Chapter 58Neonatal Morbidities of Prenatal andPerinatal Origin James M. Greenberg, MD, Vivek Narendran, MD, Kurt R. Schibler, MD, Barbara B. Warner, MD, Beth Haberman, MD, and Edward F. Donovan, MDObstetric and Postnatal Common MorbiditiesManagement Decisions of Pregnancy andThe nature of obstetric clinical practice requires consideration of two Neonatal Outcomespatients: mother and fetus. The intrinsic biologic interdependence ofone with the other creates challenges not typically encountered in Complications of pregnancy that affect infant well-being may beother realms of medical practice. Often, there is a paucity of objective immediately evident after birth, such as hypotension related to mater-data to support the evaluation of risks and beneﬁts associated with a nal hemorrhage, or may manifest hours later, such as hypoglycemiagiven clinical situation, forcing obstetricians to rely on their clinical related to maternal diabetes or thrombocytopenia related to maternalacumen and experience. Family perspectives must be integrated in preeclampsia. Anemia and thyroid disorders related to transplacentalclinical decision making, along with the advice and counsel of other passage of maternal IgG antibodies to platelets or thyroid, respectively,clinical providers. In this chapter, we review how to best use neonato- may manifest days after delivery.logic expertise in the obstetric decision-making process. Diabetes during pregnancy serves as an example. Infants born to Optimal perinatal care often derives from collaboration between women with diabetes are often macrosomic, increasing the risk ofthe obstetrician and neonatologist during pregnancy and especially shoulder dystocia and birth injury. After delivery, these infants mayaround the time of labor to eliminate ambiguity and confusion in the have signiﬁcant hypoglycemia, polycythemia, and electrolyte distur-delivery room and to ensure that patients and families understand the bances, which require close surveillance and treatment. Lung matura-rationale for obstetric and postnatal management decisions. The neo- tion is delayed in the infants born to women with diabetes, increasingnatologist can provide information regarding risks to the fetus associ- the incidence of respiratory distress syndrome (RDS) at a given gesta-ated with delaying or initiating preterm delivery and can identify the tional age. Infants of diabetic mothers may also have delayed neuro-optimal location for delivery to ensure that skilled personnel are logic maturation, with decreased tone typically leading to delayedpresent to support the newborn infant. feeding competence. Less common complications include an increased In addition to contributing information about gestational age– incidence of congenital heart disease and skeletal malformations.speciﬁc outcomes, the neonatologist can anticipate neonatal com- These neonatal complications are typically managed without long-plications related to maternal disorders such as diabetes mellitus, term sequelae, but they are not without consequences, such as pro-hypertension, and multiple gestations or to prenatally detected fetal longed hospital stay. Neonatal complications for the infant of a womanconditions such as congenital infections, alloimmunization, or devel- with diabetes are a function of maternal glycemic control. Carefulopmental anomalies. When a lethal condition or high risk of death in antenatal attention to optimal control of blood glucose can reducethe delivery room is anticipated, the neonatologist can assist with the neonatal morbidity due to maternal diabetes.formulation of a birth plan and develop parameters for delivery room Table 58-1 summarizes other morbidities of pregnancy and theirintervention. effects on neonatal outcome. The list is not exhaustive and does not Preparing parents by describing delivery room management and take into account how multiple morbidities may interact to createresuscitation of a high-risk infant can demystify the process and reduce additional complications. All of these problems may contribute tosome of the fear anticipated by the expectant family. Premature infants increased length of hospital stay after delivery and to long-termare susceptible to thermal instability and are moved rapidly after birth morbidity.to a warming bed to prevent hypothermia while assessing the infant’s Chorioamnionitis has diverse effects on the fetus and neonatalcardiorespiratory status and vigor. The need for resuscitation is deter- outcome. It is associated with premature rupture of membranesmined by careful evaluation of cardiorespiratory parameters and and preterm delivery. Elevated levels of proinﬂammatory cytokinesappropriate response according to published Neonatal Resuscitation may predispose neonates to cerebral injury.2 Although suspected orProgram guidelines.1 proven neonatal sepsis is more common in the setting of chorioamnio-
1198 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin TABLE 58-1 MANAGEMENT CONSIDERATIONS ASSOCIATED WITH NEONATAL MANAGEMENT OF CONGENITAL MALFORMATIONS Malformation Management Considerations Clefts Alternative feeding devices (e.g., Haberman feeder), genetics evaluation, occupational or physical therapy Congenital diaphragmatic hernia Skilled airway management, pediatric surgery, immediate availability of mechanical ventilation, nitric oxide, ECMO Upper airway obstruction or micrognathia Skilled airway management, otolaryngologic evaluation, genetics evaluation and management, immediate availability of mechanical ventilation Hydrothorax Skilled airway management, nitric oxide, ECMO, chest tube placement, immediate availability of mechanical ventilation Ambiguous genitalia Endocrinology, urologic consultation, genetic proﬁle available for immediate evaluation Neural tube defects Dressings to cover defect, IV ﬂuids, neurosurgery, urologic evaluation, orthopedics evaluation and management Abdominal wall defects Saline-ﬁlled sterile bag to contain exposed abdominal contents, IV ﬂuids, pediatric surgery, genetics evaluation and management Cyanotic congenital heart disease IV access, prostaglandin E1, immediate availability of mechanical ventilation ECMO, extracorporeal membrane oxygenation; IV, intravenous.nitis, many neonates born to mothers with histologically proven day). Mothers experienced signiﬁcant third-trimester weight loss, andchorioamnionitis are asymptomatic and appear uninfected. Animal offspring were underweight.8 There is growing evidence that infantsmodels and associated epidemiologic data suggest that chorioamnio- undernourished during fetal life are at higher risk for “adult” diseasesnitis can accelerate fetal lung maturation, as measured by surfactant such as atherosclerosis and hypertension. Poor maternal nutritionproduction and function. However, preterm infants born to mothers during intrauterine life may signal the fetus to modify metabolic path-with chorioamnionitis are more likely to develop bronchopulmonary ways and blood pressure regulatory systems, with health consequencesdysplasia (BPD).3-5 The neonatal consequences of chorioamnionitis are lasting into late childhood and beyond.9 Conversely, maternal overnu-likely related to the timing, severity, and extent of the infection and the trition (i.e., excessive caloric intake) predisposes mothers to insulinassociated inﬂammatory response. resistance and large-for-gestational-age infants.10,11 The effects of preeclampsia on the neonate include intrauterine Neonatal anemia may be a consequence of perinatal events such asgrowth retardation, hypoglycemia, neutropenia, thrombocytopenia, placental abruption, ruptured vasa previa, or fetal-maternal transfu-polycythemia, and electrolyte abnormalities such as hypocalcemia. sion. At delivery, the neonate may be asymptomatic or display pro-Most of these problems appear related to placental insufﬁciency, with found effects of blood loss, including high-output heart failure ordiminished oxygen and nutrient delivery to the fetus. With delivery hypovolemic shock. The duration and extent of blood loss along withand supportive care, most of these problems will resolve with time, any fetal compensation typically determine neonatal clinical status atalthough some patients will require treatment with intravenous delivery and subsequent management. In the delivery room, promptcalcium or glucose, or both, in the early neonatal period. Similarly, recognition of acute blood loss and transfusion with type O, Rh-severe thrombocytopenia may require platelet transfusion therapy. negative blood can be a lifesaving intervention.Preeclampsia may protect against intraventricular hemorrhage (IVH) Neonates from a multifetal gestation are, on average, smaller at ain preterm infants, perhaps because of maternal treatment or other given gestational age than their singleton counterparts. They are alsounknown factors.6 Unlike intrauterine inﬂammation, preeclampsia more likely to deliver before term and therefore are more likely todoes not appear to accelerate lung maturation.7 experience the complications associated with low birth weight and Maternal autoimmune disease may affect the neonate through prematurity described in this chapter. Monochorionic twins may expe-transplacental transfer of autoantibodies. Symptoms are a function of rience twin-twin transfusion syndrome. The associated discordantthe extent of antibody transfer. Treatment is supportive and based on growth and additional problems of anemia, polycythemia, congestivethe affected neonatal organ systems. For example, maternal Graves heart failure, and hydrops may further complicate the clinical coursedisease may cause neonatal thyrotoxicosis requiring treatment with after delivery, even after amnioreduction or fetoscopic laser occlusion.propylthiouracil or β-blockers. Maternal lupus or connective tissue Cerebral lesions such as periventricular white matter injury and ven-disease is linked to congenital heart block that may require long-term tricular enlargement may occur more frequently in the setting of twin-pacing after delivery. Myasthenia gravis during pregnancy occasionally twin transfusion syndrome.12 Additional epidemiologic studies andresults in a transient form of the disease in the neonate. Supportive long-term follow-up are needed to further address this issue.therapy during the early neonatal period addresses most issues associ- Congenital malformations present signiﬁcant challenges for care-ated with maternal autoimmune disorders. Passively transferred auto- givers and families, and prenatal diagnosis is an opportunity to provideantibodies gradually clear from the neonatal circulation with a half-life anticipatory guidance. The neonatologist can facilitate delivery cover-of 2 to 3 weeks. age and ensure availability of appropriate equipment, medications, and Neonatal outcome associated with maternal nutritional status personnel. Table 58-1 summarizes some of the important consider-during pregnancy is of growing interest. The Dutch famine of 1944 to ations associated with management of congenital malformations and1945 created a unique circumstance for studying the consequences of reﬂects the importance of multidisciplinary input. Typically, thesesevere undernutrition during pregnancy (i.e., caloric intake <1000 kcal/ patients are best delivered in a setting where experienced delivery
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1199room attendance is available. If the needed consultative services andequipment are not readily available, arrangement should be made for Complications of Prematurityprompt transfer to a tertiary center. Successful transports depend Besides increased mortality risk, prematurity is associated with anon clear communication between centers, for example, regarding increased risk for morbidity in almost every major organ system. BPD,delivery of an infant with gastroschisis, so that the delivering retinopathy of prematurity, necrotizing enterocolitis, and IVH are par-hospital provides adequate intravenous hydration and protection ticularly linked to preterm births. Intrauterine growth restriction andof exposed abdominal organs, and the referral center can mobilize increased susceptibility to infection are not restricted to the pretermpediatric surgical intervention immediately on arrival of the infant but are complicated in the immature infant. Table 58-2 sum-infant. marizes common complications of prematurity by organ system. In settings of premature, preterm, or prolonged rupture of mem- The rate of preterm birth increased by 30% between 1983 andbranes and premature labor, mothers are frequently treated with anti- 2004, from 9.6% to 12.5%. Three major causes have been identiﬁedbiotics and tocolytic agents. Maternal medications administered during to explain the rise (see Chapter 29): improved gestational dating asso-pregnancy for non-obstetric diseases can have a signiﬁcant impact on ciated with increased use of early ultrasound,16 the substantial rise inthe neonate. A common challenge in many centers is the treatment of multifetal gestation associated with assisted reproductive technology,opiate-addicted mothers on methadone. The symptoms of neonatal and an increase in “indicated” preterm births.17 The latter category isabstinence syndrome vary as a function of the degree of prenatal opiate important because decisions affecting the timing and management ofexposure and age after delivery. Many infants appear neurologically preterm delivery can have a profound effect on neonatal outcome.normal at delivery, only to exhibit symptoms later on the ﬁrst or The risk of death before birth hospital discharge doubles when thesecond day or extrauterine life. Infants with neonatal abstinence syn- gestational age decreases from 27.5 weeks (10%) to 26 weeks (20%).drome typically demonstrate irritability, poor feeding, loose and fre- Delaying delivery even for a few days may substantially improvequent stools, and in severe cases, seizures. Treatment options include outcome, especially before 32 weeks, assuming that the intrauterinenonpharmacologic intervention (e.g., swaddling, minimal stimula- environment is safe to support the fetus. However, in some clinicaltion), methadone, or non-narcotic drugs such as phenobarbital. These situations with a high potential for preterm delivery, it is difﬁcult toinfants often require hospitalization for many days or weeks until their assess the quality of the intrauterine environment. Three commonirritability is under sufﬁcient control to allow for care in a home examples are preterm, premature rupture of membranes (see Chaptersetting. There is clinical evidence that neonates may also exhibit similar 31), placental abruption (see Chapter 37), and preeclampsia (seesymptoms after withdrawal from antenatal nicotine exposure.13,14 The Chapter 35). In each case, prolonging gestation to allow continuedconsequences of other illicit drug use during pregnancy have been fetal growth and maturation in utero is accompanied by an uncertainwidely studied but are difﬁcult to assess because of difﬁculties with risk of rapid change in maternal status with a corresponding increaseddiagnosis and confounding variables. Maternal cocaine abuse has been risk of fetal compromise. Tests of fetal well-being are discussed inassociated with obstetric complications such as placental abruption. Chapter 21, and clinical decision making in obstetrics is addressed inVascular compromise may predispose neonates to cerebral infarcts and Chapters 28 and 29.bowel injury. Developmental delay and behavioral problems are Obstetric decisions about the timing of delivery in the setting ofobserved, although associated factors such as poverty, lack of prenatal uncertain in utero risk are a signiﬁcant contributing factor to thecare, and low socioeconomic status also contribute. increase in late preterm births, after 32 to 34 weeks. The contribution Alloimmune hemolytic disorders such as Rh hemolytic disease of elective delivery must also be considered. Although perinatal mor-and ABO incompatibility can cause neonatal morbidity ranging fromuncomplicated hyperbilirubinemia to severe anemia, hydrops, andhigh-output congestive heart failure. Although it is uncommon, Rh TABLE 58-2 COMMON COMPLICATIONS OFhemolytic disease must be considered as a cause of unexplainedhydrops, anemia, or heart failure in infants born to Rh-negative PREMATURITY BY ORGAN SYSTEMmothers, especially if there is a possibility of maternal sensitization. Organ System MorbidityABO incompatibility is common, with up to 20% of all pregnanciespotentially at risk. The responsible isohemagglutinins have weak Pulmonary Respiratory distress syndromeafﬁnity for blood group antigens, and the degree of hemolysis and Bronchopulmonary dysplasia Pulmonary hypoplasiasubsequent jaundice varies among patients. Indirect immunoglobulin Apnea of prematurity(Coombs) testing has limited value in predicting clinically signiﬁcant Cardiovascular Patent ductus arteriosusjaundice. Neonatal morbidity is typically restricted to hyperbilirubine- Apnea and bradycardiamia requiring treatment with phototherapy. Hypotension Gastrointestinal, hepatic Necrotizing enterocolitis Dysmotility or reﬂuxPrematurity Feeding difﬁculties HypoglycemiaThe mean duration of a spontaneous singleton pregnancy is 280 days Central nervous system Intraventricular hemorrhageor 40 menstrual weeks, 38 weeks after conception. An infant delivered Periventricular leukomalacia Visual Retinopathy of prematuritybefore completion of 37 weeks’ gestation is considered to be preterm Skin Excess insensible water lossaccording to the World Health Organization (WHO) deﬁnition. Infant Hypothermiamorbidity and mortality increase with decreasing gestational age at Immunologic, hematologic Increased incidence of sepsis andbirth. The risk of poor outcome, deﬁned as death or lifelong handicap, meningitisincreases dramatically as gestational age decreases, especially for very Anemia of prematuritylow birth weight (VLBW) infants (Fig. 58-1).
1200 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin Females (n 1327) Males (n 1453) 1500 1500 1400 1400 1300 1300 1200 1200 Birth weight (g) Birth weight (g) 1100 1100 1000 1000 0.1 900 900 0.1 800 800 0.2 0.2 0.3 0.3 0.4 700 0.4 700 0.5 0.5 0.6 600 0.6 600 0.7 0.7 0.8 0.8 500 500 22 23 24 25 26 27 28 29 30 22 23 24 25 26 27 28 29 30 Gestational age (wk) Gestational age (wk) FIGURE 58-1 Estimated mortality risk by birth weight and gestational age based on singleton infants born in National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers between January 1, 1995, and December 31, 1996. Numeric values represent age- and weight- speciﬁc mortality rates per 100 births. (From Lemons JA, Bauer CR, Oh W, et al: Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 107:E1, 2001. Used with permission of the American Academy of Pediatrics.)tality continues to decrease, in part due to a decline in stillbirths,17 Classic preterm infants, typically deﬁned as those born before 32interest in understanding the extent of morbidity associated with late weeks’ gestation or weighing less than 1500 g, or both, comprise onlypreterm deliveries has intensiﬁed because of the large number of these 1.5% of all deliveries, whereas the late preterm population accountslate preterm infants and the potential to avoid morbidities, such as for 8% to 9% of all births. Even uncommon complications in the latertemperature instability, feeding problems, hyperbilirubinemia requir- preterm population may represent a signiﬁcant health care burden. Asing treatment, suspected sepsis, and respiratory distress. Infants born the number of late preterm infants continues to increase, clinicians andat 35 weeks’ gestation are nine times more likely to require mechanical policymakers will likely focus additional attention on the causes andventilation than those born at term.18 prevention of such deliveries (Fig. 58-2). Most complications of late preterm delivery are easily treated, buttheir economic and social effects are substantial, and long-termsequelae are not well understood. For example, brain growth and Decisions at the Threshold of Viabilitydevelopment proceed rapidly during the third trimester and continue Decisions regarding treatment of infants at the “limit of viability” arefor the ﬁrst several years of life. An infant born at 35 weeks’ gestation often the most difﬁcult for families and health care professionals. Thehas approximately one-half the brain volume of a term infant. Although difﬁculty stems in part from the lack of clarity in deﬁning what thatIVH is unusual after 32 weeks’ gestation, regions including the limit is, which has fallen by approximately 1 week every decade overperiventricular white matter continue to undergo rapid myelination the past 40 years. Among developed countries, most identify the limitduring this period. Studies by Stein and colleagues19 and Kirkegaard of viability at 22 to 25 weeks’ gestation.29-31 Making decisions at thisand coworkers20 demonstrate an association between late preterm early gestation requires accurate information about mortality anddelivery and long-term neurodevelopmental problems, including morbidity for this population. At 22 weeks (22 0/7days to 22 6/7 days),learning disabilities and attention deﬁcit disorders. Careful neurologic survival is rare and typically not included in studies of survival orand epidemiologic studies will be required to deﬁne any mechanistic long-term outcome. Rates of survival to hospital discharge for infantsconnection between late preterm delivery and these long-term born at 23 weeks’ gestation (23 0/7 to 23 6/7 days) range from 15% tooutcomes. 30%. Survival increases to between 30 and 55% for infants born at 24 Our growing recognition of the morbidity and mortality risks asso- weeks’ gestation.15,23,30,32-35 The Vermont-Oxford Network reportedciated with preterm delivery clearly deserve close scrutiny and further weight-based survival for more than 4000 infants born between 401study. Table 58-3 compares estimates of complication rates between and 500 g (mean gestational age of 23.3 ± 2.1 weeks) from 1996 topreterm and late preterm infants. 2000. Survival to hospital discharge was 17%.36 Although mortality
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1201 TABLE 58-3 ESTIMATED COMPLICATION RATES FOR PRETERM AND LATE PRETERM INFANTS Complication of Prematurity Incidence for Preterm Infants* Incidence for Late Preterm Infants† Respiratory distress syndrome 65% surf Rx < 1500 g 5% 80% < 27 wk21 Bronchopulmonary dysplasia 23% < 1500 g15 Uncommon Retinopathy of prematurity Approx 40% < 1500 g22-24 Intraventricular hemorrhage with ventricular 11% < 1500 g15 Rare dilation or parenchymal involvement Necrotizing enterocolitis 5-7% < 1500 g15 Uncommon Patent ductus arteriosus 30% < 1500 g15 Uncommon Feeding difﬁculty >90% 10-15%25 Hypoglycemia NA 10-15%25 *Deﬁned as <32 weeks and/or <1500 g. † Deﬁned as 32-37 weeks and/or 1500-2500 g. NA, not available; surf Rx, surfactant treatment. Peak Gestational Duration Perinatal Risk Index 1992 2002 Deaths per thousand 20 Percent 8 6 10 4 2 0 0 39 40 38 39 40 41 42 43 A Gestational age (completed weeks) B Gestational age (completed weeks) FIGURE 58-2 Peak gestational age duration and risk of intrauterine fetal demise. A, Change in peak gestational duration between 1992 and 2002. The duration of gestation decreased by a full week during that decade, from 40 weeks to 39 weeks. B, The risk of intrauterine fetal demise increases with increasing gestational age, especially beyond 40 weeks. The risk of intrauterine fetal demise likely inﬂuences obstetric decision making regarding the timing of delivery in pregnancies approaching 40 weeks’ gestation. (Data from Davidoff MJ, Dias T, Damus K, et al: Changes in the gestational age distribution among U.S: singleton births: Impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol 30:8-15, 2006; Yudkin PL, Wood L, Redman CW: Risk of unexplained stillbirth at different gestational ages. Lancet 1:1192-1194, 1987; and Smith GC: Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 184:489-496, 2001.)rates decline for each 1-week increase in gestational age at delivery, with delivery at a tertiary center, rather than neonatal transfer from anlong-term neurodevelopmental outcomes do not improve proportion- outlying facility.38-40 When families desire resuscitation or dating isately. Of infants born at less than 25 weeks’ gestation, 30% to 50% will uncertain, every attempt should be made to transfer to a tertiary centerhave moderate to severe disability, including blindness, deafness, devel- for delivery. Maternal transfer to a tertiary center and administrationopmental delays and cerebral palsy.23,30,32 The National Institute of of corticosteroids (see Chapter 23) are the only antenatal interventionsChild Health and Human Development reported neurodevelopmental that have been signiﬁcantly and consistently related to improved neo-outcomes for more than 5000 infants born between 22 and 26 weeks’ natal neurodevelopmental outcomes.37 Other attempted strategies aregestation from 1993 to 1998. Bayley mental development index (MDI) discussed in Chapter 29.and nonverbal development index (NDI) scores improved and blind-ness was reduced, but rates of severe cerebral palsy, hearing loss, Planning for Delivery at the Limits of Viabilityshunted hydrocephalus, and seizures were unchanged.37 Ideally, discussion between physicians and parents should begin before Birth weight and gender also affect survival rates. Higher weights birth in a nonemergent situation, and include both obstetric and neo-within gestational age categories and female sex consistently show a natal care providers. Even during active labor, communication with thesurvival advantage and better neurodevelopmental outcomes.15,37 Sur- family should be initiated as a foundation for postnatal discussions.vival and long-term outcomes of very preterm infants are improved The family should understand that plans made before delivery are
1202 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origininﬂuenced by maternal and fetal considerations and are based onlimited information. It should be emphasized that information avail-able only after delivery, such as birth weight and neonatal physical Respiratory Problems in theﬁndings, may change the infant’s prognosis.30 Neonatal PeriodNeonatal Resuscitation at the Limits No aspect of the transition from fetal to neonatal life is more dramaticof Viability than the process of pulmonary adaptation. In a normal term infant, theIf time allows before delivery of an infant whose gestational age is lungs expand with air, pulmonary vascular resistance rapidly decreases,near the threshold of viability, a thoughtful birth plan developed by and vigorous, consistent respiratory effort ensues within a minute ofthe parents in consultation with maternal-fetal medicine specialists separation from the placenta. The process depends on crucial physio-and the neonatologist should be established. The neonatologist can logic mechanisms, including production of functional surfactant, dila-assist families in making decisions regarding a birth plan for their tion of resistance pulmonary arterioles, bulk transfer of ﬂuid from airinfant by providing general information about the prognosis, the hos- spaces, and physiologic closure of the ductus arteriosus, foramen ovale.pital course, potential complications, survival information, and general Complications such as prematurity, infection, neuromuscular disor-health and well-being of infants delivered at the similar gestational ders, developmental defects, or complications of labor may interfereage. When time does not permit such discussions, careful evaluation with neonatal respiratory function. Common respiratory problems ofof gestational age and response to resuscitation are instrumental in neonates are reviewed in the following sections.assisting families in making decisions regarding viability or nonviabil-ity of an extremely premature infant. The presence of an experiencedpediatrician at delivery is recommended to assess weight, gestational Transient Tachypnea of the Newbornage and fetal status, and to provide medical leadership in decisions tobe made jointly with families.29,31 In cases of precipitous deliveries Deﬁnitionwhen communication with families has not occurred, physicians Transient tachypnea of the newborn (TTN), commonly known as wetshould use their best judgment on behalf of the infant to initiate resus- lungs, is a mild condition affecting term and late preterm infants. Thiscitation until families can be brought into the discussion, erring on the is the most common respiratory cause of admission to the special careside of resuscitation if the appropriate course is uncertain.29,41 nursery. Transient tachypnea is self-limiting, with no risk of recurrence Under ideal circumstances, the health care team and the infant’s or residual pulmonary dysfunction. It rarely causes hypoxic respiratoryfamily should make shared management decisions regarding these failure.43infants. The American Medical Association and American Academy ofPediatrics endorse the concept that “the primary consideration for Pathophysiologydecisions regarding life-sustaining treatment for seriously ill newborns During the last trimester, a series of physiologic events led to changesshould be what is best for the newborn,” and they recognize parents in the hormonal milieu of the fetus and its mother to facilitate neonatalas having the primary role in determining the goals of care for their transition.44 Rapid clearance of fetal lung ﬂuid is essential for successfulinfant.1,29,42 Discussions with the family should include local and transition to air breathing. The bulk of this ﬂuid clearance is mediatednational information on mortality as well as long-term outcomes. by transepithelial sodium re-absorption through amiloride sensitiveParental participation should be encouraged with open communica- sodium channels in the respiratory epithelial cells.45 The mechanismstion regarding their personal values and goals. for such an effective “self-resuscitation” soon after birth are not com- Decisions about resuscitation should be individualized to the case pletely understood. Traditional explanations based on Starling forcesand the family but should begin with parameters for care that are based and vaginal squeeze for ﬂuid clearance account only for a fraction ofon global reviews of the medical and ethical literature and expertise. the ﬂuid absorbed.The Nufﬁeld Council on Bioethics in the United Kingdom has pro-posed parameters for treating extremely premature infants that parallel Risk Factorsguidance from the American Academy of Pediatrics.1,29 When gestation Transient tachypnea is classically seen in infants delivered near term,or birth weight are associated with almost certain early death and especially after cesarean birth before the onset of spontaneous labor.46,47anticipated morbidity is unacceptably high, resuscitation is not indi- Absence of labor is accompanied by impaired surge of endogenouscated. Exceptions to comply with parental requests may be appropriate steroids and catecholamines necessary for a successful transition.48in speciﬁc cases, such as for infants born at less than 23 weeks’ gestation Additional risk factors such as multiple gestations, excessive maternalor with a birth weight of 400 g. When the prognosis is more uncertain, sedation, prolonged labor, and complications resulting from excessivesurvival is borderline with a high rate of morbidity, such as at 23 to 24 maternal ﬂuid administration have been less consistently observed.weeks’ gestation, parental views should be supported. Decisions regarding care of extremely preterm infants is always Clinical Presentationdifﬁcult for all involved. Parental involvement, active listening, and The clinical features of TTN include a combination of grunting, tachy-accurate information are critical to an optimal outcome for infants and pnea, nasal ﬂaring, and mild intercostal and subcostal retractions alongtheir families. Although parents are considered the best surrogate for with mild central cyanosis. The grunting can be fairly signiﬁcant andtheir infant, health care professionals have a legal and ethical obligation sometimes misdiagnosed as RDS resulting from surfactant deﬁciency.to provide appropriate care for the infant based on medical informa- The chest radiograph usually shows prominent perihilar streaks thattion. If agreement with the family cannot be reached, it may be appro- represent engorged pulmonary lymphatics and blood vessels. Thepriate to consult the hospital ethics committee or legal council. If the radiographic appearance and clinical symptoms rapidly improvesituation is emergent and the responsible physician concludes the within the ﬁrst 24 to 48 hours. The presence of ﬂuid in the ﬁssures isparents wishes are not in the best interest of the infant, it is appropriate a common nonspeciﬁc ﬁnding. TTN is a diagnosis of exclusion and itto resuscitate against parental objection.35 is important that other potential causes of respiratory distress in the
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1203newborn are excluded. The differential diagnosis of TTN includes third year of postnatal life. Clinical conditions associated with pulmo-pneumonia or sepsis, air leaks, surfactant deﬁciency, and congenital nary hypoplasia and approaches to prevention and treatment are dis-heart disease. Other rare diagnoses are pulmonary hypertension, cussed here.meconium aspiration, and polycythemia. Perturbation of lung development at anytime during gestation may lead to clinically signiﬁcant pulmonary hypoplasia. Two general patho-Diagnosis physiologic mechanisms contribute to pulmonary hypoplasia: extrinsicTTN is primarily a clinical diagnosis. Chest radiographs typically dem- compression and neuromuscular dysfunction. Infants with aneuploidyonstrate mild pulmonary congestion with hazy lung ﬁelds. The pul- such as trisomy 21 and those with multiple congenital anomalies ormonary vasculature may be prominent. Small accumulations of hydrops fetalis have a high incidence of pulmonary hypoplasia.extrapleural ﬂuid, especially in the minor ﬁssure on the right side, may Oligohydramnios, whether caused by premature rupture of mem-be seen. branes or diminished fetal urine production, can lead to pulmonary hypoplasia. The reduction in branching morphogenesis and surfaceManagement area for gas exchange may be lethal or clinically imperceptible. ClinicalManagement is mainly supportive. Supplemental oxygen is provided studies link the degree of pulmonary hypoplasia to the duration andto keep the oxygen saturation level greater than 90%. Infants are severity of the oligohydramnios. Similarly, pulmonary hypoplasia is ausually given intravenous ﬂuids and not fed orally until their tachy- hallmark of congenital diaphragmatic hernia (CDH), caused by extrin-pnea resolves. Rarely, infants may need continuous positive airway sic compression of the developing fetal lung by the herniated abdomi-pressure to relieve symptoms. Diuretic therapy has been shown to be nal contents. The degree of pulmonary hypoplasia in CDH is directlyineffective.49 related to the extent of herniation. Large hernias occur earlier in gesta- tion. In most cases, the contralateral lung is also hypoplastic.Neonatal Implications Lindner and associates51 report a signiﬁcant mortality risk forTTN can lead to signiﬁcant morbidity related to delayed initiation of infants born to women with premature rupture of membranes andoral feeding, which may interfere with parental bonding and establish- oligohydramnios before 20 weeks’ gestation. Their retrospective analy-ment of successful breastfeeding. The hospital stay is prolonged for sis demonstrated 69% short-term mortality risk. However, the remain-mother and infant. The existing perinatal guidelines50 recommend ing infants fared well and were discharged with apparently normalscheduling elective cesarean births only after 39 completed weeks’ ges- pulmonary function. Prediction of clinical outcome is difﬁcult fortation to reduce the incidence of TTN (Fig. 58-3). these infants. Prenatal diagnosis and treatment of pulmonary hypoplasia are discussed in Chapters 18 and 24. Postnatal treatment for pulmonaryPulmonary Hypoplasia hypoplasia is largely supportive. A subset of infants with profoundLung development begins during the ﬁrst trimester when the ventral hypoplasia have insufﬁcient surface area for effective gas exchange.foregut endoderm projects into adjacent splanchnic mesoderm (see These patients typically display profound hypoxemia, respiratory aci-Chapter 15). Branching morphogenesis, epithelial differentiation, and dosis, pneumothorax, and pulmonary interstitial emphysema. At theacquisition of a functional interface for gas exchange ensue through other end of the spectrum, some infants have no clinical evidencethe remainder of gestation and are not completed until the second or of pulmonary insufﬁciency at birth but have diminished reserves A B FIGURE 58-3 Radiographic appearance of transient tachypnea of the newborn (TTN) (A) and respiratory distress syndrome RDS (B). The radiographic characteristics of TTN include perihilar densities with fairly good aeration, bordering on hyperinﬂation. In contrast, neonates with RDS have diminished lung volumes on chest radiographs reﬂecting atelectasis associated with surfactant deﬁciency. Diffuse “ground- glass” inﬁltrates along with air bronchograms make the cardiothymic silhouette indistinct.
1204 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Originwhen stressed. In between is a cohort of patients with respiratory 50 and 80 mm Hg, with saturations between 88% and 96%. Hypercar-insufﬁciency responsive to mechanical ventilation and pharmacologic bia and hyperoxia are avoided. Heart rate, blood pressure, respiratorysupport. Typically, these patients have adequate oxygenation and ven- rate, and peripheral perfusion are monitored closely. Because sepsistilation, suggesting adequate gas exchange capacity. However, many cannot be excluded, screening blood culture and complete blood celldevelop pulmonary hypertension. The pathophysiologic sequence counts with differential counts are performed, and infants are startedbegins with limited cross-sectional area of resistance arterioles, fol- on broad-spectrum antibiotics for at least 48 hours.lowed by smooth muscle hyperplasia in these same vessels. Early useof pulmonary vasodilators such as nitric oxide is the mainstay of man- SURFACTANT THERAPYagement for increased pulmonary vasoreactivity. Optimizing pulmo- Surfactant replacement is one of the safest and most effective inter-nary blood ﬂow reduces the potential for hypoxemia thought to ventions in neonatology. The ﬁrst successful clinical trial of surfactantstimulate pathologic medial hyperplasia. If oxygenation, ventilation, use was reported in 1980 using surfactant prepared from an organicand acid-base balance are maintained, nutritional support and time solvent extract of bovine lung to treat 10 infants with RDS.54 By thecan allow sufﬁcient lung growth to support the infant’s metabolic early 1990s, widespread use of surfactant leads to a progressive decreasedemands. In many cases, the process is lengthy, requiring mechanical in RDS-associated mortality. Two strategies for treatment are com-ventilation and treatment with pulmonary vasodilators such as silde- monly used: prophylactic surfactant, in which surfactant is adminis-naﬁl, bosentan, or prostacyclin for weeks to months. Just as prenatal tered before the ﬁrst breath to all infants at risk for developing RDS,prognosis is difﬁcult to assess, predicting outcome for patients with and rescue therapy, in which surfactant is given after the onset ofpulmonary hypoplasia managed in the neonatal intensive care unit is respiratory signs. The advantages of prophylactic administrationhampered by limited data. include a better distribution of surfactant when instilled into a partially ﬂuid ﬁlled lung along with the potential to decrease trauma related to resuscitation. Avoiding treatment of unaffected infants and relatedRespiratory Distress Syndrome cost savings are the advantages of rescue therapy. Biologically activeRDS is a signiﬁcant cause of early neonatal mortality and long-term surfactant can be prepared from bovine, porcine, human, or syntheticmorbidity. However, in the past 3 decades, signiﬁcant advances have sources. When administered to patients with surfactant deﬁciency andbeen made in the management of RDS, with consequent decreases in RDS, all these preparations show improvement in oxygenation and aassociated morbidity and mortality. decreased need for ventilatory support, along with decreased air leaks and death.55 The combined use of antenatal corticosteroids and post-Perinatal Risk Factors natal surfactant improves neonatal outcome more than postnatal sur-The classic risk factors for RDS are prematurity and low birth weight. factant therapy alone.Factors that negatively affect surfactant synthesis include maternaldiabetes, perinatal asphyxia, cesarean delivery without labor, and CONTINUOUS POSITIVE AIRWAY PRESSUREgenetic factors (i.e., white race, history of RDS in siblings, male sex, In infants with acute RDS, continuous positive airway pressureand surfactant protein B deﬁciency).52 Congenital malformations that (CPAP) appears to prevent atelectasis, minimize lung injury, and pre-lead to lung hypoplasia such as diaphragmatic hernia are also associ- serve surfactant function, allowing infants to be managed withoutated with signiﬁcant surfactant deﬁciency. Prenatal assessment of fetal endotracheal intubation and mechanical ventilation. Early deliverylung maturity and treatment to induce fetal lung maturity are dis- room CPAP therapy decreases the need for mechanical ventilation andcussed in detail in Chapter 23. the incidence of long-term pulmonary morbidity.56,57 Increasing use of CPAP has led to decreased use of surfactant and decreased incidenceClinical Presentation of BPD.58 Common complications of CPAP include pneumothoraxSymptoms are typically evident in the delivery room, including tachy- and pneumomediastinum. Rarely, the increased transthoracic pressurepnea, nasal ﬂaring, subcostal and intercostal retractions, cyanosis, and leads to progressive decrease in venous return and decreased cardiacexpiratory grunting. The characteristic expiratory grunt results from output. Brief intubation and administration of surfactant followed byexpiration through a partially closed glottis, providing continuous extubation to CPAP is an additional RDS treatment strategy increas-distending airway pressure to maintain functional residual capacity ingly used in Europe and Australia.59 Prospective, randomized trialsand thereby prevent alveolar collapse. These signs of respiratory difﬁ- enrolling extremely low birth weight (ELBW) infants and comparingculty are not speciﬁc to RDS and have a variety of pulmonary and early delivery room CPAP with early prophylactic surfactant therapynonpulmonary causes, such as transient tachypnea, air leaks, congeni- are being conducted in the National Institute of Child Health andtal malformations, hypothermia, hypoglycemia, anemia, polycythe- Human Development (NICHD) Neonatal Network (i.e., SUPPORTmia, and metabolic acidosis. Progressive worsening of symptoms in trial).the ﬁrst 2 to 3 days, followed by recovery, characterizes the typicalclinical course. This timeline (curve) is modiﬁed by administration of MECHANICAL VENTILATIONexogenous surfactant with a more rapid recovery. Classic radiographic The goal of mechanical ventilation is to limit volutrauma and baro-ﬁndings include low-volume lungs with a diffuse reticulogranular trauma without causing progressive atelectasis while maintainingpattern and air bronchograms. The diagnosis can be established chem- adequate gas exchange. Complications associated with mechanicalically by measuring surfactant activity in tracheal or gastric aspirates, ventilation include pulmonary air leaks, endotracheal tube displace-but this is not routinely done.53 ment or dislodgement, obstruction, infection, and long-term compli- cations such as BPD and subglottic stenosis.ManagementInfants are managed in an incubator or under a radiant warmer in a Complicationsneutral thermal environment to minimize oxygen requirement and Acute complications include air leaks such as pneumothorax, pneu-consumption. Arterial oxygen tension (PaO2) is maintained between momediastinum, pneumopericardium, and pulmonary interstitial
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1205emphysema. The incidence of these complications has decreased sig- Because intrauterine inﬂammation is increasingly recognized asniﬁcantly with surfactant treatment. Infection, intracranial hemor- a cause of preterm parturition, antenatal inﬂammation is gainingrhage, and patent ductus arteriosus occur more frequently in VLBW more attention in the pathogenesis of BPD and other morbidities ofinfants with RDS. Long-term complications and comorbidities include prematurity.77 Chorioamnionitis has been strongly associated withBPD, poor neurodevelopmental outcomes, and retinopathy of prema- impaired pulmonary and vascular growth, a typical ﬁnding in the newturity. Incidence of these complications is inversely related to decreas- BPD.ing birth weight and gestation. Most deliveries before 30 weeks’ gestation are associated with his- Promising new therapies for the treatment of RDS include early tologic chorioamnionitis, which except for preterm initiation of laborinhaled nitric oxide and supplementary inositol for prevention of is otherwise clinically silent. The more preterm the delivery, the morelong-term pulmonary morbidity (e.g., BPD).60-62 Noninvasive respira- often histologic chorioamnionitis is detected. Increased levels of pro-tory support techniques such as synchronized nasal intermittent posi- inﬂammatory mediators in amniotic ﬂuid, placental tissues, trachealtive ventilation (SNIPPV) and high-ﬂow nasal cannulas are being aspirates, lung, and serum of ELBW preterm infants support an impor-studied to decrease ventilator-associated lung injury.63,64 tant role for both intrauterine and extrauterine inﬂammation in the development and severity of BPD. The proposed interaction between the proinﬂammatory and anti-inﬂammatory inﬂuences on the devel-Bronchopulmonary Dysplasia oping fetal and preterm lung is detailed in Figure 58-4. Several animalThe classic form of BPD was ﬁrst described65 in a group of preterm models and preterm studies demonstrate that mediators of inﬂam-infants who were mechanically ventilated at birth and who later mation, including endotoxins, tumor necrosis factor, IL-1, IL-6, IL-8,developed chronic respiratory failure with characteristic radiological and transforming growth factor α can enhance lung maturation butﬁndings. These infants were larger, late preterm infants with lung concurrently impede alveolar septation and vasculogenesis, contribut-changes attributed to mechanical trauma and oxygen toxicity. Smaller, ing to the development of BPD.78-81 Chorioamnionitis alone is associ-extremely preterm infants with lung immaturity who have received ated with BPD, but the probability is increased when these infantsantenatal glucocorticoids have developed a milder form, called new receive a second insult such as mechanical ventilation or postnatalBPD.66 This disease primarily occurs in infants weighing less than infection.82-841000 g who have very mild or no initial respiratory distress. The clini- Maternal genital mycoplasmal infection, particularly with Myco-cal diagnosis is based on the need for supplemental oxygen at 36 weeks’ plasma hominis and Ureaplasma urealyticum, is associated with pretermcorrected gestational age.67 A physiologic deﬁnition of BPD based on delivery.85 Numerous studies have isolated these organisms fromthe need for oxygen at the time of diagnosis has been developed.68 amniotic ﬂuid and placentas in women with spontaneous preterm Clinically, the transition from RDS to BPD is subtle and gradual. birth (i.e., preterm birth due to preterm labor or preterm rupture ofRadiologically, classic BPD is marked by areas of shifting focal atelec- membranes). After birth, these organisms are known to colonize andtasis and hyperinﬂation with or without parenchymal cyst formation. elicit a proinﬂammatory response in the respiratory tract, leading toChest radiographs of infants with the new BPD show bilateral haziness, BPD.reﬂecting diffuse microatelectasis without multiple cystic changes. The unpredictable variation in the incidence of BPD, despiteThese changes lead to ventilation-perfusion mismatching and increased adjusting for low birth weight and prematurity, suggests a geneticwork of breathing. Preterm infants with BPD gradually wean off predisposition to the occurrence and the severity of BPD. Expressionrespiratory support and oxygen or continue to worsen with progres- of genes critical to surfactant synthesis, vascular development, andsively severe respiratory failure, pulmonary hypertension, and a high inﬂammatory regulation are likely to play a role in the pathogenesis ofmortality risk. BPD. Twin studies have shown that the BPD status of one twin, even after correcting for contributing factors, is a highly signiﬁcant predic-Pathophysiology tor of BPD in the second twin. In this particular cohort, after control-Risk factors predisposing preterm infants to BPD include extreme pre- ling for covariates, genetic factors accounted for 53% of the variancematurity, oxygen toxicity, mechanical ventilation, and inﬂammation.69 in the liability for BPD.86 Genetic polymorphisms in the inﬂammatoryThe pathologic ﬁndings characterized by severe airway injury and response are increasingly recognized as important in the pathogenesisﬁbrosis in the old BPD have been replaced in the new BPD with large, of preterm parturition (see Chapter 28), and may be similarly impor-simpliﬁed alveolar structures, impaired capillary conﬁguration, and tant in the genesis of inﬂammatory morbidities in the preterm neonatevarious degrees of interstitial cellularity or ﬁbroproliferation.70 Airway as well.and vascular lesions tend to be associated with more severe disease. Oxygen-induced lung injury is an important contributing factor. Long-Term ComplicationsExposure to oxygen in the ﬁrst 2 weeks of life and as chronic therapy Infants with BPD have signiﬁcant pulmonary sequelae during child-has been associated in clinical studies with the severity of BPD.71,72 In hood and adolescence. Reactive airway disease occurs more frequently,animal models, hyperoxia has been shown to mimic many of the with increased risk of bronchiolitis and pneumonia. Up to 50% ofpathologic ﬁndings of BPD. Two large, randomized trials in preterm infants with BPD require readmission to hospital for lower respiratoryinfants suggested that the use of supplemental oxygen to maintain tract illness in the ﬁrst year of life.87higher saturations resulted in worsening pulmonary outcomes.73,74 BPD is an independent predictor of adverse neurologic outcomes.Barotrauma and volutrauma associated with mechanical ventilation Infants with BPD exhibit lower average IQs, academic difﬁculties,have been identiﬁed as major factors causing lung injury in preterm delayed speech and language development, impaired visual-motorinfants.75,76 Surfactant replacement therapy is beneﬁcial in decreasing integration, and behavior problems.88 Sparse data also suggest ansymptoms of RDS and improving survival. The efﬁcacy of surfactant increased risk for attention deﬁcit disorders, memory and learningto decrease the incidence of subsequent BPD is less well established. deﬁcits. Delayed growth occurs in 30% to 60% of infants with BPD atChronic inﬂammation and edema associated with positive-pressure 2 years. The degree of long-term growth delay is inversely proportionalventilation cause surfactant protein inactivation. to birth weight and directly proportional to the severity of BPD.
1206 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal OriginPrevention Strategies the myenteric plexus progresses through the third trimester. Intrauter-Several strategies to decrease the incidence of BPD have been tried, ine passage of meconium is unusual before 36 weeks and does notincluding administration of surfactant in the delivery room, antioxi- typically occur for several days after preterm delivery. The potential fordant superoxide dismutase and vitamin A supplementation, optimiz- intrauterine meconium passage increases with each week of gestationing ﬂuid and parenteral nutrition, aggressive treatment of patent thereafter.91 The physiologic stimuli for passage of meconium are stillductus arteriosus, minimizing mechanical ventilation, limiting expo- incompletely understood. Clinical experience and epidemiologic datasure to high levels of oxygen, and infection prevention. Table 58-4 suggest that a stressed fetus may pass meconium before birth. Infantsenumerates current strategies and their relative effectiveness in pre- born through meconium-stained amniotic ﬂuid have a lower pHventing BPD.89 Large, controlled clinical trials and meta-analysis have and are likely to have nonreassuring fetal heart tracings.92not demonstrated a signiﬁcant impact of these pharmacologic and Meconium-stained amniotic ﬂuid at delivery occurs in 12% to 15%nutritional interventions.90 The multifactorial nature of BPD suggests of all deliveries and occurs more frequently in post-term gestationthat targeting individual pathways is unlikely to have a signiﬁcant effect and in African Americans.93on outcome. Strategies to address several pathways simultaneously are In contrast to meconium-stained amniotic ﬂuid, meconium aspira-more promising (Fig. 58-4). tion syndrome is unusual. Meconium aspiration syndrome is a clinical diagnosis that includes delivery through meconium-stained amniotic ﬂuid along with respiratory distress and a characteristic appearance on chest radiographs. Approximately 2% of deliveries with meconium-Meconium-Stained Amniotic Fluid and stained amniotic ﬂuid are complicated by meconium aspiration syn-Meconium Aspiration Syndrome drome, but the reported incidence varies widely.94,95 The severity of theThe signiﬁcance and management of meconium-stained amniotic syndrome varies. The hallmarks of severe disease are the need for posi-ﬂuid has evolved with time. Meconium is present in the fetal intestine tive-pressure ventilation and the presence of pulmonary hypertension.by the second trimester. Maturation of intestinal smooth muscle and Severe meconium aspiration is associated with signiﬁcant mortality and morbidity risk, including air leak, chronic lung disease, and devel- opmental delay. A relationship between meconium-stained amniotic ﬂuid and TABLE 58-4 BRONCHOPULMONARY DYSPLASIA meconium aspiration syndrome has been presumed since the 1960s, PREVENTION STRATEGIES when the strategy of tracheal suctioning in the delivery room to prevent meconium aspiration was proposed.96 By the 1970s, this practice was Evidence or clinically established and afﬁrmed by retrospective reviews. Oropha- Relative Quality of ryngeal suctioning on the perineum before delivery of the chest to Intervention Effectiveness Data complement tracheal suctioning was also recommended. However, Antenatal steroids + Strong additional studies did not verify the beneﬁt of tracheal suctioning. Early surfactant ++ Strong Tracheal suctioning did not affect the incidence of meconium aspira- Postnatal systemic steroid ++ Moderate tion syndrome in vigorous infants in large, prospective, randomized Vitamin A + High trial.97 Another prospective, randomized, controlled study in 2514 Antioxidants − Moderate infants to determine the efﬁcacy of oropharyngeal suctioning before Permissive hypercapnia +++ Minimal delivery of the fetal shoulders in infants born through meconium- Fluid restriction ++ Moderate stained amniotic ﬂuid also found no reduction in meconium High-frequency ventilation ± Moderate Delivery room management ++++ Animal data aspiration syndrome.98 Amnioinfusion during labor to dilute the con- Inhaled nitric oxide + Minimal centration of meconium has also been studied to prevent meconium Continuous positive airway +++ Moderate aspiration, but a randomized trial found no reduction in the incidence pressure used early or severity of meconium aspiration.99 These well-designed clinical trials support the notion that meconium-stained amniotic ﬂuid may Pro-infammatory Chorioamnionitis Resuscitation Mechanical Oxygen Sepsis ventilation pneumonia Preterm fetal Transitional Preterm Altered lung lung lung postnatal lung development and BPD Antenatal corticosteroids Indomethacin Postnatal corticosteroidsFIGURE 58-4 Role of inﬂammation in thepathogenesis of bronchopulmonary dysplasia Anti-infammatory(BPD).
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1207not have a true mechanistic, pathophysiologic connection with meco- hypertension tends to mimic prenatal physiology when pulmonarynium aspiration syndrome. vascular resistance is necessarily high. In 2001, Ghidini and Spong100 questioned the connection between First principles of management include optimal oxygenation andmeconium-stained amniotic ﬂuid and meconium aspiration syndrome. ventilation through elimination of ventilation-perfusion mismatch.Reports describe infants born through clear amniotic ﬂuid with respi- When positive-pressure ventilation is employed, overdistention mustratory distress with pulmonary hypertension and other clinical char- be avoided to minimize the risk of lung injury and BPD. Treatmentacteristics of meconium aspiration syndrome.101 Experimental data of pulmonary hypertension has been revolutionized by pharmaco-suggest that factors promoting fetal acidosis and hypoxemia promote logic interventions that speciﬁcally reduce pulmonary vascular resis-remodeling of resistance pulmonary arteries. These same factors can tance. Of these, nitric oxide is the best studied, with clear evidence ofpromote intrauterine meconium passage. However, the remodeling, efﬁcacy for treatment of pulmonary hypertension in the settingperhaps exacerbated by inﬂammation from infection or by meconium, of meconium aspiration syndrome or sepsis.107 Clinical experienceproduces a clinical syndrome called meconium aspiration syndrome.102,103 with other pulmonary vasodilators, including sildenaﬁl, bosentan,The incidence of meconium aspiration syndrome has decreased in and prostacyclin, is increasing and has proved useful in certain clini-several centers over the past several years, perhaps a consequence cal situations.108of improvements in obstetric assessment and management,104,105 Excessive proliferation of medial smooth muscle or its presence inincluding a reduction in the incidence of post-term deliveries. vessels ordinarily devoid of smooth muscle complicates the treatmentOur center has experienced a decline in meconium aspiration syn- of pulmonary hypertension. This pathologic remodeling can occur indrome while concurrently pursuing a policy of no routine tracheal utero or during postnatal life. The stimuli for this process are notsuctioning for infants born through meconium-stained amniotic understood, but typically include hypoxic stress of extended durationﬂuid. and volutrauma associated with mechanical ventilation. Pulmonary Treatment of severe meconium aspiration syndrome has dramati- vasodilators become less effective as remodeling progresses, promptingcally improved in recent years, leading to decreases in morbidity and clinicians to pursue “gentle” ventilation strategies.109 By focusing onmortality. Signiﬁcant advances have come from treatment of pulmo- preductal rather than postductal oxygen saturations, lower ventilatornary hypertension with selective pulmonary vasodilators, including settings can be achieved, reducing the risk of remodeling.inhaled nitric oxide, sildenaﬁl, and bosentan. These improve oxygen-ation and enable less injurious ventilator strategies with reduced sub-sequent morbidity from air leak and chronic lung disease. Exogenoussurfactant administration may be another useful treatment modality. Gastrointestinal Problems inAlthough the mechanism is unclear, this intervention reduces ventila-tion-perfusion mismatch and probably reduces the risk of ventilator- Neonatal Periodassociated lung injury.106 Necrotizing enterocolitis (NEC) is a devastating complication of pre- The current state of knowledge regarding meconium-stained amni- maturity and the most common gastrointestinal emergency in theotic ﬂuid and meconium aspiration syndrome presents challenges for neonatal period. It affects 1% to 5% of infants admitted to neonatalobstetricians and neonatologists. The incidence of meconium aspira- intensive care units.110 The reported incidence is 4% to 13%111 intion syndrome has decreased, but the reasons for the decline are not VLBW infants (<1500 g). NEC is characterized by an inﬂammationreadily apparent. The Neonatal Resuscitation Program35 protocol for of the intestines, which can progress to transmural necrosis and per-delivery room management no longer recommends tracheal suction- foration. The onset typically occurs within the ﬁrst 2 to 3 weeks ofing for vigorous infants, implying that airway management leading to life, but it can occur well beyond the ﬁrst month. The mortality rateestablishment of ventilation should take precedence. Meconium or related to NEC ranges from 10% to 30% for all cases and up to 50%other material obstructing the airway should be cleared, but suctioning for infants requiring surgery.111-114 As more preterm and low-birth-an unobstructed airway at the expense of delaying initiation of effec- weight infants survive the initial days of life, the number of infantstive ventilation may be deleterious. A collaborative approach between at risk for NEC has increased. From 1982 to 1992, although overallobstetrician and neonatologist is paramount. Personnel skilled in U.S. neonatal mortality rates declined, the mortality rates for NECestablishment of ventilation and airway patency should attend any increased.26infant expected to be depressed at delivery. A variety of antenatal and postnatal exposures have been suggested as risk factors for the development of NEC.112,113,115 Gestational age and birth weight are consistently related to NEC. Among prenatal factors,Pulmonary Hypertension indomethacin tocolysis has been most often reported. Some studiesAt delivery the normal transition from fetal to neonatal pulmonary report reduced incidence of NEC in infants treated with antenatalcirculation is mediated by a rapid, dramatic decrease in pulmonary steroids.116-118vascular resistance. Endothelial cell shape change, relaxation of pulmo- Initial trials on use of indomethacin as a tocolytic showed nonary arteriolar smooth muscle, and alveolar gaseous distention all adverse neonatal affects although sample sizes were small.119,120contribute to this process. Several pathologic processes, including con- Although some subsequent case reports and retrospective reviewsgenital malformations, sepsis, and pneumonia, can alter this sequence suggested indomethacin might be associated with adverse neonatalto produce neonatal pulmonary hypertension. It typically accompanies outcomes, including NEC,121,122 others found no association123,124 ofpulmonary hypoplasia when diminished surface area for gas exchange indomethacin tocolysis with NEC when used as a single agent but didand inadequate pulmonary blood ﬂow lead to hypoxia and remodeling ﬁnd an increased risk when used as part of double-agent tocolyticof the resistance pulmonary arterioles. These vessels are more prone therapy, even after controlling for neonatal sepsis. A meta-analysis ofto constriction under conditions of acidosis and hypoxemia, resulting randomized, controlled trials and observational studies from 1966in the right to left shunting of deoxygenated blood characteristic of though 2004 found no signiﬁcant association between indomethacinneonatal persistent pulmonary hypertension. In neonates, pulmonary tocolysis and NEC in either study type, although the pooled sample
1208 CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Originsize of the published randomized, controlled trials limited statistical are adversely affected. NEC is an independent risk factor for develop-power.125 There is insufﬁcient evidence to alter use of antenatal indo- ment of cerebral palsy and developmental delay.129,130,132 For infantsmethacin in relationship to NEC (see Chapter 29). with surgical NEC, depending on the amount of bowel lost, there is Postnatal interventions to prevent the development of NEC risk of short gut syndrome requiring parenteral nutrition and, ulti-include alterations in feeding type and advancements, oral antibiot- mately, small bowel or liver transplantation. NEC is the single mostics, immune globulin use and vitamin supplementation. Decreased common cause of the short gut syndrome in children.27-29incidence of NEC has been demonstrated only for human milk. Ameta-analysis of randomized, controlled trials evaluating use ofhuman milk and NEC found a fourfold decrease (relative risk [RR] Hyperbilirubinemia= 0.25; 95% conﬁdence interval [CI], 0.06 to 0.98) with the use of Hyperbilirubinemia is common; 60% of term infants and 80% ofhuman milk.126 Mothers of infants at risk, particularly those less than preterm infants develop jaundice in the ﬁrst week of life.133 Bilirubin32 weeks’ gestation, should be encouraged to supply breast milk for levels are elevated in neonates due to increased production coupledtheir infant. Providing early prenatal and postnatal counseling on use with decreased excretion. Increased production is related to higherof human milk increases the initiation of lactation and neonatal rates of red cell turnover and shorter red cell life span.134 Rates ofintake of mother’s milk without increasing maternal stress or excretion are lower because of diminished activity of glucoronosyl-anxiety.127 Newer preventive interventions being explored include the transferase, limiting bilirubin conjugation, and increased enterohe-use of probiotics and growth factors aimed at protecting the gut patic circulation. In most cases, jaundice has no clinical signiﬁcanceepithelium.128 because bilirubin levels remain low, and it is transient. Less than 3% NEC may present slowly or as a sudden catastrophic event. Abdom- develop levels greater than 15 mg/dL.133 Risk factors for developmentinal distention occurs early, with bloody stools present in 25% of of severe jaundice are outlined in Table 58-5.cases.110 The radiographic hallmark is the presence of pneumatosis Several important risk factors have their origin in the prenatal andintestinalis or portal venous gas (see Fig. 58-2). Progression may be perinatal environment. Hyperbilirubinemia is seen more frequently inrapid, resulting in bowel perforation with evidence of free air on the infants of mothers who are diabetic (IDM). The pathogenesis ofradiograph. Early management consists of bowel decompression, increased bilirubin in IDM infants is uncertain but has been attributedintravenous antibiotics, and respiratory and cardiovascular support as to polycythemia as well as increased red cell turnover.136,137 Prenatally,indicated. The single absolute indication for surgical intervention is maternal blood group immunization may result from blood transfu-pneumoperitoneum (Fig. 58-5). sion or fetal maternal hemorrhage. Although the prevalence of Rh(D) For infants who survive NEC, morbidity is high, including high immunization has signiﬁcantly decreased with the advent of preven-rates of growth failure, chronic lung disease, and nosocomial infec- tion programs, including use of Rh immune globulin, antibodies totions.129-131 Lengths of stay and hospital costs are signiﬁcantly length- other blood group antigens may still occur. ABO hemolytic disease, aened, particularly in surgical NEC.131 Long-term neurologic outcomes common cause of severe jaundice in the newborn, rarely causes hemo- A B FIGURE 58-5 Diagnosis and pathology of necrotizing enterocolitis. A, Typical radiographic appearance of necrotizing enterocolitis, demonstrating pneumatosis and intramural gas. B, Intraoperative photograph of the small bowel, which contains intramural gas.
CHAPTER 58 Neonatal Morbidities of Prenatal and Perinatal Origin 1209 TABLE 58-5 COMMON CLINICAL RISK FACTORS brain.141 At what level more subtle neurologic abnormalities appear FOR SEVERE HYPERBILIRUBINEMIA remains unclear.139 Management of hyperbilirubinemia is aimed at the prevention of Jaundice in the ﬁrst 24 hours bilirubin encephalopathy while minimizing interference with breast- Visible jaundice before discharge feeding and unnecessary parental anxiety. Key elements in prevention Previous jaundiced sibling include systematic evaluation of newborns before discharge for the Exclusive breastfeeding presence of jaundice and its risk factors, promotion and support of Bruising, cephalohematoma successful breastfeeding, interpretation of jaundice levels based on the East Asian, Mediterranean, or Native American origin or ethnicity Maternal age >25 years hour of life, parental education, and appropriate neonatal follow-up Male sex based on time of discharge.139 Treatment of severe hyperbilirubinemia Unrecognized hemolysis (i.e., ABO, Rh, c, C, E, Kell, and other should be initiated promptly when identiﬁed. Guidelines for treatment minor blood group antigens) with phototherapy and exchange transfusion vary with gestational age, Glucose–6-phosphate dehydrogenase deﬁciency the presence or absence of risk factors, and the hour of life. Nomo- Infant of a diabetic mother grams to guide patient management are available from the American Academy of Pediatrics.139 Kernicterus is largely preventable. It requires Adapted from Centers for Disease Control and Prevention: Kernicterus in full-term infants; United States, 1994-1998. Report No.: 50(23), 2001. close collaboration between prenatal and postnatal caretakers for accu- rate dissemination of information regarding risk factors for parents and caregivers.lytic disease in the fetus. Other antibodies associated with hemolyticdisease in the fetus and newborn are discussed in Chapter 26. A fetus Feeding Problemswho is apparently unaffected in utero may have continued hemolysis Feeding problems related to complications of prematurity, congenitalpostnatally; physicians caring for the newborn should be notiﬁed of anomalies, or gastrointestinal disorders contribute signiﬁcantly toany maternal sensitization. length of stay for hospitalized newborns. In a study of children referred Other perinatal factors associated with severe hyperbilirubinemia to an interdisciplinary feeding team, 38% were born preterm.145 Pre-include delivery before 38 weeks. Infants born at 36 to 37 weeks’ gesta- mature infants with a history of neonatal chronic lung disease or neu-tion have an almost sixfold increase of signiﬁcant hyperbilirubine- rologic injury such as IVH or periventricular leukomalacia (PVL) andmia138 and require close surveillance and monitoring, especially if those with a history of NEC are at the highest risk for long-termbreastfed.139 Feeding difﬁculties, also common for the near term infant, feeding problems. These medically complex infants often have otherincrease this risk still further and may result in delayed hospital dis- comorbidities, such as tracheomalacia, chronic aspiration, and gastro-charge or readmission for the infant. The presence of bruising or a esophageal reﬂux (GER), that interfere with normal maturational pat-cephalohematoma, more common after instrumented or difﬁcult terns of feeding. Premature infants with complex medical problemsdeliveries, will also increase risk. Polymorphisms of genes coding for often require prolonged intubation and mechanical ventilation withenzymes mediating bilirubin catabolism may also contribute to the delayed initiation of enteral feeding, all of which have been associateddevelopment of severe hyperbilirubinemia.140 with subsequent feeding difﬁculties. These infants often have difﬁculty The primary consequence of severe hyperbilirubinemia is poten- integrating sensory input because of medical interventions and neuro-tial neurotoxicity. Kernicterus is a neurologic syndrome resulting logic immaturity. All of these factors combine to increase the risk offrom deposition of unconjugated bilirubin in the basal ganglia and developing oral aversion.brainstem nuclei, and neuronal necrosis.141 Clinical features may be Infants with congenital anomalies are also at high risk for feedingacute or chronic, resulting in tone and movement disorders such as disorders. Infants with tracheoesophageal ﬁstula with esophagealchoreoathetosis and spastic quadriplegia, mental retardation, and sen- atresia often have difﬁculty feeding due to tracheomalacia, recurrentsorineural hearing loss.142 A number of factors inﬂuence the neuro- esophageal stricture, and GER, which are known associates of thistoxic effects of bilirubin, making prediction of outcome difﬁcult. disorder. Infants with CDH have an extremely high incidence of oralBilirubin more easily enters the brain if it is not bound to albumin, aversion and growth problems in addition to the pulmonary complica-is unconjugated, or there is increased permeability of the blood brain tions. Surviving infants and children with CDH have a 60% to 80%barrier.142 Conditions such as prematurity that alter albumin levels or incidence of associated GER which has been shown to persist intothat alter the blood brain barrier such as infection, acidosis, and pre- adulthood.146-151 Often, GER is severe, refractory to medical therapy,maturity affect bilirubin entry into the brain. As a result, there is no and requires a surgical antireﬂux procedure. Infants with CDH oftenserum level of bilirubin that predicts outcome. In early studies of have inadequate caloric intake due to fatigue or oral aversion andinfants with Rh hemolytic disease, kernicterus developed in 8% of increased energy requirements leading to poor growth. Often theseinfants with serum bilirubin concentrations of 19 to 24 mg/dL, 33% infants require supplemental tube feedings by nasogastric, nasojejunal,with levels of 25 to 29 mg/dL, and 73% of infants with levels of 30 or gastrostomy feeding tube. These feeding difﬁculties may last severalto 40 mg/dL.141 years and are often accompanied by a behavioral-based feeding Levels of indirect bilirubin below 25 mg/dL in otherwise term component.healthy infants without hemolytic disease are unlikely to result in ker- Infants with congenital or acquired gastrointestinal abnormalitiesnicterus without other risk factors, as indicated in a study of 140 term often have associated feeding difﬁculties. Infants with conditions suchand near-term infants with levels above 25 mg/dL, in which no cases as gastroschisis with or without associated intestinal atresias oftenof kernicterus occurred.143 Kernicterus has however been reported in require prolonged hospitalization because of a slow tolerance of enteralotherwise healthy breastfed term newborns at levels above 30 mg/dL.144 feedings and a higher risk for NEC after gastroschisis repair.152,153 TheyOne of the most important of these risk factors is prematurity. The often have dysmotility and severe GER with oral aversion.154 A smallless mature the infant the greater the susceptibility of the neonatal percentage of patients have long-term intolerance of enteral feedings