73 Neonatal Morbidities of Prenatal and Perinatal Origin

JAMES M. GREENBERG, MD | BETH HABERMAN, MD | VIVEK NARENDRAN, MD | AMY T. NATHAN, MD | KURT SCHIBLER, MD

Obstetric Decisions and COMMON MORBIDITIES OF PREGNANCY AND Neonatal Outcomes NEONATAL OUTCOME The nature of obstetrics clinical practice requires consideration Complications of pregnancy that affect infant well-being may of two patients: mother and fetus. The intrinsic biological inter- be immediately evident after birth, such as hypotension related dependence of one with the other creates unique challenges not to maternal hemorrhage, or may present hours later, such as typically encountered in other realms of medical practice. Often hypoglycemia related to maternal diabetes, or thrombocyto- there is a paucity of objective data to support the evaluation of penia related to maternal preeclampsia. Anemia and thyroid risks and benefits associated with a given clinical situation, disorders related to transplacental passage of maternal immu- forcing obstetricians to rely on their clinical acumen and expe- noglobulin G (IgG) antibodies to fetal red blood cell anti- rience. Family perspectives must be integrated in clinical deci- gens or to thyroid, respectively, may even present days after sion making, along with the advice and counsel of other clinical delivery. providers. This chapter reviews how to best utilize neonatology Diabetes during pregnancy can serve as a prototypic expertise in the obstetric decision-making process. example. Infants born to women with diabetes are often macro- somic, increasing the risk of shoulder dystocia and birth injury. THE PERINATAL CONSULTATION AND THE After delivery, these infants may have significant hypoglycemia, ROLE OF THE NEONATOLOGIST polycythemia, and electrolyte disturbances, which require close surveillance and treatment. Lung maturation is delayed in the Optimal perinatal care often derives from collaboration between infant of a diabetic mother (IDM), increasing the incidence the obstetrician and neonatologist during pregnancy, and espe- of respiratory distress syndrome (RDS) at a given gestational cially around the time of labor, to eliminate ambiguity and age. The IDM also has delayed neurologic maturation, with confusion in the delivery room and to assure that patients and decreased tone typically leading to delayed onset of feeding families understand the rationale for obstetric and postnatal competence. Less common complications include an increased management decisions. The neonatologist can provide infor- incidence of congenital heart disease and skeletal malforma- mation regarding risks to the fetus associated with delaying or tions. Most neonatal complications of maternal diabetes are initiating preterm birth and can identify the optimal location managed without long-term sequelae, but may prolong length for delivery to ensure that skilled personnel are present to of hospital stay. Anticipatory guidance for parents can decrease support the newborn infant. anxiety and improve readiness for hospital discharge. Neonatal In addition to contributing information about gestational complications for the IDM are a function of maternal glyce- age–specific outcomes, the neonatologist can also anticipate mic control; thus careful screening by physicians and attention neonatal complications related to maternal disorders such as by patients will reduce neonatal morbidity due to maternal diabetes mellitus, hypertension, and multiple gestation, or pre- diabetes. natally detect fetal conditions such as congenital infections, Other morbidities of pregnancy and their effects on neonatal alloimmunization, or anomalies. When a lethal condition or outcome are summarized in Table 73.1. The list is not exhaus- high risk of death in the delivery room is anticipated, the neo- tive, and does not take into account how multiple morbidities natologist can assist with the formulation of a birth plan and may interact to create additional complications. Any of these develop parameters for delivery room intervention. problems may contribute to increased length of hospital stay Preparing parents by description of delivery room man- after delivery as well as long-term morbidity. agement and resuscitation of a high-risk infant can demystify Chorioamnionitis has diverse effects on the fetus and on the process and reduce some of the fear anticipated by the neonatal outcome. It is associated with premature rupture of expectant family. Making parents aware that premature infants membranes and therefore preterm birth. Elevated levels of pro- are susceptible to thermal instability will reduce their anxiety inflammatory cytokines may predispose neonates to cerebral when the newborn is rapidly moved to a warming bed after injury.2 While suspected or proven neonatal sepsis is more birth. The need for resuscitation is determined by careful common in the setting of chorioamnionitis, many neonates evaluation of cardiorespiratory parameters and appropri- born to mothers with histologically proven chorioamnionitis ate response according to published Neonatal Resuscitation are asymptomatic and appear unaffected, with normal preg- Program guidelines.1 nancy outcomes. Animal models and associated epidemiologic 1309

TABLE Other Morbidities of Pregnancy and Their Effects on Neonatal Outcome 73.1 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. data suggest that chorioamnionitis can accelerate fetal lung (caloric intake <1000 kcal/d). Mothers experienced significant maturation as measured by surfactant production and function. third-trimester weight loss and offspring were underweight.9 However, preterm infants born to mothers with chorioamnio- Low maternal body mass index (BMI) is associated with nitis are more likely to develop bronchopulmonary dysplasia increased risk of preterm birth.10 There is now growing evi- (BPD).3–5 The neonatal consequences of chorioamnionitis are dence that infants undernourished during fetal life have higher likely related to the timing, severity, and extent of the infection risk for development of “adult” diseases such as atherosclero- and associated inflammatory response. sis and hypertension. Poor maternal nutrition during intra- The effects of preeclampsia on the neonate are well known uterine life may signal the fetus to modify metabolic pathways and include intrauterine growth restriction (IUGR), hypo- and blood pressure regulatory systems with long-term health glycemia, neutropenia, thrombocytopenia, polycythemia, and consequences lasting into late childhood and beyond.11 Con- electrolyte abnormalities such as hypocalcemia. Most of these versely, maternal overnutrition as defined by excessive caloric problems relate to placental insufficiency with diminished intake predisposes mothers to insulin resistance and large-for- oxygen and nutrient delivery to the fetus. With delivery and gestational-age infants. In general, maternal BMI and birth supportive care, most of these problems will resolve with time, weight have increased over time even though mean gestational although some patients will require treatment with intravenous age at delivery has declined.12–15 Elevated maternal BMI is asso- calcium and/or glucose in the early neonatal period. Similarly, ciated with excess stillbirth and neonatal mortality, and may severe thrombocytopenia may require platelet transfusion increase the risk for preterm birth.16 Maternal obesity (BMI therapy. Some studies suggest preeclampsia may protect against >30) is a risk factor for developmental delay within a cohort of intraventricular hemorrhage (IVH) in preterm infants, perhaps extremely preterm infants and for cerebral palsy (CP) among a because of maternal treatment or other unknown factors.6 In term population.17,18 contrast to intrauterine inflammation, preeclampsia does not Neonatal anemia may be a consequence of perinatal events appear to accelerate lung maturation.7 Predicting the conse- such as placental abruption, ruptured vasa previa, or fetal- quences of maternal preeclampsia on neonatal outcome remains maternal transfusion. At delivery, the neonate may be asymp- difficult.8 tomatic or display profound effects of blood loss, including Maternal autoimmune disease may affect the neonate high-output heart failure or hypovolemic shock. The duration through transplacental transfer of autoantibodies. The extent and extent of blood loss along with any fetal compensation of antibody transfer drives severity of symptoms. Treatment is determines neonatal clinical status at delivery and subsequent supportive and based on the affected neonatal organ system. management. In the delivery room, prompt recognition of For example, maternal Graves disease may cause neonatal thy- acute blood loss and transfusion with O-negative blood can be rotoxicosis requiring treatment with propylthiouracil or a lifesaving intervention. β-blockers. Maternal lupus or connective tissue disease is linked Neonates from a multifetal gestation are, on average, smaller to congenital heart block that may require long-term atrial at a given gestational age than their singleton counterparts. pacing after delivery. Myasthenia gravis during pregnancy can They are also more likely to deliver before term, and therefore promote a transient form of the disease in the neonate. Sup- are more likely to experience complications associated with low portive therapy during the early neonatal period will address birth weight and prematurity described elsewhere in this most issues associated with maternal autoimmune disorders. chapter. Identical twins may also experience twin-twin trans- Passively transferred autoantibodies gradually clear from the fusion syndrome. The associated discordant growth and addi- neonatal circulation with a half-life of 2–3 weeks. tional problems of anemia, polycythemia, congestive heart Neonatal outcome associated with maternal nutritional failure, and hydrops may further complicate the clinical course status during pregnancy is of growing interest. The Dutch following delivery, even after amnioreduction or selective feto- famine of 1944–1945 created a unique circumstance for study- scopic laser photocoagulation. Of additional concern are cere- ing the consequences of severe undernutrition during pregnancy bral lesions such as periventricular white matter injury and

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 73 Neonatal Morbidities of Prenatal and Perinatal Origin 1311 ventricular enlargement that may occur more frequently in the anemia, hydrops, and high-output congestive heart failure. Rh setting of twin-twin transfusion syndrome.19 Additional epide- hemolytic disease is now uncommon, but it still must be con- miologic studies and long-term follow-up are needed to further sidered as a cause of unexplained hydrops, anemia, and/or heart address this issue. failure in infants born to Rh-negative mothers, especially if Congenital malformations present significant challenges for there is a possibility of maternal sensitization. ABO incompat- caregivers and families. Prenatal diagnosis offers opportunity to ibility is common, with up to 20% of all pregnancies potentially plan for delivery room management and provide anticipatory at risk. The responsible isohemagglutinins have weak affinity guidance. Choosing the site of delivery should be based on opti- for blood group antigens. Therefore the degree of hemolysis mizing availability of appropriate expertise. The neonatologist and subsequent jaundice varies from patient to patient. Indirect can facilitate appropriate delivery coverage and ensure avail- immunoglobulin (Coombs) testing has limited value in pre- ability of appropriate equipment, medications, and personnel. dicting clinically significant jaundice. The neonatal morbidity Table 73.1 summarizes some of the important considerations is typically restricted to hyperbilirubinemia requiring treatment associated with neonatal management of congenital malforma- with phototherapy. tions. Management considerations include availability of expertise and equipment needed for optimal management. Prematurity Table 73.1 reflects the importance of multidisciplinary input for optimal management of patients with congenital malforma- The mean duration of a spontaneous singleton pregnancy is tions. Typically, such patients are best delivered in a setting with 282 days, or 40 menstrual weeks (38 postconceptional weeks). experienced delivery room attendants. If needed consultative An infant delivered prior to completion of the 37th week of services or equipment is not readily available, arrangements gestation is considered preterm (World Health Organization should be made for prompt transfer to a tertiary care center. definition). Infant morbidity and mortality increase with Successful transports depend on clear communication between decreasing gestational age at birth. The risk of poor outcome, centers. For example, prompt notification of the delivery of defined as death or lifelong handicap, increases dramatically as an infant with gastroschisis ensures that the delivering hospi- gestational age decreases, especially for very-low-birth-weight tal will provide adequate intravenous hydration and protec- infants.25,26 The interplay between birth weight and gestational tion of exposed viscera, while alerting the referral center to age, first documented by Lemons and colleagues,27 remains valid organize availability of pediatric surgery expertise immediately (Fig. 73.1). on arrival. In settings of premature, preterm, or prolonged rupture of COMPLICATIONS OF PREMATURITY membranes and premature labor, mothers are frequently treated with antibiotics and tocolytic agents. Maternal medications Beyond increased mortality risk, prematurity is also associated administered during pregnancy for nonobstetric diseases can with increased risk of morbidity in nearly every major organ have a significant impact on the neonate. A common challenge system. Retinopathy of prematurity, BPD, necrotizing enteroco- in many centers evolved from the treatment of opiate-addicted litis (NEC), and IVH are particularly linked to the preterm state. mothers with methadone or buprenorphine.20,21 The symptoms IUGR and increased susceptibility to infection are not restricted of neonatal abstinence syndrome vary as a function of the to the preterm infant but are complicated in the immature degree of prenatal opiate exposure and age after delivery. Many infant. Table 73.2 summarizes common complications of pre- infants will appear neurologically normal at delivery, only to maturity by organ system. 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 frequent stools, and, in severe cases, seizures. Treatment options TABLE Common Complications of Prematurity by include nonpharmacologic intervention (swaddling, minimal 73.2 Organ System stimulation); methadone, morphine, or buprenorphine; or Organ System Morbidity nonnarcotic drugs such as phenobarbital. Often these infants require hospitalization for many days or weeks until their irri- Pulmonary Respiratory distress syndrome tability is under sufficient control to allow for care in a home Bronchopulmonary dysplasia Pulmonary hypoplasia setting. There is clinical evidence that neonates may also exhibit Apnea of prematurity similar symptoms following withdrawal from antenatal nico- Cardiovascular Patent ductus arteriosus tine exposure.22–24 The consequences of other illicit drug use Apnea and bradycardia during pregnancy have been widely studied, but are more dif- Hypotension ficult to assess due to difficulties with diagnosis and confound- Gastrointestinal/Liver Necrotizing enterocolitis Dysmotility/reflux ing variables. Maternal cocaine abuse has been associated with Feeding difficulties obstetric complications such as placental abruption. In the Hypoglycemia neonate, vascular compromise is suspected to predispose these Central nervous Intraventricular hemorrhage patients to cerebral infarcts and bowel injury. Developmental system Periventricular leukomalacia Cerebral palsy delay and behavioral problems are also noted, although associ- Attention deficit disorders ated factors such as poverty, lack of prenatal care, and low Visual Retinopathy of prematurity socioeconomic status clearly contribute as well. Skin Excess insensible water loss Alloimmune hemolytic disorders such as Rh hemolytic Hypothermia disease and ABO incompatibility can cause neonatal morbidity Immune/Hematologic Increased incidence of sepsis/meningitis Anemia of prematurity ranging from uncomplicated hyperbilirubinemia to severe

Females (n ϭ 1327) Males (n ϭ 1453) 1500 1500

1400 1400

1300 1300

1200 1200

1100 1100

1000 1000 0.1 900 900 Birth weight (g) Birth weight (g) 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 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.)

The preterm birth rate increased by 30% between 1983 and potential to avoid morbidities such as temperature instability, 2004, from 9.6% to 12.5%, before declining modestly. Major feeding problems, hyperbilirubinemia requiring treatment, sus- causes posited for this increase included a substantial rise in mul- pected sepsis, and respiratory distress. Infants born at 35 weeks’ tifetal gestation associated with assisted reproductive technology gestation are nine times more likely to require mechanical ven- (ART) and an increase in “indicated” preterm births (see Chapter tilation than those born at term.31 29).28,29 This last category has major import because decisions Most complications of late preterm birth are easily treated, affecting the timing and management of preterm birth can have but their economic and social impacts are substantial, and long- a profound effect on neonatal outcome. The risk of death prior term sequelae are not well understood. For example, brain to hospital discharge doubles when the gestational age decreases growth and development proceeds rapidly during the third tri- from 27.5 weeks (10%) to 26 weeks (20%). Delaying delivery mester and continues for the first several years of life. An infant even for a few days may substantially improve outcome, espe- born at 35 weeks’ gestation has approximately one-half the cially before 32 weeks, if the intrauterine environment is safe to brain volume of a term infant. Although IVH is unusual after support the fetus. However, in some clinical situations with a 32 weeks’ gestation, regions of the fetal brain, including the high potential for preterm birth, it is difficult to assess the quality periventricular white matter, continue to undergo rapid myelin- of the intrauterine environment. Three common examples are ation during this period. Studies demonstrate an association preterm premature rupture of the fetal membranes (Chapter 42), between late preterm birth and long-term neurodevelopmental placental abruption (Chapter 46), and preeclampsia (Chapter problems, including learning disabilities and attention deficit 48). In each case, prolonging gestation to allow continued fetal disorders.32–36 Additional neurologic and epidemiologic studies growth and maturation in utero is accompanied by an uncertain will be required to define mechanistic connections between late risk of rapid change in maternal status with a corresponding preterm birth and these long-term outcomes. It is also impor- increased risk of fetal compromise. Tests of fetal well-being are tant to recognize that infants born late preterm experience discussed in Chapter 34, and clinical decision making in obstet- excess infant mortality (death before 12 months) compared to rics is addressed in Chapters 28 and 29. their full-term counterparts. The infant mortality rate for 34–36 Obstetric decisions about timing of delivery in the setting of weeks’ gestation is three times higher than that for infants deliv- uncertain in utero risk are a contributing factor to the increase ered at 40 weeks.37 Recent efforts to decrease late preterm births in late preterm births (after 32–34 weeks’ gestation). The con- through reductions in elective delivery before 39 weeks demon- tribution of truly elective preterm birth must also be consid- strate meaningful progress.38 ered. While perinatal mortality continues to decrease, in part Our growing recognition of the morbidity and mortality due to a decline in stillbirths,30 interest in understanding mor- risks associated with preterm birth clearly deserves further bidity associated with late preterm birth has intensified because study. Table 73.3 compares estimates of complication rates of the large number of these late preterm infants and the between preterm and late preterm infants.

Note that extremely preterm infants, typically defined as professionals. The difficulty stems in part from the lack of those born prior to 32 weeks’ gestation and/or weighing less clarity in defining what that limit is. Indeed, it has fallen by than 1500 g, comprise only 1.5%–2% of all deliveries, while the approximately 1 week every decade over the past 40 years. late preterm population accounts for 8%–9% of all births. Thus Among developed countries, most identify the limit of extra- even uncommon complications in the later preterm population uterine viability at 22–25 weeks’ gestation.45–50 Making decisions may represent a significant health care burden. Recent efforts at this early gestational age requires accurate information focused on elimination of elective deliveries before 39 weeks regarding mortality and morbidity. At 22 weeks (22 0/7days to have seen genuine, sustainable reductions.38 Additional atten- 22 6/7 days) survival is very rare.49 Rates of survival to hospital tion to the causes and prevention of late preterm deliveries is discharge range from 15% to 30% for infants born at 23 weeks’ also warranted (Fig. 73.2). 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 DECISIONS AT THE THRESHOLD OF VIABILITY The Vermont–Oxford Network reported weight-based survival for over 4000 infants born between 401 and 500 g (mean ges- Decisions regarding treatment of infants at the “limit of viabil- tational age, 23.3 ± 2.1 weeks) from 1996 to 2000. Survival to ity” are often the most difficult for families and health care hospital discharge was 17%.54 While mortality rates fell for each 1-week increase in gestational age at delivery, long-term neurodevelopmental outcomes TABLE Estimates of Complication Rates Between did not improve proportionately. Of infants born at less than 73.3 Preterm and Late Preterm Infants 25 weeks’ gestation, 30%–50% will have moderate to severe disability, including blindness, deafness, developmental delays’ Complication of Incidence in Incidence in 46,48,51 Prematurity Preterma Late Pretermb and CP. A study from The National Institute of Child Health and Human Development (NICHD) Neonatal Research Respiratory distress 65% surf RX <1500 g 5% Network reported mortality and neurodevelopmental outcomes syndrome 80% <27 weeks39 25,40 for 4274 infants born between 22 and 24 weeks’ gestation from Bronchopulmonary 23% <1500 g Uncommon 55 dysplasia 2000 to 2011. Survival rates with and without neurodevelop- Retinopathy of ≈40% <1500 g41,42 mental impairment increased over the study period, especially prematurity at 23 and 24 weeks’ gestation, but intact survival before 23 weeks Intraventricular 11% <1500 g25 Rare remained rare and did not improve over time. hemorrhage with ventricular dilation Birth weight and gender also affect survival rates. Higher or parenchymal weights within gestational age categories and female gender involvement consistently show a survival advantage and better neurodevel- Necrotizing 5%–7% <1500 g25 Uncommon opmental outcomes.25,55 Survival and long-term outcomes of enterocolitis very preterm infants are improved with delivery at a tertiary Patent ductus 30% <1500 g25 Uncommon arteriosus care center, rather than neonatal transfer from an outlying 56–58 Feeding difficulty >90% 10%–15%41 facility. When families desire resuscitation, or dating is Hypoglycemia NA 10%–15%41 uncertain, every attempt should be made to transfer to a tertiary aDefined as less than 32 weeks and/or less than 1500 g. care center for delivery. Maternal transfer to a tertiary care bDefined as 32–38 weeks and/or 1500–2500 g. center and administration of corticosteroids (see Chapter 36) NA, Not available; surf RX, surfactant treatment. are the only antenatal interventions that have been significantly

Peak Gestational Duration Perinatal Risk Index

1992 2002

20 8

Percent 6 10 4 Deaths per thousand 2

0 0 39 40 38 39 40 41 42 43 A Gestational age (completed weeks) B Gestational age (completed weeks)

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.

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1314 PART 6 The Neonate and consistently related to improved neonatal neurodevelop- indicated. Exceptions to comply with parental requests may be mental outcomes.55 Other attempted strategies are discussed in considered in specific cases. Where prognosis is more uncertain, Chapter 29. with borderline survival and high morbidity rates (e.g., 23–24 weeks’ gestation), parental views should be supported. Planning for Delivery at the Limits of Viability Decisions regarding care of extremely preterm infants are Ideally, discussion between physicians and parents should begin always difficult. Parental involvement, active listening, and prior to birth in a nonemergent situation, and include both accurate information are critical to an optimal outcome for obstetrics and neonatal care providers. Even during active labor, infants and their families. While parents are considered the best communication with the family should be initiated as a founda- surrogate for their infant, health care professionals have a legal tion for postnatal discussions. The family should understand and ethical obligation to provide appropriate care for the infant that plans made before delivery are influenced by maternal and based on current medical information. If agreement with the fetal considerations, and based on limited information. It family cannot be reached, it may be appropriate to consult the should be emphasized that information available only after hospital ethics committee or legal counsel. If the situation is delivery, such as birth weight and neonatal physical findings, emergent and the responsible physician concludes that the may change the infant’s prognosis.46 parents’ wishes are not in the best interest of the infant, it can be appropriate to resuscitate over parental objection.63,64 Neonatal Resuscitation at the Limits of Viability If time allows before delivery of an infant whose gestational age is near the threshold of viability, a thoughtful birth plan devel- Prenatal and Perinatal Morbidities oped by the parents in consultation with maternal-fetal medi- RESPIRATORY PROBLEMS IN THE cine specialists and the neonatologist should be established. The NEONATAL PERIOD neonatologist can assist families in making decisions regarding a birth plan for their infant by providing general information No aspect of the transition from fetal to neonatal life is more about prognosis, likely hospital course, potential complications, dramatic than the process of pulmonary adaptation. In a normal survival information, and general health and well-being of term infant, lungs expand with air, pulmonary vascular resis- infants delivered at a similar gestational age. When time does tance rapidly decreases, and vigorous, consistent respiratory not permit such discussions, careful evaluation of gestational effort ensues within a minute of separation from the placenta. age and response to resuscitation are instrumental in assisting The process is dependent on crucial physiologic mechanisms, families in making decisions regarding viability or nonviability including production of functional surfactant, dilation of high- of an extremely premature infant. The presence of an experi- resistance pulmonary arterioles, bulk transfer of fluid from air- enced pediatrician at delivery is recommended to assess weight, spaces, and physiologic closure of the ductus arteriosus and gestational age, and fetal status and to provide medical leader- foramen ovale. Complications such as prematurity, infection, ship in decisions to be made jointly with families.53,55 In cases neuromuscular disorders, developmental defects, or complica- of precipitous deliveries wherein communication with families tions of labor may interfere with the transition to normal neo- has not occurred, the physician should use his/her best judg- natal respiratory function. Common respiratory problems of ment on behalf of the infant to initiate resuscitation until fami- neonates are reviewed in the following sections. lies can be brought into the discussion, erring on the side of resuscitation if the appropriate course is uncertain.59,60 Transient Tachypnea of the Newborn Under ideal circumstances, the health care team and the Definition. Transient tachypnea of the newborn (TTN), com- infant’s family should make shared management decisions monly known as “wet lungs,” is a mild condition affecting term regarding these infants. The American Medical Association and and late preterm infants. This is the most common “respiratory American Academy of Pediatrics endorse the concept that “the cause” of admission to the special care nursery. TTN is self- primary consideration for decisions regarding life sustaining limiting, with no risk of recurrence or residual pulmonary dys- treatment for seriously ill newborns should be what is best for function. It rarely causes hypoxic respiratory failure.65 the newborn,” and recognize parents as having the primary role in determining the goals of care for their infant.1,48,61 Discus- Pathophysiology. During the last trimester, a series of physi- sions with the family should include local and national infor- ologic events leads to changes in the hormonal milieu of the mation on mortality as well as long-term outcomes. Every effort fetus and its mother to facilitate neonatal transition.60 Rapid should be made to utilize up-to-date data. Health care providers clearance of fetal lung fluid is essential for successful transition tend to be more pessimistic when considering outcomes based to air breathing. The bulk of this fluid clearance is mediated solely on experience and subjective reasoning.62 Parental par- by transepithelial sodium reabsorption through amiloride- ticipation should be encouraged, with open communication sensitive sodium channels in the respiratory epithelial cells.66 regarding their personal values and goals. The mechanisms for such an effective “self-resuscitation” soon Decisions regarding resuscitation should be individualized after birth are not completely understood. Traditional explana- to the case and the family, but should begin with parameters for tions based on Starling forces and vaginal squeeze for fluid care that are based on global reviews of the medical and ethical clearance account only for a fraction of the fluid absorbed. literature and expertise. The Nuffield Council on Bioethics, in the United Kingdom, has proposed parameters for treating Risk Factors. This condition is classically seen in infants deliv- extremely premature infants that parallel guidance from the ered late preterm or early term, especially after cesarean birth American Academy of Pediatrics.1,45 Where gestation or birth before the onset of spontaneous labor.67,68 Absence of labor is weight are associated with almost certain early death, and antic- accompanied by an impaired surge of the endogenous steroids ipated morbidity is unacceptably high, resuscitation is not and catecholamines necessary for a successful transition.69

Additional risk factors such as multiple gestations, excessive branching morphogenesis and surface area for gas exchange maternal sedation, prolonged labor, and complications result- may be lethal or clinically imperceptible. Clinical studies link ing from excessive maternal fluid administration have been less the degree of pulmonary hypoplasia to the duration and sever- consistently observed. ity of the oligohydramnios. Similarly, pulmonary hypoplasia is a hallmark of congenital diaphragmatic hernia (CDH), due to Clinical Presentation. The clinical features of TTN include extrinsic compression of the developing fetal lung by the herni- a combination of grunting, tachypnea, nasal flaring, and mild ated abdominal contents. The degree of pulmonary hypoplasia intercostal and subcostal retractions along with mild central in CDH is directly related to the extent of herniation. Large cyanosis. The grunting can be prominent and is sometimes hernias occur earlier in gestation. In most cases, the contra- misdiagnosed as RDS secondary to surfactant deficiency. The lateral lung is also hypoplastic.73 Recent studies document some chest radiograph usually shows prominent perihilar streaking degree of catch-up lung growth following delivery. that represents engorged pulmonary lymphatics and blood Lindner and colleagues74 report significant mortality risk in vessels. The presence of fluid in the fissures is a common, non- infants born to women with premature rupture of membranes specific finding. Clinical symptoms rapidly improve in the first and oligohydramnios prior to 20 weeks’ gestation. The retro- 24–48 hours after birth. TTN is a diagnosis of exclusion, and spective analysis demonstrated 69% short-term mortality risk. it is important that other potential causes of respiratory dis- However, the remainder of the infants did well and were distress in the newborn are excluded. The differential diagnosis charged with apparently normal pulmonary function. Predic- of TTN includes pneumonia/sepsis, air leaks, surfactant defi- tion of clinical outcome is difficult in these infants.74,75 (Prenatal ciency, and congenital heart disease. Other rare diagnoses are diagnosis and treatment of pulmonary hypoplasia is discussed pulmonary hypertension (PHT), meconium aspiration, and in Chapters 18 and 24.) polycythemia.70 Postnatal treatment for pulmonary hypoplasia is largely supportive. A subset of infants with profound hypoplasia will have Diagnosis. This is primarily a clinical diagnosis. As noted, insufficient surface area for effective gas exchange. These chest radiographs typically demonstrate mild pulmonary con- patients typically display profound hypoxemia, respiratory aci- gestion, with hazy lung fields. The pulmonary vasculature may dosis, pneumothorax, and pulmonary interstitial emphysema. be prominent. Small accumulations of extrapleural fluid may At the other end of the spectrum, some infants will have no be seen, especially in the minor fissure on the right side. clinical evidence of pulmonary insufficiency at birth, but have diminished reserves when stressed. In between is a cohort of Management. Management is mainly supportive. Supplemen- patients with respiratory insufficiency responsive to mechanical tal oxygen is provided to keep the O2 saturations greater than ventilation and pharmacologic support. Typically, these patients 90%. Infants are usually given intravenous fluids and not fed have adequate oxygenation and ventilation, suggesting adequate orally until their tachypnea resolves. Rarely, infants may need gas exchange capacity. However, many develop PHT. The patho- continuous positive airway pressure (CPAP) to relieve symp- physiologic sequence begins with limited cross-sectional area of toms. Diuretic therapy is not effective.71 resistance arterioles, followed by smooth muscle hyperplasia in these same vessels. Early use of pulmonary vasodilators such Neonatal Implications. TTN can lead to morbidity related to as nitric oxide is the mainstay of management for increased delayed initiation of oral feeding, which may, in turn, interfere pulmonary vasoreactivity. Optimizing pulmonary blood flow with parental bonding and establishment of successful breast- reduces the potential for hypoxemia thought to stimulate feeding. The hospital stay is prolonged for mother and infant. pathologic medial hyperplasia. If oxygenation, ventilation, and Current perinatal guidelines72 recommending scheduling of acid-base balance are maintained, nutritional support over time elective cesarean births after 39 completed weeks of gestation can allow sufficient lung growth to support the infant’s meta- should reduce the incidence of TTN. bolic demands. In many cases the process is lengthy, requiring mechanical ventilation and treatment with pulmonary vasodi- Pulmonary Hypoplasia lators such as sildenafil, bosentan, or prostacyclin for weeks to Lung development begins during the first trimester when the months. Prognostic indicators for CDH such as percent pre- ventral foregut endoderm projects into adjacent splanchnic dicted lung volume and lung area–to–head circumference ratio mesoderm (see Chapter 16). Branching morphogenesis, epithe- measurements are useful for guiding management and parental lial differentiation, and acquisition of a functional interface for counseling.76 Otherwise, defining risk and predicting outcome gas exchange ensue through the remainder of gestation and are for patients with pulmonary hypoplasia managed in the neona- not completed until the second or third year of postnatal life. tal intensive care unit is hampered by limited data. Clinical conditions associated with pulmonary hypoplasia and approaches to prevention and treatment are discussed here. Respiratory Distress Syndrome Perturbation of lung development at any time during gesta- RDS is a significant cause of early neonatal mortality and long- tion may lead to clinically significant pulmonary hypoplasia. term morbidity. However, in the last three decades, significant Two general pathophysiologic mechanisms contribute to pul- advances have been made in the management of RDS with a monary hypoplasia: extrinsic compression, and neuromuscular consequent decrease in associated morbidity and mortality. dysfunction. Infants with aneuploidy, such as trisomy 21, and those with multiple congenital anomalies or hydrops fetalis Perinatal Risk Factors. The classic risk factors for RDS are have a high incidence of pulmonary hypoplasia. prematurity and low birth weight. Factors that negatively affect Oligohydramnios, whether due to very preterm premature surfactant synthesis include maternal diabetes, perinatal rupture of the membranes or diminished fetal urine produc- asphyxia, cesarean birth without labor, and genetic factors tion, can lead to pulmonary hypoplasia. The reduction in (Caucasian race, history of RDS in siblings, male sex, and

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.

Continuous Positive Airway Pressure. In infants with acute labeled the “new BPD.”95 This disease now primarily occurs in RDS, CPAP appears to prevent atelectasis, minimize lung injury, infants less than 1000 g who have very mild or no initial respira- and preserve surfactant function, allowing infants to be managed tory distress. The clinical diagnosis is based on the need for without endotracheal intubation and mechanical ventilation. supplemental oxygen at 36 weeks’ corrected gestational age.96 A Early delivery-room CPAP therapy decreases the need for physiologic definition of BPD based on the need for oxygen at mechanical ventilation and the incidence of long-term pulmo- the time of diagnosis is now the basis for diagnosis.96 Recent nary morbidity.83,84 Increasing use of CPAP has led to decreased large prospective studies of extremely preterm infants at high use of surfactant and decreased BPD.85 Common complications risk for BPD demonstrate the importance of strict diagnostic of CPAP include pneumothorax and pneumomediastinum. criteria.40 Rarely, the increased transthoracic pressure leads to progressive Clinically, the transition from RDS to BPD is subtle and decrease in venous return and decreased cardiac output. Brief gradual. Radiographic manifestations of classic BPD include intubation and administration of surfactant followed by transi- areas of shifting focal atelectasis and hyperinflation with or tion to CPAP is an additional RDS treatment strategy increas- without parenchymal cyst formation. Chest radiographs of ingly used in Europe and Australia.86 infants with the new BPD show bilateral haziness reflect- Recently, the advantages of CPAP have been combined with ing diffuse microatelectasis without multiple cystic changes. less invasive surfactant administration, which has led to reduced These changes lead to ventilation-perfusion mismatching and need for mechanical ventilation and BPD.87 Prospective, ran- increased work of breathing. Preterm infants with BPD either domized trials in extremely-low-birth-weight (ELBW) infants gradually wean off respiratory support and oxygen or continue comparing early delivery-room CPAP to early prophylactic sur- to worsen with progressively severe respiratory failure, PHT, factant therapy demonstrate equivalency as defined by death or and a high mortality risk. BPD.88 Three meta-analyses of these trials support the superior- ity of delivery-room CPAP in reducing BPD. These findings led Pathophysiology. Risk factors predisposing preterm infants to to the recommendation by the European Association of Perina- BPD include extreme prematurity, oxygen toxicity, mechanical tal Medicine and the American Academy of Pediatrics to endorse ventilation, and inflammation.97 The pathologic findings char- delivery-room CPAP as the primary mode of respiratory acterized by severe airway injury and fibrosis in the old BPD support for treating RDS.89 have been replaced in the new BPD with large simplified alveo- Mechanical Ventilation. The goal of mechanical ventilation lar structures, impaired capillary configuration, and variable is to limit volutrauma and barotrauma without causing pro- degrees of interstitial cellularity and/or fibroproliferation.98 gressive atelectasis while maintaining adequate oxygenation and Airway and vascular lesions tend to be associated with more gas exchange. Complications associated with mechanical venti- severe disease. lation include pulmonary air leaks, endotracheal tube displace- Oxygen-induced lung injury is an important contributing ment or dislodgement, obstruction, infection, and long-term factor. Exposure to oxygen in the first 2 weeks of life and as complications such as BPD and subglottic stenosis. chronic therapy has been associated in clinical studies with the Other Treatments. Studies of early inhaled nitric oxide and severity of BPD.99,100 In animal models, hyperoxia has been supplementary myo-inositol for prevention of long-term pul- shown to mimic many of the pathologic findings of BPD. Two monary morbidity failed to demonstrate significant effective- large randomized trials in preterm infants have recently sug- ness.90,91 Noninvasive respiratory support techniques such as gested that the use of supplemental oxygen to maintain higher synchronized nasal intermittent positive-pressure ventilation saturations resulted in worsening pulmonary outcomes.101 Con- and high-flow nasal cannula are currently under study to cerns regarding oxygen toxicity are reflected in the most recent decrease ventilator-associated lung injury.92,93 update of the neonatal resuscitation guidelines. Blended oxygen or, if not available, room air is now recommended for initial Complications of Respiratory Distress Syndrome. Acute resuscitation of preterm infants in the delivery room, along complications include pneumothorax, pneumomediastinum, with continuous monitoring via pulse oximetry.102 pneumopericardium, and pulmonary interstitial emphysema. Barotrauma and volutrauma associated with mechanical The incidence of these complications has decreased signifi- ventilation have been identified as major factors causing lung cantly with surfactant treatment. Infection, intracranial hemor- injury in preterm infants.103,104 Surfactant replacement therapy rhage, and patent ductus arteriosus occur more frequently in is beneficial in decreasing symptoms of RDS and improving very-low-birth-weight infants with RDS. Long-term complica- survival. The efficacy of surfactant to decrease the incidence of tions and comorbidities include BPD, poor neurodevelopmen- subsequent BPD is less well established. Chronic inflammation tal outcomes, and retinopathy of prematurity. Incidence of and edema associated with positive-pressure ventilation cause these complications is inversely related to decreasing birth surfactant protein inactivation. weight and gestation. Because intrauterine inflammation is increasingly recognized as a cause of preterm parturition, antenatal inflammation Bronchopulmonary Dysplasia is gaining more attention in the pathogenesis of BPD and The classic form of BPD was first described94 in a group of other morbidities of prematurity.105 Chorioamnionitis has been preterm infants who were mechanically ventilated at birth and shown to be strongly associated with impaired pulmonary and who later developed chronic respiratory failure with character- vascular growth, a typical finding in the new BPD. Most deliver- istic chest radiographic findings. These infants were larger, late ies before 30 weeks’ gestation are associated with histologic preterm infants with lung changes attributed to mechanical chorioamnionitis, which except for preterm initiation of labor ventilation and oxygen toxicity. More recently, smaller, extremely is often otherwise clinically silent. The more preterm the deliv- preterm infants with lung immaturity and prenatal exposure to ery, the more often histologic chorioamnionitis is detected. antenatal glucocorticoids have developed a more subtle form, Increased levels of proinflammatory mediators in amniotic

Proinflammatory

Chorioamnionitis Resuscitation Mechanical Oxygen Sepsis ventilation pneumonia

Preterm fetal Transitional Preterm Altered lung lung lung postnatal lung development and BPD

Antenatal corticosteroids Indomethacin Postnatal corticosteroids

Antiinflammatory

Figure 73.4 Role of inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD). fluid, placental tissues, tracheal aspirates, lung, and serum of tract illness in the first year of life.114 Among preterm infants ELBW preterm infants support an important role for both born at less than 29 weeks’ gestation, a large, multicenter study intrauterine and extrauterine inflammation in the development identified important perinatal risk factors, including male and severity of BPD. The proposed interaction between the gender, IUGR, maternal smoking, race/ethnicity, intubation at proinflammatory and antiinflammatory influences on the delivery, and public insurance, as predictors of respiratory developing fetal and preterm lung is detailed in Fig. 73.4. Several outcome at 1 year of age.115 animal models and preterm studies demonstrate that mediators Moreover, BPD is an independent predictor of adverse neu- of inflammation, including endotoxins, tumor necrosis factor-α, rologic outcomes. Infants with BPD exhibit lower average IQs, interleukin (IL)-1, IL-6, IL-8, and transforming growth factor-α, academic difficulties, delayed speech and language develop- can enhance lung maturation but concurrently impede alveolar ment, impaired visual-motor integration, and behavior prob- septation and vasculogenesis, contributing to the development lems.49 Sparse data also suggest an increased risk for attention of BPD.106–108 Chorioamnionitis alone is associated with BPD, deficit disorders and memory and learning deficits. Delayed but the probability is increased when these babies receive a growth occurs in 30%–60% of infants with BPD at 2 years second insult such as mechanical ventilation or postnatal of age. The degree of long-term growth delay is inversely infection.109–111 proportional to birth weight and directly proportional to the Maternal genital mycoplasma infection, particularly with severity of BPD. Mycoplasma hominus and Ureaplasma urealyticum, is associated with preterm birth.112 Numerous studies have isolated these Prevention Strategies. Several strategies to decrease the inci- organisms from amniotic fluid and placentas in women with dence of BPD have been tried, including administration of spontaneous preterm birth due to preterm labor or preterm surfactant in the delivery room, less invasive modes of surfac- rupture of membranes. Following birth, these organisms are tant administration,116 administering surfactant mixed with known to colonize and elicit a proinflammatory response in the budesonide,117,118 early caffeine therapy, antioxidant superoxide respiratory tract leading to BPD. dismutase, long-chain polyunsaturated fatty acid,119 vitamin A The unpredictable variation in the incidence of BPD, despite supplementation, optimizing fluid and parenteral nutrition, adjusting for low birth weight and prematurity, suggests a aggressive treatment of patent ductus arteriosus, minimizing genetic predisposition to its occurrence and severity. Expression mechanical ventilation, limiting exposure to high levels of of genes critical to surfactant synthesis, vascular development, oxygen, and infection prevention. Table 73.4 enumerates current and inflammatory regulation is likely to play a role in the patho- strategies and their relative effectiveness to prevent BPD.120 genesis of BPD. Twin studies have recently shown that the BPD Large, controlled clinical trials and meta-analyses have not status of one twin, even after correcting for contributing factors, demonstrated a significant impact of these pharmacologic and is a highly significant predictor of BPD in the second twin. In nutritional interventions.121 The multifactorial nature of BPD this cohort, after controlling for covariates, genetic factors suggests that targeting individual pathways is unlikely to have a accounted for 53% of the variance in the liability for BPD.113 significant effect on outcome. Strategies to address several path- Genetic polymorphisms in the inflammatory response are ways simultaneously are more promising. increasingly recognized as important in the pathogenesis of preterm parturition (see Chapter 7), and may be similarly Meconium-Stained Amniotic Fluid and Meconium important in the genesis of inflammatory morbidities in the Aspiration Syndrome preterm neonate. The significance and management of meconium-stained amniotic fluid has evolved with time. Meconium is present in the Long-Term Complications. Infants with BPD have significant fetal intestine by the second trimester. Maturation of intestinal pulmonary sequelae during childhood and adolescence. Reac- smooth muscle and the myenteric plexus progresses through tive airways disease occurs more frequently, with increased risk the third trimester. Thus intrauterine passage of meconium is of bronchiolitis and pneumonia. Up to 50% of infants with unusual before 36 weeks, and neonatal passage of meconium BPD require readmission to a hospital for lower respiratory does not typically occur for several days following preterm

suctioning prior to delivery of the fetal shoulders in infants TABLE Bronchopulmonary Dysplasia Prevention born through meconium-stained amniotic fluid also found no 73.4 Strategies reduction in meconium aspiration syndrome.129 Amnioinfusion Evidence/ during labor to dilute the concentration of meconium has also Relative Quality been studied to prevent meconium aspiration, but a recent ran- Intervention Effectivenessa of Data domized trial found no reduction in the incidence or severity 130 Antenatal steroids + Strong of meconium aspiration. These well-designed clinical trials Early delivery room surfactant ++ Strong reinforce the notion that meconium-stained amniotic fluid may Surfactant mixed with budesonide +++ Minimal not have a true mechanistic, pathophysiologic connection with Less invasive surfactant ++ Moderate meconium aspiration syndrome. administration In 2001, Ghidini and Spong131 questioned the connection Early caffeine ++ Moderate Postnatal systemic steroid ++ Moderate between meconium-stained amniotic fluid and meconium Vitamin A + High aspiration syndrome. Reports describe infants born through Antioxidants − Moderate clear amniotic fluid with respiratory distress, PHT, and other Permissive hypercapnia +++ Minimal clinical characteristics of meconium aspiration syndrome.132 Fluid restriction ++ Moderate High-frequency ventilation +/− Moderate Experimental data suggest that factors promoting fetal acidosis Delivery room management ++++ Moderate and hypoxemia promote remodeling of resistance pulmonary Inhaled nitric oxide + Minimal arteries. These same factors can promote intrauterine meco- Early use of continuous positive +++ Strong nium passage. However, the remodeling, perhaps exacerbated airway pressure by inflammation from infection or by meconium, produces a Stem cell–based therapies ++ Minimal clinical syndrome currently called meconium aspiration syn- aRelative effectiveness of each intervention to reduce the severity of drome.133,134 It is interesting to note that the incidence of meco- bronchopulmonary dysplasia. The range of symbols from − through nium aspiration syndrome has clearly decreased in several ++++ is based on published literature and clinical experience. 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. birth. The potential for intrauterine meconium passage increases My center has experienced a decline in meconium aspiration with each week of gestation after 36 weeks.122 The physiologic syndrome while concurrently pursuing a policy of no routine stimuli for in utero passage of meconium are still incompletely tracheal suctioning for infants born through meconium-stained understood. Clinical experience and epidemiologic data suggest amniotic fluid. that a stressed fetus may pass meconium prior to birth. Infants Treatment of severe meconium aspiration syndrome has born through meconium-stained amniotic fluid have lower pH dramatically improved in recent years, leading to decreases in and are likely to have nonreassuring fetal heart tracings.123 morbidity and mortality. Significant advances have come from Meconium-stained amniotic fluid at delivery occurs in treatment of PHT with selective pulmonary vasodilators, 12%–15% of all deliveries, and occurs more frequently in post- including inhaled nitric oxide, sildenafil, and bosentan. These term gestation and in African Americans.124 agents not only improve oxygenation but also allow less injuri- In contrast to meconium-stained amniotic fluid, meconium ous ventilator strategies with reduced subsequent morbidity aspiration syndrome is unusual. Meconium aspiration syn- from air leak and chronic lung disease. Exogenous surfactant drome is a clinical diagnosis that by definition includes delivery administration is another useful treatment modality. Although through meconium-stained amniotic fluid along with respira- the mechanism is unclear, this intervention reduces ventilation- tory distress and a characteristic chest radiographic appearance. perfusion mismatch and probably reduces the risk of ventilator- Approximately 2% of deliveries with meconium-stained amni- associated lung injury.137 otic fluid are complicated by meconium aspiration syndrome, The current state of knowledge regarding meconium-stained but the reported incidence varies widely.125,126 The severity of amniotic fluid and meconium aspiration syndrome presents the syndrome is also variable. The hallmarks of severe disease challenges for obstetricians and neonatologists. While the inci- are the need for positive-pressure ventilation and the presence dence of meconium aspiration syndrome has decreased, the of PHT. Severe meconium aspiration is associated with signifi- reasons for the decline are not readily apparent. Previously the cant mortality and morbidity risk, including air leak, chronic Neonatal Resuscitation Program1 protocol for delivery room lung disease, and developmental delay. management recommended tracheal suctioning only for A relationship between meconium-stained amniotic fluid depressed infants, implying that airway management to support and meconium aspiration syndrome has been presumed since ventilation should take precedence over tracheal suctioning. the 1960s, when the strategy of tracheal suctioning in the deliv- More recently, studies have challenged its role even in nonvigor- ery room to prevent meconium aspiration was proposed.127 By ous infants. As a result, the new Neonatal Resuscitation Program the 1970s this practice was clinically established and affirmed guidelines no longer recommend routine endotracheal suction- by retrospective reviews. Oropharyngeal suctioning on the ing even in nonvigorous infants at birth. Meconium or other perineum before delivery of the chest to complement tracheal material obstructing the airway should be cleared, but suction- suctioning was also recommended. However, additional studies ing an unobstructed airway at the expense of delaying initiation did not verify the benefit of tracheal suctioning. Tracheal suc- of effective ventilation may be deleterious. As always, a collab- tioning did not affect the incidence of meconium aspiration orative approach between obstetrician and neonatologist is syndrome in vigorous infants in a large, prospective, random- paramount. Personnel skilled in establishment of ventilation ized trial.128 Another prospective, randomized, controlled study and airway patency should attend any infant expected to be in 2514 infants to determine the efficacy of oropharyngeal depressed at delivery.

number of infants at risk of NEC has increased. From 1982 to Pulmonary Hypertension 1992, while overall US neonatal mortality rates declined, the At delivery, the normal transition from fetal to neonatal pulmo- mortality rates for NEC increased.42 nary circulation is mediated by a rapid, dramatic decrease in A variety of antenatal and postnatal exposures have been pulmonary vascular resistance. Endothelial cell shape change, suggested as risk factors for the development of NEC.147,148,150 relaxation of pulmonary arteriolar smooth muscle, and alveolar Gestational age and birth weight are consistently related to gaseous distention all contribute to this process.138 Endogenous NEC. Some studies report reduced incidence of NEC in infants nitric oxide is crucial for modulating pulmonary vascular resis- treated with antenatal steroids.151–153 Among prenatal factors, tance. Nitric oxide is synthesized from L-arginine derived from indomethacin tocolysis has been most often reported. Initial the urea cycle reaction. Recently, polymorphisms in urea cycle trials on use of indomethacin as a tocolytic showed no adverse enzyme genes were shown to be associated with PHT.139 Several neonatal affects, although sample sizes were small.154,155 Subse- pathologic processes, including congenital malformations, quent case reports and retrospective reviews suggested indo- hypoxia, sepsis, and pneumonia, can alter this sequence to methacin may be associated with adverse neonatal outcomes, produce neonatal PHT. The use of selective serotonin reuptake including NEC.156,157 Others found no association158,159 of inhibitors in the second half of pregnancy is associated with a indomethacin tocolysis with NEC when used as a single agent, slight increase in the incidence of PHT.140 As noted earlier, PHT but did find increased risk when used as part of double-agent typically accompanies pulmonary hypoplasia where diminished tocolytic therapy. A meta-analysis of randomized controlled surface area for gas exchange and inadequate pulmonary blood trials and observational studies from 1966 through 2004 found flow leads to hypoxia and remodeling of the resistance pulmo- no significant association between indomethacin tocolysis and nary arterioles. These vessels are more prone to constriction NEC in either study type, although the pooled sample size of under conditions of acidosis and hypoxemia, resulting in the the published randomized controlled trials limited statistical right-to-left shunting of deoxygenated blood characteristic of power.160 A retrospective cohort study of 63 infants exposed to neonatal persistent PHT. antenatal indomethacin found an association with early-onset First principles of management include optimal oxygenation NEC, within the first 14 days of life, after controlling for a and ventilation through elimination of ventilation-perfusion variety of covariates (adjusted odds ratio = 7.2; 95% confidence mismatch. When positive-pressure ventilation is employed, interval [CI], 2.5–20.6).161 A larger multicenter study is needed overdistention must be avoided to minimize the risk of lung to corroborate these results, and the risks of indomethacin injury and BPD. Treatment of PHT has been revolutionized by must be weighed against the benefits of transiently delaying pharmacologic interventions that specifically reduce pulmo- preterm birth. nary vascular resistance. Of these, nitric oxide is the best studied, Postnatal interventions to prevent the development of NEC with clear evidence of efficacy for treatment of PHT in the include alterations in feeding type and use of human milk and setting of meconium aspiration syndrome.141,142 Clinical experi- probiotics. Decreased incidence of NEC has been demonstrated ence with other pulmonary vasodilators, including sildenafil, with ingestion of human milk. A meta-analysis of randomized bosentan, milrinone, and prostacyclin, is increasing and has controlled trials evaluating use of human milk and NEC found proven useful in certain clinical situations.143 a fourfold decrease (relative risk = 0.25; 95% CI. 0.06–0.98) with Excessive proliferation of medial smooth muscle or its pres- the use of human milk.161 A large prospective study of preterm ence in vessels ordinarily devoid of smooth muscle complicates neonates born before 32 weeks’ gestation showed small but the treatment of PHT. This pathologic remodeling can occur significant reductions in relative risk for NEC among those fed in utero or during postnatal life. The stimuli for this process human milk.162 are not understood, but typically include hypoxic stress of Mothers of infants at risk, particularly those less than 32 extended duration and volutrauma associated with mechani- weeks’ gestation, should be encouraged to supply breast milk cal ventilation. Pulmonary vasodilators become less effective as for their infants. Providing early pre- and postnatal counseling remodeling progresses, prompting clinicians to pursue “gentle” on use of human milk increases the initiation of lactation and ventilation strategies.144 By focusing on preductal rather than neonatal intake of mother’s milk without increasing maternal postductal oxygen saturations, lower ventilator settings can be stress or anxiety.163 Alternations in the gut microbiome are asso- achieved, reducing the risk of remodeling. ciated with NEC.164 Although the role of probiotics remains a promising intervention, it is still controversial, with no consen- GASTROINTESTINAL PROBLEMS IN THE sus regarding organism or dose,157 and additional data required NEONATAL PERIOD for the highest-risk group, ELBW infants. NEC may present slowly or as a sudden, catastrophic event. Necrotizing Enterocolitis Abdominal distention occurs early, with bloody stools present NEC is a devastating complication of prematurity and the most in 25% of cases.145 The radiographic hallmark is the presence common gastrointestinal emergency in the neonatal period. It of pneumatosis intestinalis, and/or portal venous gas (Fig. affects 1%–5% of infants admitted to the neonatal intensive 73.5). Progression may be rapid, resulting in bowel perforation care unit.145 The reported incidence is 4%–13%146 in very-low- with evidence of free air on the radiograph. Early management birth-weight infants (<1500 g). NEC is characterized by an consists of bowel decompression and intravenous antibiot- inflammation of the intestines, which can progress to transmu- ics, with respiratory and cardiovascular support as indicated. ral necrosis and perforation. The onset is typically within the The single absolute indication for surgical intervention is first 2–3 weeks of life, but can occur well beyond the first month. pneumoperitoneum. Mortality related to NEC ranges from 10% to 30% and up to For infants who survive NEC, morbidity is high, including 50% among infants requiring surgery.146–149 As more preterm high rates of growth failure, chronic lung disease, and nosoco- and low-birth-weight infants survive the initial days of life, the mial infections.51,165,166 Duration of inpatient hospital stay and

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. cost are significantly increased, particularly in NEC requiring surgical intervention.166 Long-term neurologic outcomes are BOX 73.1 COMMON CLINICAL RISK FACTORS FOR SEVERE HYPERBILIRUBINEMIA also adversely affected. NEC is an independent risk factor for development of CP and developmental delay.55,165,167 For infants Jaundice in the first 24 hours with NEC requiring surgical intervention, depending on the Visible jaundice before discharge Previous jaundiced sibling amount of bowel lost, there is risk of short bowel syndrome Exclusive breastfeeding requiring parenteral nutrition, and ultimately small bowel and/ Bruising, cephalohematoma or liver transplant. NEC remains the single most common cause East Asian, Mediterranean, or Native American race of short bowel syndrome in children.43–45 Maternal age >25 years Male sex Hyperbilirubinemia Unrecognized hemolysis (i.e., ABO, Rhesus, anti-c, C, E, Kell, and other minor blood group antigens) Hyperbilirubinemia is common: 60% of term infants and Glucose-6-phosphate dehydrogenase deficiency 80% of preterm infants develop jaundice in the first week of Infant of a diabetic mother life.168 Bilirubin levels are elevated in neonates due to increased production coupled with decreased excretion. Increased pro- Data from Centers for Disease Control and Prevention. Kernicterus in full-term infants—United States, 1994–1998. MMWR Morb duction is related to higher rates of red cell turnover and Mortal Wkly Rep. 2001;50(23):491–494. shorter red cell life span.169 Rates of excretion are lower because of diminished activity of glucuronyl transferase, limiting bilirubin conjugation, and increased enterohepatic circulation. In most cases jaundice has no clinical significance because bilirubin levels remain low, and it is transient. Less decreased with the advent of prevention programs, including 168 than 3% of patients develop levels greater than 15 mg/dL. use of Rho(D) immune globulin, antibodies to other blood Risk factors for development of severe jaundice are outlined group antigens may still occur. ABO hemolytic disease, a in Box 73.1.170 common cause of severe jaundice in the newborn, rarely if ever Many important risk factors for hyperbilirubinemia causes hemolytic disease in the fetus. Other antibodies associ- originate in the prenatal and perinatal environment. Hyper- ated with hemolytic disease in the fetus and newborn are dis- bilirubinemia is seen more frequently in the IDM. The patho- cussed in detail in Chapter 38. It is important to recall that a genesis of increased bilirubin in the IDM is uncertain but has fetus that is apparently unaffected in utero may have continued been attributed to polycythemia as well as increased red cell postnatal hemolysis; physicians caring for the newborn must be turnover.171,172 informed of any maternal sensitization. Prenatal maternal blood group immunization may result Another perinatal factor associated with severe hyperbiliru- from blood transfusion or fetal-maternal hemorrhage. While binemia is delivery before 38 weeks’ gestation. Infants born at the prevalence of Rho(D) immunization has significantly 36–37 weeks have an almost sixfold increase of significant

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1322 PART 6 The Neonate hyperbilirubinemia173 and require close surveillance and monitoring, especially if breastfed.174 Feeding difficulties, also Feeding Problems common for the near-term infant, increase this risk still further Feeding problems related to complications of prematurity, and may result in delayed hospital discharge or readmission for congenital anomalies, or gastrointestinal disorders contribute the infant. The presence of bruising or a cephalohematoma, significantly to length of stay for hospitalized newborns. In a more common after instrumented or difficult deliveries, will study of children referred to an interdisciplinary feeding team, also increase risk. Polymorphisms of genes coding for enzymes 38% were born preterm.182 Premature infants with a history of mediating bilirubin catabolism may also contribute to the neonatal chronic lung disease, neurologic injury such as IVH or development of severe hyperbilirubinemia.175 periventricular leukomalacia (PVL), and those with a history of The primary consequence of severe hyperbilirubinemia is NEC are at the highest risk of long-term feeding problems. These potential neurotoxicity. Kernicterus is a neurologic syndrome medically complex infants often have other comorbidities such resulting from deposition of unconjugated bilirubin in the as tracheomalacia, chronic aspiration, and gastroesophageal basal ganglia and brainstem nuclei, and neuronal necrosis.176 reflux (GER) that interfere with normal maturational patterns Clinical features may be acute or chronic, resulting in tone of feeding. Premature infants with complex medical problems and movement disorders such as chorioathetosis and spastic often require prolonged intubation and mechanical ventilation quadriplegia, mental retardation, and sensorineural hearing with delayed initiation of enteral feeding, all of which have been loss.177 Several factors influence the neurotoxic effects of associated with subsequent feeding difficulties. Because of these bilirubin, making prediction of outcome difficult. Bilirubin medical interventions and neurologic immaturity, these infants more easily enters the brain if it is not bound to albumin, often have difficulty integrating sensory input. These factors if it is unconjugated, or if there is increased permeability of combine to increase the risk of developing oral aversion. the blood-brain barrier.177 Conditions that alter albumin levels, Infants with congenital anomalies are also at high risk of such as prematurity, or that alter the blood-brain barrier, such developing feeding disorders. Infants with tracheoesophageal as infection, acidosis, and prematurity, affect bilirubin entry fistula with esophageal atresia often have difficulty feeding due into the brain. As a result, there is no serum level of biliru- to tracheomalacia, recurrent esophageal stricture, and GER, bin that predicts outcome. In early studies of infants with Rh which are known associates of this disorder. Infants with CDH hemolytic disease, kernicterus developed in 8% of infants with have an extremely high incidence of oral aversion and growth serum bilirubin levels of 19–24 mg/dL, in 33% of infants with problems in addition to the pulmonary complications. Surviv- levels of 25–29 mg/dL, and in 73% of infants with levels of ing infants and children with CDH have a 60%–80% incidence 30–40 mg/dL.178 of associated GER that can persist into adulthood.183–188 Often, Levels of indirect bilirubin below 25 mg/dL in otherwise this GER is severe, is refractory to medical therapy, and requires healthy term infants without hemolytic disease are unlikely to a surgical antireflux procedure. Infants with CDH often have result in kernicterus without other risk factors, as indicated in inadequate caloric intake due to fatigue or oral aversion and a study of 140 term and near-term infants with levels above increased energy requirements leading to poor growth. These 25 mg/dL, in which no cases of kernicterus occurred.179 infants typically require supplemental tube feedings by naso- However, kernicterus has been reported in otherwise healthy gastric, nasojejunal, or gastrostomy feeding tube. Feeding dif- breastfed term newborns at levels above 30 mg/dL.180 One of ficulties may last several years and are often accompanied by the most important of these risk factors is prematurity. The less behavior-based feeding difficulties. mature the infant, the greater the susceptibility of the neonatal Finally, infants with either congenital or acquired gastro- brain.178 Levels of bilirubin contributing to subtler neurologic intestinal abnormalities frequently experience associated feed abnormalities remain unclear.174 ing difficulties. Infants with conditions such as gastroschisis Management of hyperbilirubinemia is aimed at the pre- with or without associated intestinal atresias often require pro- vention of bilirubin encephalopathy while minimizing inter- longed hospitalization because of a slow tolerance of enteral ference with breastfeeding and unnecessary parental anxiety. feedings and a higher risk of NEC following gastroschisis Key elements in prevention include systematic evaluation of repair.189,190 They often have gastrointestinal dysmotility and newborns prior to discharge for the presence of jaundice and severe GER with oral aversion.190 A small percentage of patients its risk factors, promotion and support of successful breast- have long-term intolerance of enteral feedings and require pro- feeding, interpretation of jaundice levels based on the hour longed total parenteral nutrition (TPN). Patients requiring of life, parental education, and appropriate neonatal follow- long-term TPN may develop liver injury and cholestasis and up based on time of discharge.174 Treatment of severe hyper- ultimately may require liver/small bowel transplantation. bilirubinemia should be initiated promptly when identified. Infants who develop short bowel syndrome secondary to NEC Guidelines for treatment with phototherapy and exchange also have difficulties tolerating enteral feedings depending on transfusion vary with gestational age, the presence or absence the length and function of the remaining bowel. Like patients of risk factors, and the hour of life. Nomograms to guide with gastroschisis, infants with severe short bowel syndrome patient management are available from the American Academy may require prolonged TPN and may go on to develop liver of Pediatrics.174 Kernicterus is largely preventable. Close col- and/or intestinal failure requiring transplantation. laboration between prenatal and postnatal caregivers ensures Premature infants and infants with congenital anomalies or accurate dissemination of information regarding risk factors acquired gastrointestinal abnormalities are at high risk for long- for parents and clinical providers to facilitate prompt recog- term feeding problems. It is important to counsel families nition and treatment of significant hyperbilirubinemia. In regarding this risk, including its impact on hospital length of general, predicting nonhemolytic neonatal hyperbilirubine- stay. Also, minimizing iatrogenic oral aversion is crucial. Involv- mia can be based on readily available maternal and obstetric ing a feeding specialist early in a medically complex infant’s risk factors.181 course may lessen the impact.

NEONATAL MANAGEMENT OF Apgar score with other markers such as fetal acidemia and the NEUROLOGIC PROBLEMS need for CPR in the delivery room predicts a significantly increased risk of brain injury.205,206 Perlman and Risser docu- Hypoxic-Ischemic Encephalopathy mented a 340-fold increased risk of seizures and associated Injury to the brain sustained during the perinatal period was moderate to severe encephalopathy in association with a once thought to be one of the most common causes of death 5-minute Apgar score of 5 or less, delivery room intubation or or severe, long-term neurologic deficits in children.191 However, CPR, and an umbilical cord arterial pH of less than 7.00.206a reviews of multiple studies show that only 10% of brain injury is related to perinatal or intrapartum events.192–194 There is Neonatal Encephalopathy. Neonatal encephalopathy is clini- increasing recognition that events occurring well before labor cally characterized by depressed level of consciousness, abnor- contribute more significantly to the etiology of brain injury. mal muscle tone and reflexes, abnormal respiratory pattern, and Despite improvements in perinatal practice over recent years, seizures.207 These findings may result from a hypoxic-ischemic the incidence of hypoxic-ischemic encephalopathy has remained event but can also be due to a variety of other conditions such stable at 1–2 babies per 1000 term births.195,196 Strategies for as metabolic disorders, neuromuscular disorders, toxin expo- prevention of brain injury have been mainly supportive since sure, and chromosomal abnormalities or syndromes. Not all prevention has been difficult due to the lack of clinically reli- infants with neonatal encephalopathy develop permanent able indicators and the fact that often the initiating event occurs neurologic impairment. The Sarnat staging system is used to prior to the onset of labor. However, since the brain injury that classify the degree of encephalopathy and predict neurologic develops is initiated by the hypoxic-ischemic event but also outcome.202 Infants with mild encephalopathy (Sarnat stage 1) affected by a “reperfusion phase” of injury, treatment strate- generally have a favorable outcome. Infants with moderate gies such as head or total-body cooling target this process of encephalopathy (Sarnat stage 2) develop long-term neurologic ongoing injury.197,198 compromise in 20%–25% of cases, and infants with severe encephalopathy (Sarnat stage 3) have a greater than 80% risk Definition of “Asphyxia.” The brain injury referred to as of death or long-term neurologic sequelae.207 hypoxic-ischemic encephalopathy occurs due to impaired cerebral blood flow likely as a consequence of interrupted placental Multiorgan Injury. In addition to neurologic compromise, blood flow leading to impaired gas exchange.199 If gas exchange interruption of placental blood flow can also result in systemic is persistently impaired, then hypoxemia and hypercapnia organ injury. Animal models and clinical studies have demon- develop with resultant fetal acidosis or what has been referred strated that the kidney is exquisitely sensitive to reductions in to as “asphyxia.” Severe fetal acidemia, defined as an umbilical renal blood flow.208,209 The result of decreased renal perfusion is arterial pH of less than 7.00, is associated with an increased risk acute tubular necrosis with varying degrees of oliguria and of adverse neurologic outcome.200,201 However, even with this azotemia. Fluid retention and hyponatremia can develop due to degree of acidemia, only a small portion of infants develop the combination of impaired renal function and the release of significant encephalopathy and subsequent sustained neuro- antidiuretic hormone. Other organ systems are also sensitive to logic injury.202 Therefore fetal scalp blood sampling and umbili- reduced blood flow. Decreased blood flow to the gastrointestinal cal cord gas data do not have great sensitivity in the prediction tract can lead to luminal ischemia and an increased risk of NEC. of long-term neurologic impairment. Decreased pulmonary blood flow can result in persistent PHT of the newborn. Lack of blood flow to the liver can result in Clinical Markers. Other clinical measures to identify fetal hepatocellular injury and impaired synthetic function, leading stress, such as fetal heart rate abnormalities, meconium-stained to hypoglycemia and disseminated intravascular coagulation. amniotic fluid, low Apgar scores, and need for cardiopulmonary Suppression of parathyroid hormone release can lead to hypo- resuscitation (CPR) in the delivery room, do not reliably iden- calcemia and hypomagnesemia. These electrolyte abnormalities tify infants at high risk of brain injury when used in isolation. can further affect myocardial function. Muscle can be affected Despite the widespread use of electronic fetal heart rate moni- by electrolyte abnormalities and direct cellular injury, leading toring, which detects changes in fetal heart rate related to fetal to rhabdomyolysis.199 oxygenation, there has been no reduction in the incidence of C P. 200 In 2005, an American College of Obstetricians and Gyne- Neuropathology. The reduction in cerebral blood flow associ- cologists (ACOG) Practice Bulletin, “Intrapartum Fetal Heart ated with a hypoxic-ischemic event sets off a complex cascade Rate Monitoring,”201 concluded that electronic fetal heart rate of regional circulatory factors and biochemical changes at the monitoring has a high false-positive rate for the prediction of cellular level. Hypoxia induces a switch from normal oxidative adverse outcomes and is associated with an increase in operative phosphorylation to anaerobic metabolism, leading to depletion deliveries without any reduction in CP. Meconium-stained of high-energy phosphate reserves, accumulation of lactic acid, amniotic fluid is commonly seen during labor but no data exist and inability to maintain cellular functions.199,210 The end result to associate it with adverse neurologic outcome. Apgar scores is cellular energy failure, metabolic acidosis, release of gluta- were originally introduced to identify infants in need of resus- mate and intracellular calcium, lipid peroxidation, buildup of citation and not to predict neurologic outcome. Apgar scores nitric oxide, and eventual cell death.198,207,211 It is this process are not specific to an infant’s acid-base status but can also reflect of cellular injury that is being targeted for neuroprotection drug use, metabolic disorder, trauma, hypovolemia, infection, strategies (see later). neuromuscular disorder, or congenital anomalies. However, a persistently low Apgar score after 5 minutes despite intensive Neuroimaging. Diffusion-weighted magnetic resonance imag CPR has been associated with increased morbidity and mortal- ing (MRI) has become the gold standard to define the extent and ity.178,199,203,204 Furthermore, the combination of a low 5-minute potentially the timing of the brain injury. Diffusion-weighted

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1324 PART 6 The Neonate techniques can detect signal changes due to reduced brain water diffusivity within the first 24–48 hours of the insult.198,212–214 Intraventricular Hemorrhage Magnetic resonance spectroscopy can also detect alterations IVH, or germinal matrix hemorrhage, occurs most commonly in metabolites such as lactate, N-acetylaspartate, choline, and in preterm infants and is a major cause of mortality and long- creatinine in specific regions of the brain indicating injury.212,215 term disability. Bleeding originates in the subependymal germi- However, MRI is difficult to perform in an unstable patient, nal matrix but may rupture through the ependyma into the and therefore computed tomography (CT) may be prefer- ventricular system. IVH is graded into four categories: able as the initial study for term infants, and ultrasound for Grade 1: Bleeding localized to the germinal matrix preterm infants. Grade 2: Bleeding into the ventricle but the clot does not distend the ventricle Neuroprotection Strategies. Brain cooling by selective cooling Grade 3: Bleeding into the ventricle with ventricular of the head or systemic hypothermia has been studied as a dilation therapy to reduce neurologic injury due to neonatal hypoxic- Grade 4: Intraparenchymal extension ischemic encephalopathy. Five large randomized controlled The diagnosis is made most commonly by cranial ultrasound, trials (see Pfister and Soll216 and references therein) collectively with most hemorrhages occurring within 6 hours of birth and demonstrate significant reduction in a combined outcome of 90% within the first 5 days of age.224 death or long-term major neurodevelopmental disability at 18 months’ follow-up. Additional work is required to define popu- Incidence. The incidence of IVH has decreased significantly lations most likely to benefit from treatment, as well as duration with improvements in perinatal care such as maternal transfer of the therapeutic window, optimal target temperatures, and to a tertiary care center and administration of antenatal ster- safety for preterm infants. Since these studies, multiple other oids. From 1990 to 1999 the incidence of IVH reported in randomized clinical trials have shown that hypothermia either infants less than 1000 g birth weight was 43%, with 13% being by selective head cooling or whole body cooling is associated grade 3 or 4. In 2000–2002, the overall incidence of IVH with a reduction in death and severe neurodevelopmental dis- decreased to 22%; only 3% were severe despite improvements ability at 18 months of age in term infants with moderate to in survival.225 Lower gestational age is associated with an severe hypoxic-ischemic encephalopathy (see Tagin and cowork- increased risk of severe IVH.203,218 ers217 and references therein). Therefore therapeutic hypothermia is now standard of care for infants of 36 weeks’ gestation Pathogenesis. Both anatomic and physiologic factors have or greater with moderate to severe hypoxic-ischemic encepha- been implicated in the pathogenesis of IVH. The germinal lopathy and should be initiated as soon as possible following matrix is composed of thin-walled blood vessels that lack sup- birth. Head and total body cooling appear equally efficacious portive tissue. These fragile vessels tend to rupture spontane- with similar safety profiles.218 ously or in response to stress such as hypoxia-ischemia, changes Future efforts are being focused on early identification of in blood pressure and/or cerebral perfusion, and pneumotho- those infants at the greatest risk for hypoxic-ischemic injury races. In addition to these structural factors, premature infants and defining the therapeutic window for effective treatment. have an immature cerebrovascular autoregulation system or a This window was initially thought to be limited to within 6 so-called pressure-passive circulation in response to systemic hours of delivery; however, ongoing studies are evaluating the hypotension, which makes them more susceptible to hemor- benefit of late hypothermia >( 6 hours after birth). Variation in rhage.209,224,226 Immaturities in the coagulation system and practice among neonatologists emphasizes the need for ongoing increased fibrinolytic activity of premature infants may also investigation.219 play a role.226–229 Infants at highest risk are those with evidence of a sentinel event during labor, pronounced respiratory and neuromuscular Outcomes. Although it has been generally thought that infants depression at delivery with persistently low Apgar scores, the with grade 1 or 2 IVH have similar outcomes to those without need for delivery room resuscitation, severe fetal acidemia cranial ultrasound abnormalities, a recent study by Patra and (defined as an umbilical artery pH< 7.00 and/or base deficit associates suggests that ELBW infants with grade 1 or 2 IVH ≥16 mEq/L), and evidence of an early abnormal neurologic have worse neurodevelopmental outcomes at 20 months’ cor- examination, seizures, and/or an abnormal amplitude- rected age compared to those with normal cranial ultrasounds.230 integrated electroencephalogram.198,206,220–222 Possible pharma- Infants with grade 3 IVH have adverse neurologic outcome in cologic adjunctive therapies in addition to hypothermia are also about 35% of cases. In those who develop posthemorrhagic being investigated.222,223 hydrocephalus requiring surgical intervention, the disability rate increases to about 60%.204 Grade 4 IVH is associated with Summary. Hypoxic-ischemic brain injury due to intrapartum the highest mortality rates, and 80%–90% are associated with asphyxia is a rare but serious cause of long-term neurodevelop- a poor neurologic outcome.178 mental disability. It is often difficult to define a specific intrapartum event since the initiating event may occur before the Antenatal Prevention. The only therapies shown to decrease onset of labor. Early identification of at-risk newborns by neu- the incidence of IVH in premature infants are antenatal corti- roimaging techniques, amplitude-integrated electroencepha- costeroid administration and maternal transfer to a tertiary care lography findings, history, and clinical examination may provide center for delivery. Multiple studies have shown that the admin- an opportunity to ameliorate the effects of ongoing brain injury istration of corticosteroids prior to preterm birth to induce lung using neuroprotective strategies. The goal of these therapeutic maturity has significantly reduced the incidence of RDS, mor- interventions is the reduction of long-term neurodevelopmen- tality, and severe IVH. According to a meta-analysis of four tal disabilities, including CP. trials of 596 infants from 24 to 33 weeks’ gestation, antenatal

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 73 Neonatal Morbidities of Prenatal and Perinatal Origin 1325 corticosteroid therapy was associated with a relative risk reduc- have cardiopulmonary instability are at the highest risk. Other tion for IVH of 0.57 (95% CI, 0.41–0.78).205 Maternal transfer intrauterine factors such as infection, prolonged preterm pre- to a tertiary care center for gestational age less than 32 weeks mature rupture of the membranes, first-trimester hemorrhage, has been shown to decrease the incidence of death or major placental abruption, and prolonged tocolysis have all been asso- morbidity, including IVH.57 Antenatal phenobarbital, vitamin ciated with increased risk of PVL. The reported incidence of K, and magnesium sulfate have failed to demonstrate a consis- PVL detected by ultrasound examination in very-low-birth- tent decrease in overall IVH, severe IVH, or death.231–233 weight infants is 5%–15%.246 However, ultrasound often fails to identify subtle evidence of diffuse white matter injury, and Postnatal Prevention. The goal of postnatal prevention has MRI may be a more sensitive imaging study.247 The diagno- been blood pressure stabilization to prevent fluctuations in sis of PVL at autopsy in preterm infants with normal cranial cerebral perfusion, correction of coagulation disturbances, imaging suggests that that the true incidence of PVL may be and stabilization of germinal matrix vasculature.224 Postnatal underestimated. administration of phenobarbital and muscle paralysis has been shown to stabilize blood pressure, but neither has been found to Neuropathology. Focal necrosis most commonly occurs in the decrease the incidence of IVH or neurologic impairment.234,235 cerebral white matter at the level of the trigone of the lateral Routine use of paralytics to prevent IVH in ventilated preterm ventricles and around the foramen of Monro.246 These sites neonates is not recommended. Fresh-frozen plasma and etham- make up the border zones of the long penetrating arteries. sylate to promote platelet adhesiveness and correct coagula- Classically, these lesions undergo a coagulative necrosis that tion disorders also do not reduce the incidence of IVH.231,236–238 results in cyst formation or focal glial scars.209 A more diffuse Indomethacin remains the most promising preventive therapy type of injury may also occur in conjunction with focal necro- for IVH due to its ability to constrict the cerebral vascula- sis but is more frequently recognized as an independent entity. ture, inhibit prostaglandin and free radical production, and Diffuse white matter injury seems to affect premyelinating oli- mature the germinal matrix vasculature.236,239,240 Prophylactic godendrocytes and leads to global loss of these cells and an indomethacin decreases the incidence of severe IVH. Follow- increase in hypertrophic astrocytes in response to the diffuse up studies have shown slight improvement in cognitive func- injury.209,246,248,249 This loss of oligodendrocytes leads to white tion in infants who received prophylactic indomethacin but matter volume loss and ventriculomegaly. no difference in the incidence of CP.241–243 Prophylactic indomethacin remains reserved for preterm infants at high risk Pathogenesis. The pathogenesis of PVL is primarily by of IVH. A recent study has called into question its direct hypoxia-ischemia leading to neuronal injury due to free radical effect on IVH.244 exposure, cytokine toxicity, and exposure to excessive excitatory neurotransmitters such as glutamate.209 Vascular anatomic Posthemorrhagic Hydrocephalus. The most serious compli- factors seem to play a role as well. As mentioned previously, cation of IVH is posthemorrhagic hydrocephalus due to PVL tends to occur in arterial end zones or so-called border obstruction of cerebrospinal fluid (CSF) flow. This occurs when zones250 (see Fig. 7 in Volpe246). The arterial supply is composed multiple blood clots obstruct CSF reabsorption channels, of long penetrating arteries that terminate deep in the periven- leading to transforming growth factor-1β–stimulated produc- tricular white matter; basal penetrating arteries, which supply tion of extracellular matrix proteins such as fibronectin and the immediate periventricular area; and short penetrating arter- laminin, which ultimately leads to scar formation.245 Progressive ies, which supply the subcortical white matter. Focal necrosis ventricular dilation can worsen brain injury due to damage to occurs most commonly in the anterior and posterior periven- periventricular white matter secondary to increased intracranial tricular border zones since in premature infants these vessels pressure and edema.206 Therapies such as serial lumbar punc- are immature. Diffuse white matter injury may also occur due tures, diuretics, and intraventricular fibrinolytic therapy are to vascular immaturity. At early gestations (24–28 weeks), there ineffective and may even be harmful.234 Although surgical shunt are few anastomoses between the long and short penetrators. placement carries significant risk of shunt complications and Thus arterial border zones may occur in the subcortical and infection, it remains the definitive therapy for progressive post- remote periventricular areas, resulting in a more diffuse type hemorrhagic hydrocephalus. of injury.246 The preterm brain is also vulnerable to ischemia due to Summary. IVH due to a fragile germinal matrix and an unsta- impaired cerebrovascular regulation. Preterm infants exhibit a ble cerebrovascular autoregulatory system remains a significant pressure-passive circulation; a decrease in systemic blood pres- cause of neurologic morbidity in preterm infants. Infants with sure is associated with a decrease in cerebral perfusion, leading cardiorespiratory complications are at highest risk. Antenatal to ischemia.246,251,252 Also, immature oligodendrocytes seem to corticosteroids are the most effective preventive therapy cur- be more sensitive to free radical injury, cytokine effects, and the rently available. Despite significant reduction in the incidence presence of glutamate (see Fig. 9 in Allan and Volpe253). of severe IVH, new prevention and treatment therapies for hydrocephalus are needed. Clinical Outcomes. The most common long-term sequela of PVL is spastic diplegia, a form of CP wherein the lower extremi- Periventricular Leukomalacia ties are more affected than the upper extremities. The descend- PVL refers to injury to the deep cerebral white matter in two ing fibers of the motor cortex, which regulate function of the characteristic patterns, described as focal periventricular necro- lower extremities, traverse the periventricular area and are most sis and diffuse cerebral white matter injury. This type of brain likely to be injured. More severe injury with lateral extension injury typically affects premature infants and is a common may be associated with spastic quadriplegia or other manifesta- cause of CP. Preterm infants who have suffered an IVH and/or tions such as cognitive, visual, or auditory impairments.

Summary. PVL is a major cause of neurologic morbidity in encephalomalacia, gliosis, and ventriculomegaly for remote premature infants, especially those less than 1000 g birth weight. events. Magnetic resonance angiography may be useful in some Prevention is currently the only strategy to treat PVL. Avoidance cases to confirm arterial occlusion, although is not commonly of fluctuations in blood pressure and cerebral vasoconstrictors used unless a vascular malformation is suspected. Functional such as extreme hypocarbia are important due to the known MRI may be valuable in the future to understand how the brain immaturity in cerebrovascular autoregulation of preterm reorganizes following perinatal stroke.255,266,267 Electroencepha- infants. Future investigational strategies targeting the cascade of lography may detect subclinical seizures, which may cause sec- oligodendroglial death may be promising. ondary brain injury.255 Further diagnostic studies focused on risk factors for peri- Perinatal Stroke natal ischemic stroke should include blood tests for coagulation Arterial ischemic stroke (AIS) in neonates is defined as a cere- disturbances and genetic predispositions, urine toxicology for brovascular event around the time of birth with resultant clini- metabolic disorders and toxins such as cocaine, echocardio- cal and/or radiographic evidence of focal cerebral arterial gram, infection workup (including lumbar puncture), maternal infarction.254 The majority of cases occur in the distribution of testing for acquired coagulation disorders such as antiphospho- the middle cerebral artery.211,255–257 AIS accounts for most peri- lipid antibodies, and an assessment of the placenta.211 natal ischemic strokes. When diagnosis is based on symptoms in the neonatal period, the reported incidence is 1 in 4000 live Outcome. Perinatal ischemic stroke is the most common cause births.211,258,259 The incidence of perinatal ischemic strokes that of hemiplegic CP.211 Although not all survivors of perinatal were asymptomatic in the neonatal period and diagnosed later stroke suffer long-term disabilities, 50%–75% of infants who is unknown. suffered a perinatal stroke will have a neurologic deficit or seizures.250,255,268–270 Lee and colleagues reported a population- Clinical Presentation. Neonatal seizures are the most common based study of neonatal AIS showing that 32% of infants with clinical presentation and can be focal in origin without other AIS who presented with symptoms in the neonatal period went signs of neonatal encephalopathy.211,260 Many infants are sys- on to develop CP, whereas 82% of infants diagnosed retrospec- temically ill and the diagnosis is made with neuroimaging to tively developed CP.250 Because cases identified retrospectively rule out evidence of hypoxic-ischemic injury or bleeding. Neo- presented because of hemiparesis, they were more likely to be nates with focal neurologic signs account for about 30% of classified as having CP. cases.255,259,261–263 Perinatal stroke may also be identified retrospectively in initially well-appearing infants who present in later Summary. Perinatal ischemic stroke is a major cause of long- months with signs of hemiparesis, developmental delay, or sei- term neurologic disability. Treatment is purely supportive and zures.211,264 In these cases, neuroimaging reveals a remote injury management is via rehabilitation focusing on muscle strength- often in the distribution of the middle cerebral artery. ening and prevention of contractures. Neuroprotective strategies and approaches to prevention are needed. Advanced Pathophysiology and Risk Factors. The mechanisms of peri- neuroimaging techniques to better understand how the brain natal stroke are thought to be multifactorial. Regional ischemia reorganizes following this type of injury are currently being with subsequent hypoxia and infarction clearly plays a role. utilized as research tools. Also, a relative hypercoagulable state in newborns due to the presence of fetal hemoglobin, polycythemia, and activation of Cerebral Palsy coagulation factors in the fetus and mother around the time of As early as 1862, William John Little described the relation- birth seems to increase the risk of a thromboembolic event ship between children with motor abnormalities and preg- leading to stroke.211,265 Risk factors for perinatal stroke include nancy complications such as difficult labor, neonatal asphyxia, maternal and placental disorders, neonatal hypoxic-ischemic and premature birth.212 CP is a clinical diagnosis that refers injury, hematologic disorders, infection, cardiac disorders, to a group of nonprogressive motor impairments. In 2005, trauma, and drugs.211 However, many mothers have no obvious the International Committee on Cerebral Palsy Classification risk factors at the time of delivery.263 defined CP as “a group of developmental disorders of movement and posture, which cause activity limitations that are Neuroimaging and Electroencephalographic Assessment. attributed to nonprogressive disturbances that occurred in Although cranial ultrasound is the easiest to perform, it is not the developing fetal or infant brain. The motor disorders of a sensitive indicator of perinatal stroke.210 Little information CP are often accompanied by disturbances of sensation, cog- exists on prenatal cranial ultrasound. However, prenatal ultra- nition, communication, perception, and/or behavior, and/or sounds may demonstrate areas of unilateral echolucencies, by a seizure disorder.”213 Despite improvements in perinatal which may represent areas later identified as prenatal stroke. CT care, the prevalence of CP has remained relatively unchanged imaging can usually be performed readily in neonates and over the past 50 years with an incidence of 1.5–3.5 per 1000 usually does not require sedation. CT evidence of perinatal live births.207,271–273 ischemic stroke includes focal hypodensity with or without intraparenchymal hemorrhage, abnormal grey-white matter Classification. Traditionally, CP has been classified by topog- differentiation, and evidence of volume loss or porencephaly if raphy based on the affected limb involvement (i.e., monoplegia, the injury is remote (Fig. 73.6).211 hemiplegia, diplegia, triplegia, and quadriplegia) and a descrip- MRI with diffusion-weighted imaging is the most sensitive tion of the predominant type of tone or movement abnormality method, especially in the setting of early infarction. MRI may (i.e., spastic, dyskinetic, ataxic, hypotonic, or mixed). The Inter- be able to demonstrate restricted diffusion within a vascular national Committee on Cerebral Palsy Classification has pro- distribution for acute stroke as well as chronic changes such as posed a new classification system that additionally considers

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. the presence or absence of associated impairments, other and 0.1% for visual impairment.276 With improvements in sur- anatomic involvement besides limbs, radiologic findings, and vival for ELBW infants (defined as <1000 g birth weight), there causation.213 are concerns that disability rates will increase as well. Several authors have reported increasing neurodevelopmental disabil- Etiology. CP is a result of injury to the developing brain that ity rates for ELBW infants born in the 1990s, with rates of CP occurs during prenatal, perinatal, or postnatal life. The large ranging from 8% to 19%, rates of developmental disability from majority (75%–80%) of cases of CP have been attributed to 19% to 49%, rates of hearing impairment from 1% to 4%, and events during pregnancy. Ten percent are attributable to intra- rates of visual impairment from 1% to 4%.48,167,277–279 When partum events such as birth asphyxia,192,274,275 and 10% follow extreme prematurity is considered, Shankaran and coworkers postnatal causes such as head injury or central nervous system showed that surviving infants born at the threshold of viability infection.214,215 Risk factors of CP include prematurity, multiple (defined as birth weight< 750 g, gestational age <24 weeks, and gestation, IUGR, intracranial hemorrhage, PVL, infections, pla- a 1-minute Apgar of ≤3) had neurodisability rates of 60%, with cental pathology, genetic syndromes, structural brain abnor- nearly one-third of infants having CP.280 The increase in dis- malities, birth asphyxia or trauma, and kernicterus. The origins ability rates have been postulated to be related to heavy use of of CP tend to be multifactorial, but in some cases no cause is postnatal steroids to treat neonatal chronic lung disease and identified. Some of the more common risk factors are discussed high rates of sepsis in this population. Poor neurodevelopmen- here in detail; the roles of intracranial hemorrhage, PVL, and tal outcomes have been associated with widespread use of post- birth asphyxia contributing to CP have been discussed in previ- natal steroids in the 1990s, so that routine use of this therapy ous sections of this chapter. to treat chronic lung disease is now discouraged.47,281–283 The Prematurity. Prematurity and low birth weight are the most association between sepsis and CP has also been identified in important identifiable risk factors for CP, with an increased multiple studies and is discussed in a later section. prevalence of CP associated with decreasing gestational age and With recent improvements in the survival of extremely-low- decreasing birth weight as compared to term infants. For com- gestational-age neonates, strategies to reduce associated mor- parison purposes, it is important to consider the rates of CP bidity are increasingly important. Decreased rates of CP have and neurosensory impairments in term infants. Msall reported been reported in ELBW infants born between 2000 and 2002, a rates of disability in term infants as follows: 0.2% for CP, time period associated with increased use of antenatal steroids, 2%–3% for cognitive impairment, 0.1%–0.3% for hearing loss, decreased use of postnatal steroids, and decreased incidence of

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1328 PART 6 The Neonate nosocomial sepsis.225 Chronic lung disease is an independent malformations, or constitutional small stature. Furthermore, risk factor for neurodevelopmental disability for which studies of risk of CP often use birth weight alone to define improved strategies are needed. Inhaled nitric oxide for preterm their population of interest, which could explain the observed infants with respiratory failure has been studied, and improved increased risk of CP associated with low birth weight. This cognitive outcome in infants treated with inhaled nitric oxide increased risk of CP could actually be due to effects of IUGR has been reported,284,285 but this has not been consistently since these cohort studies include both more mature SGA observed in ELBW infants.90,286,287 infants and preterm infants with equivalent birth weights.306,307 Multiple Births. The risk of developing CP is significantly Therefore the terminology used affects how data may be higher in multiple gestations compared to singleton births. Data interpreted. from CP registries show that the risk for developing CP in Many studies have demonstrated that SGA term or preterm twins is 4–5 times greater than in singletons; for triplets the infants greater than 33 weeks’ gestation have the highest risk of risk is 12–13 times greater.207,220,288,289 Although twins comprise developing CP.299–301 The Surveillance of Cerebral Palsy in only 1.6% of the population, they have a 5%–10% incidence Europe Collaborative Group reported that babies born between of C P. 290,291 The higher rate of CP in multiple births may relate 32 and 42 weeks’ gestation and with a birth weight less than the to preterm birth, along with complications associated with 10th percentile were 4–6 times more likely to develop CP than multiple gestation such as placental and cord abnormalities, infants with a birth weight between the 25th and 75th percen- intraplacental shunting, structural anomalies, and difficulties tiles.307 For infants born at less than 33 weeks’ gestation with at delivery. fetal growth restriction, the association is less clear because this The incidence of CP increases as birth weight decreases. population has the highest risk of adverse neurodevelopmental Infants with birth weights less than 1500 g comprise 0.9% of outcome. Therefore it is difficult to separate the risk due purely singletons, 9.4% of twins, 32.2% of triplets, and 73.3% of qua- to growth restriction versus the effect of prematurity in general. druplets.220 Population-based registries have also broken down Other factors shown to increase the risk of CP include the sever- the risks of CP per 1000 neonatal survivors related to birth ity of the SGA, male gender, and asphyxia.309 weight groups as follows: 66.5 for infants less than 1000 g, 57.4 Growth-restricted infants may be more susceptible to for infants 1000–1499 g, and 8.9 for infants 1500–2499 g.292 intrapartum hypoxia, which then leads to adverse neurologic However, twins with birth weight greater than 2500 g have a outcome. Data from the Collaborative Perinatal Project showed three- to fourfold increased risk of developing CP compared that infants with IUGR had similar incidences of CP compared to singletons.220 It is unclear why this risk increases near term, to non-IUGR infants when examined at 7 years of age in the but it is thought to be due to an increased risk of asphyxia absence of intrapartum hypoxia. However, when intrapartum and/or fetal growth restriction that occurs more commonly in hypoxia was identified, the children with IUGR had an increased multiples. incidence of neurodevelopmental disability compared to those The risk of CP is also increased with the fetal death of a without IUGR.236 The relative risk of CP due to intrapartum co-twin and is higher in same-gender versus discordant-gender hypoxia was actually lower in a study of infants who were SGA twins.293–296 Furthermore, when both twins are born alive and compared with appropriate-for-gestational-age infants.302 These one twin dies in infancy, the risk is even greater than if one twin conflicting results suggest that other factors may be involved. died in utero, again with same-gender twins having a greater Perinatal Infections. Maternal, intrauterine, and neonatal risk than discordant-gender twins.220 These data suggest that infections have all been associated with CP. Congenital viral monochorionicity plays a significant role in the pathogenesis of infections such as TORCH infections—including toxoplasmo- CP, likely due to the placental vascular anastomoses. sis, rubella, cytomegalovirus (CMV), herpes simplex virus Finally, ART remains associated with an elevated risk for (HSV), and syphilis—may account for 5%–10% of cases of CP. multiple gestations. The increased risk of CP associated with Maternal infection and inflammation have been associated with ART is largely due to the higher percentage of preterm births an increased incidence of preterm birth, which is also a risk in such pregnancies. However, a Danish study suggested that in factor for the development of CP. Intraamniotic infection, also vitro fertilization pregnancies may carry an increased risk of CP referred to as clinical chorioamnionitis, has been associated not attributable to birth weight or gestation.221 Therefore this with premature rupture of the fetal membranes and subsequent increased risk of CP associated with ART requires further study preterm birth.310,311 Chorioamnionitis has also been associated (see also Chapter 41). with an increased risk of developing CP via several likely mech- Growth Restriction. There is much debate in the litera- anisms. An increased risk of IVH and PVL has been associated ture as to whether infants with fetal growth restriction have with maternal chorioamnionitis and premature rupture of an increased incidence of CP. Many authors have reported an membranes in numerous studies.312–316 Histologic chorioamni- increased risk of CP in infants who are considered “small for onitis without clinical signs of intraamniotic infection has also gestational age” (SGA).297–302 However, fetal growth restriction been linked to increased risk of IVH, PVL, and CP.317–321 is a distinct clinical entity. Fetal growth restriction refers to In recent years, laboratory and clinical evidence has emerged failure of a fetus to grow at a predicted rate using fetal growth that supports the hypothesis that intrauterine infection and standards as opposed to neonatal growth standards. These fetal inflammation lead to the production of proinflammatory cyto- growth standards are derived using ultrasound measurements kines, which are responsible for white matter brain injury and of healthy fetuses in utero at each gestational age and can take ultimately CP. These cytokines are potentially toxic to develop- into account variables such as fetal sex, ethnicity, parity, and ing oligodendrocytes in fetal white matter and cause reduced maternal height and weight.303–305 SGA refers to infants who myelination and subsequent white matter injury.313,322,323 In are statistically smaller than average at a given gestational age addition, various cytokines could have a direct toxic effect on but does not consider potential etiologies of SGA such as chro- cerebral white matter by increasing the production of nitric mosomal anomalies, congenital infections, structural brain oxide synthase, cyclooxygenase, other associated free radicals,

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 73 Neonatal Morbidities of Prenatal and Perinatal Origin 1329 and excitatory amino acids.323–326 This relationship between birth since these factors seem to be the most significant con- elevated cytokine levels and the development of white matter tributors to the development of CP. Strategies commonly used injury has been seen in both preterm and term infants. A four- to reduce intrapartum hypoxia, such as fetal heart monitor- to sixfold increased risk for white matter injury has been associ- ing, maternal oxygen administration, repositioning, and strict ated with elevated levels of IL-1β from amniotic fluid and from guidelines for oxytocin use, have not affected the rate of CP.337 umbilical cord blood in preterm infants.327,328 In a study of term Fetal heart rate monitoring could even increase the prevalence infants who went on to develop CP, stored blood samples had of CP by increasing the risk of chorioamnionitis.338,339 Fetal significantly increased levels of the cytokines IL-1, IL-8, IL-9, heart rate monitoring increases the rate of operative interven- tumor necrosis factor-β, and RANTES (regulated on activa- tions without any reduction in the rate of CP.201 Reduction tion, normal T cell expressed and secreted).329 Furthermore, of perinatal intracranial injuries associated with the decreased the combination of intrauterine infection and intrapartum use of forceps and vacuum extraction in the last 20 years is hypoxia has been correlated with a dramatic increase in the a positive trend that may contribute to a reduction in the incidence of CP.330 incidence of CP.207,340 Neonatal infection has also been associated with the devel- Preterm birth accounts for approximately 35% of CP cases.341 opment of CP due to direct central nervous system damage Therefore it is logical that strategies to reduce the incidence of (e.g., in meningitis) or to a systemic inflammatory response preterm birth will reduce the incidence of CP, provided these syndrome that leads to sepsis, shock, and multi–organ system interventions do not increase the risk of an in utero insult. failure. Preterm infants who develop infection seem to be at Prevention of preterm birth has proved elusive, making strate- higher risk.331,332 A study of 6093 ELBW survivors born between gies to reduce morbidity more immediately promising. However, 1993 and 2001 found an 8% incidence of CP among infants recent literature has shown that the following strategies are who did not develop a postnatal infection, and a 20% incidence helpful to reduce the rate of preterm birth: limiting the number of CP in infants whose hospital course was complicated by of embryos transferred with in vitro fertilization, programs sepsis, NEC, or meningitis.145 The infected infants also had an supporting smoking cessation, screening for and treatment of extremely high risk of cognitive impairment, defined as a Bayley asymptomatic bacteriuria during pregnancy, the use of anti- Mental Development Index less than 70, at 18 months com- platelet drugs to prevent preeclampsia, the use of prophylactic pared to noninfected infants (33%–42% versus 22%, respec- progesterone in women with prior preterm births or shortened tively).279 Another study in ELBW survivors found that NEC cervices at midgestation, and the use of cervical cerclage for requiring surgical intervention was associated with a significant women with a previous preterm birth and short cervix.45,342,343 increase in the incidence of both CP and developmental dis- Antenatal steroids decrease the incidence of several morbidities abilities compared to those without NEC.167 strongly associated with CP, including IVH, PVL,205,344 RDS, and Placental Abnormalities. Since the placenta supplies nutri- chronic lung disease. Postnatal steroids to treat neonatal chronic ents and oxygen to the developing fetus and acts as a barrier lung disease, however, are associated with a significant increase to protect the fetus from infectious organisms, toxins, trauma, risk of CP.281,345–347 and immune mediators, placental abnormalities can predispose Another strategy to reduce CP in preterm infants is the fetuses to adverse outcomes. Placental abnormalities associated administration of magnesium sulfate prior to delivery. The with CP can fall into three categories. The first encompasses proposed mechanism of benefit is the ability of magnesium events that occur during or prior to labor, also known as “senti- sulfate to stabilize vascular tone, reduce reperfusion injury, nel lesions,” which can cause fetal hypoxia. These lesions include and reduce cytokine-mediated injury.348,349 Several observa- uteroplacental separation, fetal hemorrhage, and umbilical cord tional studies note an association between maternal admin- occlusion.333 The next category is made up of thromboinflam- istration of magnesium sulfate either for preeclampsia or matory processes that affect fetal circulation and include fetal preterm labor and a reduced risk of CP.350–353 However, other thrombotic vasculopathy, chronic villitis, meconium-associated authors have reported no protective effect of magnesium.354–360 fetal vascular necrosis, and fetal vasculitis related to chorioam- The Australasian Collaborative Trial of Magnesium Sulphate nionitis.333,334 The third category includes processes that cause examined the efficacy of magnesium sulfate given to women decreased placental reserve, such as chronic placental insuf- at risk for preterm birth at less than 30 weeks’ gestation solely ficiency, chronic villitis, chronic abruption, chronic vascular for neuroprotection. This study was a much larger random- obstruction, and perivillous fibrin deposition.335 Evaluation ized controlled trial (n = 1062) and the authors reported a of the placenta in the cause of neonatal encephalopathy may lower incidence of CP in magnesium sulfate–treated pregnan- provide some insight into the fetal intrauterine environment cies, although not statistically significant (6.8% versus 8.2%), and its contribution to the neurologic impairment. and no serious harmful effects to women or their children.233 Coimpairments. Historically, CP has been defined strictly Marret and associates, with the PREMAG trial group, showed by the location and degree of motor impairment. However, that magnesium sulfate given to pregnant women before 33 associated coimpairments such as disturbances in sensation, weeks’ gestation with planned or expected delivery within 24 cognition, communication, perception, and behavior are hours did not show any differences in total death or severe common, as are seizures. A definition that includes coimpair- white matter injury at hospital discharge but was associated ments has been proposed.213,272 A Dutch population study of with significant reductions in late death or gross motor dys- children with CP reported that 40% had seizures, 65% had function at 2 years of age.361,362 The largest study (n = 2241) cognitive deficits (IQ <85), and 34% had visual impairments.336 evaluating the effect of magnesium sulfate for the prevention Hearing impairments and feeding difficulties are also common. of CP by Rouse and colleagues and the NICHD Maternal-Fetal Medicine Units Network showed a reduction in the rate of Strategies to Reduce Cerebral Palsy. Strategies to reduce CP moderate or severe CP.363 The ACOG Committee on Obstetric have focused on preventing asphyxia and delaying premature Practice and the Society for Maternal-Fetal Medicine issued

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1330 PART 6 The Neonate a statement in 2010 recommending the use of magnesium sulfate before anticipated early preterm birth for fetal neu- Group B β-Hemolytic Streptococcus roprotection, although they do not indicate a specific gesta- Group B β-hemolytic streptococcus (GBS) was first recognized tional age.363a While this recommendation remains in place, as a cause of early-onset neonatal sepsis in the 1970s. By the further studies may provide additional clarification (see also 1990s GBS was a leading cause of serious neonatal infections. Chapter 41). The organism is a common colonizing constituent of the vagina and rectum in 10%–30% of pregnant women. GBS colonization Summary. CP is a significant adverse event with origins in is more common in African-American women as well as those pregnancy. Many risk factors have been identified, although with a previous history of a neonate with GBS disease or a sometimes no etiologic factor is found. Strategies to reduce history of a GBS urinary tract infection. Epidemiologic studies asphyxia and delay preterm birth have not shown a significant demonstrated that most invasive, early-onset neonatal GBS decrease in rates of CP. Since most CP is related to extremely disease involves vertical transmission from mother to fetus preterm birth and the survival rate of these ELBW infants is during labor. This observation led to studies of intrapartum improving, strategies to reduce neonatal brain injury such as antibiotic prophylaxis with penicillin G or ampicillin. The the use of antenatal steroids are currently the most promising. success of this strategy prompted the publication of guidelines Future trials of antenatal neuroprotection for preterm infants for intrapartum antibiotic prophylaxis by the Centers for may prove beneficial to combat inflammatory or cytokine- Disease Control and Prevention.366 A follow-up study com- mediated brain injury. pleted in 2005 confirmed the success of this strategy.308 Most invasive, serious GBS cases now seen are in infants born to NEONATAL INFECTIOUS DISEASE PROBLEMS mothers with negative GBS screening cultures who have pre- sumably converted to GBS-positive carrier status in the interval Neonatal infection is a significant cause of neonatal morbidity between screening and delivery367 (see Chapter 51). Rapid GBS and mortality in preterm and term infants. The risk of infection screening technology may allow for identification of these is inversely related to gestational age. The clinical manifesta- women when they present in labor.368 There is some concern tions of neonatal infection vary by pathogen and age of acquisi- that intrapartum antibiotic prophylaxis may be associated with tion. The spectrum of pathogens causing neonatal infection is a higher incidence of serious bacterial infections later in infancy. broad and has changed over the decades.364 However, the cor- This was most pronounced when broad-spectrum antibiotics nerstones of management remain prevention whenever possi- were used for intrapartum prophylaxis rather than penicillin ble, early detection, and focused treatment. G.369 At present the advantages of intrapartum antibiotic pro- Compared with older children and adults, neonatal host phylaxis to reduce the risk of invasive neonatal GBS disease defense is blunted by incomplete development and experience clearly outweigh any risks, especially if penicillin is employed. with self versus nonself discrimination.365 All components of the neonatal immune system are deficient, a circumstance that Chorioamnionitis is exacerbated by preterm birth. Nonspecific immunity is defec- The relationship between chorioamnionitis and neonatal infec- tive at several levels. Skin and mucosal barriers are immature, tion is complex and remains incompletely understood. Some especially in preterm infants. Levels of nonspecific antibacterial studies demonstrate a direct correlation between chorioamnio- proteins such as lysozyme and lactoferrin are low. Neutrophil nitis and neonatal infection. Other poor neonatal outcomes, numbers are low, with limited storage pools available to clear including RDS and BPD, are also associated with chorioamnio- bacteria. Key neutrophil functions, including chemotaxis, nitis.111,370 However, other clinical series and studies using phagocytosis, and intracellular killing, are limited. Thus the animal model systems reach essentially the opposite conclusion, neonate is poorly equipped to clear transient bacteremia and that chorioamnionitis protects against these same out- localize bacterial infection. Specific humoral and cell-mediated comes.371,372 Some of the confusion is grounded in definitions immune functions are also very limited. Circulating immuno- of chorioamnionitis. Clinical chorioamnionitis, as character- globulin levels are very low compared to adult levels. The ized by maternal fever and uterine tenderness, is probably a very neonate acquires virtually all circulating IgG from the mother different pathophysiologic process from clinically silent histo- via transplacental transport. The bulk of this antibody is trans- logic chorioamnionitis commonly seen in association with ferred during the third trimester, making the preterm infant preterm birth.373,374 Whether these represent different disease profoundly deficient in protective maternally derived immuno- entities or simply different manifestations of the same disease globulins. B-cell function is immature as well. The primary spectrum is not clear. It is evident that the fetal response to antibody response to infection mediated by the infant is pro- infection has important consequences for the neonate. Studies duction of immunoglobulin M. While T lymphocytes are utilizing proteomic analysis of amniotic fluid or cervicovaginal present at birth, their function is nearly undetectable by stan- fluid show promise for relating the diagnosis of chorioamnio- dard functional assays. nitis to neonatal clinical course.375–377 The nature of neonatal immune function accounts for the clinical manifestations of most early-onset infections. Nonspe- Cytomegalovirus cific signs such as lethargy, poor feeding, temperature instabil- Human CMV is transmitted horizontally (by direct person-to- ity, decreased tone, apnea, and altered perfusion may or may person contact with virus-containing secretions) and vertically not be present. Fever is uncommon, as are localized processes (from mother to infant during pregnancy or after birth), and such as cellulitis, abscesses, or osteomyelitis. When present, they via transfusion of blood products or organ transplantation are usually accompanied by bacteremia. Similarly, bacteremia from previously infected donors. Vertical transmission of CMV must always be presumed in neonates with culture-proven to infants occurs by one of the following routes of transmission: meningitis or urinary tract infections. (1) in utero by transplacental passage of maternal blood-borne

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Although fetal infection can by routine screening of all pregnant women and appropriate occur after maternal primary infection or after reactivation of immunoprophylaxis of infants born to HBsAg-positive women infection during pregnancy, sequelae are far more common in and infants born to women with unknown HBsAg status; (3) infants exposed to maternal primary infection, with 10%–20% routine immunization of children and adolescents who have of infants manifesting neurodevelopmental impairment or previously not been immunized; and (4) immunization of pre- sensorineural hearing loss in childhood.380 viously nonimmunized adults at increased risk of infection. Congenital CMV infection is usually clinically silent. Some Two types of products are available for HBV immuno- infected infants who appear healthy at birth are subsequently prophylaxis. Hepatitis B immune globulin (HBIG) provides found to develop hearing loss or learning disabilities. Approxi- short-term protection (3–6 months) and is indicated only in mately 10% of infants with congenital CMV infection exhibit postexposure circumstances. Hepatitis B vaccine is used for pre- evidence of profound involvement at birth, including IUGR, exposure and postexposure protection and provides long-term jaundice, purpura, hepatosplenomegaly, microcephaly, intrace- protection. Preexposure immunization with hepatitis B vaccine rebral calcifications, and retinitis.381 Studies of ganciclovir treat- is the most effective means to prevent HBV transmission. To ment for congenital CMV suggest benefits for long-term hearing decrease the HBV transmission rate, universal immunization outcomes. Although long-term ganciclovir therapy was well is necessary. Postexposure prophylaxis with either hepatitis B tolerated during clinical trials, concerns remain regarding vaccine and HBIG or hepatitis B vaccine alone can prevent longer-term toxicity. Parents should be carefully counseled infection after exposure to HBV. The effectiveness of postexpo- before starting treatment.382,383 sure immunoprophylaxis is related to the time elapsed between Infection acquired intrapartum from maternal cervical exposure and administration. Immunoprophylaxis is most secretions or postpartum from human milk usually is not asso- effective if given within 12–24 hours of exposure. Serologic ciated with clinical illness. Infections resulting from transfusion testing of all pregnant women for HBsAg is essential for iden- of blood products from CMV-seropositive donors and from tifying women whose infants will require postexposure prophy- CMV-positive human milk to preterm infants have been associ- laxis beginning at birth. ated with serious systemic infections, including lower respira- Hepatitis B vaccines are highly effective and safe. These vac- tory tract infection. Transmission of CMV by transfusion to cines are 90%–95% efficacious for preventing HBV infection. newborn infants has been reduced by using CMV antibody– Studies in preterm infants and low-birth-weight infants negative blood donors, by freezing erythrocytes in glycerol, (<2000 g) have demonstrated decreased seroconversion rates or by removal of leukocytes by filtration prior to administra- following administration of hepatitis B vaccination. However, tion.384 CMV transmission by human milk is also decreased by 1 month chronologic age medically stable preterm infants by pasteurization.385 However, freeze-thawing is probably not should be immunized, regardless of initial birth weight or ges- effective.386 If fresh donor milk is needed for infants born to tational age. Routine postimmunization testing for HBsAb is CMV antibody–negative mothers, provision of these infants not necessary for most infants. However, postimmunization with milk from only CMV antibody–negative women should testing for HBsAg and HBsAb at 9–18 months is recommended be pursued. for infants born to HBsAg-positive mothers. A recent report suggested a high prevalence of occult infection in children born Hepatitis B Virus to HBsAg-positive mothers despite immunoprophylaxis.388 Hepatitis B virus (HBV) is a DNA virus whose important com- Because HBV infection may result in severe disease in the ponents include an outer lipoprotein envelope containing hepa- mother and chronic infection in the newborn infant, pregnancy titis B surface antigen (HBsAg) and an inner nucleocapsid is not considered a contraindication to immunization. Immu- containing the hepatitis B core antigen. Only antibody to HBsAg nization of pregnant women with hepatitis B vaccine has not (HBsAb) provides protection from HBV infection. Perinatal been associated with adverse effects on the developing fetus. transmission of HBV is highly efficient and usually occurs from Lactation is also not a contraindication to immunization. blood exposure during labor and delivery. In utero transmission of HBV is rare, less than 2% of perinatal infections in most Herpes Simplex Virus studies. The risk of an infant acquiring HBV from an infected Neonatal HSV infections range from localized skin lesions to mother due to perinatal exposure is 70%–90% for infants born overwhelming disseminated disease. The latter has a case fatal- to mothers who are HBsAg and hepatitis B e antigen (HBeAg) ity rate greater than 50%, even with prompt initiation of anti- positive. The risk is 5%–20% for infants born to mothers who viral therapy. Vertical transmission is the likely mode of are HBeAg negative. Age at the time of acute infection is the transmission for most cases. Mothers with a history of previous primary determinant of risk of progression to chronic HBV disease appear to convey at least some type-specific immunity infection. More than 90% of infants with perinatal infection to the neonate. Most mothers of severely infected infants have will develop chronic HBV infection. Between 25% and 50% of no recognized history of HSV and no evidence of active disease children infected between 1 and 5 years of age become chroni- on physical examination. At present, no vaccines or screening cally infected, whereas only 2%–6% of older children or adults protocols for HSV are generally available.389,390 develop chronic HBV infection.387 The goals of HBV prevention programs are to prevent acute Human Immunodeficiency Virus HBV infection and to decrease the rates of chronic HBV infec- Landmark studies in the 1990s391,392 demonstrated the value of tion and HBV-related chronic liver disease. Over the past two intrapartum antiretroviral therapy to reduce the risk of

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 1332 PART 6 The Neonate maternal-fetal transmission of human immunodeficiency virus Rubella virus can be isolated most consistently from throat or (HIV). Improvements in the quality and availability of rapid nasal swabs by inoculation of appropriate cell culture. Blood, HIV testing hold out promise for more timely and accurate urine, CSF, and pharyngeal swab specimens can also yield virus identification of infected women and their newborn infants. in congenitally infected infants. The risk of congenital HIV is reduced to approximately 1% Infants with congenital rubella should be considered conta- when HIV-positive mothers receive antiretroviral therapy gious until at least 1 year of age, unless nasopharyngeal and during labor and treatment is continued for the neonate within urine cultures are repeatedly negative for rubella virus. Infec- 12 hours of delivery. Breastfeeding is contraindicated, unless tion precautions should be considered for children up to 3 years there is no access to clean water and infant formula. of age who are hospitalized for congenital cataract extraction. Laboratory diagnosis of HIV infection during infancy Caregivers of these infants and children should be made aware depends on detection of virus or viral nucleic acid. Cord blood of the potential hazard to susceptible pregnant contacts. should not be used for this early test because of possible con- tamination by maternal blood. A positive result identifies Chlamydia infants who have been infected in utero. Approximately 93% of In the newborn period, Chlamydia trachomatis is associated infected infants have detectable HIV DNA at 2 weeks and nearly with conjunctivitis and pneumonia. Acquisition of C. tracho- all HIV-infected infants have positive HIV DNA polymerase matis occurs in approximately 50% of infants born vaginally to chain reaction assay results by 1 month of age. A test within the infected mothers and in some infants delivered by cesarean first 14 days of age will facilitate decisions regarding initiation section with intact membranes.395 Neonatal chlamydial con- of antiretroviral therapy. Transplacental passage of antibodies junctivitis is characterized by ocular congestion, edema, and complicates use of antibody-based assays for diagnosis of infec- discharge developing a few days to several weeks after birth and tion in infants because all infants born to HIV-seropositive generally lasting 1 to 2 weeks. Pneumonia in infants is usually mothers have passively acquired maternal antibodies. an insidious afebrile illness occurring between 2 and 20 weeks Antiretroviral therapy is indicated for most HIV-infected after birth. It is characterized by a staccato cough, tachypnea, children. Initiation of therapy depends on virologic, immuno- and rales on physical examination. Pulmonary hyperinflation logic, and clinical criteria. Because therapeutic options for HIV and infiltrates are demonstrated on the chest radiograph. infection continue to evolve, consultation with an expert in The recommended topical prophylaxis for gonococcal oph- pediatric HIV management is recommended. thalmia with erythromycin or tetracycline for all newborn infants will not prevent chlamydial conjunctivitis or extraoc- Rubella cular infections.396 Infants with chlamydial conjunctivitis are Humans are the only source of rubella infection. Peak incidence treated with oral erythromycin base or ethylsuccinate (50 mg/ of infection is in late winter and early spring. Before widespread kg/d in four divided doses) for 14 days. Alternatively, oral sul- use of rubella vaccine, rubella was an epidemic disease with fonamides may be used after the immediate neonatal period for most cases occurring in children. The incidence of rubella has infants who do not tolerate erythromycin. Because the efficacy decreased 99% from the prevaccine era. Although the number of treatment is about 80%, follow-up of infants is recom- of susceptible people has decreased since the introduction and mended. In some instances, a second course of therapy may be widespread use of rubella vaccine, serologic surveys indicate required. that approximately 10% of the US-born population older than Chlamydial pneumonia is treated with oral azithromycin 5 years of age is susceptible. The percentage of susceptible (20 mg/kg/d) for 3 days or erythromycin base or ethylsuccinate people who are foreign born or from areas with poor vaccine (50 mg/kg/d in four divided doses) for 14 days. Detection and coverage is higher. The risk of congenital rubella syndrome is treatment of C. trachomatis infections before delivery is the highest in infants of women born outside the United States. most effective way to reduce the risk of neonatal conjunctivitis Although rubella is no longer endemic in the United States,393 and pneumonia. documented outbreaks of rubeola among unvaccinated popula- tions in the United States remains a concern and raises the Gonococcal Infections theoretical possibility of exposure during pregnancy.394 Infection with Neisseria gonorrhoeae in the newborn infant Congenital rubella syndrome is characterized by a constel- usually involves the eyes. Other types of gonococcal infections lation of anomalies that may include ophthalmologic (cata- include arthritis, disseminated disease with bacteremia, menin- racts, microphthalmos, pigmentary retinopathy, and congenital gitis, scalp abscess, or vaginitis. Microscopic examination of glaucoma), cardiac (patent ductus arteriosus and peripheral Gram-stained smears of exudates from the eyes, skin lesions, pulmonary artery stenosis), auditory (sensorineural hearing synovial fluid, and, when clinically warranted, CSF may be impairment), and neurologic (meningoencephalitis, behavioral useful in the initial evaluation. Identification of gram-negative abnormalities, and mental retardation) abnormalities. Neonatal intracellular diplococci in these smears can be helpful if the manifestations of congenital rubella syndrome include growth organism is not recovered in culture. N. gonorrhoeae can be retardation, interstitial pneumonia, radiolucent bone disease, cultured from normally sterile sites such as blood, CSF, and hepatosplenomegaly, thrombocytopenia, and dermal eryth- synovial fluid. ropoiesis, also termed “blueberry muffin lesions.” The occur- For routine ophthalmia neonatorum prophylaxis of infants rence of congenital defects varies with timing of the maternal immediately after birth, 1% tetracycline or 0.5% erythromycin infection. ophthalmic ointment is instilled into each eye. Silver nitrate, Detection of rubella-specific immunoglobulin M antibody while effective, causes more chemical irritation than antimicro- usually indicates recent postnatal infection or congenital infec- bials and is no longer available in the United States. Prophylaxis tion in a newborn infant; however, both false-positive and false- may be delayed for as long as 1 hour after birth to facilitate negative results occur. Congenital infection can be confirmed parent-infant bonding. None of the topical agents is effective by stable or increasing rubella-specific IgG over several months. against C. trachomatis.396 When prophylaxis is administered,

Downloaded for Rodrigo Terra ([email protected]) at Clinica Alemana de Santiago - JCon from ClinicalKey.com by Elsevier on October 19, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 73 Neonatal Morbidities of Prenatal and Perinatal Origin 1333 infants born to mothers with known gonococcal infection rarely evaluated if born to a mother with positive nontreponemal and develop gonococcal ophthalmia. However, because gonococcal treponemal test results if the mother has any of the following ophthalmia or disseminated disease occasionally can occur in conditions: (1) syphilis has not been treated or treatment has this situation, infants born to mothers known to have gonor- not been documented, (2) syphilis during pregnancy was rhea should receive a single dose of ceftriaxone, 125 mg IV or treated with a nonpenicillin regimen, (3) syphilis was treated IM. Preterm and low-birth-weight infants are given 25–50 mg/ less than 1 month prior to delivery because treatment failures kg of ceftriaxone to a maximum dose of 125 mg. occur and efficacy cannot be assumed, and (4) syphilis was Infants with clinical evidence of ophthalmia neonatorum, treated before pregnancy but with insufficient follow-up to scalp abscess, or disseminated disease should be hospitalized. assess the response to treatment and current infection status. Cultures of the blood, eye discharge, or other sites of infection Evaluation for syphilis in an infant should include physical such as CSF should be performed to confirm the diagnosis and examination, a quantitative nontreponemal syphilis test of determine antimicrobial susceptibility. Tests for concomitant serum from the infant, a Venereal Disease Research Laboratory infection with C. trachomatis, syphilis, and HIV infection (VDRL) test of the CSF and analysis of the CSF for cells and should be performed. Recommended treatment, including for protein concentration, long-bone radiographs, and a complete ophthalmia neonatorum, is ceftriaxone (25–50 mg/kg IV or IM, blood cell and platelet count. Other clinically indicated tests not to exceed 125 mg) given once. Infants with gonococcal oph- might include a chest radiograph, liver function tests, ultraso- thalmia should receive eye irrigations with saline solution nography, ophthalmologic examination, and an auditory brain- immediately and at frequent intervals until the discharge is stem response test. Pathologic examination of the placenta or eliminated. Topical antimicrobial treatment alone is inadequate umbilical cord using specific antitreponemal antibody staining and is unnecessary when recommended systemic antimicrobial is also recommended. treatment is provided. Infants with gonococcal ophthalmia Infants should be treated for congenital syphilis if they have should be hospitalized and evaluated for disseminated infec- proven or probable disease demonstrated by one or more of the tion. Recommended therapy for arthritis and septicemia is cef- following: (1) physical, laboratory, or radiographic evidence of triaxone or cefotaxime for 7 days. If meningitis is documented, active disease; (2) positive placenta or umbilical cord test results treatment should continue for a total of 10–14 days. for treponemes using direct fluorescent antibody T. pallidum staining or darkfield microscope test; (3) a reactive result on Syphilis VDRL on testing of CSF; or (4) a serum quantitative nontrepo- Congenital syphilis remains a significant public health problem nemal titer at least fourfold higher than the mother’s titer using in the United States. It is contracted from an infected mother the same test and preferably the same laboratory. If the infant’s via transplacental transmission of Treponema pallidum at any titer is less than four times that of the mother, congenital syphilis time during the pregnancy or delivery. Intrauterine syphilis can still can be present. When circumstances warrant evaluation of cause stillbirth, hydrops fetalis, or preterm birth. Affected an infant for syphilis, the infant should be treated if test results infants may present with edema, hepatosplenomegaly, lymph- cannot exclude infection, if the infant cannot be adequately adenopathy, mucocutaneous lesions, osteochondritis, pseudo- evaluated, or if adequate follow-up cannot be ensured. paralysis, rash, or snuffles at birth or within the first 2 months Infants with proven congenital syphilis should be treated of life. However, lack of these findings does not rule out neo- with aqueous crystalline penicillin G. The dosage should be natal disease. Additionally, hemolytic anemia or thrombocyto- based on chronologic, not gestational, age. The dose of penicil- penia may be identified on laboratory evaluation. Untreated lin G is 100,000–150,000 U/kg/d administered as 50,000 U/kg infants, regardless of whether they have manifestations in per dose IV every 12 hours during the first 7 days of life, then infancy, may develop late manifestations, usually after 2 years every 8 hours thereafter for a total of 10 days. Alternatively, of age and involving the bones, central nervous system, eyes, penicillin G procaine 50,000 U/kg/d IM for 10 day may be joints, and teeth. Some consequences of intrauterine infection considered; however, adequate CSF concentrations may not be may not become apparent until many years after birth. achieved with this regimen. Definitive diagnosis is established by identification of spiro- chetes by darkfield microscope examination or by direct fluo- Key Points rescent antibody tests of lesion exudates or tissue such as the placenta or umbilical cord. Presumptive diagnosis is possible • Neonates experience a broad spectrum of morbidities; using nontreponemal and treponemal tests. The use of only one these include those associated with prematurity such as type of test for diagnosis is insufficient, because false-positive respiratory distress syndrome, bronchopulmonary dyspla- nontreponemal tests occur with various medical conditions and sia, and intraventricular hemorrhage. false-positive treponemal tests can occur with other spirochetal • Birth asphyxia and infections also remains challenging, diseases. especially in the developing world. No newborn infant should be discharged from the hospital • Many neonatal morbidities are still difficult to prevent, but without determination of the mother’s serologic status for obstetrical decision-making can make a difference in syphilis.397 All infants born to seropositive mothers require a outcomes. careful examination and a quantitative nontreponemal syphilis • Preterm birth remains the most significant driver of neona- test. The laboratory test performed in the infant should be the tal morbidity and mortality. Management strategies to miti- same as that performed in the mother, ideally from the same gate preterm delivery, even for a few days, may improve testing facility, so that comparison of titer results is facilitated. outcomes. Whenever possible, close collaboration and com- An infant should be evaluated for congenital syphilis if the munication between the delivery physician and the newborn maternal titer has increased fourfold, if the infant titer is four- physician is the best way to optimize birth outcomes. fold greater than the mother’s titer, or if the infant has clinical

manifestations of syphilis. Additionally, the infant should be A full reference list is available online at ExpertConsult.com.

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