lungs with a diffuse reticulogranular pattern and air bronchograms (Fig. 73.3). The diagnosis can be established chemically by measuring surfactant activity in tracheal or gastric aspirates, but this is not routinely done.79

Management PrinciplesGeneral Measures. Infants are managed in an incubator or

under a radiant warmer in a neutral thermal environment to minimize oxygen requirement and consumption. Arterial oxygen tension (arterial partial pressure of oxygen) is main-tained between 50 and 80 mm Hg with saturations between 88% and 96%. Hypercarbia and hyperoxia are avoided. Heart rate, blood pressure, respiratory rate, and peripheral perfusion are monitored closely. Because sepsis cannot be excluded,

A B

Figure 73.3 Appearance of transient tachypnea of the newborn (TTN) and respiratory distress syndrome (RDS) on chest radiography. (A) The radiographic characteristics of TTN include perihilar densities with good aeration, bordering on hyperinflation. (B) In contrast, neonates with RDS have diminished lung volumes on chest radiography reflecting atelectasis associated with surfactant deficiency. Diffuse ground-glass infiltrates along with air bronchograms make the cardiothymic silhouette indistinct.



labeled the “new BPD.”95 This disease now primarily occurs in infants less than 1000 g who have very mild or no initial respira-tory distress. The clinical diagnosis is based on the need for supplemental oxygen at 36 weeks’ corrected gestational age.96 A physiologic definition of BPD based on the need for oxygen at the time of diagnosis is now the basis for diagnosis.96 Recent large prospective studies of extremely preterm infants at high risk for BPD demonstrate the importance of strict diagnostic criteria.40

Clinically, the transition from RDS to BPD is subtle and gradual. Radiographic manifestations of classic BPD include areas of shifting focal atelectasis and hyperinflation with or without parenchymal cyst formation. Chest radiographs of infants with the new BPD show bilateral haziness reflect-ing diffuse microatelectasis without multiple cystic changes. These changes lead to ventilation-perfusion mismatching and increased work of breathing. Preterm infants with BPD either gradually wean off respiratory support and oxygen or continue to worsen with progressively severe respiratory failure, PHT, and a high mortality risk.

Pathophysiology. Risk factors predisposing preterm infants to BPD include extreme prematurity, oxygen toxicity, mechanical ventilation, and inflammation.97 The pathologic findings char-acterized by severe airway injury and fibrosis in the old BPD have been replaced in the new BPD with large simplified alveo-lar structures, impaired capillary configuration, and variable degrees of interstitial cellularity and/or fibroproliferation.98 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 first 2 weeks of life and as chronic therapy has been associated in clinical studies with the severity of BPD.99,100 In animal models, hyperoxia has been shown to mimic many of the pathologic findings of BPD. Two large randomized trials in preterm infants have recently sug-gested that the use of supplemental oxygen to maintain higher saturations resulted in worsening pulmonary outcomes.101 Con-cerns regarding oxygen toxicity are reflected in the most recent update of the neonatal resuscitation guidelines. Blended oxygen or, if not available, room air is now recommended for initial resuscitation of preterm infants in the delivery room, along with continuous monitoring via pulse oximetry.102

Barotrauma and volutrauma associated with mechanical ventilation have been identified as major factors causing lung injury in preterm infants.103,104 Surfactant replacement therapy is beneficial in decreasing symptoms of RDS and improving survival. The efficacy of surfactant to decrease the incidence of subsequent BPD is less well established. Chronic inflammation and edema associated with positive-pressure ventilation cause surfactant protein inactivation.

Because intrauterine inflammation is increasingly recog-nized as a cause of preterm parturition, antenatal inflammation is gaining more attention in the pathogenesis of BPD and other morbidities of prematurity.105 Chorioamnionitis has been shown to be strongly associated with impaired pulmonary and vascular growth, a typical finding in the new BPD. Most deliver-ies before 30 weeks’ gestation are associated with histologic chorioamnionitis, which except for preterm initiation of labor is often otherwise clinically silent. The more preterm the deliv-ery, the more often histologic chorioamnionitis is detected. Increased levels of proinflammatory mediators in amniotic

Continuous Positive Airway Pressure. In infants with acute RDS, CPAP appears to prevent atelectasis, minimize lung injury, and preserve 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 pulmo-nary morbidity.83,84 Increasing use of CPAP has led to decreased use of surfactant and decreased BPD.85 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 transi-tion to CPAP is an additional RDS treatment strategy increas-ingly used in Europe and Australia.86

Recently, the advantages of CPAP have been combined with less invasive surfactant administration, which has led to reduced need for mechanical ventilation and BPD.87 Prospective, ran-domized trials in extremely-low-birth-weight (ELBW) infants comparing early delivery-room CPAP to early prophylactic sur-factant therapy demonstrate equivalency as defined by death or BPD.88 Three meta-analyses of these trials support the superior-ity of delivery-room CPAP in reducing BPD. These findings led to the recommendation by the European Association of Perina-tal Medicine and the American Academy of Pediatrics to endorse delivery-room CPAP as the primary mode of respiratory support for treating RDS.89

Mechanical Ventilation. The goal of mechanical ventilation is to limit volutrauma and barotrauma without causing pro-gressive atelectasis while maintaining adequate oxygenation and gas exchange. Complications associated with mechanical venti-lation include pulmonary air leaks, endotracheal tube displace-ment or dislodgement, obstruction, infection, and long-term complications such as BPD and subglottic stenosis.

Other Treatments. Studies of early inhaled nitric oxide and supplementary myo-inositol for prevention of long-term pul-monary morbidity failed to demonstrate significant effective-ness.90,91 Noninvasive respiratory support techniques such as synchronized nasal intermittent positive-pressure ventilation and high-flow nasal cannula are currently under study to decrease ventilator-associated lung injury.92,93

Complications of Respiratory Distress Syndrome. Acute complications include pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema. The incidence of these complications has decreased signifi-cantly with surfactant treatment. Infection, intracranial hemor-rhage, and patent ductus arteriosus occur more frequently in very-low-birth-weight infants with RDS. Long-term complica-tions and comorbidities include BPD, poor neurodevelopmen-tal outcomes, and retinopathy of prematurity. Incidence of these complications is inversely related to decreasing birth weight and gestation.

Bronchopulmonary DysplasiaThe classic form of BPD was first described94 in a group of preterm infants who were mechanically ventilated at birth and who later developed chronic respiratory failure with character-istic chest radiographic findings. These infants were larger, late preterm infants with lung changes attributed to mechanical ventilation and oxygen toxicity. More recently, smaller, extremely preterm infants with lung immaturity and prenatal exposure to antenatal glucocorticoids have developed a more subtle form,



tract illness in the first year of life.114 Among preterm infants born at less than 29 weeks’ gestation, a large, multicenter study identified important perinatal risk factors, including male gender, IUGR, maternal smoking, race/ethnicity, intubation at delivery, and public insurance, as predictors of respiratory outcome at 1 year of age.115

Moreover, BPD is an independent predictor of adverse neu-rologic outcomes. Infants with BPD exhibit lower average IQs, academic difficulties, delayed speech and language develop-ment, impaired visual-motor integration, and behavior prob-lems.49 Sparse data also suggest an increased risk for attention deficit disorders and memory and learning deficits. Delayed growth occurs in 30%–60% of infants with BPD at 2 years of age. The degree of long-term growth delay is inversely proportional to birth weight and directly proportional to the severity of BPD.

Prevention Strategies. Several strategies to decrease the inci-dence of BPD have been tried, including administration of surfactant in the delivery room, less invasive modes of surfac-tant administration,116 administering surfactant mixed with budesonide,117,118 early caffeine therapy, antioxidant superoxide dismutase, long-chain polyunsaturated fatty acid,119 vitamin A supplementation, optimizing fluid and parenteral nutrition, aggressive treatment of patent ductus arteriosus, minimizing mechanical ventilation, limiting exposure to high levels of oxygen, and infection prevention. Table 73.4 enumerates current strategies and their relative effectiveness to prevent BPD.120 Large, controlled clinical trials and meta-analyses have not demonstrated a significant impact of these pharmacologic and nutritional interventions.121 The multifactorial nature of BPD suggests that targeting individual pathways is unlikely to have a significant effect on outcome. Strategies to address several path-ways simultaneously are more promising.

Meconium-Stained Amniotic Fluid and Meconium Aspiration SyndromeThe significance and management of meconium-stained amni-otic fluid 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. Thus intrauterine passage of meconium is unusual before 36 weeks, and neonatal passage of meconium does not typically occur for several days following preterm

fluid, placental tissues, tracheal aspirates, lung, and serum of ELBW preterm infants support an important role for both intrauterine and extrauterine inflammation in the development and severity of BPD. The proposed interaction between the proinflammatory and antiinflammatory influences on the developing fetal and preterm lung is detailed in Fig. 73.4. Several animal models and preterm studies demonstrate that mediators of inflammation, including endotoxins, tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-8, and transforming growth factor-α, can enhance lung maturation but concurrently impede alveolar septation and vasculogenesis, contributing to the development of BPD.106–108 Chorioamnionitis alone is associated with BPD, but the probability is increased when these babies receive a second insult such as mechanical ventilation or postnatal infection.109–111

Maternal genital mycoplasma infection, particularly with Mycoplasma hominus and Ureaplasma urealyticum, is associated with preterm birth.112 Numerous studies have isolated these organisms from amniotic fluid and placentas in women with spontaneous preterm birth due to preterm labor or preterm rupture of membranes. Following birth, these organisms are known to colonize and elicit a proinflammatory 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 its occurrence and severity. Expression of genes critical to surfactant synthesis, vascular development, and inflammatory regulation is likely to play a role in the patho-genesis of BPD. Twin studies have recently shown that the BPD status of one twin, even after correcting for contributing factors, is a highly significant predictor of BPD in the second twin. In this cohort, after controlling for covariates, genetic factors accounted for 53% of the variance in the liability for BPD.113 Genetic polymorphisms in the inflammatory response are increasingly recognized as important in the pathogenesis of preterm parturition (see Chapter 7), and may be similarly important in the genesis of inflammatory morbidities in the preterm neonate.

Long-Term Complications. Infants with BPD have significant pulmonary sequelae during childhood and adolescence. Reac-tive airways disease occurs more frequently, with increased risk of bronchiolitis and pneumonia. Up to 50% of infants with BPD require readmission to a hospital for lower respiratory

Chorioamnionitis

Antenatal corticosteroids Indomethacin

Antiinflammatory

Proinflammatory

Postnatal corticosteroids

Preterm fetallung

Transitionallung

Pretermpostnatal lung

Altered lungdevelopment

and BPD

Resuscitation Mechanicalventilation

Oxygen Sepsispneumonia

Figure 73.4 Role of inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD).



suctioning prior to delivery of the fetal shoulders in infants born through meconium-stained amniotic fluid also found no reduction in meconium aspiration syndrome.129 Amnioinfusion during labor to dilute the concentration of meconium has also been studied to prevent meconium aspiration, but a recent ran-domized trial found no reduction in the incidence or severity of meconium aspiration.130 These well-designed clinical trials reinforce the notion that meconium-stained amniotic fluid may not have a true mechanistic, pathophysiologic connection with meconium aspiration syndrome.

In 2001, Ghidini and Spong131 questioned the connection between meconium-stained amniotic fluid and meconium aspiration syndrome. Reports describe infants born through clear amniotic fluid with respiratory distress, PHT, and other clinical characteristics of meconium aspiration syndrome.132 Experimental data suggest that factors promoting fetal acidosis and hypoxemia promote remodeling of resistance pulmonary arteries. These same factors can promote intrauterine meco-nium passage. However, the remodeling, perhaps exacerbated by inflammation from infection or by meconium, produces a clinical syndrome currently called meconium aspiration syn-drome.133,134 It is interesting to note that the incidence of meco-nium aspiration syndrome has clearly decreased in several centers over the past several years, perhaps a consequence of improvements in obstetric assessment and management,135,136 including a reduction in the incidence of postterm deliveries. My center has experienced a decline in meconium aspiration syndrome while concurrently pursuing a policy of no routine tracheal suctioning for infants born through meconium-stained amniotic fluid.

Treatment of severe meconium aspiration syndrome has dramatically improved in recent years, leading to decreases in morbidity and mortality. Significant advances have come from treatment of PHT with selective pulmonary vasodilators, including inhaled nitric oxide, sildenafil, and bosentan. These agents not only improve oxygenation but also allow less injuri-ous ventilator strategies with reduced subsequent morbidity from air leak and chronic lung disease. Exogenous surfactant administration is another useful treatment modality. Although the mechanism is unclear, this intervention reduces ventilation-perfusion mismatch and probably reduces the risk of ventilator-associated lung injury.137

The current state of knowledge regarding meconium-stained amniotic fluid and meconium aspiration syndrome presents challenges for obstetricians and neonatologists. While the inci-dence of meconium aspiration syndrome has decreased, the reasons for the decline are not readily apparent. Previously the Neonatal Resuscitation Program1 protocol for delivery room management recommended tracheal suctioning only for depressed infants, implying that airway management to support ventilation should take precedence over tracheal suctioning. More recently, studies have challenged its role even in nonvigor-ous infants. As a result, the new Neonatal Resuscitation Program guidelines no longer recommend routine endotracheal suction-ing even in nonvigorous infants at birth. Meconium or other material obstructing the airway should be cleared, but suction-ing an unobstructed airway at the expense of delaying initiation of effective ventilation may be deleterious. As always, a collab-orative 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.

birth. The potential for intrauterine meconium passage increases with each week of gestation after 36 weeks.122 The physiologic stimuli for in utero passage of meconium are still incompletely understood. Clinical experience and epidemiologic data suggest that a stressed fetus may pass meconium prior to birth. Infants born through meconium-stained amniotic fluid have lower pH and are likely to have nonreassuring fetal heart tracings.123 Meconium-stained amniotic fluid at delivery occurs in 12%–15% of all deliveries, and occurs more frequently in post-term gestation and in African Americans.124

In contrast to meconium-stained amniotic fluid, meconium aspiration syndrome is unusual. Meconium aspiration syn-drome is a clinical diagnosis that by definition includes delivery through meconium-stained amniotic fluid along with respira-tory distress and a characteristic chest radiographic appearance. Approximately 2% of deliveries with meconium-stained amni-otic fluid are complicated by meconium aspiration syndrome, but the reported incidence varies widely.125,126 The severity of the syndrome is also variable. The hallmarks of severe disease are the need for positive-pressure ventilation and the presence of PHT. Severe meconium aspiration is associated with signifi-cant mortality and morbidity risk, including air leak, chronic lung disease, and developmental delay.

A relationship between meconium-stained amniotic fluid and meconium aspiration syndrome has been presumed since the 1960s, when the strategy of tracheal suctioning in the deliv-ery room to prevent meconium aspiration was proposed.127 By the 1970s this practice was clinically established and affirmed by retrospective reviews. Oropharyngeal suctioning on the perineum before delivery of the chest to complement tracheal suctioning was also recommended. However, additional studies did not verify the benefit of tracheal suctioning. Tracheal suc-tioning did not affect the incidence of meconium aspiration syndrome in vigorous infants in a large, prospective, random-ized trial.128 Another prospective, randomized, controlled study in 2514 infants to determine the efficacy of oropharyngeal

InterventionRelative Effectivenessa

Evidence/Quality of Data

Antenatal steroids + StrongEarly delivery room surfactant ++ StrongSurfactant mixed with budesonide +++ MinimalLess invasive surfactant

administration++ Moderate

Early caffeine ++ ModeratePostnatal systemic steroid ++ ModerateVitamin A + HighAntioxidants − ModeratePermissive hypercapnia +++ MinimalFluid restriction ++ ModerateHigh-frequency ventilation +/− ModerateDelivery room management ++++ ModerateInhaled nitric oxide + MinimalEarly use of continuous positive

airway pressure+++ Strong

Stem cell–based therapies ++ Minimal

aRelative effectiveness of each intervention to reduce the severity of bronchopulmonary dysplasia. The range of symbols from − through ++++ is based on published literature and clinical experience.

TABLE

73.4 Bronchopulmonary Dysplasia Prevention Strategies



number of infants at risk of NEC has increased. From 1982 to 1992, while overall US neonatal mortality rates declined, the mortality rates for NEC increased.42

A variety of antenatal and postnatal exposures have been suggested as risk factors for the development of NEC.147,148,150 Gestational age and birth weight are consistently related to NEC. Some studies report reduced incidence of NEC in infants treated with antenatal steroids.151–153 Among prenatal factors, indomethacin tocolysis has been most often reported. Initial trials on use of indomethacin as a tocolytic showed no adverse neonatal affects, although sample sizes were small.154,155 Subse-quent case reports and retrospective reviews suggested indo-methacin may be associated with adverse neonatal outcomes, including NEC.156,157 Others found no association158,159 of indomethacin tocolysis with NEC when used as a single agent, but did find increased risk when used as part of double-agent tocolytic therapy. A meta-analysis of randomized controlled trials and observational studies from 1966 through 2004 found no significant association between indomethacin tocolysis and NEC in either study type, although the pooled sample size of the published randomized controlled trials limited statistical power.160 A retrospective cohort study of 63 infants exposed to antenatal indomethacin found an association with early-onset NEC, within the first 14 days of life, after controlling for a variety of covariates (adjusted odds ratio = 7.2; 95% confidence interval [CI], 2.5–20.6).161 A larger multicenter study is needed to corroborate these results, and the risks of indomethacin must be weighed against the benefits of transiently delaying preterm birth.

Postnatal interventions to prevent the development of NEC include alterations in feeding type and use of human milk and probiotics. Decreased incidence of NEC has been demonstrated with ingestion of human milk. A meta-analysis of randomized controlled trials evaluating use of human milk and NEC found a fourfold decrease (relative risk = 0.25; 95% CI. 0.06–0.98) with the use of human milk.161 A large prospective study of preterm neonates born before 32 weeks’ gestation showed small but significant reductions in relative risk for NEC among those fed human milk.162

Mothers of infants at risk, particularly those less than 32 weeks’ gestation, should be encouraged to supply breast milk for their infants. Providing early pre- and postnatal counseling on use of human milk increases the initiation of lactation and neonatal intake of mother’s milk without increasing maternal stress or anxiety.163 Alternations in the gut microbiome are asso-ciated with NEC.164 Although the role of probiotics remains a promising intervention, it is still controversial, with no consen-sus regarding organism or dose,157 and additional data required for the highest-risk group, ELBW infants.

NEC may present slowly or as a sudden, catastrophic event. Abdominal distention occurs early, with bloody stools present in 25% of cases.145 The radiographic hallmark is the presence of pneumatosis intestinalis, and/or portal venous gas (Fig. 73.5). Progression may be rapid, resulting in bowel perforation with evidence of free air on the radiograph. Early management consists of bowel decompression and intravenous antibiot-ics, with respiratory and cardiovascular support as indicated. The single absolute indication for surgical intervention is pneumoperitoneum.

For infants who survive NEC, morbidity is high, including high rates of growth failure, chronic lung disease, and nosoco-mial infections.51,165,166 Duration of inpatient hospital stay and

Pulmonary HypertensionAt delivery, the normal transition from fetal to neonatal pulmo-nary circulation is mediated by a rapid, dramatic decrease in pulmonary vascular resistance. Endothelial cell shape change, relaxation of pulmonary arteriolar smooth muscle, and alveolar gaseous distention all contribute to this process.138 Endogenous nitric oxide is crucial for modulating pulmonary vascular resis-tance. Nitric oxide is synthesized from L-arginine derived from the urea cycle reaction. Recently, polymorphisms in urea cycle enzyme genes were shown to be associated with PHT.139 Several pathologic processes, including congenital malformations, hypoxia, sepsis, and pneumonia, can alter this sequence to produce neonatal PHT. The use of selective serotonin reuptake inhibitors in the second half of pregnancy is associated with a slight increase in the incidence of PHT.140 As noted earlier, PHT typically accompanies pulmonary hypoplasia where diminished surface area for gas exchange and inadequate pulmonary blood flow leads to hypoxia and remodeling of the resistance pulmo-nary 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 PHT.

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 PHT has been revolutionized by pharmacologic interventions that specifically reduce pulmo-nary vascular resistance. Of these, nitric oxide is the best studied, with clear evidence of efficacy for treatment of PHT in the setting of meconium aspiration syndrome.141,142 Clinical experi-ence with other pulmonary vasodilators, including sildenafil, bosentan, milrinone, and prostacyclin, is increasing and has proven useful in certain clinical situations.143

Excessive proliferation of medial smooth muscle or its pres-ence in vessels ordinarily devoid of smooth muscle complicates the treatment of PHT. 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 mechani-cal ventilation. Pulmonary vasodilators become less effective as remodeling progresses, prompting clinicians to pursue “gentle” ventilation strategies.144 By focusing on preductal rather than postductal oxygen saturations, lower ventilator settings can be achieved, reducing the risk of remodeling.

GASTROINTESTINAL PROBLEMS IN THE NEONATAL PERIOD

Necrotizing EnterocolitisNEC is a devastating complication of prematurity and the most common gastrointestinal emergency in the neonatal period. It affects 1%–5% of infants admitted to the neonatal intensive care unit.145 The reported incidence is 4%–13%146 in very-low-birth-weight infants (<1500 g). NEC is characterized by an inflammation of the intestines, which can progress to transmu-ral necrosis and perforation. The onset is typically within the first 2–3 weeks of life, but can occur well beyond the first month. Mortality related to NEC ranges from 10% to 30% and up to 50% among infants requiring surgery.146–149 As more preterm and low-birth-weight infants survive the initial days of life, the



decreased with the advent of prevention programs, including use of Rho(D) immune globulin, antibodies to other blood group antigens may still occur. ABO hemolytic disease, a common cause of severe jaundice in the newborn, rarely if ever causes hemolytic disease in the fetus. Other antibodies associ-ated with hemolytic disease in the fetus and newborn are dis-cussed in detail in Chapter 38. It is important to recall that a fetus that is apparently unaffected in utero may have continued postnatal hemolysis; physicians caring for the newborn must be informed of any maternal sensitization.

Another perinatal factor associated with severe hyperbiliru-binemia is delivery before 38 weeks’ gestation. Infants born at 36–37 weeks have an almost sixfold increase of significant

cost are significantly increased, particularly in NEC requiring surgical intervention.166 Long-term neurologic outcomes are also adversely affected. NEC is an independent risk factor for development of CP and developmental delay.55,165,167 For infants with NEC requiring surgical intervention, depending on the amount of bowel lost, there is risk of short bowel syndrome requiring parenteral nutrition, and ultimately small bowel and/or liver transplant. NEC remains the single most common cause of short bowel syndrome in children.43–45

HyperbilirubinemiaHyperbilirubinemia is common: 60% of term infants and 80% of preterm infants develop jaundice in the first week of life.168 Bilirubin levels are elevated in neonates due to increased production coupled with decreased excretion. Increased pro-duction is related to higher rates of red cell turnover and shorter red cell life span.169 Rates of excretion are lower because of diminished activity of glucuronyl transferase, lim-iting bilirubin conjugation, and increased enterohepatic cir-culation. In most cases jaundice has no clinical significance because bilirubin levels remain low, and it is transient. Less than 3% of patients develop levels greater than 15 mg/dL.168 Risk factors for development of severe jaundice are outlined in Box 73.1.170

Many important risk factors for hyperbilirubinemia originate in the prenatal and perinatal environment. Hyper-bilirubinemia is seen more frequently in the IDM. The patho-genesis of increased bilirubin in the IDM is uncertain but has been attributed to polycythemia as well as increased red cell turnover.171,172

Prenatal maternal blood group immunization may result from blood transfusion or fetal-maternal hemorrhage. While the prevalence of Rho(D) immunization has significantly

A B

Figure 73.5 Diagnosis and pathology of necrotizing enterocolitis. (A). Typical radiographic appearance of necrotizing enterocolitis demonstrat-ing pneumatosis and intramural gas. (B). Intraoperative photo of small bowel containing intramural gas.

BOX 73.1 COMMON CLINICAL RISK FACTORS FOR SEVERE HYPERBILIRUBINEMIA

Jaundice in the first 24 hoursVisible jaundice before dischargePrevious jaundiced siblingExclusive breastfeedingBruising, cephalohematomaEast Asian, Mediterranean, or Native American raceMaternal age >25 yearsMale sexUnrecognized hemolysis (i.e., ABO, Rhesus, anti-c, C, E, Kell,

and other minor blood group antigens)Glucose-6-phosphate dehydrogenase deficiencyInfant of a diabetic mother

Data from Centers for Disease Control and Prevention. Kernicterus in full-term infants—United States, 1994–1998. MMWR Morb Mortal Wkly Rep. 2001;50(23):491–494.



Feeding ProblemsFeeding problems related to complications of prematurity, congenital anomalies, or gastrointestinal disorders contribute significantly to length of stay for hospitalized newborns. In a study of children referred to an interdisciplinary feeding team, 38% were born preterm.182 Premature infants with a history of neonatal chronic lung disease, neurologic injury such as IVH or periventricular leukomalacia (PVL), and those with a history of NEC are at the highest risk of long-term feeding problems. These medically complex infants often have other comorbidities such as tracheomalacia, chronic aspiration, and gastroesophageal reflux (GER) that interfere with normal maturational patterns of feeding. Premature infants with complex medical problems often require prolonged intubation and mechanical ventilation with delayed initiation of enteral feeding, all of which have been associated with subsequent feeding difficulties. Because of these medical interventions and neurologic immaturity, these infants often have difficulty integrating sensory input. These factors combine to increase the risk of developing oral aversion.

Infants with congenital anomalies are also at high risk of developing feeding disorders. Infants with tracheoesophageal fistula with esophageal atresia often have difficulty feeding due to tracheomalacia, recurrent esophageal stricture, and GER, which are known associates of this disorder. Infants with CDH have an extremely high incidence of oral aversion and growth problems in addition to the pulmonary complications. Surviv-ing infants and children with CDH have a 60%–80% incidence of associated GER that can persist into adulthood.183–188 Often, this GER is severe, is refractory to medical therapy, and requires a surgical antireflux procedure. Infants with CDH often have inadequate caloric intake due to fatigue or oral aversion and increased energy requirements leading to poor growth. These infants typically require supplemental tube feedings by naso-gastric, nasojejunal, or gastrostomy feeding tube. Feeding dif-ficulties may last several years and are often accompanied by behavior-based feeding difficulties.

Finally, infants with either congenital or acquired gastro-intestinal abnormalities frequently experience associated feed-ing difficulties. Infants with conditions such as gastroschisis with or without associated intestinal atresias often require pro-longed hospitalization because of a slow tolerance of enteral feedings and a higher risk of NEC following gastroschisis repair.189,190 They often have gastrointestinal dysmotility and severe GER with oral aversion.190 A small percentage of patients have long-term intolerance of enteral feedings and require pro-longed total parenteral nutrition (TPN). Patients requiring long-term TPN may develop liver injury and cholestasis and ultimately may require liver/small bowel transplantation. Infants who develop short bowel syndrome secondary to NEC also have difficulties tolerating enteral feedings depending on the length and function of the remaining bowel. Like patients with gastroschisis, infants with severe short bowel syndrome may require prolonged TPN and may go on to develop liver and/or intestinal failure requiring transplantation.

Premature infants and infants with congenital anomalies or acquired gastrointestinal abnormalities are at high risk for long-term feeding problems. It is important to counsel families regarding this risk, including its impact on hospital length of stay. Also, minimizing iatrogenic oral aversion is crucial. Involv-ing a feeding specialist early in a medically complex infant’s course may lessen the impact.

hyperbilirubinemia173 and require close surveillance and moni-toring, especially if breastfed.174 Feeding difficulties, also common for the near-term infant, increase this risk still further and may result in delayed hospital discharge or readmission for the infant. The presence of bruising or a cephalohematoma, more common after instrumented or difficult deliveries, will also increase risk. Polymorphisms of genes coding for enzymes mediating bilirubin catabolism may also contribute to the development of severe hyperbilirubinemia.175

The primary consequence of severe hyperbilirubinemia is potential neurotoxicity. Kernicterus is a neurologic syndrome resulting from deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei, and neuronal necrosis.176 Clinical features may be acute or chronic, resulting in tone and movement disorders such as chorioathetosis and spastic quadriplegia, mental retardation, and sensorineural hearing loss.177 Several factors influence the neurotoxic effects of bilirubin, making prediction of outcome difficult. Bilirubin more easily enters the brain if it is not bound to albumin, if it is unconjugated, or if there is increased permeability of the blood-brain barrier.177 Conditions that alter albumin levels, such as prematurity, or that alter the blood-brain barrier, such as infection, acidosis, and prematurity, affect bilirubin entry into the brain. As a result, there is no serum level of biliru-bin that predicts outcome. In early studies of infants with Rh hemolytic disease, kernicterus developed in 8% of infants with serum bilirubin levels of 19–24 mg/dL, in 33% of infants with levels of 25–29 mg/dL, and in 73% of infants with levels of 30–40 mg/dL.178

Levels of indirect bilirubin below 25 mg/dL in otherwise healthy term infants without hemolytic disease are unlikely to result in kernicterus 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.179 However, kernicterus has been reported in otherwise healthy breastfed term newborns at levels above 30 mg/dL.180 One of the most important of these risk factors is prematurity. The less mature the infant, the greater the susceptibility of the neonatal brain.178 Levels of bilirubin contributing to subtler neurologic abnormalities remain unclear.174

Management of hyperbilirubinemia is aimed at the pre-vention of bilirubin encephalopathy while minimizing inter-ference with breastfeeding and unnecessary parental anxiety. Key elements in prevention include systematic evaluation of newborns prior to discharge for the presence of jaundice and its risk factors, promotion and support of successful breast-feeding, interpretation of jaundice levels based on the hour of life, parental education, and appropriate neonatal follow-up based on time of discharge.174 Treatment of severe hyper-bilirubinemia should be initiated promptly when identified. Guidelines for treatment with phototherapy and exchange transfusion vary with gestational age, the presence or absence of risk factors, and the hour of life. Nomograms to guide patient management are available from the American Academy of Pediatrics.174 Kernicterus is largely preventable. Close col-laboration between prenatal and postnatal caregivers ensures accurate dissemination of information regarding risk factors for parents and clinical providers to facilitate prompt recog-nition and treatment of significant hyperbilirubinemia. In general, predicting nonhemolytic neonatal hyperbilirubine-mia can be based on readily available maternal and obstetric risk factors.181



Apgar score with other markers such as fetal acidemia and the need for CPR in the delivery room predicts a significantly increased risk of brain injury.205,206 Perlman and Risser docu-mented a 340-fold increased risk of seizures and associated moderate to severe encephalopathy in association with a 5-minute Apgar score of 5 or less, delivery room intubation or CPR, and an umbilical cord arterial pH of less than 7.00.206a

Neonatal Encephalopathy. Neonatal encephalopathy is clini-cally characterized by depressed level of consciousness, abnor-mal muscle tone and reflexes, abnormal respiratory pattern, and seizures.207 These findings may result from a hypoxic-ischemic event but can also be due to a variety of other conditions such as metabolic disorders, neuromuscular disorders, toxin expo-sure, and chromosomal abnormalities or syndromes. Not all infants with neonatal encephalopathy develop permanent neurologic impairment. The Sarnat staging system is used to classify the degree of encephalopathy and predict neurologic outcome.202 Infants with mild encephalopathy (Sarnat stage 1) generally have a favorable outcome. Infants with moderate encephalopathy (Sarnat stage 2) develop long-term neurologic compromise in 20%–25% of cases, and infants with severe encephalopathy (Sarnat stage 3) have a greater than 80% risk of death or long-term neurologic sequelae.207

Multiorgan Injury. In addition to neurologic compromise, interruption of placental blood flow can also result in systemic organ injury. Animal models and clinical studies have demon-strated that the kidney is exquisitely sensitive to reductions in renal blood flow.208,209 The result of decreased renal perfusion is acute tubular necrosis with varying degrees of oliguria and azotemia. Fluid retention and hyponatremia can develop due to the combination of impaired renal function and the release of antidiuretic hormone. Other organ systems are also sensitive to reduced blood flow. Decreased blood flow to the gastrointestinal tract can lead to luminal ischemia and an increased risk of NEC. Decreased pulmonary blood flow can result in persistent PHT of the newborn. Lack of blood flow to the liver can result in hepatocellular injury and impaired synthetic function, leading to hypoglycemia and disseminated intravascular coagulation. Suppression of parathyroid hormone release can lead to hypo-calcemia and hypomagnesemia. These electrolyte abnormalities can further affect myocardial function. Muscle can be affected by electrolyte abnormalities and direct cellular injury, leading to rhabdomyolysis.199

Neuropathology. The reduction in cerebral blood flow associ-ated with a hypoxic-ischemic event sets off a complex cascade of regional circulatory factors and biochemical changes at the cellular level. Hypoxia induces a switch from normal oxidative phosphorylation to anaerobic metabolism, leading to depletion of high-energy phosphate reserves, accumulation of lactic acid, and inability to maintain cellular functions.199,210 The end result is cellular energy failure, metabolic acidosis, release of gluta-mate and intracellular calcium, lipid peroxidation, buildup of nitric oxide, and eventual cell death.198,207,211 It is this process of cellular injury that is being targeted for neuroprotection strategies (see later).

Neuroimaging. Diffusion-weighted magnetic resonance imag-ing (MRI) has become the gold standard to define the extent and potentially the timing of the brain injury. Diffusion-weighted

NEONATAL MANAGEMENT OF NEUROLOGIC PROBLEMS

Hypoxic-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 deficits in children.191 However, reviews of multiple studies show that only 10% of brain injury is related to perinatal or intrapartum events.192–194 There is increasing recognition that events occurring well before labor contribute more significantly to the etiology of brain injury. Despite improvements in perinatal practice over recent years, the incidence of hypoxic-ischemic encephalopathy has remained stable at 1–2 babies per 1000 term births.195,196 Strategies for prevention of brain injury have been mainly supportive since prevention has been difficult due to the lack of clinically reli-able indicators and the fact that often the initiating event occurs prior to the onset of labor. However, since the brain injury that develops is initiated by the hypoxic-ischemic event but also affected by a “reperfusion phase” of injury, treatment strate-gies such as head or total-body cooling target this process of ongoing injury.197,198

Definition of “Asphyxia.” The brain injury referred to as hypoxic-ischemic encephalopathy occurs due to impaired cere-bral blood flow likely as a consequence of interrupted placental blood flow leading to impaired gas exchange.199 If gas exchange is persistently impaired, then hypoxemia and hypercapnia develop with resultant fetal acidosis or what has been referred to as “asphyxia.” Severe fetal acidemia, defined as an umbilical arterial pH of less than 7.00, is associated with an increased risk of adverse neurologic outcome.200,201 However, even with this degree of acidemia, only a small portion of infants develop significant encephalopathy and subsequent sustained neuro-logic injury.202 Therefore fetal scalp blood sampling and umbili-cal cord gas data do not have great sensitivity in the prediction of long-term neurologic impairment.

Clinical Markers. Other clinical measures to identify fetal stress, such as fetal heart rate abnormalities, meconium-stained amniotic fluid, low Apgar scores, and need for cardiopulmonary resuscitation (CPR) in the delivery room, do not reliably iden-tify infants at high risk of brain injury when used in isolation. Despite the widespread use of electronic fetal heart rate moni-toring, which detects changes in fetal heart rate related to fetal oxygenation, there has been no reduction in the incidence of CP.200 In 2005, an American College of Obstetricians and Gyne-cologists (ACOG) Practice Bulletin, “Intrapartum Fetal Heart Rate Monitoring,”201 concluded that electronic fetal heart rate monitoring has a high false-positive rate for the prediction of adverse outcomes and is associated with an increase in operative deliveries without any reduction in CP. Meconium-stained amniotic fluid is commonly seen during labor but no data exist to associate it with adverse neurologic outcome. Apgar scores were originally introduced to identify infants in need of resus-citation and not to predict neurologic outcome. Apgar scores are not specific to an infant’s acid-base status but can also reflect drug use, metabolic disorder, trauma, hypovolemia, infection, neuromuscular disorder, or congenital anomalies. However, a persistently low Apgar score after 5 minutes despite intensive CPR has been associated with increased morbidity and mortal-ity.178,199,203,204 Furthermore, the combination of a low 5-minute



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

Grade 1: Bleeding localized to the germinal matrixGrade 2: Bleeding into the ventricle but the clot does not

distend the ventricleGrade 3: Bleeding into the ventricle with ventricular

dilationGrade 4: Intraparenchymal extension

The diagnosis is made most commonly by cranial ultrasound, with most hemorrhages occurring within 6 hours of birth and 90% within the first 5 days of age.224

Incidence. The incidence of IVH has decreased significantly with improvements in perinatal care such as maternal transfer to a tertiary care center and administration of antenatal ster-oids. From 1990 to 1999 the incidence of IVH reported in infants less than 1000 g birth weight was 43%, with 13% being grade 3 or 4. In 2000–2002, the overall incidence of IVH decreased to 22%; only 3% were severe despite improvements in survival.225 Lower gestational age is associated with an increased risk of severe IVH.203,218

Pathogenesis. Both anatomic and physiologic factors have been implicated in the pathogenesis of IVH. The germinal matrix is composed of thin-walled blood vessels that lack sup-portive tissue. These fragile vessels tend to rupture spontane-ously or in response to stress such as hypoxia-ischemia, changes in blood pressure and/or cerebral perfusion, and pneumotho-races. In addition to these structural factors, premature infants have an immature cerebrovascular autoregulation system or a so-called pressure-passive circulation in response to systemic hypotension, which makes them more susceptible to hemor-rhage.209,224,226 Immaturities in the coagulation system and increased fibrinolytic activity of premature infants may also play a role.226–229

Outcomes. Although it has been generally thought that infants with grade 1 or 2 IVH have similar outcomes to those without cranial ultrasound abnormalities, a recent study by Patra and associates suggests that ELBW infants with grade 1 or 2 IVH have worse neurodevelopmental outcomes at 20 months’ cor-rected age compared to those with normal cranial ultrasounds.230 Infants with grade 3 IVH have adverse neurologic outcome in about 35% of cases. In those who develop posthemorrhagic hydrocephalus requiring surgical intervention, the disability rate increases to about 60%.204 Grade 4 IVH is associated with the highest mortality rates, and 80%–90% are associated with a poor neurologic outcome.178

Antenatal Prevention. The only therapies shown to decrease the incidence of IVH in premature infants are antenatal corti-costeroid administration and maternal transfer to a tertiary care center for delivery. Multiple studies have shown that the admin-istration of corticosteroids prior to preterm birth to induce lung maturity has significantly reduced the incidence of RDS, mor-tality, and severe IVH. According to a meta-analysis of four trials of 596 infants from 24 to 33 weeks’ gestation, antenatal

techniques can detect signal changes due to reduced brain water diffusivity within the first 24–48 hours of the insult.198,212–214 Magnetic resonance spectroscopy can also detect alterations in metabolites such as lactate, N-acetylaspartate, choline, and creatinine in specific regions of the brain indicating injury.212,215 However, MRI is difficult to perform in an unstable patient, and therefore computed tomography (CT) may be prefer-able as the initial study for term infants, and ultrasound for preterm infants.

Neuroprotection Strategies. Brain cooling by selective cooling of the head or systemic hypothermia has been studied as a therapy to reduce neurologic injury due to neonatal hypoxic-ischemic encephalopathy. Five large randomized controlled trials (see Pfister and Soll216 and references therein) collectively demonstrate significant reduction in a combined outcome of death or long-term major neurodevelopmental disability at 18 months’ follow-up. Additional work is required to define popu-lations most likely to benefit from treatment, as well as duration of the therapeutic window, optimal target temperatures, and safety for preterm infants. Since these studies, multiple other randomized clinical trials have shown that hypothermia either by selective head cooling or whole body cooling is associated with a reduction in death and severe neurodevelopmental dis-ability at 18 months of age in term infants with moderate to severe hypoxic-ischemic encephalopathy (see Tagin and cowork-ers217 and references therein). Therefore therapeutic hypother-mia is now standard of care for infants of 36 weeks’ gestation or greater with moderate to severe hypoxic-ischemic encepha-lopathy and should be initiated as soon as possible following birth. Head and total body cooling appear equally efficacious with similar safety profiles.218

Future efforts are being focused on early identification of those infants at the greatest risk for hypoxic-ischemic injury and defining the therapeutic window for effective treatment. This window was initially thought to be limited to within 6 hours of delivery; however, ongoing studies are evaluating the benefit of late hypothermia (>6 hours after birth). Variation in practice among neonatologists emphasizes the need for ongoing investigation.219

Infants at highest risk are those with evidence of a sentinel event during labor, pronounced respiratory and neuromuscular depression at delivery with persistently low Apgar scores, the need for delivery room resuscitation, severe fetal acidemia (defined as an umbilical artery pH <7.00 and/or base deficit ≥16 mEq/L), and evidence of an early abnormal neurologic examination, seizures, and/or an abnormal amplitude-integrated electroencephalogram.198,206,220–222 Possible pharma-cologic adjunctive therapies in addition to hypothermia are also being investigated.222,223

Summary. Hypoxic-ischemic brain injury due to intrapartum asphyxia is a rare but serious cause of long-term neurodevelop-mental disability. It is often difficult to define a specific intra-partum event since the initiating event may occur before the onset of labor. Early identification of at-risk newborns by neu-roimaging techniques, amplitude-integrated electroencepha-lography findings, 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 neurodevelopmen-tal disabilities, including CP.



have cardiopulmonary instability are at the highest risk. Other intrauterine factors such as infection, prolonged preterm pre-mature rupture of the membranes, first-trimester hemorrhage, placental abruption, and prolonged tocolysis have all been asso-ciated with increased risk of PVL. The reported incidence of PVL detected by ultrasound examination in very-low-birth-weight infants is 5%–15%.246 However, ultrasound often fails to identify subtle evidence of diffuse white matter injury, and MRI may be a more sensitive imaging study.247 The diagno-sis of PVL at autopsy in preterm infants with normal cranial imaging suggests that that the true incidence of PVL may be underestimated.

Neuropathology. Focal necrosis most commonly occurs in the cerebral white matter at the level of the trigone of the lateral ventricles and around the foramen of Monro.246 These sites make up the border zones of the long penetrating arteries. Classically, these lesions undergo a coagulative necrosis that results in cyst formation or focal glial scars.209 A more diffuse type of injury may also occur in conjunction with focal necro-sis but is more frequently recognized as an independent entity. Diffuse white matter injury seems to affect premyelinating oli-godendrocytes and leads to global loss of these cells and an increase in hypertrophic astrocytes in response to the diffuse injury.209,246,248,249 This loss of oligodendrocytes leads to white matter volume loss and ventriculomegaly.

Pathogenesis. The pathogenesis of PVL is primarily by hypoxia-ischemia leading to neuronal injury due to free radical exposure, cytokine toxicity, and exposure to excessive excitatory neurotransmitters such as glutamate.209 Vascular anatomic factors seem to play a role as well. As mentioned previously, PVL tends to occur in arterial end zones or so-called border zones250 (see Fig. 7 in Volpe246). The arterial supply is composed of long penetrating arteries that terminate deep in the periven-tricular 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 periven-tricular border zones since in premature infants these vessels are immature. Diffuse white matter injury may also occur due to vascular immaturity. At early gestations (24–28 weeks), there are few anastomoses between the long and short penetrators. Thus arterial border zones may occur in the subcortical and remote periventricular areas, resulting in a more diffuse type of injury.246

The preterm brain is also vulnerable to ischemia due to impaired cerebrovascular regulation. Preterm infants exhibit a pressure-passive circulation; a decrease in systemic blood pres-sure is associated with a decrease in cerebral perfusion, leading to ischemia.246,251,252 Also, immature oligodendrocytes seem to be more sensitive to free radical injury, cytokine effects, and the presence of glutamate (see Fig. 9 in Allan and Volpe253).

Clinical Outcomes. The most common long-term sequela of PVL is spastic diplegia, a form of CP wherein the lower extremi-ties are more affected than the upper extremities. The descend-ing fibers of the motor cortex, which regulate function of the lower extremities, traverse the periventricular area and are most likely to be injured. More severe injury with lateral extension may be associated with spastic quadriplegia or other manifesta-tions such as cognitive, visual, or auditory impairments.

corticosteroid therapy was associated with a relative risk reduc-tion for IVH of 0.57 (95% CI, 0.41–0.78).205 Maternal transfer to a tertiary care center for gestational age less than 32 weeks has been shown to decrease the incidence of death or major morbidity, including IVH.57 Antenatal phenobarbital, vitamin K, and magnesium sulfate have failed to demonstrate a consis-tent decrease in overall IVH, severe IVH, or death.231–233

Postnatal Prevention. The goal of postnatal prevention has been blood pressure stabilization to prevent fluctuations in cerebral perfusion, correction of coagulation disturbances, and stabilization of germinal matrix vasculature.224 Postnatal administration of phenobarbital and muscle paralysis has been shown to stabilize blood pressure, but neither has been found to decrease the incidence of IVH or neurologic impairment.234,235 Routine use of paralytics to prevent IVH in ventilated preterm neonates is not recommended. Fresh-frozen plasma and etham-sylate to promote platelet adhesiveness and correct coagula-tion disorders also do not reduce the incidence of IVH.231,236–238 Indomethacin remains the most promising preventive therapy for IVH due to its ability to constrict the cerebral vascula-ture, inhibit prostaglandin and free radical production, and mature the germinal matrix vasculature.236,239,240 Prophylactic indomethacin decreases the incidence of severe IVH. Follow-up studies have shown slight improvement in cognitive func-tion in infants who received prophylactic indomethacin but no difference in the incidence of CP.241–243 Prophylactic indo-methacin remains reserved for preterm infants at high risk of IVH. A recent study has called into question its direct effect on IVH.244

Posthemorrhagic Hydrocephalus. The most serious compli-cation of IVH is posthemorrhagic hydrocephalus due to obstruction of cerebrospinal fluid (CSF) flow. This occurs when multiple blood clots obstruct CSF reabsorption channels, leading to transforming growth factor-1β–stimulated produc-tion of extracellular matrix proteins such as fibronectin and laminin, which ultimately leads to scar formation.245 Progressive ventricular dilation can worsen brain injury due to damage to periventricular white matter secondary to increased intracranial pressure and edema.206 Therapies such as serial lumbar punc-tures, diuretics, and intraventricular fibrinolytic therapy are ineffective and may even be harmful.234 Although surgical shunt placement carries significant risk of shunt complications and infection, it remains the definitive therapy for progressive post-hemorrhagic hydrocephalus.

Summary. IVH due to a fragile germinal matrix and an unsta-ble cerebrovascular autoregulatory system remains a significant cause of neurologic morbidity in preterm infants. Infants with cardiorespiratory complications are at highest risk. Antenatal corticosteroids are the most effective preventive therapy cur-rently available. Despite significant 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 characteristic patterns, described as focal periventricular necro-sis and diffuse cerebral white matter injury. This type of brain injury typically affects premature infants and is a common cause of CP. Preterm infants who have suffered an IVH and/or



encephalomalacia, gliosis, and ventriculomegaly for remote events. Magnetic resonance angiography may be useful in some cases to confirm arterial occlusion, although is not commonly used unless a vascular malformation is suspected. Functional MRI may be valuable in the future to understand how the brain reorganizes following perinatal stroke.255,266,267 Electroencepha-lography may detect subclinical seizures, which may cause sec-ondary brain injury.255

Further diagnostic studies focused on risk factors for peri-natal ischemic stroke should include blood tests for coagulation disturbances and genetic predispositions, urine toxicology for metabolic disorders and toxins such as cocaine, echocardio-gram, infection workup (including lumbar puncture), maternal testing for acquired coagulation disorders such as antiphospho-lipid antibodies, and an assessment of the placenta.211

Outcome. Perinatal ischemic stroke is the most common cause of hemiplegic CP.211 Although not all survivors of perinatal stroke suffer long-term disabilities, 50%–75% of infants who suffered a perinatal stroke will have a neurologic deficit or sei-zures.250,255,268–270 Lee and colleagues 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 retrospec-tively developed CP.250 Because cases identified retrospectively presented because of hemiparesis, they were more likely to be classified as having CP.

Summary. Perinatal ischemic stroke is a major cause of long-term neurologic disability. Treatment is purely supportive and management is via rehabilitation focusing on muscle strength-ening and prevention of contractures. Neuroprotective strate-gies and approaches to prevention are needed. Advanced neuroimaging techniques to better understand how the brain reorganizes following this type of injury are currently being utilized as research tools.

Cerebral PalsyAs early as 1862, William John Little described the relation-ship between children with motor abnormalities and preg-nancy complications such as difficult labor, neonatal asphyxia, and premature birth.212 CP is a clinical diagnosis that refers to a group of nonprogressive motor impairments. In 2005, the International Committee on Cerebral Palsy Classification defined CP as “a group of developmental disorders of move-ment and posture, which cause activity limitations that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of CP are often accompanied by disturbances of sensation, cog-nition, communication, perception, and/or behavior, and/or by a seizure disorder.”213 Despite improvements in perinatal care, the prevalence of CP has remained relatively unchanged over the past 50 years with an incidence of 1.5–3.5 per 1000 live births.207,271–273

Classification. Traditionally, CP has been classified by topog-raphy based on the affected limb involvement (i.e., monoplegia, hemiplegia, diplegia, triplegia, and quadriplegia) and a descrip-tion of the predominant type of tone or movement abnormality (i.e., spastic, dyskinetic, ataxic, hypotonic, or mixed). The Inter-national Committee on Cerebral Palsy Classification has pro-posed a new classification system that additionally considers

Summary. PVL is a major cause of neurologic morbidity in premature infants, especially those less than 1000 g birth weight. Prevention is currently the only strategy to treat PVL. Avoidance of fluctuations in blood pressure and cerebral vasoconstrictors such as extreme hypocarbia are important due to the known immaturity in cerebrovascular autoregulation of preterm infants. Future investigational strategies targeting the cascade of oligodendroglial death may be promising.

Perinatal StrokeArterial ischemic stroke (AIS) in neonates is defined as a cere-brovascular event around the time of birth with resultant clini-cal and/or radiographic evidence of focal cerebral arterial infarction.254 The majority of cases occur in the distribution of the middle cerebral artery.211,255–257 AIS accounts for most peri-natal ischemic strokes. When diagnosis is based on symptoms in the neonatal period, the reported incidence is 1 in 4000 live births.211,258,259 The incidence of perinatal ischemic strokes that were asymptomatic in the neonatal period and diagnosed later is unknown.

Clinical Presentation. Neonatal seizures are the most common clinical presentation and can be focal in origin without other signs of neonatal encephalopathy.211,260 Many infants are sys-temically ill and the diagnosis is made with neuroimaging to rule out evidence of hypoxic-ischemic injury or bleeding. Neo-nates with focal neurologic signs account for about 30% of cases.255,259,261–263 Perinatal stroke may also be identified retro-spectively in initially well-appearing infants who present in later months with signs of hemiparesis, developmental delay, or sei-zures.211,264 In these cases, neuroimaging reveals a remote injury often in the distribution of the middle cerebral artery.

Pathophysiology and Risk Factors. The mechanisms of peri-natal stroke are thought to be multifactorial. Regional ischemia with subsequent hypoxia and infarction clearly plays a role. Also, a relative hypercoagulable state in newborns due to the presence of fetal hemoglobin, polycythemia, and activation of coagulation factors in the fetus and mother around the time of birth seems to increase the risk of a thromboembolic event leading to stroke.211,265 Risk factors for perinatal stroke include maternal and placental disorders, neonatal hypoxic-ischemic injury, hematologic disorders, infection, cardiac disorders, trauma, and drugs.211 However, many mothers have no obvious risk factors at the time of delivery.263

Neuroimaging and Electroencephalographic Assessment. Although cranial ultrasound is the easiest to perform, it is not a sensitive indicator of perinatal stroke.210 Little information exists on prenatal cranial ultrasound. However, prenatal ultra-sounds may demonstrate areas of unilateral echolucencies, which may represent areas later identified as prenatal stroke. CT imaging can usually be performed readily in neonates and usually does not require sedation. CT evidence of perinatal ischemic stroke includes focal hypodensity with or without intraparenchymal hemorrhage, abnormal grey-white matter differentiation, and evidence of volume loss or porencephaly if the injury is remote (Fig. 73.6).211

MRI with diffusion-weighted imaging is the most sensitive method, especially in the setting of early infarction. MRI may be able to demonstrate restricted diffusion within a vascular distribution for acute stroke as well as chronic changes such as



and 0.1% for visual impairment.276 With improvements in sur-vival for ELBW infants (defined as <1000 g birth weight), there are concerns that disability rates will increase as well. Several authors have reported increasing neurodevelopmental disabil-ity rates for ELBW infants born in the 1990s, with rates of CP ranging from 8% to 19%, rates of developmental disability from 19% to 49%, rates of hearing impairment from 1% to 4%, and rates of visual impairment from 1% to 4%.48,167,277–279 When extreme prematurity is considered, Shankaran and coworkers showed that surviving infants born at the threshold of viability (defined as birth weight <750 g, gestational age <24 weeks, and a 1-minute Apgar of ≤3) had neurodisability rates of 60%, with nearly one-third of infants having CP.280 The increase in dis-ability rates have been postulated to be related to heavy use of postnatal steroids to treat neonatal chronic lung disease and high rates of sepsis in this population. Poor neurodevelopmen-tal outcomes have been associated with widespread use of post-natal steroids in the 1990s, so that routine use of this therapy to treat chronic lung disease is now discouraged.47,281–283 The association between sepsis and CP has also been identified in multiple studies and is discussed in a later section.

With recent improvements in the survival of extremely-low-gestational-age neonates, strategies to reduce associated mor-bidity are increasingly important. Decreased rates of CP have been reported in ELBW infants born between 2000 and 2002, a time period associated with increased use of antenatal steroids, decreased use of postnatal steroids, and decreased incidence of

the presence or absence of associated impairments, other anatomic involvement besides limbs, radiologic findings, and causation.213

Etiology. CP is a result of injury to the developing brain that occurs during prenatal, perinatal, or postnatal life. The large majority (75%–80%) of cases of CP have been attributed to events during pregnancy. Ten percent are attributable to intra-partum events such as birth asphyxia,192,274,275 and 10% follow postnatal causes such as head injury or central nervous system infection.214,215 Risk factors of CP include prematurity, multiple gestation, IUGR, intracranial hemorrhage, PVL, infections, pla-cental pathology, genetic syndromes, structural brain abnor-malities, birth asphyxia or trauma, and kernicterus. The origins of CP tend to be multifactorial, but in some cases no cause is identified. Some of the more common risk factors are discussed here in detail; the roles of intracranial hemorrhage, PVL, and birth asphyxia contributing to CP have been discussed in previ-ous sections of this chapter.

Prematurity. Prematurity and low birth weight are the most important identifiable risk factors for CP, with an increased prevalence of CP associated with decreasing gestational age and decreasing birth weight as compared to term infants. For com-parison purposes, it is important to consider the rates of CP and neurosensory impairments in term infants. Msall reported rates of disability in term infants as follows: 0.2% for CP, 2%–3% for cognitive impairment, 0.1%–0.3% for hearing loss,

A B

Figure 73.6 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 obtained 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.



malformations, or constitutional small stature. Furthermore, studies of risk of CP often use birth weight alone to define their population of interest, which could explain the observed increased risk of CP associated with low birth weight. This increased risk of CP could actually be due to effects of IUGR since these cohort studies include both more mature SGA infants and preterm infants with equivalent birth weights.306,307 Therefore the terminology used affects how data may be interpreted.

Many studies have demonstrated that SGA term or preterm infants greater than 33 weeks’ gestation have the highest risk of developing CP.299–301 The Surveillance of Cerebral Palsy in Europe Collaborative Group reported that babies born between 32 and 42 weeks’ gestation and with a birth weight less than the 10th percentile were 4–6 times more likely to develop CP than infants with a birth weight between the 25th and 75th percen-tiles.307 For infants born at less than 33 weeks’ gestation with fetal growth restriction, the association is less clear because this population has the highest risk of adverse neurodevelopmental outcome. Therefore it is difficult to separate the risk due purely to growth restriction versus the effect of prematurity in general. Other factors shown to increase the risk of CP include the sever-ity of the SGA, male gender, and asphyxia.309

Growth-restricted infants may be more susceptible to intrapartum hypoxia, which then leads to adverse neurologic outcome. Data from the Collaborative Perinatal Project showed that infants with IUGR had similar incidences of CP compared to non-IUGR infants when examined at 7 years of age in the absence of intrapartum hypoxia. However, when intrapartum hypoxia was identified, the children with IUGR had an increased incidence of neurodevelopmental disability compared to those without IUGR.236 The relative risk of CP due to intrapartum hypoxia was actually lower in a study of infants who were SGA compared with appropriate-for-gestational-age infants.302 These conflicting results suggest that other factors may be involved.

Perinatal Infections. Maternal, intrauterine, and neonatal infections have all been associated with CP. Congenital viral infections such as TORCH infections—including toxoplasmo-sis, rubella, cytomegalovirus (CMV), herpes simplex virus (HSV), and syphilis—may account for 5%–10% of cases of CP. Maternal infection and inflammation have been associated with an increased incidence of preterm birth, which is also a risk factor for the development of CP. Intraamniotic infection, also referred to as clinical chorioamnionitis, has been associated with premature rupture of the fetal membranes and subsequent preterm birth.310,311 Chorioamnionitis has also been associated with an increased risk of developing CP via several likely mech-anisms. An increased risk of IVH and PVL has been associated with maternal chorioamnionitis and premature rupture of membranes in numerous studies.312–316 Histologic chorioamni-onitis without clinical signs of intraamniotic infection has also been linked to increased risk of IVH, PVL, and CP.317–321

In recent years, laboratory and clinical evidence has emerged that supports the hypothesis that intrauterine infection and inflammation lead to the production of proinflammatory cyto-kines, which are responsible for white matter brain injury and ultimately CP. These cytokines are potentially toxic to develop-ing oligodendrocytes in fetal white matter and cause reduced myelination and subsequent white matter injury.313,322,323 In addition, various cytokines could have a direct toxic effect on cerebral white matter by increasing the production of nitric oxide synthase, cyclooxygenase, other associated free radicals,

nosocomial sepsis.225 Chronic lung disease is an independent 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,284,285 but this has not been consistently observed in ELBW infants.90,286,287

Multiple Births. The risk of developing CP is significantly higher in multiple gestations compared to singleton births. Data from CP registries show that the risk for developing CP in twins is 4–5 times greater than in singletons; for triplets the risk is 12–13 times greater.207,220,288,289 Although twins comprise only 1.6% of the population, they have a 5%–10% incidence of CP.290,291 The higher rate of CP in multiple births may relate to preterm birth, along with complications associated with multiple gestation such as placental and cord abnormalities, intraplacental shunting, structural anomalies, and difficulties at delivery.

The incidence of CP increases as birth weight decreases. Infants with birth weights less than 1500 g comprise 0.9% of singletons, 9.4% of twins, 32.2% of triplets, and 73.3% of qua-druplets.220 Population-based registries have also broken down the risks of CP per 1000 neonatal survivors related to birth weight groups as follows: 66.5 for infants less than 1000 g, 57.4 for infants 1000–1499 g, and 8.9 for infants 1500–2499 g.292 However, twins with birth weight greater than 2500 g have a three- to fourfold increased risk of developing CP compared to singletons.220 It is unclear why this risk increases near term, but it is thought to be due to an increased risk of asphyxia and/or fetal growth restriction that occurs more commonly in multiples.

The risk of CP is also increased with the fetal death of a co-twin and is higher in same-gender versus discordant-gender twins.293–296 Furthermore, when both twins are born alive and one twin dies in infancy, the risk is even greater than if one twin died in utero, again with same-gender twins having a greater risk than discordant-gender twins.220 These data suggest that monochorionicity plays a significant role in the pathogenesis of CP, likely due to the placental vascular anastomoses.

Finally, ART remains associated with an elevated risk for multiple gestations. The increased risk of CP associated with ART is largely due to the higher percentage of preterm births in such pregnancies. However, a Danish study suggested that in vitro fertilization pregnancies may carry an increased risk of CP not attributable to birth weight or gestation.221 Therefore this increased risk of CP associated with ART requires further study (see also Chapter 41).

Growth Restriction. There is much debate in the litera-ture as to whether infants with fetal growth restriction have an increased incidence of CP. Many authors have reported an increased risk of CP in infants who are considered “small for gestational age” (SGA).297–302 However, fetal growth restriction is a distinct clinical entity. Fetal growth restriction refers to failure of a fetus to grow at a predicted rate using fetal growth standards as opposed to neonatal growth standards. These fetal growth standards are derived using ultrasound measurements of healthy fetuses in utero at each gestational age and can take into account variables such as fetal sex, ethnicity, parity, and maternal height and weight.303–305 SGA refers to infants who are statistically smaller than average at a given gestational age but does not consider potential etiologies of SGA such as chro-mosomal anomalies, congenital infections, structural brain



birth since these factors seem to be the most significant con-tributors to the development of CP. Strategies commonly used to reduce intrapartum hypoxia, such as fetal heart monitor-ing, maternal oxygen administration, repositioning, and strict guidelines for oxytocin use, have not affected the rate of CP.337 Fetal heart rate monitoring could even increase the prevalence of CP by increasing the risk of chorioamnionitis.338,339 Fetal heart rate monitoring increases the rate of operative interven-tions without any reduction in the rate of CP.201 Reduction of perinatal intracranial injuries associated with the decreased use of forceps and vacuum extraction in the last 20 years is a positive trend that may contribute to a reduction in the incidence of CP.207,340

Preterm birth accounts for approximately 35% of CP cases.341 Therefore it is logical that strategies to reduce the incidence of preterm birth will reduce the incidence of CP, provided these interventions do not increase the risk of an in utero insult. Prevention of preterm birth has proved elusive, making strate-gies to reduce morbidity more immediately promising. However, recent literature has shown that the following strategies are helpful to reduce the rate of preterm birth: limiting the number of embryos transferred with in vitro fertilization, programs supporting smoking cessation, screening for and treatment of asymptomatic bacteriuria during pregnancy, the use of anti-platelet drugs to prevent preeclampsia, the use of prophylactic progesterone in women with prior preterm births or shortened cervices at midgestation, and the use of cervical cerclage for women with a previous preterm birth and short cervix.45,342,343 Antenatal steroids decrease the incidence of several morbidities strongly associated with CP, including IVH, PVL,205,344 RDS, and chronic lung disease. Postnatal steroids to treat neonatal chronic lung disease, however, are associated with a significant increase risk of CP.281,345–347

Another strategy to reduce CP in preterm infants is the administration of magnesium sulfate prior to delivery. The proposed mechanism of benefit is the ability of magnesium sulfate to stabilize vascular tone, reduce reperfusion injury, and reduce cytokine-mediated injury.348,349 Several observa-tional studies note an association between maternal admin-istration of magnesium sulfate either for preeclampsia or preterm labor and a reduced risk of CP.350–353 However, other authors have reported no protective effect of magnesium.354–360 The Australasian Collaborative Trial of Magnesium Sulphate examined the efficacy of magnesium sulfate given to women at risk for preterm birth at less than 30 weeks’ gestation solely for neuroprotection. This study was a much larger random-ized controlled trial (n = 1062) and the authors reported a lower incidence of CP in magnesium sulfate–treated pregnan-cies, although not statistically significant (6.8% versus 8.2%), and no serious harmful effects to women or their children.233 Marret and associates, with the PREMAG trial group, showed that magnesium sulfate given to pregnant women before 33 weeks’ gestation with planned or expected delivery within 24 hours did not show any differences in total death or severe white matter injury at hospital discharge but was associated with significant reductions in late death or gross motor dys-function at 2 years of age.361,362 The largest study (n = 2241) evaluating the effect of magnesium sulfate for the prevention of CP by Rouse and colleagues and the NICHD Maternal-Fetal Medicine Units Network showed a reduction in the rate of moderate or severe CP.363 The ACOG Committee on Obstetric Practice and the Society for Maternal-Fetal Medicine issued

and excitatory amino acids.323–326 This relationship between elevated cytokine levels and the development of white matter injury has been seen in both preterm and term infants. A four- to sixfold increased risk for white matter injury has been associ-ated with elevated levels of IL-1β from amniotic fluid and from umbilical cord blood in preterm infants.327,328 In a study of term infants who went on to develop CP, stored blood samples had significantly increased levels of the cytokines IL-1, IL-8, IL-9, tumor necrosis factor-β, and RANTES (regulated on activa-tion, normal T cell expressed and secreted).329 Furthermore, the combination of intrauterine infection and intrapartum hypoxia has been correlated with a dramatic increase in the incidence of CP.330

Neonatal infection has also been associated with the devel-opment of CP due to direct central nervous system damage (e.g., in meningitis) or to a systemic inflammatory response syndrome that leads to sepsis, shock, and multi–organ system failure. Preterm infants who develop infection seem to be at higher risk.331,332 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.145 The infected infants also had an extremely high risk of cognitive impairment, defined as a Bayley Mental Development Index less than 70, at 18 months com-pared to noninfected infants (33%–42% versus 22%, respec-tively).279 Another study in ELBW survivors found that NEC requiring surgical intervention was associated with a significant increase in the incidence of both CP and developmental dis-abilities compared to those without NEC.167

Placental Abnormalities. Since the placenta supplies nutri-ents and oxygen to the developing fetus and acts as a barrier to protect the fetus from infectious organisms, toxins, trauma, and immune mediators, placental abnormalities can predispose fetuses to adverse outcomes. Placental abnormalities associated with CP can fall into three categories. The first encompasses events that occur during or prior to labor, also known as “senti-nel lesions,” which can cause fetal hypoxia. These lesions include uteroplacental separation, fetal hemorrhage, and umbilical cord occlusion.333 The next category is made up of thromboinflam-matory processes that affect fetal circulation and include fetal thrombotic vasculopathy, chronic villitis, meconium-associated fetal vascular necrosis, and fetal vasculitis related to chorioam-nionitis.333,334 The third category includes processes that cause decreased placental reserve, such as chronic placental insuf-ficiency, chronic villitis, chronic abruption, chronic vascular obstruction, and perivillous fibrin deposition.335 Evaluation of the placenta in the cause of neonatal encephalopathy may provide some insight into the fetal intrauterine environment and its contribution to the neurologic impairment.

Coimpairments. Historically, CP has been defined strictly by the location and degree of motor impairment. However, associated coimpairments such as disturbances in sensation, cognition, communication, perception, and behavior are common, as are seizures. A definition that includes coimpair-ments has been proposed.213,272 A Dutch population study of children with CP reported that 40% had seizures, 65% had cognitive deficits (IQ <85), and 34% had visual impairments.336 Hearing impairments and feeding difficulties are also common.

Strategies to Reduce Cerebral Palsy. Strategies to reduce CP have focused on preventing asphyxia and delaying premature



Group B β-Hemolytic Streptococcus

Group B β-hemolytic streptococcus (GBS) was first recognized as a cause of early-onset neonatal sepsis in the 1970s. By the 1990s GBS was a leading cause of serious neonatal infections. The organism is a common colonizing constituent of the vagina and rectum in 10%–30% of pregnant women. GBS colonization is more common in African-American women as well as those with a previous history of a neonate with GBS disease or a history of a GBS urinary tract infection. Epidemiologic studies demonstrated that most invasive, early-onset neonatal GBS disease involves vertical transmission from mother to fetus during labor. This observation led to studies of intrapartum antibiotic prophylaxis with penicillin G or ampicillin. The success of this strategy prompted the publication of guidelines for intrapartum antibiotic prophylaxis by the Centers for Disease Control and Prevention.366 A follow-up study com-pleted in 2005 confirmed the success of this strategy.308 Most invasive, serious GBS cases now seen are in infants born to mothers with negative GBS screening cultures who have pre-sumably converted to GBS-positive carrier status in the interval between screening and delivery367 (see Chapter 51). Rapid GBS screening technology may allow for identification of these women when they present in labor.368 There is some concern that intrapartum antibiotic prophylaxis may be associated with a higher incidence of serious bacterial infections later in infancy. This was most pronounced when broad-spectrum antibiotics were used for intrapartum prophylaxis rather than penicillin G.369 At present the advantages of intrapartum antibiotic pro-phylaxis to reduce the risk of invasive neonatal GBS disease clearly outweigh any risks, especially if penicillin is employed.

ChorioamnionitisThe relationship between chorioamnionitis and neonatal infec-tion is complex and remains incompletely understood. Some studies demonstrate a direct correlation between chorioamnio-nitis and neonatal infection. Other poor neonatal outcomes, including RDS and BPD, are also associated with chorioamnio-nitis.111,370 However, other clinical series and studies using animal model systems reach essentially the opposite conclusion, that chorioamnionitis protects against these same out-comes.371,372 Some of the confusion is grounded in definitions of chorioamnionitis. Clinical chorioamnionitis, as character-ized by maternal fever and uterine tenderness, is probably a very different pathophysiologic process from clinically silent histo-logic chorioamnionitis commonly seen in association with preterm birth.373,374 Whether these represent different disease entities or simply different manifestations of the same disease spectrum is not clear. It is evident that the fetal response to infection has important consequences for the neonate. Studies utilizing proteomic analysis of amniotic fluid or cervicovaginal fluid show promise for relating the diagnosis of chorioamnio-nitis to neonatal clinical course.375–377

CytomegalovirusHuman CMV is transmitted horizontally (by direct person-to-person contact with virus-containing secretions) and vertically (from mother to infant during pregnancy or after birth), and via transfusion of blood products or organ transplantation from previously infected donors. Vertical transmission of CMV to infants occurs by one of the following routes of transmission: (1) in utero by transplacental passage of maternal blood-borne

a statement in 2010 recommending the use of magnesium sulfate before anticipated early preterm birth for fetal neu-roprotection, although they do not indicate a specific gesta-tional age.363a While this recommendation remains in place, further studies may provide additional clarification (see also Chapter 41).

Summary. CP is a significant adverse event with origins in pregnancy. Many risk factors have been identified, although sometimes no etiologic factor is found. Strategies to reduce asphyxia and delay preterm birth have not shown a significant decrease in rates of CP. Since most CP is related to extremely preterm birth and the survival rate of these ELBW infants is improving, strategies to reduce neonatal brain injury such as the use of antenatal steroids are currently the most promising. Future trials of antenatal neuroprotection for preterm infants may prove beneficial to combat inflammatory or cytokine-mediated brain injury.

NEONATAL INFECTIOUS DISEASE PROBLEMS

Neonatal infection is a significant cause of neonatal morbidity and mortality in preterm and term infants. The risk of infection is inversely related to gestational age. The clinical manifesta-tions of neonatal infection vary by pathogen and age of acquisi-tion. The spectrum of pathogens causing neonatal infection is broad and has changed over the decades.364 However, the cor-nerstones of management remain prevention whenever possi-ble, early detection, and focused treatment.

Compared with older children and adults, neonatal host defense is blunted by incomplete development and experience with self versus nonself discrimination.365 All components of the neonatal immune system are deficient, a circumstance that is exacerbated by preterm birth. Nonspecific immunity is defec-tive at several levels. Skin and mucosal barriers are immature, especially in preterm infants. Levels of nonspecific antibacterial proteins such as lysozyme and lactoferrin are low. Neutrophil numbers are low, with limited storage pools available to clear bacteria. Key neutrophil functions, including chemotaxis, phagocytosis, and intracellular killing, are limited. Thus the neonate is poorly equipped to clear transient bacteremia and localize bacterial infection. Specific humoral and cell-mediated immune functions are also very limited. Circulating immuno-globulin levels are very low compared to adult levels. The neonate acquires virtually all circulating IgG from the mother via transplacental transport. The bulk of this antibody is trans-ferred during the third trimester, making the preterm infant profoundly deficient in protective maternally derived immuno-globulins. B-cell function is immature as well. The primary antibody response to infection mediated by the infant is pro-duction of immunoglobulin M. While T lymphocytes are present at birth, their function is nearly undetectable by stan-dard functional assays.

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



decades a strategy has been progressively implemented in the United States to prevent HBV transmission. This includes the following components: (1) universal immunization of infants beginning at birth; (2) prevention of perinatal HBV infection by routine screening of all pregnant women and appropriate immunoprophylaxis of infants born to HBsAg-positive women and infants born to women with unknown HBsAg status; (3) routine immunization of children and adolescents who have previously not been immunized; and (4) immunization of pre-viously nonimmunized adults at increased risk of infection.

Two types of products are available for HBV immuno-prophylaxis. Hepatitis B immune globulin (HBIG) provides short-term protection (3–6 months) and is indicated only in postexposure circumstances. Hepatitis B vaccine is used for pre-exposure and postexposure protection and provides long-term protection. Preexposure immunization with hepatitis B vaccine is the most effective means to prevent HBV transmission. To decrease the HBV transmission rate, universal immunization is necessary. Postexposure prophylaxis with either hepatitis B vaccine and HBIG or hepatitis B vaccine alone can prevent infection after exposure to HBV. The effectiveness of postexpo-sure immunoprophylaxis is related to the time elapsed between exposure and administration. Immunoprophylaxis is most effective if given within 12–24 hours of exposure. Serologic testing of all pregnant women for HBsAg is essential for iden-tifying women whose infants will require postexposure prophy-laxis beginning at birth.

Hepatitis B vaccines are highly effective and safe. These vac-cines are 90%–95% efficacious for preventing HBV infection. Studies in preterm infants and low-birth-weight infants (<2000 g) have demonstrated decreased seroconversion rates following administration of hepatitis B vaccination. However, by 1 month chronologic age medically stable preterm infants should be immunized, regardless of initial birth weight or ges-tational age. Routine postimmunization testing for HBsAb is not necessary for most infants. However, postimmunization testing for HBsAg and HBsAb at 9–18 months is recommended for infants born to HBsAg-positive mothers. A recent report suggested a high prevalence of occult infection in children born to HBsAg-positive mothers despite immunoprophylaxis.388 Because HBV infection may result in severe disease in the mother and chronic infection in the newborn infant, pregnancy is not considered a contraindication to immunization. Immu-nization of pregnant women with hepatitis B vaccine has not been associated with adverse effects on the developing fetus. Lactation is also not a contraindication to immunization.

Herpes Simplex VirusNeonatal HSV infections range from localized skin lesions to overwhelming disseminated disease. The latter has a case fatal-ity rate greater than 50%, even with prompt initiation of anti-viral 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-specific 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. At present, no vaccines or screening protocols for HSV are generally available.389,390

Human Immunodeficiency VirusLandmark studies in the 1990s391,392 demonstrated the value of intrapartum antiretroviral therapy to reduce the risk of

virus or (2) through an infected maternal genital tract, and (3) postnatally by ingestion of CMV-positive human milk.378,379

Approximately 1% of all liveborn infants are infected in utero and excrete CMV at birth. Risk to the fetus is great-est in the first 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 infection, with 10%–20% of infants manifesting neurodevelopmental impairment or sensorineural hearing loss in childhood.380

Congenital CMV infection is usually clinically silent. Some infected infants who appear healthy at birth are subsequently found to develop hearing loss or learning disabilities. Approxi-mately 10% of infants with congenital CMV infection exhibit evidence of profound involvement at birth, including IUGR, jaundice, purpura, hepatosplenomegaly, microcephaly, intrace-rebral calcifications, and retinitis.381 Studies of ganciclovir treat-ment for congenital CMV suggest benefits for long-term hearing outcomes. Although long-term ganciclovir therapy was well tolerated during clinical trials, concerns remain regarding longer-term toxicity. Parents should be carefully counseled before starting treatment.382,383

Infection acquired intrapartum from maternal cervical secretions or postpartum from human milk usually is not asso-ciated with clinical illness. Infections resulting from transfusion of blood products from CMV-seropositive donors and from CMV-positive human milk to preterm infants have been associ-ated with serious systemic infections, including lower respira-tory tract infection. Transmission of CMV by transfusion to newborn infants has been reduced by using CMV antibody–negative blood donors, by freezing erythrocytes in glycerol, or by removal of leukocytes by filtration prior to administra-tion.384 CMV transmission by human milk is also decreased by pasteurization.385 However, freeze-thawing is probably not effective.386 If fresh donor milk is needed for infants born to CMV antibody–negative mothers, provision of these infants with milk from only CMV antibody–negative women should be pursued.

Hepatitis B VirusHepatitis B virus (HBV) is a DNA virus whose important com-ponents include an outer lipoprotein envelope containing hepa-titis B surface antigen (HBsAg) and an inner nucleocapsid containing the hepatitis B core antigen. Only antibody to HBsAg (HBsAb) provides protection from HBV infection. Perinatal transmission of HBV is highly efficient and usually occurs from blood exposure during labor and delivery. In utero transmission of HBV is rare, less than 2% of perinatal infections in most studies. The risk of an infant acquiring HBV from an infected mother due to perinatal exposure is 70%–90% for infants born to mothers who are HBsAg and hepatitis B e antigen (HBeAg) positive. The risk is 5%–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 and 5 years of age become chroni-cally infected, whereas only 2%–6% of older children or adults develop chronic HBV infection.387

The goals of HBV prevention programs are to prevent acute HBV infection and to decrease the rates of chronic HBV infec-tion and HBV-related chronic liver disease. Over the past two



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 congenitally infected infants.

Infants with congenital rubella should be considered conta-gious until at least 1 year of age, unless nasopharyngeal and urine cultures are repeatedly negative for rubella virus. Infec-tion precautions should be considered for children up to 3 years of age 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.

ChlamydiaIn the newborn period, Chlamydia trachomatis is associated with conjunctivitis and pneumonia. Acquisition of C. tracho-matis occurs in approximately 50% of infants born vaginally to infected mothers and in some infants delivered by cesarean section with intact membranes.395 Neonatal chlamydial con-junctivitis is characterized by ocular congestion, edema, and discharge developing a few days to several weeks after birth and generally 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 hyperinflation and infiltrates are demonstrated on the chest radiograph.

The recommended topical prophylaxis for gonococcal oph-thalmia with erythromycin or tetracycline for all newborn infants will not prevent chlamydial conjunctivitis or extraoc-cular infections.396 Infants with chlamydial conjunctivitis are treated with oral erythromycin base or ethylsuccinate (50 mg/kg/d in four divided doses) for 14 days. Alternatively, oral sul-fonamides may be used after the immediate neonatal period for infants who do not tolerate erythromycin. Because the efficacy 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/d) for 3 days or erythromycin base or ethylsuccinate (50 mg/kg/d 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 arthritis, disseminated disease with bacteremia, menin-gitis, scalp abscess, or vaginitis. Microscopic examination of Gram-stained smears of exudates from the eyes, skin lesions, synovial fluid, and, when clinically warranted, CSF may be useful in the initial evaluation. Identification of gram-negative intracellular diplococci in these smears can be helpful if the organism is not recovered in culture. N. gonorrhoeae can be cultured from normally sterile sites such as blood, CSF, and synovial fluid.

For routine ophthalmia neonatorum prophylaxis of infants immediately after birth, 1% tetracycline or 0.5% erythromycin ophthalmic ointment is instilled into each eye. Silver nitrate, while effective, causes more chemical irritation than antimicro-bials and is no longer available in the United States. Prophylaxis may be delayed for as long as 1 hour after birth to facilitate parent-infant bonding. None of the topical agents is effective against C. trachomatis.396 When prophylaxis is administered,

maternal-fetal transmission of human immunodeficiency virus (HIV). Improvements in the quality and availability of rapid HIV testing hold out promise for more timely and accurate identification of infected women and their newborn infants. The risk of congenital HIV is reduced to approximately 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 con-tamination by maternal blood. A positive result identifies infants who have been infected in utero. Approximately 93% of infected infants have detectable HIV DNA at 2 weeks and nearly all HIV-infected infants have positive HIV DNA polymerase chain reaction assay results by 1 month of age. A test within the first 14 days of age will facilitate decisions regarding initiation of antiretroviral therapy. Transplacental passage of antibodies complicates use of antibody-based assays for diagnosis of infec-tion 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, immuno-logic, and clinical criteria. Because therapeutic options for HIV infection continue to evolve, consultation with an expert in pediatric HIV management is recommended.

RubellaHumans are the only source of rubella 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 prevaccine era. Although the number of susceptible people has decreased since the introduction and widespread use of rubella vaccine, serologic surveys indicate that approximately 10% of the US-born population older than 5 years of age 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 in infants of women born outside the United States. Although rubella is no longer endemic in the United States,393 documented outbreaks of rubeola among unvaccinated popula-tions in the United States remains a concern and raises the theoretical possibility of exposure during pregnancy.394

Congenital rubella syndrome is characterized by a constel-lation of anomalies that may include ophthalmologic (cata-racts, microphthalmos, pigmentary retinopathy, and congenital glaucoma), cardiac (patent ductus arteriosus and peripheral pulmonary artery stenosis), auditory (sensorineural hearing impairment), and neurologic (meningoencephalitis, behavioral abnormalities, and mental retardation) abnormalities. Neonatal manifestations of congenital rubella syndrome include growth retardation, interstitial pneumonia, radiolucent bone disease, hepatosplenomegaly, thrombocytopenia, and dermal eryth-ropoiesis, also termed “blueberry muffin lesions.” The occur-rence of congenital defects varies with timing of the maternal infection.

Detection of rubella-specific immunoglobulin M antibody usually indicates recent postnatal infection or congenital infec-tion in a newborn infant; however, both false-positive and false-negative results occur. Congenital infection can be confirmed by stable or increasing rubella-specific IgG over several months.



evaluated if born to a mother with positive nontreponemal and treponemal test results if the mother has any of the following conditions: (1) syphilis has not been treated or treatment has not been documented, (2) syphilis during pregnancy was treated with a nonpenicillin regimen, (3) syphilis was treated less than 1 month prior to delivery because treatment failures occur and efficacy cannot be assumed, and (4) syphilis was treated before pregnancy but with insufficient follow-up to assess the response to treatment and current infection status.

Evaluation for syphilis in an infant should include physical examination, a quantitative nontreponemal syphilis test of serum from the infant, a Venereal Disease Research Laboratory (VDRL) test of the CSF and analysis of the CSF for cells and protein concentration, long-bone radiographs, and a complete blood cell and platelet count. Other clinically indicated tests might include a chest radiograph, liver function tests, ultraso-nography, ophthalmologic examination, and an auditory brain-stem response test. Pathologic examination of the placenta or umbilical cord using specific antitreponemal antibody staining is also recommended.

Infants should be treated for congenital syphilis if they have proven or probable disease demonstrated by one or more of the following: (1) physical, laboratory, or radiographic evidence of active disease; (2) positive placenta or umbilical cord test results for treponemes using direct fluorescent antibody T. pallidum staining or darkfield microscope test; (3) a reactive result on VDRL on testing of CSF; or (4) a serum quantitative nontrepo-nemal titer at least fourfold higher than the mother’s titer using the same test and preferably the same laboratory. If the infant’s titer is less than four times that of the mother, congenital syphilis still can be present. When circumstances warrant evaluation of an infant for syphilis, the infant should be treated if test results cannot exclude infection, if the infant cannot be adequately evaluated, or if adequate follow-up cannot be ensured.

Infants with proven congenital syphilis should be treated with aqueous crystalline penicillin G. The dosage should be based on chronologic, not gestational, age. The dose of penicil-lin G is 100,000–150,000 U/kg/d administered as 50,000 U/kg per dose IV every 12 hours during the first 7 days of life, then every 8 hours thereafter for a total of 10 days. Alternatively, penicillin G procaine 50,000 U/kg/d IM for 10 day may be considered; however, adequate CSF concentrations may not be achieved with this regimen.

Key Points• Neonates experience a broad spectrum of morbidities;

these include those associated with prematurity such as respiratory distress syndrome, bronchopulmonary dyspla-sia, and intraventricular hemorrhage.

• Birth asphyxia and infections also remains challenging, especially in the developing world.

• Many neonatal morbidities are still difficult to prevent, but obstetrical decision-making can make a difference in outcomes.

• Preterm birth remains the most significant driver of neona-tal morbidity and mortality. Management strategies to miti-gate preterm delivery, even for a few days, may improve outcomes. Whenever possible, close collaboration and com-munication between the delivery physician and the newborn physician is the best way to optimize birth outcomes.

A full reference list is available online at ExpertConsult.com.

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 gonor-rhea should receive a single dose of ceftriaxone, 125 mg IV or IM. Preterm and low-birth-weight infants are given 25–50 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 confirm the diagnosis and determine antimicrobial susceptibility. Tests for concomitant infection with C. trachomatis, syphilis, and HIV infection should be performed. Recommended treatment, including for ophthalmia neonatorum, is ceftriaxone (25–50 mg/kg IV or IM, not to exceed 125 mg) given once. Infants with gonococcal oph-thalmia should receive eye irrigations 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 antimicrobial treatment is provided. Infants with gonococcal ophthalmia should be hospitalized and evaluated for disseminated infec-tion. Recommended therapy for arthritis and septicemia is cef-triaxone or cefotaxime for 7 days. If meningitis is documented, treatment should continue for a total of 10–14 days.

SyphilisCongenital syphilis remains a significant public health problem in the United States. It is contracted from an infected mother via transplacental transmission of Treponema pallidum at any time during the pregnancy or delivery. Intrauterine syphilis can cause stillbirth, hydrops fetalis, or preterm birth. Affected infants may present with edema, hepatosplenomegaly, lymph-adenopathy, mucocutaneous lesions, osteochondritis, pseudo-paralysis, rash, or snuffles at birth or within the first 2 months of life. However, lack of these findings does not rule out neo-natal disease. Additionally, hemolytic anemia or thrombocyto-penia may be identified on laboratory evaluation. Untreated infants, regardless of whether they have manifestations in infancy, may develop late manifestations, usually after 2 years of age and involving the bones, central nervous system, eyes, joints, and teeth. Some consequences of intrauterine infection may not become apparent until many years after birth.

Definitive diagnosis is established by identification of spiro-chetes by darkfield microscope examination or by direct fluo-rescent antibody tests of lesion exudates or tissue such as the placenta or umbilical cord. Presumptive diagnosis is possible using nontreponemal and treponemal tests. The use of only one type of test for diagnosis is insufficient, because false-positive nontreponemal tests occur with various medical conditions and false-positive treponemal tests can occur with other spirochetal diseases.

No newborn infant should be discharged from the hospital without determination of the mother’s serologic status for syphilis.397 All infants born to seropositive mothers require a careful examination and a quantitative nontreponemal syphilis test. The laboratory test performed in the infant should be the same as that performed in the mother, ideally from the same testing facility, so that comparison of titer results is facilitated. An infant should be evaluated for congenital syphilis if the maternal titer has increased fourfold, if the infant titer is four-fold greater than the mother’s titer, or if the infant has clinical manifestations of syphilis. Additionally, the infant should be


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73 Neonatal Morbidities of Prenatal and Perinatal Origin 1333.e1

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73 - neonatal morbidities of prenatal and perinatal origin

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