High risk pregnancy

Chapter 52 twin–twin transfusion. We anticipate based on our early expe- treatment groups be delivered, resuscitated, and intensively rience and that of others [13] that the risk profile with percuta- managed in a unit experienced in caring for critically ill new- neous micro-endoscopy will be similar to percutaneous borns with suspected pulmonary hypoplasia. Attempts to sonography-guided procedures (see below). The periopera- improve outcome for severe CDH by treatments either before tive management is very different compared to the more or after birth have proven to be double-edged swords. Inten- invasive procedures. Although patients are treated with pro- sive care after birth has improved survival but has increased phylactic indomethacin and antibiotics, uterine relaxation long-term sequelae in survivors, and is expensive. Interven- from inhalational agents is not required and may in fact be det- tion before birth may increase lung size, but prematurity rimental. Therefore, we generally use regional anesthesia. caused by the intervention itself can be detrimental. In our Ultrasound is again critical for safe uterine access to determine study, babies with severe CDH who had tracheal occlusion the best entry point. This is based on fetal position, placental before birth were born on average at 31 weeks, as a conse- location, membrane position in multiple gestations, and quence of the intervention. The observation that their rates of uterine vascularity. Postoperative tocolytic therapy is usually survival and respiratory outcomes (including duration of based on contraction activity. A 24–48-hour course of oxygen requirement) were comparable to infants without tra- indomethacin or nifedipine is often all that is required. In cases cheal occlusion who were born at 37 weeks, suggests that tra- where there are significant postoperative changes in uterine cheal occlusion improved pulmonary hypoplasia, but the size, such as with interventions for twin–twin transfusion syn- improvement in lung growth was adversely affected by pul- drome (TTTS), prophylactic intravenous magnesium sulfate monary immaturity related to earlier delivery. may be helpful. This has to be balanced against the risk of port site hemorrhage, which may be more likely in our experience The current results underscore the role of randomized trials with a greater degree of uterine relaxation. in evaluating promising new therapies. This is the second NIH-sponsored trial comparing a new prenatal intervention Indications for fetoscopic surgery (FETENDO) for severe fetal CDH. The first trial showed that complete sur- gical repair of the anatomic defect (which required hysterot- Congenital diaphragmatic hernia omy), although feasible, was no better than postnatal repair in improving survival and was ineffective when the liver as well The fundamental problem in babies born with a congenital as the bowel were herniated [15]. That trial led to the abandon- diaphragmatic hernia (CDH) is pulmonary hypoplasia. ment of open complete repair at our institution and subse- Research in experimental animal models and later in human quently around the world. Information derived from that trial patients over two decades has aimed to improve growth of the regarding measures of severity of pulmonary hypoplasia hypoplastic lungs before they are needed for gas exchange at (including liver herniation and the development of the birth. Anatomic repair of the hernia by open hysterotomy lung : head ratio [LHR], area of contralateral lung in axial plane proved feasible but did not decrease mortality and was aban- at level of four chamber view of heart, normalized to head doned. Fetal tracheal occlusion was developed as an alterna- circumference) led to the development of an alternative tive strategy to promote fetal lung growth by preventing physiologic strategy to enlarge the hypoplastic fetal lung by normal egress of lung fluid. Occlusion of the fetal trachea was temporary tracheal occlusion and to the development of shown to stimulate fetal lung growth in a variety of animal less-invasive fetal endoscopic techniques that did not require models. Techniques to achieve reversible fetal tracheal occlu- hysterotomy to achieve temporary, reversible tracheal occlu- sion were explored in animal models and then applied clini- sion [16,17]. cally, evolving from external metal clips placed on the trachea by open hysterotomy or fetoscopic neck dissection, to internal Our ability to accurately diagnose and assess severity of tracheal occlusion with a detachable silicone balloon placed CDH before birth has improved dramatically. Fetuses with by fetal bronchoscopy through a single 5-mm uterine port, as CDH who have associated anomalies do poorly, whereas described above. fetuses with isolated CDH, no liver herniation, and an LHR above 1.4 have an excellent prognosis (100% in our experi- Our initial experience suggested that fetal endoscopic tra- ence). In this study, fetuses with an LHR between 0.9 and 1.4 cheal occlusion improved survival in human fetuses with had a chance of survival greater than 80% when delivered at a severe CDH. To evaluate this novel therapy, we conducted a tertiary care center. The small number of fetuses with LHR randomized controlled trial comparing tracheal occlusion below 0.9 had a poor prognosis in both treatment groups, and with standard care. Survival with fetal endoscopic tracheal should be the focus of further studies [18]. occlusion (73%) met expectations (predicted 75%) and appeared better than that of historic controls (37%), but proved Because tracheal occlusion does work in enlarging hypo- no better than that of concurrent randomized controls. The plastic lungs, approaches to tracheal occlusion other than that higher than expected survival in the standard care group may used here might be beneficial. Although the duration of occlu- be because the study design mandated that patients in both sion in this study (36.2 ± 14.7 days) is comparable with that studied in animal models [18,19], the optimal timing and dura- tion of occlusion is not known in humans. Short-term occlu- 438

Fetal Surgery sion later in gestation and earlier occlusion (with possible more recently by fetocystoscopic ablation of urethral valves reversal in utero) have been studied in animal models [21,22] [32]. Treatment with shunting has been relatively disappoint- and applied in humans. It is also possible that the risk of pre- ing, as shunts often migrate or do not remain patent. Even mature rupture of membranes leading to preterm labor and when adequately decompressed, the obstructed bladder may delivery might be reduced by using smaller 2-mm fetoscopes not cycle correctly, resulting in a severe bladder dysfunction percutaneously and by newly developed techniques to seal requiring surgery after birth. We have now developed a per- membranes. Fetuses with an LHR less than 0.9 have poor sur- cutaneous fetal cystoscopic technique to disrupt posterior ure- vival and remain the focus for new treatment strategies either thral valves through a single 3-mm port. before or after birth. Fetal intervention guided by sonography Twin–twin transfusion syndrome The first fetal procedure, developed in the early 1980s, was TTTS was one of the first entities to be treated endoscopically percutaneous sonographically guided placement of fetal at UCSF. It is a complication of monochorionic multiple gesta- bladder catheter shunt. Many other catheter-shunt procedures tions resulting from an imbalance in blood flow through vas- have been developed and described [33]. More recently, we cular communications, such that one twin is compromised have developed percutaneous sonographically guided radio- and the other favored. It is the most common serious complica- frequency ablation procedures for management of anomalous tion of monochorionic twin gestations, affecting between 4% multiple gestations. All these procedures we now group as and 35% of monochorionic twin pregnancies, or approxi- ‘fetal intervention guided by sonography’ (FIGS). Very com- mately 0.1–0.9 per 1000 births each year in the USA. Yet, despite plicated procedures may still require laparotomy (Lap-FIGS). the relatively low incidence, TTTS disproportionately accounts for 17% of all perinatal mortality associated with twin gesta- Percutaneous or micro-FIGS is used to sample or drain fetal tions [23]. Standard therapy has been limited to serial amnio- blood, urine, and fluid collection, to sample fetal tissue, to reduction, which appears to improve the overall outcome but place catheter shunts in the fetal bladder, chest, abdomen, or has little impact on the more severe end of the spectrum ventricles, and to perform radiofrequency ablation (RFA). The in TTTS. In addition, survivors of TTTS treated by serial most common indication at UCSF is RFA for acardiac twins/ amnioreduction have an 18–26% incidence of significant neu- twin reversed arterial perfusion (TRAP) sequence or mono- rologic and cardiac morbidity. Selective fetoscopic laser photo- chorionic twins for selective reduction. Other operators have coagulation of communicating vessels has emerged as an used bipolar coagulation or umbilical cord ligation for similar alternative treatment strategy with at least comparable, if not indications. Compared with the 17-gauge RFA needles we superior, survival to serial amnioreduction, as demonstrated use, these techniques are more invasive, using at least 3-mm in a randomized trial in Europe [24]. trochars. Additionally, the length of the cord or its position may preclude use of these instruments. The perioperative Urinary tract obstruction management of these patients is similar to the current micro- FETENDO patients. The procedures are performed under As a group at UCSF we are particularly enthusiastic about the spinal anesthesia, with prophylactic antibiotics and indomet- potential of fetal intervention in bladder outlet obstruction by acin. Postoperative tocolysis is rarely necessary and the percutaneous fetal cystoscopy. Fetal urethral obstruction pro- patients are frequently discharged within hours of the proce- duces pulmonary hypoplasia and renal dysplasia, and these dure. Ultrasound is critical both for the planning and execu- often-fatal consequences can be ameliorated by urinary tract tion of the procedure. We attempt to avoid entry into the sac of decompression before birth. The natural history of untreated a normal twin if at all possible. The RFA needle is guided into fetal urinary tract obstruction is well documented, and selec- the abdominal cord insertion of the abnormal twin under tion criteria based on fetal urine electrolyte and B2 microglob- ultrasound guidance. The tines (thin wires protruding out of ulin levels and the sonographic appearance of fetal kidneys the needle like hooks) are then deployed and energy delivered have proven reliable [24–27]. Of all fetuses with urinary tract to the device to create thermal injury to the tissue. The device dilatation, the vast majority do not require intervention. we currently use measures the temperature at the tines. This However, fetuses with bilateral hydronephrosis and bladder allows us to use an energy level to provide the quickest obliter- distension resulting from urethral obstruction subsequently ation of the vascular communications possible. This is of developing oligohydramnios require treatment. Depending benefit as there are theoretical concerns regarding the differ- on the gestational age, the fetus can be delivered early for ential obliteration of arterial and venous vessels, which might postnatal decompression. Alternatively, the bladder can be place the normal twin at risk for exsanguination. Ultrasound is decompressed in utero by a catheter vesicoamniotic shunt also used to monitor the procedure and welfare of the normal (e.g., Harrison shunt) placed percutaneously under sono- twin. Thermal injury can be monitored by watching for the graphic guidance [29], by fetoscopic vesicostomy [30,31], or characteristic out-gassing in the tissue. Once active energy 439

Chapter 52 delivery to the device has ceased, color-flow Doppler can be an enlarged intra-abdominal umbilical vein in the pump twin used to detect any residual flow, both in the cord and the sac, and significant blood flow into the acardiac twin. Fetal abnormal fetus. Once absence of blood flow is confirmed, the echocardiography shows increased biventricular output in tines are retracted and the device then withdrawn. We have the pump twin with some increased pulsatility in the ductus not found an increased frequency of adverse outcomes with a venosus. The multidisciplinary team meets with the patient transplacental approach. We have had good success with this and her family and discusses the management options approach with a survival rate of close to 95% and a mean gesta- and risks and benefits of each. They decide to proceed tional age at delivery of over 35 weeks and an average time with RFA. from procedure of over 11 weeks. There has been no maternal pulmonary edema or blood loss. The procedure is performed the next day, under spinal anesthesia in the operating room. The RFA device is deployed There are a few complicated FIGS procedures that may percutaneously under ultrasound guidance into the abdomen require maternal laparotomy to allow fetal positioning and of the acardiac twin at the level of the cord insertion. The device sonography directly on the uterus (Lap-FIGS). A few simple is energized, and the tissue is heated acutely. After cool down, structural cardiac defects that interfere with development ultrasound documents cessation of blood flow based on color may benefit from prenatal correction. For example, if obstruc- flow and pulse Doppler. The patient stays hospitalized over- tion of blood flow across the pulmonary or aortic valve inter- night. The next day a repeat ultrasound confirms no acute feres with development of the ventricles or pulmonary or changes in the pump twin without residual flow into the acar- systemic vasculature, relief of the anatomic obstruction may diac twin. She is discharged home to return to the care of her allow normal development with an improved outcome. Alter- referring perinatologist and primary obstetrician. Several natively, congenital aortic stenosis may lead to hypoplastic months later she delivers a healthy infant at term by induced left heart syndrome. Stenotic aortic valves have been dilated vaginal delivery. by a balloon catheter placed using both FIGS and Lap-FIGS, with some promising results [33]. The procedure is technically References difficult. Several centers are developing experimental tech- niques to correct fetal heart defects [34]. 1 Golombeck K, Ball RH, Lee H, et al. Maternal morbidity after fetal surgery. Am J Obstet Gynecol 2006;194:834–9. In summary, fetal surgery has evolved considerably since its birth at UCSF two decades ago. The indications remain 2 Adzick NS, Harrison MR, Glick PL, et al. Fetal surgery in the quite limited, but numerically have the potential to expand as primate. III. Maternal outcome after fetal surgery. J Pediatr Surg patients and providers become increasingly informed. Recent 1986;21:477–80. advances in the development of less invasive fetal endoscopic (FETENDO) and sonography-guided techniques (FIGS) have 3 Bruner JP, Tulipan N, Reed G, et al. Intrauterine repair of spina extended the indications for fetal intervention. bifida: preoperative predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 2004;190:1305–12. Case presentation 4 Johnson MP, Sutton LN, Rintoul N, et al. Fetal myelomeningocele The patient is a 36-year-old G3P2 at 18 weeks’ gestation. She repair: short-term clinical outcomes. Am J Obstet Gynecol was referred to a perinatologist for evaluation because an 2003;189:482–7. ultrasound was suspicious for a twin pregnancy with demise of an anomalous fetus with a cystic hygroma. 5 DiFederico EM, Burlingame JM, Kilpatrick SJ, Harrison MR, Matthay MA. Pulmonary edema in obstetric patients is rapidly The perinatologist performed a detailed ultrasound and resolved except in the presence of infection or of nitroglycerin identified a monochorionic diamnionic twin pregnancy. One tocolysis after open fetal surgery. Am J Obstet Gynecol twin is morphologically normal and the other has a torso with 1998;179:925–33. edematous skin and no heart and is of similar size to the normal twin. The blood flow in the cord is reversed with flow in the 6 Wilson RD, Johnson MP, Crombleholme TM, et al. single artery towards the anomalous twin. This therefore is an Chorioamniotic membrane separation following open fetal acardiac twin and the situation represents TRAP. The perina- surgery: pregnancy outcome. Fetal Diagn Ther 2003;18:314–20. tologist discusses with the patient and her partner that in cases of TRAP, the normal or pump twin is at risk of cardiac failure, 7 Bruner JP, Tulipan NB, Richards WO, Walsh WF, Boehm FH, hydrops, and stillbirth. They discuss the management options Vrabcak EK. In utero repair of myelomeningocele: a comparison of including observation or intervention with bipolar cord coag- endoscopy and hysterotomy. Fetal Diagn Ther 2000;15:83–8. ulation or RFA. 8 Farrell JA, Albanese CT, Jennings RW, Kilpatrick SJ, Bratton BJ, The family is seen for evaluation. Ultrasound documents Harrison MR. Maternal fertility is not affected by fetal surgery. the previous findings and also identifies polyhydramnios and Fetal Diagn Ther 1999;14:190–2. 9 Bouchard S, Davey MG, Rintoul NE, Walsh DS, Rorke LB, Adzick NS. Correction of hindbrain herniation and anatomy of the vermis after in utero repair of myelomeningocele in sheep. J Pediatr Surg 2003;38:451–8. 10 Adzick NS, Harrison MR, Glick PL, et al. Fetal cystic adenomatoid malformation: prenatal diagnosis and natural history. J Pediatr Surg 1985;20:483–8. 440

11 Adzick NS, Glick PL, Harrison MR, et al. Compensatory lung Fetal Surgery growth after pneumonectomy in the fetus. Surg Forum 1986;37:648–9. 23 Quintero RA. Twin–twin transfusion syndrome. Clin Perinatol 2003;30:591–600. 12 MacGillivray TE, Harrison MR, Goldstein RB, Adzick NS. Disappearing fetal lung lesions. J Pediatr Surg 1993;28:1321–4. 24 Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe 13 Blott M, Nicolaides KH, Greenough A. Postnatal respiratory twin-to-twin transfusion syndrome. N Engl J Med function after chronic drainage of fetal pulmonary cyst. Am J 2004;351:136–44. Obstet Gynecol 1988;159:858–65. 25 Adzick NS, Harrison MR, Glick PL, Flake AW. Fetal urinary tract 14 Hirose S, Farmer DL, Lee H, Nobuhara KK, Harrison MR. The ex obstruction: experimental pathophysiology. Semin Perinatol utero intrapartum treatment procedure: looking back at the EXIT. 1985;9:79–90. J Pediatr Surg 2003;39:375–80. 26 Crombleholme TM, Harrison MR, Golbus MS, et al. Fetal 15 Harrison MR, Adzick NS, Bullard KM, et al. Correction of intervention in obstructive uropathy: prognostic indicators and congenital diaphragmatic hernia in utero VII: a prospective trial. efficacy of intervention. Am J Obstet Gynecol 1990;162:1239–44. J Pediatr Surg 1997;32:1637–42. 27 Manning FA, Harrison MR, Rodeck C. Catheter shunts for fetal 16 Harrison MR, Adzick NS, Flake AW, et al. Correction of hydronephrosis and hydrocephalus. Report of the International congenital diaphragmatic hernia in utero VIII: response of the Fetal Surgery Registry. N Engl J Med 1986;315:336–4. hypoplastic lung to tracheal occlusion. J Pediatr Surg 1996;31:1339–48. 28 Nicolaides KH, Cheng HH, Snijders RJ, Moniz CF. Fetal urine biochemistry in the assessment of obstructive uropathy. Am J 17 Skarsgard ED, Meuli M, VanderWall KJ, Bealer JF, Adzick NS, Obstet Gynecol 1992;166:932–7. Harrison MR. Fetal endoscopic tracheal occlusion (‘Fetendo- PLUG’) for congenital diaphragmatic hernia. J Pediatr Surg 29 Glick PL, Harrison MR, Adzick NS, Noall RA, Villa RL. 1996;31:1335–8. Correction of congenital hydronephrosis in utero IV: in utero decompression prevents renal dysplasia. J Pediatr Surg 18 Lipshutz GS, Albanese CT, Feldstein VA, et al. Prospective 1984;19:649–5. analysis of lung-to-head ratio predicts survival for patients with prenatally diagnosed congenital diaphragmatic hernia. J Pediatr 30 Johnson MP, Bukowski TP, Reitleman C, Isada NB, Pryde PG, Surg 1997;32:1634–6. Evans MI. In utero surgical treatment of fetal obstructive uropathy: a new comprehensive approach to identify appropriate 19 Papadakis K, De Paepe ME, Tackett LD, Piasecki GJ, Luks FI. candidates for vesicoamniotic shunt therapy. Am J Obstet Gynecol Temporary tracheal occlusion causes catch-up lung maturation in 1994;170:1770–6. a fetal model of diaphragmatic hernia. J Pediatr Surg 1998;33:1030–7. 31 Crombleholme TM, Harrison MR, Langer JC, et al. Early experience with open fetal surgery for congenital 20 VanderWall KJ, Bruch SW, Meuli M, et al. Fetal endoscopic hydronephrosis. J Pediatr Surg 1988;23:1114–21. (‘Fetendo’) tracheal clip. J Pediatr Surg 1996;31:1101–3. 32 MacMahon RA, Renou PM, Shekelton PA, Paterson PJ. In utero 21 Luks FI, Wild YK, Piasecki GJ, De Paepe ME. Short-term tracheal cystostomy. Lancet 1992;340:123. occlusion corrects pulmonary vascular anomalies in the fetal lamb with diaphragmatic hernia. Surgery 2000;128:266–72. 33 Wilson RD, Baxter JK, Johnson MP, et al. Thoracoamniotic shunts: fetal treatment of pleural effusions and congenital cystic 22 Flageole H, Evrard VA, Piedboeuf B, Laberge JM, Lerut TE, adenomatoid malformations. Fetal Diagn Ther 2004;19:413–2. Deprest JA. The plug–unplug sequence: an important step to achieve type II pneumocyte maturation in the fetal lamb model. 34 Allan LD, Maxwell D, Tynan M. Progressive obstructive lesions J Pediatr Surg 1998;33:299–303. of the heart: an opportunity for fetal therapy. Fetal Ther 1991;6: 173–6. 35 Hanley FL. Fetal cardiac surgery. Adv Cardiac Surg 1994;5:47–74. 441

53 Problems in the newborn Avroy A. Fanaroff Background—the population; statistical dren had a major sensorineural disability (bilateral blindness, definitions: infant mortality deafness, cerebral palsy of such severity that the child did not walk or walked with great difficulty, or had an intelligence More than half of neonatal deaths in the USA still occur in the quotient greater than 2 standard deviations below the mean); approximately 60,000 very low birth weight (VLBW) infants 11% had cerebral palsy. Risk factors during the initial hospital- born each year, but advances in neonatal and perinatal care ization for major disability at 5 years of age were grade 3 or 4 have improved the chances of survival for such infants. Hence, intraventricular hemorrhage (IVH), cystic periventricular leu- in 2006, in excess of 80% of low birthweight (LBW) infants were komalacia, postnatal steroid therapy, and surgery before dis- the beneficiaries of antenatal corticosteroids with an attendant charge. Among the almost half of the cohort who had none of survival rate of approximately 85%. Factors influencing sur- these risk factors, the rate of survival without major sen- vival rate include antenatal corticosteroids, birthweight, ges- sorineural disability was 93%, similar to the rate among the tational age, gender, race, mode, and site of delivery. There is normal birthweight controls [3–5]. improved survival with advancing birthweight and gesta- tional age. Almost 60% of infants with a birthweight of Parents and physicians of extremely preterm neonates 501–750 g, 90% of 751–1000 g infants, and in excess of 95% of require reliable information on their prognosis for survival infants who weigh 1001–1500 g survive to hospital discharge. and survival without disability in order to make informed Survival almost doubles at 23–24 weeks (30–60%), increasing decisions about how to best provide for their care. This steadily between 25 and 27 weeks, and leveling off thereafter information is, of necessity, offset in time from current (80% at 25 weeks, 85% at 26 weeks, 90% at 27 weeks, and 92% at practice and is often not specific to the institution caring for 28 weeks). Although there were dramatic increases in survival the infant or to the individual infant. Current estimates of the following the introduction of surfactant and widespread use range in survival without impairment (calculated from the of antenatal corticosteroids, mortality rates appear to have product of the lowest survival and the lowest survival without leveled off. impairment rates vs. the highest survival and highest survival without impairment rates) at 23 weeks is 4–28%; Whether the dramatic improvements in survival of extre- at 24 weeks 12–49%; and at 25 weeks 23–78%. Moreover, mely preterm infants have resulted in increased rates and although preterm infants may not be neurodevelopmentally absolute numbers of disabled survivors has been a matter of impaired at follow-up, they are at significant risk of much debate and concern for physicians caring for these academic difficulties so that they are more likely to be enrolled infants. Interpretation of the literature on long-term outcome in special education classes and are at increased risk for of extremely preterm infants is limited by small sample sizes, developing attention deficit hyperactivity disorder (ADHD) lack of population- and gestational age-based samples, differ- compared with the term controls. Fewer VLBW infants ing proportions of inborn infants, different times of assess- ultimately graduate from high school compared with their ment and outcome measures, inconsistent classification of term peers. neurodevelopmental impairment, and excessive loss to follow-up [1,2]. In summary, advances in perinatal care have led to the sur- vival of increasing numbers of children born at the lower limits The rate of preterm survival without major sensorineural of viability. VLBW children have poorer outcomes relative to disability at 2 years, based on infants who had survived to normal birthweight term controls in neurologic and health initial hospital discharge, was 80%. Twenty percent of the chil- status, cognitive-neuropsychological skills, school perform- ance, academic achievement, and behavior. Outcomes are 442

Problems in the Newborn highly variable but are related to medical risk factors, neonatal shivering is rarely seen in term infants and never in preterm medical complications of prematurity, and social risk factors. infants. Nonshivering thermogenesis is initiated by Attention is increasingly focused on long-term outcome as an lipolysis in the richly vascular brown adipose tissue. Thermo- indicator of the individual infant’s medical and social risk genesis must begin shortly after birth and continue for several factors, as well as the quality of the medical care the infant hours. Because thermogenesis requires adequate oxygena- received. Systematic evaluation of risk factors (e.g., inflamma- tion, a distressed neonate with hypoxemia cannot produce tory exposures, nutritional status, brain injury on magnetic an adequate amount of heat to increase its temperature and resonance imaging), and care practices (e.g., ventilatory man- body temperature falls. This is notable in preterm infants agement) may identify strategies and interventions needed to where the inability to accommodate to cold stress has long achieve further improvements in the outcome of babies born been recognized as a major difference between the preterm at the limits of viability. and the term neonate. Thermoregulation Thermal regulation under special circumstances Thermoregulation of the fetus The delivery room The metabolic rate of the fetus per tissue weight is relatively high when compared with that of an adult. Moreover, heat is At delivery, newborn infants rapidly lose heat by evaporative, transferred to the fetus via the placenta and the uterus, result- radiant, and convective heat losses. Heat losses by conduction ing in a 0.5°C higher temperature than that of the mother. Also, are minimal unless the infant is placed on a cold surface. Heat any changes in the maternal temperature are closely followed losses may be minimized by immediately drying infants with in the fetus to maintain this gradient. The maternal arterial dry, prewarmed towels, and wrapping and placing them temperature is the single most important factor in thermoreg- under a radiant warmer. The delivery room should be kept ulation of the fetus. The fetus does not independently regulate reasonably warm (more than 25°C) and both term and preterm its body temperature. If the pregnant woman develops pro- infants should be dried with prewarmed blankets, wrapped, longed and high fever, it reduces the efficiency of the placenta and placed under a radiant warmer. in dissipating the heat generated by the fetus. This causes hyperthermia of the fetus, which could result in teratogenesis, Preterm infants are especially prone to hypothermia imme- spontaneous abortion, stillbirth, or premature delivery. diately following birth. Excessive evaporative heat loss and Maternal fever early in pregnancy is potentially teratogenic. the relatively cool ambient temperature of the delivery room may be important contributing factors. It is important to keep The umbilical circulation transfers 85% of the heat produced the delivery room warm and in controlled trials which evalu- by the fetus to the maternal circulation. The remaining 15% is ate the effect of placing infants <29 weeks gestation in poly- dissipated through the fetal skin to the amnion, and is then urethane bags up to their necks immediately after delivery transferred through the uterine wall to the maternal abdomen. even before being dried, the infants had higher mean admis- As long as fetal heat production and loss are appropriately bal- sion temperatures upon arrival in the nursery and the conclu- anced, the temperature differential between the fetus and the sion is that polyurethane occlusive skin wrapping prevents mother remains constant. However, if the umbilical circula- rather than delays heat loss at delivery in very preterm tion is interrupted for any reason, the fetal temperature will infants. rise and the fetus may become profoundly hyperthermic which may adversely affect brain development. Whereas the Radiant warmers neonate will generate extra heat by nonshivering thermogene- sis, this mechanism is inhibited in the fetus by adenosine and Rapid, safe warming of hypothermic infants can be accom- prostaglandin E2 derived from the placenta. Both these agents plished with radiant warmers. These heating devices maintain have strong antilipolytic actions. body temperature by providing radiant heat. Radiant warmers allow for easy accessibility to the infant and are used predomi- Thermal regulation after birth nantly in the delivery room and in the care of ill infants who need intensive monitoring and frequent interventions. The At birth neonates rapidly drop their temperature in response optimal skin temperature for the control of radiant heaters is to the relatively cold extrauterine environment together with undetermined, but radiant warmers should be used only with large convective, radiant, and evaporative heat loss. That is a servocontrol and an abdominal skin temperature set at why it is critically important to rapidly dry and warm high risk 36.5°C. Such constraints as possible dislodgement of the probe neonates. The neonate must accelerate heat production which and the need for the thermistor to be covered by an aluminum occurs predominantly by nonshivering thermogenesis as patch should be clearly understood by those who operate radiant warmers. Radiant warmers significantly increase 443

Chapter 53 insensible water loss, especially in preterm infants (50% or circulatory insufficiency. Causes of anemia in the neonatal more). This can result in rapid dehydration unless there is suf- period include the following. ficient water replacement. Obstetric accidents and malformations of the placenta Transport and cord Newborn infants, especially those who are preterm, are at risk This subgroup includes rupture of a normal or abnormal of hypothermia while being transported from delivery umbilical cord. Rupture of the normal umbilical cord is rare room to nursery, from one hospital to another, or to and and may result from an unattended precipitous delivery. from the operating room. Formerly, a prewarmed, double- Severe fetal hemorrhage may accompany placenta previa, walled transport incubator or a single-walled transporter abruptio placentae, or incision of the placenta or umbilical with the infant dressed and/or covered by a blanket or silver cord during cesarean delivery. Failure of the infant to receive swaddler helped prevent a fall in body temperature. the usual placental transfusion during the cesarean delivery More recently, the infants are immediately covered with and clamping the cord with the infant above the placenta plastic bags. Transport by aircraft increases the risk of hypo- aggravates the situation, because fetoplacental hemorrhage thermia by radiant heat loss, so the use of a double-walled will occur. It may be extremely difficult to distinguish the transporter is recommended to decrease the loss of body tem- infant with hypovolemic shock from the severely asphyxiated perature. For procedures, the infant should be placed under a newborn; both may be extremely pale with evidence of poor radiant warmer with servocontrol on a continuously warmed perfusion and circulatory insufficiency. mattress, in a draft-free, humidified (50%) room to minimize heat loss. Occult hemorrhage prior to birth Induced cooling Although some degree of hemorrhage from the fetus into the maternal circulation occurs during 50% of pregnancies, it has Hypothermia is protective against brain injury after asphyxia- been estimated that in only 1% will the amount of fetal loss tion in animal models. Recent randomized trials of hypother- exceed 40 mL and cause anemia in the newborn. Massive mia have been completed in infants with a gestational age of at fetal–maternal hemorrhage, defined as more than 150 mL fetal least 36 weeks who were admitted to the hospital at or before blood in the maternal circulation, is said to account for 3% 6 hours of age with either severe acidosis or perinatal of perinatal mortality and occurs in approximately 1 in 800 complications and resuscitation at birth and who had moder- deliveries. Some of the causes of fetal–maternal hemorrhage ate or severe encephalopathy [6,7]. In both trials, death or include amniocentesis, external version, fundal pressure dur- moderate or severe disability was reduced with cooling. Also ing the second stage of labor, the use of intravenous oxytoxics, there were no differences noted in the frequency of clinically trauma, placenta previa, and abruptio placentae [8]. important complications. Shankaran et al. [6] reported no increase in major disability such as cerebral palsy among sur- The clinical manifestations of fetal–maternal hemorrhage vivors. Moderate cooling offers a new therapy for asphyxia depend on the timing and acuity. Chronic bleeding results in a neonatorum. very pale infant, not necessarily in distress or manifesting any features of shock but with enlargement of the liver and spleen. Anemia The blood smear is typically microcytic and hypochromic, and there is no evidence of hemolysis. Fetal cells can be demon- Anemia is defined as a hemoglobin level less than 12 g/100 mL strated in the maternal circulation, usually by means of in the first week of life. The hemoglobin and hematocrit peak at the acid elution technique of Kleihauer and Betke. If fetal– 3–12 hours of age as levels both rise 2–3 g/100 mL and 3–6%, maternal hemorrhage of significant proportions has occurred respectively. The capillary values for both hemoglobin and acutely, the clinical features of shock and hypoperfusion pre- hematocrit are consistently higher than venous or arterial dominate. The red blood cell morphology is normocytic and measurements. normochromic, and no hepatosplenomegaly is present. In contrast with the infants with chronic loss, who require only There are many causes of anemia in the neonatal period. iron supplementation, these latter infants are in dire need of Anemia may result from one of three causes: hemorrhage, fluid replacement to restore intravascular volume, and then hemolysis, and failure of red blood cell production. The pres- blood transfusion. ence of severe anemia at the time of delivery or on the first day of life is usually the result of hemorrhage or hemolysis result- Internal hemorrhage ing from isoimmunization. When the anemia is secondary to acute blood loss at the time of birth, there may be evidence of There are many potential sites for blood loss in the newborn. The detection of anemia during the first days of life should 444

Problems in the Newborn initiate a careful evaluation to determine the source of blood Toxoplasma gondii, other viruses, rubella, cytomegalovirus, loss. The finding of a large cephalohematoma or extensive and herpes simplex), a full coagulation profile, red blood cell swelling of the scalp associated with a subaponeurotic collec- enzymes, and hemoglobin electrophoresis are analyzed as tion of blood is a common site of blood loss. Infants delivered indicated by the history and physical examination. in the breech position may have significant blood loss into the muscles and manifest bruising but not necessarily swelling. If significant hemorrhage has occurred and the neonate The advent of ultrasonography and computed tomography manifests shock with reduced blood pressure and metabolic (CT) has facilitated the search for intracranial and intra- acidosis, arrangements should be made for immediate blood abdominal sites of blood loss. transfusion. In the meantime, circulation is supported with fluid pushes to expand the intravascular volume, and mechan- Traditionally, adrenal hemorrhage, rupture of the liver, and ical ventilation to optimize oxygenation. rupture of the spleen all accompany difficult and traumatic deliveries of both macrosomic and premature infants, and Respiratory disorders are more likely to be noted with breech presentation. The usual clinical manifestations of shock are accompanied by Respiratory distress syndrome specific abdominal findings, which includes periumbilical discoloration. Clinical features Iatrogenic blood loss Respiratory distress syndrome (RDS) remains a major cause of morbidity in newborn babies. The greatest risk factor appears Iatrogenic blood loss is associated with excessive blood with- to be low gestational age, whereas other risk factors include drawal, bleeding from inadequate clamping of the umbilical maternal diabetes, hydrops fetalis, and perinatal asphyxia. cord, bleeding associated with improper management of the Although the diagnosis can be established biochemically by umbilical arterial catheters, or excessive bleeding following documentation of surfactant deficiency in amniotic fluid or in procedures such as circumcision. It is important to monitor tracheal or gastric aspirate, this is rarely performed and a clini- closely the volume of blood withdrawn from sick neonates, to cal diagnosis is made, hence statistical data on the prevalence restrict the number of laboratory investigations, and to draw must be interpreted with caution. Nonetheless, the incidence the minimal volume of blood necessary. Strict adherence to of RDS probably exceeds 80% at a gestation of less than protocols regarding care of catheters diminishes the risks of 27 weeks, although severity varies widely. With improved hemorrhage from this source. survival, sequelae have increased dramatically, especially bronchopulmonary dysplasia (BPD), because of the disease Hemolytic anemias process as well as modes of treatment [26–29]. There are many causes of hemolytic disease in the newborn. Impaired or delayed surfactant synthesis superimposed on The presence of jaundice distinguishes hemolytic anemia a structurally immature lung appears to be key to the patho- from that characterized by blood loss. Major categories of genesis of RDS. The resultant decrease in lung compliance hemolysis of significance in the neonatal period are as leads to alveolar hypoventilation and ventilation–perfusion follows: imbalance. This in turn leads to hypoxemia, which may cause 1 Isoimmunization metabolic acidosis, and both may contribute to pulmonary 2 Congenital defects of the red blood cell vasoconstriction and aggravate hypoxemia. Meanwhile, high 3 Acquired defects of the red blood cell inspired oxygen and barotrauma from assisted ventilation initiate an inflammatory process in the immature lung that The problem of isoimmunization is dealt with in Chapter 36. paves the way for development of chronic neonatal lung Congenital defects of the red blood cell, which include the disease or BPD. enzymatic defects, are characterized by specific morphology of the red blood cell or the presence of abnormal hemoglobin. Infants with RDS typically present with a combination of Among the causes of acquired defects of the red blood cell are tachypnea, nasal flaring, subcostal and intercostal retractions, a variety of bacterial and viral infections (notably parvovirus cyanosis, and expiratory grunting. Retractions are prominent which may cause aplastic anemia) and a multitude of drugs and are the result of the very compliant ribcage being drawn and toxins. in on inspiration as the infant generates high intrathoracic pressures to expand the poorly compliant lungs. The typical In summary, hemorrhage is the most common cause of early expiratory grunt is thought to result from partial closure anemia. The cause is usually apparent from the history. The of the glottis during expiration and, in this way, acts as a initial evaluation requires a complete blood count with smear means of trapping alveolar air and maintaining an adequate and reticulocyte count, total and direct bilirubin, blood type end-expiratory lung volume (or functional residual capacity, and Coombs’ test, and the Kleihauer–Betke test on maternal FRC). Although these signs are characteristic of neonatal blood. TORCH titers (for a group of infections comprising 445

Chapter 53 respiratory disease, they may result from a wide variety of respiratory acidosis, alkali therapy is not indicated until some nonpulmonary causes, such as hypothermia, hypoglycemia, form of assisted ventilation has been initiated. anemia, polycythemia, or metabolic acidosis. Furthermore, such nonpulmonary conditions may complicate the clinical It is customary to maintain a venous hematocrit of at least course of RDS. 40% during the acute phase of RDS to support an adequate oxygen-carrying capacity. Arterial oxygen tension (Pao 2) is A constant feature of RDS in the pre-surfactant era was the maintained at 50–80 mmHg. Although umbilical arterial cath- early onset of clinical signs of the disease, typically within 1–2 eters still form the basic means of arterial sampling in infants hours of delivery. The uncomplicated natural course of clini- with RDS, the list of catheter-related thrombotic, embolic, and cal disease was characterized by a progressive worsening of ischemic complications is formidable. Saturation is monitored symptoms, with a peak severity by days 2–3 and onset of continuously, with efforts made to keep the saturation at recovery by 72 hours. This is now rare because all but the 89–94%. mildest cases of RDS are treated with exogenous surfactant. RDS requiring assisted ventilation may be complicated by the Surfactant therapy development of air leaks, significant shunting through a patent ductus arteriosus, or BPD, and the infant’s recovery may be Surfactant therapy has been a major advance in the care of delayed for days to months. infants with RDS. All regimens of surfactant therapy appear to decrease the incidence of air leaks and improve oxygenation of The typical radiographic features consist of a diffuse reticu- ventilated preterm infants. More strikingly, mortality from logranular pattern in both lung fields with superimposed air RDS, and even overall mortality of preterm infants, is signifi- bronchograms. These findings cannot be reliably differenti- cantly reduced, especially when multiple-dose surfactant ated from those of neonatal pneumonia, most commonly therapy is used for these infants. In contrast with the impres- caused by group B streptococci. This problem has been the sive improvement in mortality, the incidence of BPD, IVH, major reason for the widespread use of antibiotics in the initial sepsis, and symptomatic patent ductus arteriosus appears management of infants with RDS. unaltered in most studies [9–17]. Management The overall incidence of BPD has not been reduced by the use of surfactant therapy. This may be a consequence of In an infant with respiratory symptoms (especially if preterm), enhanced survival, and there is evidence that surfactant has there is a tendency to conclude that underlying pulmonary increased the rate of survival without BPD. Presumably, BPD parenchymal disease is present; however, the differential is more likely to be a direct consequence of barotrauma in the diagnosis is extensive. Disorders of the upper airway (e.g., preterm survivors of neonatal intensive care who have a more choanal atresia, micrognathia), larynx, trachea, intrathoracic advanced gestational age, and such diverse factors as impaired airway, chest wall, central nervous system, cardiovascular respiratory drive, nutritional compromise, intercurrent infec- system, and musculoskeletal system—together with hemato- tion, and congestive heart failure are less of a problem than in logic and metabolic problems or sepsis—may be easily con- the smallest survivors of assisted ventilation. fused with lung disorders. Analysis of simple laboratory data includes blood gases, hematocrit, blood sugar, and white Transient tachypnea blood cell count with differential, together with appropriate radiographic studies. Transient tachypnea typically presents as respiratory distress in term infants or preterm infants who are close to term. The General measures clinical features comprise various combinations of mild cya- nosis, grunting, flaring, retracting, and tachypnea in the first Infants with respiratory difficulty require an optimal thermal few hours after birth associated with a modest requirement for environment to minimize oxygen consumption and oxygen supplemental oxygen. The chest radiograph shows prominent requirements. The ability to supply an adequate caloric intake perihilar streaking which may represent engorgement of the to the critically ill infant receiving respiratory assistance is periarterial lymphatics that participate in the clearance of facilitated by intravenous hyperalimentation including lipid alveolar fluid. The radiographic appearance can usually solutions commencing on the first day after birth. be readily distinguished from the diffuse reticulogranular pattern with air bronchograms that is characteristic of RDS. Metabolic acidosis is most often encountered when the infant has been depressed at birth and required resuscitation. Patchy infiltrates that clear within 48 hours and are associ- A subsequent metabolic acidosis out of proportion to the ated with perihilar streaking are probably also manifestations degree of respiratory distress may signify hypoperfusion, of transient tachypnea. Differentiation from neonatal pneu- sepsis, or an IVH. It is not necessary to correct metabolic or res- monia or meconium aspiration can be extremely difficult, piratory acidosis if the pH is greater than 7.25, whereas a pH of especially if antenatal or postnatal history includes risk factors less than 7.20 typically requires intervention. In the case of for these disorders. Transient tachypnea of the newborn by 446

Problems in the Newborn definition is self-limiting with no risk of recurrence or residual 7000 pulmonary dysfunction. 6000 Extracorporeal membrane oxygenation 5000 94% Cases Indications and patient selection 4000 Diseases Because of the invasive nature of extracorporeal membrane Cases 3000 oxygenation (ECMO), most notably the need to ligate the right common carotid artery in many patients and the risk of major 2000 78% 52% 75% hemorrhage resulting from systemic heparinization, ECMO 1000 PPHN continues to be reserved for neonates who do not respond to MAS 84% CDH Sepsis maximal conventional support and are believed to have a 0 RDS chance of survival of 20% or less [18]. Because of the high risk of intracranial hemorrhage in babies born before 34 weeks’ Figure 53.1 ELSO registry – outcomes with ECMO according to diagnosis. gestation, ECMO is currently applicable only to term or near- Modified from Martin RJ, Fanaroff AA, Walsh MC (eds). Fanaroff and term infants. In general, to be considered for ECMO therapy, a Martin’s Neonatal-Perinatal Medicine, 8th edn. Philadelphia: Mosby Elsevier, baby must have completed 34 weeks’ gestation, weigh at least 2006 with permission. CDH, congenital diaphragmatic hernia; MAS, 2 kg, and have a reversible cause of pulmonary or cardiac meconium aspiration syndrome; PPHN, persistent pulmonary hypertension failure. Meconium aspiration syndrome is the most frequent of the newborn; RDS, respiratory distress syndrome. cause of respiratory failure leading to ECMO. Other common underlying conditions are diaphragmatic hernia, sepsis, con- children with diaphragmatic hernia. Sensorineural hearing genital pneumonia, RDS, and perinatal asphyxia. Persistent loss is a common complication of ECMO and was noted in 29 pulmonary hypertension of the newborn (PPHN) is almost of 111 (26%) ECMO graduates. The need for early, routine, always a major contributing factor, usually accompanied by audiologic evaluations throughout childhood for all ECMO varying degrees of myocardial dysfunction. Primary cardiac graduates is apparent. failure is a relatively rare indication for ECMO and the success of the procedure in these patients is limited. Jaundice The survival rate for ECMO patients listed in the Extracor- Bilirubin is produced from breakdown of hemoglobin, poreal Life Support Organization (ELSO) Registry based at the myoglobin cytochromes, and other heme-containing com- University of Michigan as of July 1997 is 80.4% [19]. For the pounds mainly in the liver, spleen, and bone marrow. The years 1973–82 the survival rate was 57.8%, rising to 82.2% in indirect bilirubin so formed is water-insoluble but fat-soluble, 1983–89. The survival rate has declined slightly in 1990–97 to and hence potentially toxic to the central nervous system. 79.8%, reflecting a change in the patient mix toward a greater Beta-glucuronidase present in human milk enhances the reab- proportion of more difficult cases. The prognosis for survival sorption of bilirubin from the gut [20]. In the fetus, the indirect depends mainly on birthweight, gestational age, and the bilirubin is transported across the placenta. Hyperbilirubine- underlying diagnosis (Fig. 53.1). Admission pH may also be a mia is observed either when production of bilirubin is useful prognostic feature. enhanced (e.g., hemolysis) or when elimination is reduced. Serious complications of ECMO are not frequent but can be An elevated bilirubin level (hyperbilirubinemia) is the most devastating. Of greatest concern are those related to systemic common problem encountered in the full-term neonate and is heparinization and to the ligation of the carotid and perhaps a significant problem in the late preterm infant (36–38 weeks). jugular vessels. Intracranial hemorrhage occurs in approxi- Hyperbilirubinemia is clinically relevant in the neonate mately 16% of patients and is more frequent in babies of 34– because it has been associated with kernicterus (yellow stain- 35 weeks’ gestation. Other significant complications include ing of the basal ganglia and hippocampus). Most reports indi- internal hemorrhage, renal failure, and seizures. Cerebral in- cate that in term infants, without evidence of hemolysis, farction, predominantly involving the right hemisphere, is an kernicterus is unlikely to occur if the serum bilirubin is main- occasional occurrence in patients who were hypotensive at the tained below 25 mg/dL, although kernicterus has been time of carotid artery ligation. Follow-up data suggest that reported at autopsy in low birthweight infants when the serum despite the extreme severity of their neonatal illness, most bilirubin never exceeded 10 mg/dL. There has been a resur- ECMO graduates survive the experience without apparent gence of kernicterus in term and near-term infants attributable neurologic or developmental impairment. Transient feeding to early discharge, poorly supervised breast feeding, and inad- problems are a frequent occurrence and may delay discharge. equate follow-up most notably of late preterm infants (13– However, they rarely persist beyond a few weeks, except in 15 weeks’ gestation) [21,22]. Clinical manifestations of kernicterus in the full-term infant include temperature instability, lethargy, poor feeding, 447

Chapter 53 high-pitched cry, vomiting, and hypotonia. Subsequently, be indicated. An abdominal ultrasonograph may prove irritability, opisthotonus, sun-setting appearance of the eyes, extremely productive, as may CT scan of the liver. A liver and seizures may occur. “Wind-milling” movements of the biopsy may be indicated. extremities have been reported. Pulmonary or gastric hemorrhage may occur as a terminal event. Long-term Persistent elevation of the indirect bilirubin occurs sequelae include the spastic or athetoid form of cerebral predominantly with hemolytic disease, hypothyroidism, or palsy, hearing loss (especially high-tone), paralysis of upward breastmilk jaundice. The latter has been attributed at various gaze, and enamel hypoplasia. In the preterm infant, times to hormones in the breastmilk, to nonesterified fatty fisting, apnea, and increased tone may be the only acute mani- acids in the breastmilk that inhibit glucuronyl transferase, festations. The search continues for a method of identifying and to the presence of β-glucuronidase in human milk, infants at greatest risk to determine if and when encephalo- which enhances the enterohepatic circulation of bilirubin. pathy is imminent. ABO incompatibility is the most common cause of hemolytic disease in the newborn. A very high anti-A or anti-B antibody Jaundice usually progresses from the head and neck to the titer may be found in the maternal serum; the infant’s trunk and limbs. It disappears in the reverse direction. The blood smear reveals abundant spherocytes, and the reticulo- onset of significant jaundice within the first 36 hours of life, cyte count may be elevated. Hemolytic disease of the persistence beyond the first week of life, a serum bilirubin that newborn, secondary to Rh incompatibility, has become is rapidly rising or has exceeded the 90th percentile for age in extremely rare with the widespread screening and use of Rh hours according to the Bhutani nomogram or a combination immunoglobulin, so that g6PD deficiency has become more thereof, is an indication for investigation of the jaundice [23]. important [25]. Generally, the serum bilirubin ranges between 6 and 7 mg/dL between days 2 and 4 and infants with bilirubin levels above Treatment the 90th percentile for their age (in hours) require investiga- tion and treatment [23]. It is important to ensure adequate hydration of jaundiced neonates. This has generated considerable controversy Bilirubin can now be detected noninvasively via transcuta- because proponents of breastfeeding are convinced that sup- neous monitors. Maisels and Kring [24] sequentially followed plementation with formula or water decreases the success of infants’ bilirubin levels using the transcutaneous technology. breastfeeding. Evidence is strongly mounting to indicate that They concluded that infants who require closer evaluation a reduced calorie or fluid intake is responsible for the early and observation initially are those whose bilirubin levels are elevated bilirubin levels noted among breastfed infants. ≥95th percentile (i.e., increasing more rapidly than 0.22 mg/ Breastfeeding should not be discontinued during the first dL/hour in the first 24 hours, 0.15 mg/dL/hour at 24–48 days of life. hours, and 0.06 mg/dL/hour after 48 hours). Phototherapy has been extensively used for the treatment of In determining the cause of jaundice the important histori- jaundice [26]. Light reduces bilirubin levels predominantly by cal data include the blood types of the parents and the isoim- photoisomerization and, to a lesser extent, photo-oxidation. mune status, ethnic origin of parents, maternal drug history, Essentially during photoisomerization, bilirubin is rapidly gestation, mode of delivery, past history with regard to jaun- converted from a relatively insoluble state to water-soluble diced neonates, stooling pattern, and method of feeding. Jaun- photoisomers. When bilirubin is exposed to light, native dice associated with breastfeeding is the most common cause bilirubin is converted to photobilirubin and the structural of hyperbilirubinemia in the otherwise healthy full-term isomer lumirubin. Lumirubin appears to be the principal infant. route of pigment elimination during phototherapy. Before phototherapy is ordered, the cause of the hyperbilirubinemia The presence of plethora, bruising, and cephalohematoma should be investigated. Most recent studies on the should be sought. Hepatosplenomegaly accompanied by natural history of jaundice reveal that the early use of pallor, purpura, and rashes may indicate congenital infection phototherapy offers no advantage, and prophylactic photo- or hemolytic disease. The initial evaluation should always therapy, even in tiny immature infants, has not proved to be include a complete blood count with smear and reticulocyte necessary. count, blood type of mother and infant, direct antibody test, total and direct bilirubin level, and urinalysis to rule out infec- Guidelines for the use of phototherapy and exchange trans- tion and galactosemia. If the infant is sick with the jaundice, a fusions are outlined in guidelines published by the American blood culture, spinal tap, and chest radiograph are also indi- Academy of Pediatrics [27]. It is important to recognize that cated. If the direct bilirubin exceeds 10% of the total, this indi- these are only guidelines. Therapy should always be dictated cates either biliary obstruction or hepatocellular damage. by the clinical condition and clinical evaluation, not merely by Therefore, in addition to the aforementioned studies, serum laboratory tests. In bruised, asphyxiated, acidotic, or poten- protein and protein electrophoresis, serum transaminases, α1- tially septic infants, more liberal indications for treatment are antitrypsin concentration, hepatitis-associated antigens and often used (Fig. 53.2). titers, TORCH titers, sweat chloride, and clotting profile may 448

Problems in the Newborn 25 428 during prenatal and early postnatal growth [29–34]. As an infant may have a limited ability to synthesize optimal levels Serum bilirubin (mg/dL)20 342 of AA and DHA from linoleic and linolenic acid, these two µmol/L257 fatty acids may be essential. Infant formulas in the USA have High risk zone 95% 171 only recently been supplemented with AA and DHA. 85 15 HLigohwinintetermrmeeddiaiateterirsikskzzoonnee The majority of proteins in milk are blood plasma derived. 10 Other proteins such as alpha-lactalbumin are unique to the mammary gland and are synthesized de novo upon Low risk zone stimulation by prolactin, insulin, and cortisol. Enzymes and bioactive substances, which may have both local and systemic 5 effects, add credence to the concept of human milk as a dynamic substance with nutritive as well as nonnutritive 00 functions. 0 12 24 36 48 60 72 84 96 108 120 132 144 Postnatal age (h) Human milk is a dynamic substance, its characteristics evolving as the infant matures. For example, early milk or Figure 53.2 Nomogram for designation of risk in 2840 well newborns at colostrum has higher concentrations of protein and minerals 36 or more weeks’ gestational age with birthweight 2000 g or more, or 35 or than does mature milk, but lower concentrations of fat. This more weeks’ gestational age and birthweight 2500 g or more based on the relationship reverses as the infant matures. Also, within a hour-specific serum bilirubin values. From Subcommittee on given breastfeeding session, the milk first ingested by the Hyperbilirubinemia, Pediatrics 2004;114:297–316 with permission. infant has a lower fat content (fore milk), and as the infant con- tinues to nurse over the next several minutes, the fat content Lactation increases (hind milk), facilitating satiety in the infant. There are various enzymes in human milk, some specific for the bio- A mother’s decision to breastfeed her baby, and facilitating synthesis of milk components in the mammary gland (e.g., her lactation success, commences during pregnancy and is lactose synthetase, fatty acid synthetase, and thioesterase) and heavily influenced by all her caregivers. In view of the unique some specific for the digestion of proteins, fats, and carbohy- content of human milk together with the short- and long-term drates that facilitate food breakdown and absorption of human benefits of feeding human milk to the neonate, every effort milk by the infant. In addition, certain enzymes serve as trans- should be made to encourage breastfeeding. port moieties for other substances such as zinc, selenium, and magnesium. When discussing nutritional support the clinician should mention the psychosocial aspects of breastfeeding as well as Human milk also contains a host of hormones, enzymes, the compelling nutritional and immunologic advantages of cytokines, growth factors, and a myriad of nutrients including breastmilk over formula. Breastfed infants have improved immunoglobulins, lactoferrin, lysozyme, glycoconjugates, general health, growth, and development, with fewer and less oligosaccharides, and various types of white blood cells that severe episodes of diarrhea, less sudden infant deaths, fewer protects the intestine from infectious pathogens and intact lower respiratory infections or otitis media, less bacteremia, dietary antigens. Indeed, there is a wide repertoire of antibac- bacterial meningitis, urinary tract infection, and necrotizing terial, antiviral, antifungal, and food antibodies in human milk enterocolitis. Breastfeeding has also been related to possible that reflect the antigenic repertoire of the mother’s intestine enhancement of cognitive development. There are also con- and respiratory tract. Therefore mother’s milk is a significant siderable emotional and physical benefits for the mother. source of passively provided secretory immunoglobulin A (sIgA)-specific antibody for the infant during the time of Properties of human milk reduced neonatal gut immune function. Assuming mother and infant, who are closely associated, share common gut The major component of human milk is water, making up flora, then the antigen specificity of mother’s milk sIgA approximately 50% of the milk by volume. There is a balance will be directed against the same antigens present in the of proteins (the major components of which are alpha- neonate’s gut. lactalbumin and whey), carbohydrates (lactose), and fats [28]. The fats are composed of cholesterol, triglycerides, short-chain Whereas human milk is a unique species-specific nutritive fatty acids and long-chain polyunsaturated (LCP) fatty acids. fluid, commercially available formulas are not. In fact, formu- The LCP fatty acids (16- to 22-carbon length) are needed for las are inert nutritive fluids whose composition is modeled brain and retinal development. Large amounts of omega-6 after human milk. Each provides adequate amounts of protein, and omega-3 LCP fatty acids, predominantly the 20-carbon fat, carbohydrate, minerals, and vitamins for the growth of arachidonic acid (AA) and the 22-carbon docosahexaenoic normal infants. Further, long-term epidemiologic studies acid (DHA), are deposited in the developing brain and retina demonstrated a number of interesting differences between breastfed and formula-fed infants. More specifically, studies 449

Chapter 53 of infants during the first years of life demonstrated a protec- tion. The condition is more common amongst first time tive effect of human milk against infectious disease [35–40]. mothers. Human milk is the preferred feeding for all infants, including premature and sick newborns, with rare exceptions. When Breastmilk jaundice refers to an elevation of indirect direct breastfeeding is not possible, expressed human milk, bilirubin in a breastfed newborn that develops following the fortified when necessary for the premature infant, should be first 4–7 days of life, persists, and has no other identifiable provided. Before advising against breastfeeding or recom- cause. In contrast, breastfeeding jaundice occurs before the mending premature weaning, the practitioner should weigh first 4–7 days of life and is caused by insufficient production or thoughtfully the benefits of breastfeeding against the risks of intake of breastmilk. not receiving human milk [41]. Breastmilk jaundice is thought to be caused by a substance Neonates, especially those born prematurely with an imma- or substances in the breastmilk that inhibits uridine diphos- ture or unsensitized immune system, are highly dependent on phoglucuronic acid (UDPGA) glucuronyl transferase result- the delivery of substances to the gut to help stimulate gut epi- ing in a prolonged unconjugated hyperbilirubinemia. thelial cell proliferation and closure from the outside world. In Lipoprotein lipase, found in some breastmilk, produces non- addition, there appears to be a critical period in brain develop- esterified long-chain fatty acids, is one such substance. Another ment when diet influences later outcome; as a consequence, mechanism is enhanced enterohepatic circulation of bilirubin preterm infants who receive mother’s milk are afforded a induced by beta glucuronidase which is abundant in breast- lower risk of adverse neurodevelopmental sequelae. It is rec- milk and not found in formula. ommended then that premature infants receive mother’s milk with fortification [42,43]. References There are a few situations where feeding human milk to 1 Lorenz JM, Paneth N, Jetton JR, den Ouden L, Tyson JE. neonates is contraindicated. Galactosemia is one of the few Comparison of management strategies for extreme prematurity absolute contraindications to the use of human milk. Other sit- in New Jersey and the Netherlands: outcomes and resource uations include maternal chemotherapy; illegal drug use by expenditure. Pediatrics 2001;108:1269–74. the mother or radioactive isotopes that mandate temporary interruption of breastfeeding; untreated active tuberculosis; 2 Marlow N, Wolke D, Bracewell MA, Samara M, EPICure Study and the infant in the USA whose mother has been infected with Group. Neurologic and developmental disability at six years the human immunodeficiency virus. Most prescribed and of age after extremely preterm birth. N Engl J Med 2005;352: over the counter medications are safe for the breastfed 9–19. infant [44]. 3 Doyle LW, Victorian Infant Collaborative Study Group. Neonatal Case presentation intensive care at the borderline viability—is it worth it? Early Hum Dev 2004;80:103–13. A term infant, birthweight 3700 g, who is exclusively breastfed becomes lethargic and is noted to be jaundiced on the fourth 4 Doyle LW, Victorian Infant Collaborative Study Group. day of life. His weight is 3367 g (down 9% from birthweight), Evaluation of neonatal intensive care for extremely low birth the hematocrit is 60%, and the infant’s serum sodium is weight infants in Victoria over two decades: I. Effectiveness. 147 meq/L. There is no history of vomiting, diarrhea, or exces- Pediatrics 2004;113:505–9. sive voiding. He has only had two wet diapers in the past 24 hours. 5 Doyle LW, Victorian Infant Collaborative Study Group. Evaluation of neonatal intensive care for extremely low birth Whereas weight loss and jaundice are common in breastfed weight infants in Victoria over two decades: II. Efficiency. babies, this combination of severe dehydration with hyper- Pediatrics 2004;113:510–4. natremia and jaundice is not very common. These findings reflect usually an inadequate intake of milk. Normal babies 6 Shankaran S, Laptook AR, Ehrenkranz RA, et al. National lose 1–2% of their body weight per day until the mother’s milk Institute of Child Health and Human Development Neonatal comes in (usually by day 3); and thereafter they rapidly gain Research Network.Whole-body hypothermia for neonates with weight. Infants receiving insufficient breastmilk often appear hypoxic-ischemic encephalopathy. N Engl J Med 2005;353: to be content (i.e., they cry less in contrast to the irritable 1574–84. formula-fed infants who are not getting sufficient milk). 7 Gluckman PD, Wyatt JS, Azzopardi D et al. Selective head cooling The condition known as “hypernatremic dehydration” with mild systemic hypothermia after neonatal encephalopathy: results when newborn infants are unable to establish a suffi- multicentre randomised trial. Lancet 2005;365:663–70. cient transfer of breastmilk during nursing, either because they do not latch on well or there is inadequate milk produc- 8 Malcus P, Bjorklund LJ, Lilja M, Teleman P, Laurini R. Massive feto-maternal hemorrhage: Diagnosis by cardiotocography, Doppler ultrasonography and ST waveform analysis of fetal electrocardiography. Fetal Diagn Ther 206;21:8–12. 9 Horbar JD, Wright LL, Soll RF, et al. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1993;123:757–66. 450

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54 Neonatal encephalopathy and cerebral palsy Gary D.V. Hankins and Monica Longo The incidence of cerebral palsy is 1–2 per 1000 births and has Neonatal encephalopathy remained unchanged over the last 40 years. The occurrence of cerebral palsy is independent of either geographic or economic Neonatal encephalopathy is a condition defined in and boundaries. It has also been remarkably resistant to eradica- described for term (more than 37 completed weeks’ gestation) tion by the introduction of technology such as electronic fetal and near term (more than 34 completed weeks’ gestation) heart rate monitoring or the increase in cesarean delivery rates. infants. It is a clinically defined syndrome of disturbed Indeed, the great hope of electronic fetal heart rate monitoring neurologic function manifest by difficulty with initiating was that intrapartum asphyxia would be promptly identified, and maintaining respiration, depression of tone and reflexes, delivery rapidly achieved, and neurologic injury of the infant altered level of consciousness, and often seizures. Addition- averted. This would in fact parallel the thought processes ally, it must manifest within the first week of life. The advanced by the orthopedic surgeon, Little [1], over a century differential diagnosis for neonatal encephalopathy is ago, taught that virtually all cerebral palsy was caused shown in Table 54.1. by intrapartum events, whether deprivation of oxygen, trauma, or the combination of the two. Unfortunately, despite Hypoxia sufficient to result in hypoxic ischemic encepha- an escalation of the cesarean delivery rate from approximately lopathy (HIE) is only one subset of the larger category of neo- 6% in 1970 to a rate approaching 30% nationally today [2], the natal encephalopathy. If there has been intrapartum asphyxia incidence of cerebral palsy in the USA has remained constant sufficient to result in long-term neurologic injury manifest as [3]. These facts then would seem to support the evolving cerebral palsy, then the neonate will manifest the injury as concept that cerebral palsy results from the combination of encephalopathy during labor. It is biologically implausible to the genetic make-up of the individual and the subsequent suggest that one can have sufficient intrapartum asphyxia to collision of that individual during development with the result in cerebral palsy, yet the newborn would have a com- environment that they are exposed to, both intrauterine as pletely normal hospital course during labor that was in fact well as extrauterine for the first several days, months, or years void of encephalopathy. of life. As examples, the South Australian Cerebral Palsy Research Group has recently reported that inheritance of Cerebral palsy MTHFR C677T approximately doubles the risk of cerebral palsy in preterm infants. A combination of homozygous Cerebral palsy is defined as a chronic neuromuscular disabil- MTHFR C677T and heterozygous prothrombin gene muta- ity characterized by abnormal control of movement or posture tion increased the risk of quadriplegia fivefold in all gesta- appearing early in life and not the result of recognized pro- tional ages [4]. This is clearly an example of genetic inheritance gressive disease [6]. The causes of cerebral palsy are in large leading to cerebral palsy. The same group also demonstrated part the same as the antecedents of neonatal encephalopathy that perinatal exposure to the neurotropic herpes group B (Table 54.1). In a sentinel publication, MacLennan [7] notes viruses nearly doubled the risk of cerebral palsy relative to the that epidemiologic studies suggest that in approximately 90% control group [5]. 452

Neonatal Encephalopathy and Cerebral Palsy of cases of cerebral palsy, intrapartum hypoxia could not be odds ratio. Badawi et al.’s data are striking inasmuch as the tra- the cause and in the remaining 10% intrapartum signs compat- ditional risk factors, including abnormal histopathology of the ible with damaging hypoxia may have had antenatal or intra- placenta, the need for emergency cesarean section, or the use partum origins. of vacuum or forceps to achieve vaginal delivery, were among the lowest, although statistically significant, risk factors iden- A group of investigators led by Badawi [8] reported on the tified. In contrast, family history of seizure disorder or neuro- antecedents of moderate to severe neonatal encephalopathy logic disorder and maternal thyroid disease were much more from their patient population in metropolitan Western Aus- highly associated with moderate to severe encephalopathy tralia. This study involved 164 term infants with moderate or than the traditional risk factors. This again emphasizes the severe neonatal encephalopathy and 400 randomly selected potential role of genetics in causing both encephalopathy as appropriate controls. Within their population, the prevalence well as cerebral palsy. The role of environment is also demon- of moderate or severe newborn encephalopathy was 3.8 in strated from Badawi et al.’s data, with factors such as viral 1000 term live births. The diagnosis of either moderate or illness during the index pregnancy, moderate or severe severe newborn encephalopathy was associated with a neona- antepartum bleeding, intrapartum fever, and severe pre- tal fatality rate of 9.1%. In Fig. 54.1, the risk factors for newborn eclampsia being significant increased risk factors for dev- encephalopathy in their population that achieved statistical elopment of these disorders. Thus, we return to the role of significance are shown and substratified according to whe- genetics and the impact of environment on causation of ther they occurred preconceptionally, intrapartum, or in the this neurologic injury. This is repeatedly being affirmed by antepartum period. Data shown are the increase in adjusted clinical studies employing a variety of rapidly advancing technologies [4,5]. Table 54.1 Differential diagnosis of neonatal encephalopathy. When Badawi et al. analyzed their data as regards the distri- Developmental abnormalities bution of risk factors for newborn encephalopathy, they Metabolic abnormalities concluded that in 69% of the population there were only Autoimmune disorders antepartum risk factors. In 25%, there were antepartum risk Coagulation disorders factors and potential impact of intrapartum hypoxia, but in Infections only 4% did intrapartum hypoxia seem to be the logical cause Trauma (Fig. 54.2). This team of investigators’ overall conclusions were Hypoxia that the causes of newborn encephalopathy are heterogeneous Intrauterine growth restriction (IUGR) and that many of the causal pathways start before birth. A Multiple gestations much earlier study by Blair and Stanley [9] had similarly con- Antepartum hemorrhage cluded that in only 8% of all children with spastic cerebral Chromosomal abnormalities palsy was intrapartum asphyxia the possible cause of their Persistent breech/transverse lie brain damage. Abnormal placental appearance 2.07 Preconception Emergency cesarean 2.17 Intrapartum Instrumental delivery Antepartum Family Hx seizure 2.23 2.55 Family Hx neurologic disorders 2.73 Viral illness 2.97 Moderate/severe antepartum bleeding 3.57 Intrapartum fever 3.82 Occiput posterior presentation 4.29 IUGR 3rd–9th percentile 4.37 Infertility treatment 4.43 4.44 Acute intrapartum event Fig. 54.1 Risk factors for newvorn Severe preeclampsia 6.3 encephalopathy. After Badawi et al. [8]. Hx, Maternal thyroid disease 9.7 history; IUGR, intrauterine growth restriction. 38.23 IUGR <3rd percentile 0 5 10 15 20 25 30 35 40 45 Adjusted odds ratio 453

Chapter 54 The importance of intrauterine growth restriction (IUGR) as and will be poorly tolerant of epidural-induced hypotension. a risk factor for newborn encephalopathy deserves special Fetal monitoring is necessary in the operating or delivery emphasis. In Badawi et al.’s study, growth restriction between room. In cases of cesarean delivery, the interval from fetal the 3rd and 9th percentile carried an adjusted odds ratio of 4.37 monitoring to delivery should be as short as possible. for moderate or severe neonatal encephalopathy. When the growth restriction was severe, defined as less than the 3rd per- Task force on neonatal encephalopathy and centile, the adjusted odds ratio increased to a staggering 38.23. cerebral palsy In a series reported by Cowan et al. [10], 11–15% of the popula- tion with encephalopathy were at the 3–10th percentile, com- In January 2003, a monograph summarizing the state of the pared with 13–16% when the growth restriction was less than science on neonatal encephalopathy and cerebral palsy was the 3rd percentile. Their study population was recruited from copublished by the American College of Obstetricians and the Wilhelmina Children’s Hospital, Utrecht, the Netherlands Gynecologists and the American Academy of Pediatrics. At and Hammersmith and Queen Charlotte’s Hospitals, London, the time of publication it was recognized that the topic would UK. Substantially similar results were reported from the Uni- require updating as the scientific database and knowledge on versity of California, San Francisco, and Loma Linda Chil- the topic expanded. In that monograph, the criteria to define dren’s Hospital, where newborns with either a watershed an acute event sufficient to cause cerebral palsy were listed, as predominant or a total brain/basal ganglia/thalamus pre- modified by the Task Force from the template provided by the dominant injury had a higher incidence of intrauterine growth International Cerebral Palsy Task Force (Table 54.2). It was restriction than did those infants having a normal scan [11]. emphasized that all four criteria must be met in order to make this association. Additionally, criteria were also listed that col- The clinician is thus cautioned that while all growth lectively suggest an intrapartum timing, defined as within restricted babies are at increased risk for newborn encepha- close proximity to labor and delivery (e.g., 0–48 hours), but lopathy, the risk is extraordinarily high for those infants with which were non-specific to asphyxia insults (Table 54.3). growth restriction at less than the 3rd percentile. Accordingly, Among the criteria for elucidating timing was early imag- great care in the timing and route of delivery of these fetuses is ing studies showing evidence of acute nonfocal cerebral encouraged so that they might be delivered in an optimal met- abnormalities. abolic condition. It would also seem prudent to have a neona- tologist present at the birth and to provide immediate care of Table 54.2 Essential criteria to define an acute intrapartum event sufficient the newborn. Induction of anesthesia may be a very high-risk to cause cerebral palsy (must meet all four). period, as many of these fetuses are marginally compensated 1 Evidence of a metabolic acidosis in fetal umbilical cord arterial blood Intrapartum hypoxia Unknown (2%) obtained at delivery (pH <7 and base deficit of ≥12 mmol/L) only (4%) 2 Early onset of severe or moderate neonatal encephalopathy in infants born at ≥34 weeks’ gestation Antepartum risk 3 Cerebral palsy of the spastic quadriplegic or dyskinetic type factors and 4 Exclusion of other identifiable etiologies, such as trauma, coagulation intrapartum disorders, infectious conditions, or genetic disorders hypoxia (25%) Table 54.3 Criteria that collectively suggest an intrapartum timing (within close proximity to labor and delivery, e.g., 0–48 hours) but that are Antepartum risk factors nonspecific for an asphyxial insult. only (69%) 1 A sentinel (signal) hypoxic event occurring immediately before or during Fig. 54.2 Distribution of risk factors for newborn encephalopathy. After labor Badawi et al. [8] 2 A sudden and sustained fetal bradycardia or the absence of fetal heart rate variability in the presence of persistent late or persistent variable decelerations, usually after a hypoxic sentinel event when the pattern was previously normal 3 Apgar scores of 0–3 beyond 5 minutes 4 Onset of multisystem involvement within 72 hours of birth 5 Early imaging study showing evidence of acute nonfocal cerebral abnormality 454

Neonatal Encephalopathy and Cerebral Palsy Subsequent to the publication of this monograph, three diabetes, premature ruptured membranes, preeclampsia, and important papers on neuroimaging have been published. The intrauterine growth restriction did not differ between the first of these publications was by Graham et al. [12] and dealt injury patterns. The basal ganglia/thalamus pattern was asso- with an earlier gestation than covered by the Task Force, which ciated with more severe neonatal signs, including more inten- was restricted to the term and near term infant. In contrast, sive resuscitation at birth, more severe encephalopathy, and Graham et al.’s study was of the preterm infant of 23–34 weeks’ more severe seizures. The basal ganglia/thalamus pattern gestation. The significant findings by these authors included was most highly associated with impaired motor and cogni- that in this specific population, intrapartum hypoxia ischemia tive outcome at 30 months. These authors concluded that the as manifested by metabolic acidosis was rarely associating patterns of brain injury in term neonatal encephalopathy are with white matter injury, and was not different from that seen associated with different clinical presentation and different in premature neonates without injury. neurodevelopmental outcomes. Further and contrary to prior epidemiologic studies, they noted that measured prenatal The second study was by Cowen et al. [10]. These investiga- factors did not predict the pattern of brain injury. Like Cowan tors divided their population into two groups. Group 1 was et al., they noted that the MRI findings in their cohort were con- defined as those with neonatal encephalopathy with or sistent with the recent, rather than chronic brain injury in the without seizures, and evidence of perinatal asphyxia. This majority of patients and the antenatal conditions measured group consisted of infants with neonatal encephalopathy, were remarkably similar between newborns with normal and defined by abnormal tone pattern, feeding difficulties, altered abnormal MRI scan results. They felt that these observations alertness, and at least three of the following criteria: highlighted the potential of interventions to ameliorate brain 1 Late decelerations on fetal monitoring or meconium injury in the newborn. They remarked that the dissociation of staining; antenatal risk factors from the severity of the clinical presenta- 2 Delayed onset of respiration; tions supports the hypothesis that the etiology of brain injury 3 Arterial cord blood pH <7.14; in neonatal encephalopathy is distinct from these antenatal 4 Apgar score <7 at 5 minutes; risk factors. They further noted that the watershed pattern had 5 Multiorgan failure. predominantly cognitive impairments at 30 months that were Their second group consisted of infants who had seizures not detected at 12 months of age. The cognitive deficits in this within 72 hours of birth but who did not meet the criteria for group often occurred without functional motor deficits. They neonatal encephalopathy. In the first group, brain imaging hypothesized that abnormal outcome after neonatal encepha- studies showed evidence of an acute insult without estab- lopathy may not be limited to cerebral palsy and often requires lished injury or atrophy in 80% of infants. Magnetic resonance follow-up beyond 12 months of age to be detected. imaging (MRI) showed evidence of established injury in only two infants (<1%), although tiny foci of established white Conclusions matter gliosis, in addition to acute injury, were seen in 3/21 on postmortem examination. In group 2, acute focal damage was How are we to resolve the epidemiologic studies with the noted in 62 (69%) infants. Two (3%) also had evidence of ante- more recent conclusions from imaging studies? Because new- natal injury. Cowen et al. [10] concluded that although their borns with severe encephalopathy are more likely to be identi- results could not exclude the possibility that antenatal or fied for research studies in the intensive care nursery and these genetic factors might predispose some infants to perinatal newborns are more likely to have the basal ganglia/thalamus brain injury, their data strongly suggested that events in the injury pattern, it is that possible that the prospective MRI immediate perinatal period were most important in neonatal studies of neonatal encephalopathy will over-represent peri- brain injury. A valid criticism of this study is the criteria natally acquired injury compared with population-based epi- selected for inclusion into their group 1. Either late decelera- demiologic surveys. Because population-based retrospective tions on fetal monitoring or meconium staining are notori- studies identify a preponderance of antenatal risk factors and ously poor predictors of intrapartum asphyxia. Delayed onset smaller prospective cohort studies identify the perinatal of respirations can be for numerous reasons, and a large occurrence of brain injury, there is a pressing need to establish number of babies will be born with blood pH <7.1 and almost the mechanistic link between prenatal risk factors and etiol- all will be neurologically intact. What these authors fail to tell ogy of brain injury. This is critical to the prevention of acquired us is how many of their total population would have met at neonatal brain injury and may be achieved with the develop- least three of the five criteria that they listed for inclusion in the ment and application of more accurate in utero measures of acute injury group. brain injury, such as fetal MRI. The study by Miller et al. [11] reported that the watershed Both the American College of Obstetricians and Gynecolo- pattern of injury was seen in 78 newborns (45%), the basal gists and the American Academy of Pediatrics acknowledged ganglia/thalamus pattern was seen in 44 newborns (25%), and that their 2003 summary would require updating as the normal MRI studies were seen in 51 newborns (30%). Antena- tal conditions such as maternal substance abuse, gestational 455

Chapter 54 scientific database and knowledge on the topic expanded. rendered by the pathologist despite the fact that “gross and They went on to state that only with more complete under- microscopic examinations were normal.” Cord gases were standing of the precise origins of the pathophysiology of neo- obtained at delivery and showed for the umbilical arterial natal encephalopathy and cerebral palsy could logical blood a pH of 7.273, Pco2 of 57.6, Po2 of 17.4, HCO3 of 25.9, and hypotheses be designed and tested to reduce this occurrence. base excess of –4.0. A cord venous blood gas showed a pH of Finally, they recommended several important areas of research 7.30, Pco2 of 50.0, Po2 of 18.6, HCO3 of 24.1, and base excess of – and for research funding. We would again emphasize the need 1.6. Conclusively then, the cord gases rule out “birth asphyxia” for funding and studies to address this very important issue in and the fetus was additionally delivered in an atraumatic neurodevelopment, neuroimaging, and potential improve- fashion. Fortunately, when neuropathology results were final- ments in outcomes for populations worldwide. ized they demonstrated lesions within the brain that dated at least 96 hours of age, placing the injury well before the woman Case presentation presented to the outlying hospital or before transport to the medical center. A 27-year-old G2 P0100 was accepted for maternal transport with diagnoses of 28 weeks estimated gestational age and This case demonstrates several critical points. Perhaps the severe preeclampsia. Her past medical history was significant most important is the need to be precise in the terminology for a prior intrauterine fetal demise at 31 weeks’ gestation, that that we employ and to diagnose birth asphyxia on objective pregnancy was also complicated by severe preeclampsia. Fol- rather than subjective criteria. Secondly, the value of cord lowing successful aeromedical transport, she was received in blood studies obtained at delivery and of continuous elec- Labor and Delivery where standard treatment for severe pre- tronic monitoring to exclude intrapartum asphyxia is well eclampsia was instituted, including magnesium sulfate for demonstrated. Finally, while the pathologist initially listed prevention of eclamptic seizures and betamethasone for fetal several erroneous diagnoses, largely based upon erroneous lung maturation. Because of the severity of her disease process, diagnoses contained in the pediatric chart, the record was labor induction with oxytocin was also instituted. Hydrala- eventually corrected with the neuropathology results. This zine was given in 5-mg incremental doses to control and would then point out the importance of a pathologic diagnosis reduce systolic blood pressure to less than 180 mmHg and of the intrauterine fetal demise and additionally also supply- diastolic blood pressure to less than 110 mmHg. Ten hours ing the pathologist with accurate information upon which to into the labor induction, a series of eight repetitive late deceler- base their conclusions. This case would beg for the establish- ations was noted. The oxytocin was discontinued, the woman ment of set criteria for the evaluation of a newborn with placed in left lateral position, and oxygen was administered at suspected intrapartum asphyxia to include set times for neu- 10 L/min by face mask. The fetal heart rate promptly normal- roimaging studies as well as evaluation of the newborn for ized; however, beat–beat variability was judged to be reduced multiorgan system injury or insult. consistent with the estimated gestational age as well as the administration of magnesium sulfate. References As vaginal delivery was remote, the alternative of cesarean 1 Little WJ. On the influence of abnormal parturition, difficult section was discussed because of fetal intolerance of labor. labours, premature births, and asphyxia neonatorum, on the Following informed consent, the patient was taken to the mental and physical condition of the child, especially in relation operating room for cesarean delivery. General endotracheal to deformities. Trans Obstet Soc Lond 1862;3:293–344. anesthesia was necessitated by maternal thrombocytopenia. A low vertical uterine incision was employed as the lower 2 Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, uterine segment was poorly developed and thick and a verti- Munson ML. Births: final data for 2003. Natl Vital Stat Rep cal incision would allow the most atraumatic delivery. A 970-g 2005;54:1–116. infant was delivered and passed to a neonatologist who assigned Apgar scores of 1/0/0/0/0. The fetus/infant was 3 Clark SL, Hankins GDV. Temporal and demographic trends in pronounced dead at 20 minutes of age. The admission cover cerebral palsy: fact and fiction. Am J Obstet Gynecol sheet for this infant by the pediatricians recorded a 26–29 2003;188:628–33. weeks’ estimated gestational age, male infant with severe birth asphyxia. In the diagnostic codes listed for discharge was 4 Gibson CS, MacLennan AH, Hague WM, et al. Associations included acute respiratory failure with inability to resuscitate between inherited thrombophilias, gestational age, and cerebral the infant in the delivery room and birth asphyxia. The autopsy palsy. Am J Obstet Gynecol 2005;193:1437. report also returned findings consistent with chronic intrau- terine anoxia, as well as possible acute anoxia secondary to 5 Gibson CS, MacLennan AH, Goldwater PN, et al. Neurotropic prolonged labor and difficult delivery. These diagnoses were viruses and cerebral palsy: population based case–control study. Br Med J 2006;332:76–80. 6 Ruth VJ, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis in the Apgar score. Br Med J 1988;297:24–7. 7 MacLennan A. A template for defining a causal relation between 456

Neonatal Encephalopathy and Cerebral Palsy acute intrapartum events and cerebral palsy: international of brain lesions in term infants with neonatal encephalopathy. consensus statement. Br Med J 1999;319:1054–9. Lancet 2003;361:736–42. 8 Badawi N, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors 11 Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain for newborn encephalopathy: the Western Australian case– injury in term neonatal encephalopathy. J Pediatr 2005;146:453–60. control study. Br Med J 1998;317:1554–8. 12 Graham E, Holcroft CJ, Rai KK, Donohue PK, Allen MC. Neonatal 9 Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral cerebral white matter injury in preterm infants is associated with palsy. J Pediatr 1988;112:515–9. culture positive infections and only rarely with metabolic 10 Cowan FM, Rutherford M, Groenendaal F, et al. Origin and timing acidosis. Am J Obstet Gynecol 2004;191:1305–10. 457



Index Note: page numbers in italics refer to adrenal gland, fetal 85–86 prophylactic in labor 427, 428 figures, those in bold refer to fetal adrenal zone development 334 transabdominal 322, 323, 427 tables. transcervical 425 adrenocorticotrophic hormone (ACTH) variable deceleration relief 426 abdominal circumference, fetal 82, 84, 86 amnionicity 305–306 286–287 amnionitis 346 alcohol abuse 24, 25, 26–30 amniotic fluid abdominal wall closure techniques 383 fetal effects 24, 25, 26 anencephaly 318 ABO incompatibility 448 postpartum care 29–30 aspiration 410 abortion, spontaneous 253–259 pregnancy management 26–27 clinical measurement 319 prenatal care 27, 28–29, 29 composition 316 amniocentesis 411 intramembranous flow 318 anthropomorphic factors 257–258 aldosterone 163 meconium-stained 428–429, 430 antiphospholipid antibodies 124–125, alkylating agents, teratogens 43 recirculation 318–319 alpha-fetoprotein single deepest pocket measurement 256–257 chorionic villus sampling 413–414 maternal screening 67–69, 70, 71 319, 377 early in inherited thrombophilia combined first/second trimester 76 techniques for obtaining 91 second trimester 75–76 turnover dynamics 316–319 125–126 volume 316, 376 endocrinopathies 254–255 multiple pregnancy 310 epilepsy 203–204 placenta accreta diagnosis 368 polyhydramnios 320 genetic abnormalities 253–254 amniocentesis 70, 91 subjective assessment 319 immunologic causes 257 congenital infections 419 see also oligohydramnios; infections 254 cytogenetics 415 inherited thrombophilias 125–126, diagnostic studies 415–416 polyhydramnios DNA analysis 416 amniotic fluid embolism (AFE) 280–281 255–256 early 411 procedure-induced 411, 413–414, enzymatic analysis 416 plasma products 282–283 genetic testing 409–411 recombinant factor VIIA 283 422–423 miscarriage 411 amniotic fluid index (AFI) 95, 96–97, social factors 257–258 multiple pregnancy 310, 410, 411 syphilis 225 polyhydramnios 321 101 uterine abnormalities 255 pregnancy loss risk 411 measurement 319 abruptio placentae prematurity evaluation 354 mild preeclampsia 273 eclampsia 278 prior to cordocentesis 420 oligohydramnios 321 fetal hemorrhage 444 safety 410–411 polyhydramnios 320 inherited thrombophilia 125 technique 409–410 prolonged pregnancy 377 multiple pregnancy 308 traditional 409–411 ampicillin 51, 234, 235 preterm delivery 335 ultrasound 409, 411 preterm labor 359 preterm premature rupture of the amnioinfusion 425–431 resistance 234 administration route 425 analgesia/analgesics 49–50, 401–404 membranes 346 amount infused 425 combined spinal–epidural 402 α-cells, fetal 89 chorioamnionitis 425, 426–427 multimodal 401–402 acetaminophen 49–50 complications 429 postoperative 404 acetylcholinesterase screen 70 deceleration prevention in PPROM regional 401–402 acyclovir 51–52 side-effects 402 427–428 anaphylactoid syndrome of pregnancy herpes simplex virus 228–229 indications 426, 431 during pregnancy 169 meconium-stained amniotic fluid 280 acid–base status androgens normal 105 428–429, 430 see also metabolic acidosis oligohydramnios 322, 323, 425, 426, resistance 84 activated protein C (APC) 121, 134 teratogenicity 44 acute fatty liver of pregnancy 309 427, 428, 431 459

Index anemia antidiuretic hormone (ADH) 83, 84, labor 198 fetal 223, 420 163–164 management 194–198 iron deficiency 14, 15–16 patient education 195–196 neonatal 444–445 antiepileptic drugs 201 pharmacologic therapy 196–198 see also hemolytic disease of the breastfeeding 206 severity 193, 194–195 newborn clearance 204–205 atherosclerosis, heart transplantation contraception with 201, 202 anencephaly 67 fetal syndrome 201–203 172, 174 alpha-fetoprotein maternal screening management 204–205 atosiban 359 68–69 monotherapy 202–203, 206 atrial fibrillation 158 amniotic fluid excess 318 neonatal vitamin K deficiency 205 fetal swallowing 318 postpartum 206 maternal 148 prenatal screening 203 atrial septal defect, maternal 152 anesthesia 401 teratogenicity 43, 201–204 autosomal disorders regional cesarean delivery 403–404 antihistamines 50–51 dominant 61–62 fetoscopic surgery 438 antihypertensive drugs 50, 211–212 recessive 61, 62 azathioprine 156, 158, 170 aneuploidy, fetal 72–77 preeclampsia advanced maternal age-related postpartum management 275 bacterial vaginosis 254 253–254 severe 274 preterm delivery 334 combined first and second trimester screening 76–77 teratogenicity 42–43 bacteriuria heritable factors 254 antimetabolites, teratogenicity 44–45 sickle cell disease 110 minor markers 75 antinuclear antibody (ANA) 214 streptococci group B 235 multiple pregnancy 310 antiphospholipid antibodies (APA) 123, screening 310 basilizimab 170 second trimester 124–125, 218–219 β-cells, fetal 88–89 serum screening 75–76 spontaneous abortion 256–257 bed rest sonographic screening 75 systemic lupus erythematosus 214, spontaneous abortion 253 multiple pregnancy 311 structural malformations 75 217 preterm labor 356 antiphospholipid antibody syndrome behavioral therapy, substance abuse 26 angiotensin converting enzyme (ACE) benzene 34 gene polymorphism 127 49, 217, 218, 219, 220 benzodiazepines 48 antiretroviral drugs 243, 244–247, beta agonists 105, 198 angiotensin converting enzyme (ACE) beta-adrenergic agents 198 inhibitors 247–248 betamethasone 47–48, 355 anti-SSA/Ro antibodies 217 fetal maturation 355 contraindications 170–171, 210 anti-SSB/La antibodies 217 Bifidobacterium 18 renal insufficiency 165–166 antithrombin 121–122, 134 bilirubin teratogenicity 41, 42–43, 165–166 fetal 301 angiotensin II 16 deficiency 119–120, 122, 129 neonatal jaundice 447–448, 449 angiotensin receptor blockers 165–166 antithrombin III (AT-III) 129 biophysical profile 3, 4, 95, 97, 98, 99, 101 contraindications 210 antithyroid drugs, teratogenicity 45 IUGR 292, 293 anhydramnios 322 antiviral drugs 51–52 maternal hypertension 212 antepartum fetal monitoring 95–102 anxiety, maternal 333 prolonged pregnancy 376 diagnostic conditions 100–101 aortic aneurysm rupture 151 score deterioration 292 tests 95–99 aortic coarctation, maternal 151 birth asphyxia 456 antibiotics aortic dissection, Marfan syndrome 153 birth weight amnioinfusion for chorioamnionitis aortic regurgitation, maternal 148 cigarette smoking 13 aortic root dissection, Marfan syndrome energy/protein supplementation 14 426–427 famine conditions 10 cervical incompetence management 153 neonatal deaths 442 aortic stenosis 149 preeclampsia 7 267, 268 arachidonic acid 449 repeat tendency 8 preterm birth 329 arginine vasotocin (AVT) 83 trial of labor 390 preterm labor 356 Arnold–Chiari II malformation 69 see also low birthweight; very low prophylactic open fetal surgery 436 birthweight cesarean delivery 383 arterial blood gases, pulmonary embolism blastocyst, mosaic 416 cordocentesis 420 blood gases toxicity 51 137 anticardiolipin antibodies 125, 217, 218 Asherman syndrome 255 asthma 197 spontaneous abortion 257 aspirin 49–50 pulmonary embolism 137 anticoagulant system 119 blood loss anticoagulants mechanical heart valve patients 151 cesarean delivery 15 endogenous 134 spontaneous abortion prevention 256 iatrogenic neonatal 445 mechanical heart valve anticoagulation systemic lupus erythematosus 219, placenta accreta surgery 368 placenta manual removal 383 149–151 220 placenta previa 364 pharmacology 127–129 thrombophilia 127 vasa previa 365–366 spontaneous abortion prevention 256 assisted reproduction 3, 4 anticonvulsants, fetal asthma 192–199 see also hemorrhage acute 197–198 blood pressure syndrome 201–203 assessment 194 anti-D antibody 299 chronic 196–197 pregnancy 143, 163 anti-D immunoglobulin 114 delivery 198 see also hypertension, maternal antidepressants 48–49 diagnosis 194 effects on pregnancy 192–194 fetal monitoring 197–198 inadequate control 193 460

Index blood product replacement 280, cardiac disease, New York Heart anticoagulation management 151 282–283 Association classification blood loss 15 143–145 breech presentation 397–398, 399–400 blood sampling, direct fetal 419–423 diabetes mellitus 184 blood volume in pregnancy 143, 144 cardiac disease, maternal 143–159 eclampsia 278 body mass index (BMI) 6, 9 counseling 143–146 evidence-based operative fetal cardiac abnormality risk 146 prepregnancy 10–11, 20 maternal mortality 143, 145, 149, 151, considerations 382–383 preterm delivery 10 152 fetal distress 385 bone turnover, lactation/pregnancy 16 valvular heart disease 146–151 gestational diabetes 179 bradycardia, transient fetal 422 HELLP syndrome 277 brain imaging in neonatal encephalopathy cardiac dysfunction, sickle cell disease HIV infection 248 110 hysterotomy closure 383 455 indications 385–386 brain injury, fetal hypoxic 391–392 cardiac function, pregnancy changes malpresentation of fetus 385–386 brain-sparing reflex 290, 291, 292 143, 144 maternal morbidity/mortality 382 breastfeeding 449–450 multiple pregnancy 312 cardiac output multiple prior 391 antiepileptic drugs 206 early gestation 38 perimortem 280, 283–284 benefits 18–19 mitral stenosis 147 perinatal morbidity/mortality 382 contraindications 450 pregnancy 143, 144, 149 placenta accreta 367, 368 HIV infection 248 placenta manual removal 383 medications 48, 49, 50, 51, 52 cardiac physiology, maternal 7 placenta previa 364, 365 cardiac preload, peripartum postoperative analgesia 404 teratogens 42–43, 44, 45, 46, 47 postoperative endometritis 383 rubella infection 224 cardiomyopathy 154 preeclampsia 275 transplantation patients 174 cardiogenic shock, amniotic fluid preterm labor 359 breastmilk prior indication 390 composition 19 embolism 280 prolonged pregnancy 377 drug concentrations 42 cardiomyopathy, peripartum 153–155 rate 384–385 environmental agents 42 cardiovascular drugs 157–158 repeat 384, 386 expressed 450 cardiovascular failure, amniotic fluid thrombocytopenia 116 nutritional quality 19 thromboembolism risk 135 properties 449–450 embolism 280 thromboprophylaxis 383 volume 19 carotid artery ligation 447 tonic–clonic seizures 205–206 breastmilk jaundice 448, 450 carrier screening 62–64 transplantation patients 173 breech delivery 397–400 case–control surveillance, teratogens uterine incision repair 383 labor management 399 vasa previa 367 vaginal 397–398, 400 41–42 CFTR gene 64 catheter vesicoamniotic shunt 439 chancre 225 selection criteria 398–399 CD4 counts 243, 249 chelation therapy, lead toxicity 33 technique 399 cephalohematoma 444–445 chest X-ray breech presentation 385–386 fetal risk 139–140 blood loss 445 neonatal jaundice 448 pulmonary embolism 137 cesarean delivery 399–400 cephalosporins 51 chickenpox 231–232 epidemiology 397 cerclage, cervical 266 Chlamydia trachomatis (chlamydia) 254 external cephalic version 397, 427 screening 29 complications 267 chorioamnionitis 267, 268 calcium management after 267 amnioinfusion 425, 426–427 fetal levels 16 multiple pregnancy 310–311 prematurity evaluation 354 requirements in pregnancy 12, 14, 15, preterm birth prevention 328–329 preterm birth 329 16 preterm premature rupture of the preterm premature rupture of the supplementation 16 membranes 350 membranes 346, 347 calcium-channel blockers 105, 171 prophylactic 264–265, 310–311 prophylaxis 426–427 hypertension therapy 211, 212 cerebral blood flow, fetal 290 risk with cordocentesis 420 preterm labor 357 cerebral palsy 452–454 treatment 426–427 renal insufficiency 166 multiple pregnancy 304–305 chorionic villus sampling 64, 76, 77 cervix confined placental mosaicism Canavan disease 63, 64 dysplasia treatment procedures 265 captopril 42–43 examination 354 415–416 carbamazepine cytogenetics 415 trial of labor 391 diagnostic studies 415–416 neural tube defects 17, 202 favourability in prolonged pregnancy DNA analysis 416 teratogenicity 43, 203 enzymatic analysis 416 carbohydrate, dietary 177 377 genetic testing 409, 411–417 carbohydrate intolerance 176 length surveillance 311, 337–338 limb abnormalities 414–415 cardiac abnormalities maternal cell contamination 415 fetal malformations 75 prematurity assessment 355 multiple pregnancy 310 fetal risk 146 shortening 311, 328–329, 337–338 pregnancy loss 413–414 maternal congenital 151–153 safety 413–415 cardiac afterload, peripartum see also cerclage, cervical cervix, incompetent 263–268 cardiomyopathy 154 cardiac arrest, cesarean delivery 284 biologic continuum 263 cardiac arrhythmias, maternal 156 diagnosis 263–264 cardiac contractility, peripartum management 264–265 cardiomyopathy 154 adjunctive strategies 267–268 risk factors 265 sonographic diagnosis 265–266 cesarean delivery 382–387 5-minute rule 284 abdominal wall closure 383 anesthesia 403–404 antibiotic prophylaxis 383 461

Index chorionic villus sampling (cont.) technique 420–421 deep vein thrombosis (DVT) 133 technique 412–413 twin–twin transfusion syndrome 420 clinical risk scoring system 136 transabdominal 412–413 corticosteroids D-dimer assays 135–136 transcervical 412 asthma 193, 197, 198 diagnostic algorithm 135, 136 fetal maturation 350, 355–356 risk assessment 135 chorionic villus surface area 7 fetal thrombocytopenia 115 venous imaging 136 chorionicity 305–306 HELLP syndrome 276 chromosomal anomalies immunosuppressive action 156 dehydration, hypernatremic 450 inhaled 197, 198 dehydroepiandrosterone sulfate multiple pregnancy 309 oral 197 oligohydramnios 322 systemic 198 (DHEAS) 86 cigarette smoking, birth weight 13 corticotropin-releasing hormone (CRH) fetal adrenal zone production 334 ciprofloxacin 51 delivery circle of Willis, fetal 291 81, 82, 84 acute myocardial infarction 156 cleft lip/palate, antiepileptic drug fetal stress marker 336 asthma management 198 preterm birth 333–334, 336 eclampsia 278 exposure 202, 203 coumadin 151 epilepsy 205–206 clindamycin 234, 235 coumarin derivatives 45 gestational diabetes 179 counseling HELLP syndrome 277 resistance 234 HIV infection 243 HIV infection 248 clotting factors maternal cardiac disease 143–146 maternal hypertension 212–213 multiple pregnancy 307, 309–310 multiple pregnancy 312 pregnancy 119, 135 prepregnancy for transplantation placenta previa 364, 365 see also individual factors preeclampsia 275 patients 168 preterm labor 359 coagulation cascade 283 preterm premature rupture of the sickle cell disease 111 disseminated intravascular coagulation timing for prolonged pregnancy 281 membranes 349–350 pregnancy 133–134, 143, 144 substance abuse 27 376–378 vaginal birth after cesarean delivery see also cesarean delivery; vaginal cocaine use 211 cognitive outcome, epilepsy 203 394 birth after cesarean delivery; colostrum 449 creatinine, serum levels 165, 166 vaginal delivery combined spinal–epidural analgesia 402 delivery room, thermoregulation 443 computed tomography (CT), spiral 138 elevated 211 dental amalgam 33 congenital adrenal hyperplasia (CAH) 86 cromolyn 197 depression, medications 48–49 congenital cystoid adenomatoid crown–rump length, fetal 77 dexamethasone 47–48 fetal maturation 355 malformation 433, 437 dating of pregnancy 286 diabetes 182–184 congenital diaphragmatic hernia 437, Cushing syndrome 211 antenatal testing 178–179 cyclo-oxygenase (COX) inhibitors congenital malformations 182 438–439 evaluation 182–183 congenital malformations 357–358 fetal lung maturation delay 93 cyclophosphamide gestational 176–180 anticonvulsants 17, 202, 203 delivery 179 cardiac contraindication in pregnancy 218 glucose testing 177–178 premature ovarian failure 217 postpartum care 179 fetal 75 teratogen 43 treatment 177–178 maternal 151–153 cyclosporine 156, 170, 171 insulin-dependent 182 developmental pathology 202 CYP21A2 deficiency 86, 89 perinatal mortality 182 diabetes 182 cystic fibrosis, carrier screening 62, 63, polyhydramnios association 320, fetal anticonvulsant syndrome 201–203 321 fetoscopic surgery 437, 438–439 64, 65 preconception care 182 multiple pregnancy 307, 309, 310 cystic hygroma 74–75 preconceptual 17 oligohydramnios 322, 427 cytogenetics screening in pregnancy 176–177 polyhydramnios association 320, 321 White’s classification 183 timing 202 amniocentesis 415 diaphragmatic hernia 437, 438–439 ultrasound detection 310 chorionic villus sampling 415 diazepam 48 see also neural tube defects diagnostic 419 dichorionicity 304 congenital rubella syndrome 224 cytomegalovirus (CMV) 229–231 fetal complications 307 connexin 43 334 clinical manifestations 229 diet, maternal contraction stress test (CST) 95, 97, 98, 99 diagnosis 229–230 gestational diabetes 177 contraction-associated proteins 334 management 230–231 quantity/quality 8 convulsions, eclampsia 277, 278 pathogenesis 229 see also nutrition, maternal cooling, induced 444 prevention 230–231 dietary recommendations 19–20 cord blood studies 456 transmission 229 diethylstilbestrol 44 cordocentesis 3, 4, 419–423 transplantation patients 169 in utero exposure 265 complications 422–423 1,25-dihydroxycholecalciferol 16 congenital infections 419 dacliximab 170 diphenhydramine 50–51 fetal anemia 420 danaparoid 129 disomy, uniparental 416 fetal growth restriction acid–base dating of pregnancy 286–287 disseminated intravascular coagulation D-dimer assays 135–136, 137–138 (DIC) 114, 280, 281–282 balance 420 decidua basalis deficiency 367 fetal platelet count 115–116 decidual hemorrhage see abruptio fetal thrombocytopenia 420 infections 422 placentae post-procedure monitoring 420 decidual tissue factor 119, 135 pregnancy loss 422–423 decidual-amnion-chorion inflammation quality control 420–421 sampling procedure 420 334–335 462

Index multiple pregnancy 308 neonatal 375, 452–456 factor Va 121 recombinant factor VIIA 283 antecedents 453 factor VII 133 diuresis, cardiac disease 154, 158 brain imaging 455 factor VIIa, recombinant 283 diuretics, nephrotic syndrome 164 task force 454–455 factor VIII 143 dizygotic twins 305 factor VIIIa 121 maternal age 309 end-diastolic flow 99 factor X 133–134 DNA analysis 416 endocrinopathies, spontaneous abortion fetal blood typing 300 activation 283 docosahexaenoic acid (DHA) 449 254–255 factor Xa 121, 133–134 Doppler imaging 299–300 endometritis familial dysautonomia 63, 64 arterial 291 family history, genetic screening 61 DVT 136 post-cesarean delivery 383 famine conditions 6, 10 fetal preterm premature rupture of the FDA pregnancy safety category 39–41 ferritin, serum level 14, 16 arterial 290–291, 293 membranes 346 fetal alcohol spectrum disorder 26 clinical application 292–293 β-endorphin 84 fetal anomalies see congenital intrauterine growth restriction end-stage renal disease 168 energy malformations 289–293 fetal anticonvulsant syndrome 201–203 middle cerebral artery 223, 290–291, requirements in pregnancy 12, 14, 15 fetal dysmaturity syndrome 375 supplementation 14 fetal growth restriction 299–300 enoxaparin 256 venous 291, 292, 293 environmental agents 31–35 acid–base balance 420 multiple pregnancy 311 breastmilk 42 cordocentesis 419 placenta accreta diagnosis 368 lead 32–33 nutritional 7 vasa previa 366 mercury 33–34 relative risk of delivery 10 Doppler velocimetry 95, 98–99, 101 types 34 symmetric 7 multiple pregnancy 311 enzymatic analysis 416 transplantation patients 174 Down syndrome 72–77 epidemiologic studies 31 fetal heart rate (FHR) likelihood ratios 75 epidural analgesia 402 accelerations 104, 105 minor markers 75 patient-controlled 402–403 assessment 104, 105 risk 75 epidural anesthesia baseline 104 screening 310 asthma 198 decelerations 105, 106 combined first and second trimester trial of labor 393 nonreassuring 105 epidural catheterization 402 pattern definitions 104–105 76–77 epilepsy 201–207 reassuring 105 maternal serum 310 delivery 205–206 variability 104–105 second trimester 75–76 fetal death 203 fetal heart rate tracing (FHT) 96 drug safety categories 39–41 labor 205–206 interpretation 104–106 Duchenne muscular dystrophy 62 neurodevelopmental outcome 203 fetal intervention guided by sonography ductus venosus Doppler waveform obstetric complications 205 perinatal death 203–204 (FIGS) 439–440 analysis 72–73, 291, 292 postpartum care 206 fetal loss see abortion, spontaneous duodenal atresia 75 prenatal screening 203 fetal membranes dysgenic growth restriction 7 erythema infectiosum 222 dyspnea of pregnancy 194 erythroblastosis fetalis 320 resealing 350–351 erythromycin 234, 235 see also preterm premature rupture of Ebstein anomaly 152–153 preterm birth 329 the membranes (PPROM) echocardiography resistance 234 estradiol 88 fetomaternal hemorrhage 422, 444 fetal 146 estriol fetomaternal transfusion 410 pregnancy 144 salivary 336 fetoscopic surgery (FETENDO) 437–439 eclampsia 277–278 unconjugated 75–76 factor V Leiden mutation 125 estrogens congenital diaphragmatic hernia 437, intrapartum acute myocardial placental production 334 438–439 teratogenicity 44 infarction 155 ethical issues, HIV infection 249 indications 438–439 management 277–278 euglycemia percutaneous 437–438 multiple pregnancy 308–309 maintenance 183 twin–twin transfusion syndrome 437, efavirenz 247–248 pancreas transplantation 171 Eisenmenger syndrome, maternal 152, exchange transfusion 438, 439 neonatal jaundice 448 urinary tract obstruction 437, 439 172 sickle cell disease 110–111 fetus electrocardiography (ECG) exercise, diabetic care 177 alcohol abuse effects 24, 25, 26 external cephalic version 397 antenatal surveillance 376 cardiac arrhythmias 156 failed 427 antepartum monitoring 95–102, 377 maternal 156 extracorporeal membrane oxygenation pregnancy 144 diagnostic conditions 100–101 pulmonary embolism 137 (ECMO) 447 tests 95–99 emergency care 280–284 blood sampling 419–423 enalapril 42–43 factor V Leiden (FVL) mutation 120–121, blood typing through DNA analysis encephalocele 67 126 alpha-fetoprotein maternal screening 300 preeclampsia 125 bradycardia 422 68–69 spontaneous abortion 255–256 calcium levels 16 encephalopathy comprehensive evaluation of condition hypoxic ischemic 391–392, 394, 452 3, 4 induced cooling 444 congenital heart block 217 cytomegalovirus 230 463

Index fetus (cont.) functional outcome prediction 70 Haemophilus influenzae type B vaccination death in vasa previa 365–366, 367 fusion inhibitors 247 110 distress and cesarean delivery 385 Doppler imaging 289–293 galactosemia 450 Hashimoto thyroiditis 87–88, 186 hemorrhage 444 genes 61–62 head circumference:abdominal prevention 367 genetic counseling, multiple pregnancy hyperthermia 443 circumference ratio 7 hypoxic brain injury with uterine 309–310 hearing loss, solvent abuse 34 rupture 391–392 genetic factors 374–376 heart, fetal see fetal heart rate (FHR); fetal infections 222, 223, 224, 227, 230, 231 genetic screening 61–65 diagnosis 419 heart rate tracing (FHT) liver maturity 301 newborn 65 heart block, congenital malpresentation 385–386 prenatal diagnosis 64 maturation 350, 355–356 sickle cell disease 111 fetal 217 micturition 317 genetic testing 409–417 neonatal lupus erythematosus 217, movement 95–96, 179, 212 see also amniocentesis; chorionic villus oxygen deprivation 290, 291 220 parvovirus infection 222, 223 sampling heart disease, congenital 172 placenta previa complications 364 genetics 3, 4 radiation exposure risk 139–140 genital herpes 51 antiepileptic drug exposure 202 resuscitation 105–106 genital tract cancer, immunosuppressive heart rate, fetal rubella infection 224 substance abuse effects 24, 25, 26 drugs 168 IUGR 293 surgery 433–440 German measles 224 sinusoidal tracing 366 surveillance in SLE 218 germline mosaicism 61–62 vasa previa 366 swallowing 317, 318 gestational age 286–287 heart rate, maternal 144 thermoregulation 443 heart transplantation 172 toxoplasmosis 227 accurate assessment 376 pregnancy after 156, 158 urine 317 criteria for confirmation 374 heart valve disease, maternal 146–151 varicella infection 231 dating error 373 fetal/maternal risk 148 weight inaccuracy 10 heart valves, mechanical 149–151 estimation 287 placenta previa 364 HELLP syndrome 171, 173, 275–277 mild preeclampsia 273 prolonged pregnancy 377–378 dexamethasone 48 see also gestational age; growth, fetal; repeat tendency 8 diagnostic criteria 275 intrauterine fetal death (IUFD); glomerular filtration rate (GFR) factor V Leiden mutation 125 intrauterine growth restriction early gestation 38 management 276–277 (IUGR); multiple pregnancy kidney transplantation 170 multiple pregnancy 308, 312–313 pregnancy 163 platelet transfusion 282 fibrillin, defective 153 glucocorticoids SLE differential diagnosis 216 fibrinogen 119, 135, 143, 144 systemic lupus erythematosus 218, thrombocytopenia 114 fibrinolysis 134 hemoglobin 14, 15, 16, 109 fibrinolytic system 119 219 glycosylated 182, 184 fibronectin, fetal (fFN) 336, 337–338 thrombocytopenia 114 hemoglobin S 109 glucose hemoglobin S/beta-thalassemia disease prematurity blood level determination 183 assessment 355 fetal levels 88 110 evaluation 354 maternal levels 177–178 hemoglobin SC disease 109–110 glucose challenge test 176, 180 hemoglobin SS disease 109 preterm premature rupture of the glucose tolerance testing (GTT) 176–177 hemoglobinopathies 109–110 membranes 345 gestational diabetes 179, 180 pancreas transplantation 171 carrier screening 62, 63–64 prolonged pregnancy 377 glyburide, gestational diabetes 178 see also sickle cell disease fifth disease 222 glycemic control, maternal 183–184 fish consumption 34–35 goiter, fetal 87, 89 hemolysis, elevated liver enzymes and gonadotropin releasing hormone (GnRH) low platelet count syndrome see mercury 33–34 HELLP syndrome fluconazole 46 81, 82 fluoride toxicity 18 congenital deficiency 84 hemolytic disease of the newborn fluoxetine 48–49 gonadotropins 83–84 298–301, 302, 445 foam stability index (FSI) 92 gonads, development 88 folate antagonists 17 gonorrhea screening 29 end-stage phase 299 folate/folic acid 17–18 GPIIB/IIIa receptors 133 jaundice 448 Graves’ disease 45, 87–88, 89, 188 non-RhD antibodies 301–302 fetal karyotype 254 follow-up 189 hemophilias, recombinant factor VIIa folic acid supplements 12, 13, 14, 15, growth, fetal 6–9 curves 7 283 17–18 discordance in multiple pregnancy 306 hemorrhage diabetic patients 182 evaluation 287 prenatal 21 factors affecting 8 fetal 367, 444 follicular stimulating hormone (FSH) linear 6–7 fetomaternal 422, 444 velocity 7 neonates 444–445 83–84, 88 fondaparinux 129 see also fetal growth restriction see also blood loss; intracranial formula milks 449–450 growth hormone (GH) 84–85 hemorrhage foster care placement 29 growth hormone releasing hormone fresh frozen plasma (FFP) 282–283 hemostasis (GHRH) 81, 82, 85 physiology 133–134 pregnancy changes 119, 120, 135 heparin 134 disseminated intravascular coagulation 281–282 systemic lupus erythematosus 219, 220 thrombocytopenia 128–129 464

Index heparin, low-molecular weight 128, 129 mother-to-child transmission hypoxia ischemia, intrapartum 455 mechanical heart valve anticoagulation prevention 243 hysterectomy 149–150 systemic lupus erythematosus 219 preterm premature rupture of the placenta accreta 368 thrombophilia 126–127 membranes 350 repeat cesarean delivery 384 uterine rupture 391, 392, 394 heparin, unfractionated 128, 129 screening 29 hysterotomy 433–437 mechanical heart valve anticoagulation seropositive women 243, 247–248 closure 383 149, 150, 151 testing 242–243 indications 436–437 systemic lupus erythematosus 219 transplantation patients 169 postoperative recovery 435–436 human papillomavirus (HPV) 169 risks and benefits 433–434 heparin cofactor II 134 human platelet antigens (HPAs) 115, technique 434–436 heparinization, systemic in neonates 117 ibuprofen 49–50 447 hydralazine 50, 211, 212 idiopathic thrombocytopenic purpura hepatic disease eclampsia management 278 (ITP) 113–114 acute fatty liver of pregnancy 309 hydration, preterm labor 356 immigrant women, preterm births 327 liver transplantation 171–172 hydrocephalus 69 immunoglobulin A (IgA) 449 hepatitis immunoglobulin E (IgE) 193 perinatal infection 238–240 open fetal surgery 436 immunosuppressive drugs 156, 158 hepatitis A 238 hydrops fetalis 75 hepatitis B 239 fetal circulation 174 chronic carrier state 239 parvovirus infection 222, 223 genital tract cancer 168 hepatitis D coinfection/superinfection hydroxychloroquine 218 pregnancy 169–170 1,25-hydroxycholecalciferol 17 indomethacin 198 239 21-hydroxylase deficiency 86, 89 polyhydramnios 321 screening 29 17α-hydroxyprogesterone caproate preterm labor 357–358, 359 transplantation patients 169 infections vaccination 110 (17-OHPC) 311, 329, 330, 331 asthma effects 193 hepatitis C 239–240 hyperglycemia congenital 419 liver transplantation 171 cordocentesis 422 screening 29 fetal 183 fetal 222, 223, 224, 227, 230, 231 transplantation patients 169 first trimester 17 hepatitis D 239 maternal 183 diagnosis 419 hepatitis E 238 hyperhomocysteinemia 123 intra-amniotic 354 hepatitis G 240 hypernatremic dehydration 450 perinatal 222–232 herpes, genital 51 hypertension, maternal 165–166 herpes simplex virus 227–229 chronic 210–213 streptococci group B 234–236 clinical manifestations 228 classification 210 prematurity management 354 diagnosis 228 delivery indications 212–213 preterm birth 329, 334 management 228–229 differential diagnosis 210, 211 preterm premature rupture of the pathogenesis 227–228 evaluation 210–211 preterm premature rupture of the fetal evaluation 212 membranes 345, 347, 350 gestational 271–279, 308–309 spontaneous abortion 254 membranes 350 heart transplantation 172 transplantation patients 169 transmission 227–228 kidney transplantation 170–171, 173 transplantation patients 169 medications 50 see also named infections highly active retroviral therapy (HAART) inferior vena cava, Doppler waveform teratogenicity 42–43 243, 247–248, 249 mild 272–273 291, 292, 293 homocysteine 123 multiple pregnancy 308–309 inflammatory pathway markers 336 hormones postpartum follow-up 213 inhalers, optimum technique 196 preconceptual therapy guidelines 210 inhibin 88 fetal hypothalamus 81–83 severe 279 inhibin-A serum levels 76 fetal pituitary 83–85 therapy during pregnancy 211–212 insulin placental 7 teratogenic 44 see also eclampsia; preeclampsia administration 183 hospital care for substance abuse 29–30 hyperthermia, fetal 443 fetal levels 88 human chorionic gonadotrophin (hCG) hyperthyroidism gestational diabetes 178 Down syndrome 76, 310 resistance 176, 179 first trimester screening 74 fetal 88 insulin-like growth factor I (IGF-I) 85, 89 hypothyroidism 186–187 maternal 188–189 insulin-like growth factor II (IGF-II) 89 maternal blood determination hypoglycemic agents, gestational diabetes interleukin 6 (IL-6) 336 interleukin 8 (IL-8) 336 420–421 178 internal iliac artery embolization 368 placental 88 hypotension, maternal 404 interpregnancy interval 392 human immunodeficiency virus (HIV) hypothalamic–pituitary–adrenal (HPA) intracranial aneurysm rupture 151 intracranial hemorrhage 242–249 axis 82 extracorporeal membrane oxygenation antiretroviral drugs 243, 244–247, premature activation 333–334 hypothalamus, fetal 447 247–248 hormones 81–83 fetal thrombocytopenia 114–115, 116 breastfeeding contraindication 450 ontogeny 81 intrapartum event criteria 454 counseling 243 hypothyroidism intrapartum hypoxia ischemia 455 ethical issues 249 fetal 87–88 intrauterine fetal death (IUFD) 95 infected patient identification neonatal 448 multiple gestation 306–307, 308 hypothyroidism, maternal 186–190 single in twin pregnancy 304 242–243 diagnosis 186–187 legal issues 249 follow-up 188 treatment 187–188 465

Index intrauterine growth restriction (IUGR) post-term 377 lupus nephropathy 216–217 99, 287–294 uterine rupture 393 luteinizing hormone (LH) 83–84, 88 oligohydramnios 427, 428 asymmetric 287 prophylactic amnioinfusion 427, 428 McDonald cerclage 264–265, 266 definition 287 sickle cell disease 111 α2-macroglobulin 134 Doppler imaging 289–293 status 391 macrosomia genetic syndromes 289 trial of 389–395 inherited thrombophilia 125 labor, preterm 354 diabetes mellitus 184 management 288–293 delivery 359 gestational diabetes 179 maternal hypertension 212 diagnosis 354–355 post-term infants 375 multiple pregnancy 306, 308 interventions 355–359 magnesium neonatal encephalopathy 454 neonatal morbidity/mortality deficiency 19 oligohydramnios 322 requirements in pregnancy 12, 14, 15, outcome 288 prevention 355–356 risk factors 288 tocolytic therapy 356–359 16–17 symmetric 287 transplantation patients 173 toxicity 18 systemic lupus erythematosus 217 magnesium sulfate 102, 105, 279 intravenous immunoglobulin (IVIG) see also preterm delivery; preterm asthma 198 spontaneous abortion prevention 257 premature rupture of the eclampsia management 277–278 thrombocytopenia 114, 115, 116 membranes (PPROM) preterm labor 358 iodine severe preeclampsia 273 deficiency 19, 87 lactation 449–450 magnetic resonance angiography (MRA) benefits 18–19 endemic 186 bone turnover 16 138 toxicity 18 dietary recommendations 19–20 magnetic resonance imaging (MRI) iron 15 iron requirements 15 supplementation 14–16 see also breastfeeding; breastmilk DVT 136 toxicity 18 placenta accreta diagnosis 368 iron fumarate 15 lactotrophs 85 malpresentation, fetal 385–386 iron gluconate 15 lamellar body counts 92, 93 see also breech presentation iron sulfate 15 lamotrigine Marfan syndrome, maternal 153 isotretinoin 47 maternal age clearance during pregnancy 205 dizygotic twins 309 jaundice congenital malformations 202, 203 genetic counseling 309–310 neonatal 447–448, 449 monotherapy 207 trial of labor 390 treatment 448 laparotomy, fetal intervention guided by maternal serum alpha-fetoprotein Jewish genetic diseases 62, 64, 65 sonography 440 (MSAFP) screening 67–69, 70, 71 jugular vessel ligation 447 lead toxicity 32–33 combined first/second trimester 76 lecithin:sphingomyelin (L:S) ratio 91, 93 multiple pregnancy 310 Kallmann syndrome 83–84 left ventricular failure 281 placenta accreta diagnosis 368 karyotype analysis 69–70 left ventricular filling maintenance second trimester 75–76 matrix metalloproteinases 334–335 cordocentesis 419 147–148 measles–mumps–rubella (MMR) vaccine oligohydramnios 322, 427 left ventricular function 154 Kell antibody 301, 302 leukotriene receptor antagonists 197 224 kernicterus 447–448 levothyroxine 188, 189, 190 meconium kick counts 95–96 limb reduction defects 414–415 gestational diabetes 179 lisinopril teratogenicity 42–43 lamellar body count 92 maternal hypertension 212 lithium 46 thick 429 kidney liver meconium aspiration syndrome 375, fetal bilateral cystic dysplasia 322 maternal transplantation 168–171 acute fatty liver of pregnancy 309 428–429, 430 transplantation 171–172 meconium-stained amniotic fluid graft function 170 long-chain polyunsaturated (LCP) fatty obstetric emergencies 173 428–429, 430 pancreas combination 172 acids 449 medications 38–52 rejection 170 low birthweight see also renal entries asthma 196–198 asthma association 193 breastfeeding 42–43, 48, 49, 50, 51, 52 labetalol 50 heart transplantation 172 eclampsia management 278 multiple pregnancy 304 teratogens 42–43, 44, 45, 46, 47 renal insufficiency 166 neonatal deaths 442 clearance 38, 39 lung, fetal paternal exposure 39 labor fluid 317–318 pharmacokinetics 38, 39 analgesia/anesthesia 401–403 maturity 91–93, 354 systemic lupus erythematosus 218 asthma management 198 profile 92 medroxyprogesterone acetate 44 augmentation 393 meiotic rescue 416 breech delivery 399 see also surfactant mendelian disorders 61–65 labor arrest 385 lung transplantation, maternal 172–173 mendelian inheritance 61–62 epilepsy 205–206 lupus anticoagulant 123–124, 214, 217, meningocele 67 failure to progress 385 see also myelomeningocele induction 218–219 menstrual data eclampsia 278 spontaneous abortion 256–257 inaccuracy 10 lupus erythematosus unreliable 6 neonatal 217 mercury 33–34 metabolic acidosis see also systemic lupus erythematosus intrapartum hypoxia ischemia 455 (SLE) respiratory distress syndrome 446 lupus flares 214–216 diagnosis 218 466

Index methimazole 188–189 ultrasound 311, 312 maternal hypertension 212 methimazole–carbimazole 45 uterine mechanical stretching 335 mild preeclampsia 273 methotrexate 44–45, 368 multivitamins, prenatal 12, 13, 14, 15 prolonged pregnancy 376 mycophenolate mofetil 156, 158 nuchal translucency (NT) contraindication in pregnancy 218 mycoplasma 254 Down syndrome 310 methyl mercury 33 myelomeningocele 67 sonography 72, 73, 76, 77 methyldopa 50 functional outcome 70 nutrition, maternal 6–21 open fetal surgery 436–437 assessment 11–12, 13, 14, 15 renal insufficiency 166 see also neural tube defects dietary recommendations 19–20 methylene tetrahydrofolate reductase myocardial infarction (MI), acute gestational diabetes 177 interventions 12–18 (MTHFR), thermolabile mutant maternal 155–156 gene mutation 123 myoma, submucous uterine 255 obesity 11 methyltestosterone 44 failure to progress in labor 385 metronidazole 51 nasal bone sonography 72 trial of labor 390 microcephaly natural killer (NK) cells 257 weight gain target levels 20 antiepileptic drugs 203 necrotizing enterocolitis 355 fetal swallowing 318 neonatal alloimmune thrombocytopenia obstetric complications micturition, fetal 317 antiphospholipid antibodies 124–125 middle cerebral artery (MCA) (NAIT) 115, 116–117 epilepsy 205 Doppler evaluation 223, 290–291, neonatal lupus erythematosus 217 inherited thrombophilia 125–126 299–300 neonates multiple pregnancy 308–309 IUGR fetuses 99, 290–291 systemic lupus erythematosus 217 milk, vitamin D-fortified 17 anemia 444–445 minerals, toxicity 18 cytomegalovirus 229, 230 obstetric emergencies, transplantation miscarriage see abortion, spontaneous deaths 442 patients 173–174 misoprostol 46–47 encephalopathy 452, 453–456 mitral regurgitation 148 extracorporeal membrane oxygenation oligohydramnios 321–323 mitral stenosis amnioinfusion 322, 323, 425, 426, 427, left ventricular filling maintenance 447 428, 431 147–148 genetic screening 65 clinical significance 322–323 maternal 146–148 hemorrhage 444–445 congenital anomalies 427 mitral valve prolapse, maternal 148–149 hepatitis B infection 239 definition 319, 321 mitral valvuloplasty, percutaneous herpes simplex virus infection 228 diagnosis 321–322 balloon 146 hypothermia 443 fetal swallowing 318 molybdenum toxicity 18 jaundice 447–448, 449 fetal urinary system malformations monoamnionicity 305, 307–308 morbidity/mortality prevention in 317 monochorionicity 304, 305 IUGR fetus 322 fetal complications 307–308 preterm labor 355–356 labor prophylaxis 427, 428 monozygotic pregnancy 305 respiratory disorders 445–447 membrane rupture 346 mosaic morula 416 thermal regulation 443 multiple pregnancy 305–306, 323 mosaicism varicella infection 231 postdate pregnancy 322–323, 375, confined 415–416 nephrotic syndrome, pregnancy 164–165 377 cordocentesis 419 neural tube defects 17, 18 preterm premature rupture of the mucous patches 225 antiepileptic drug exposure 202 membranes 350 müllerian duct anomalies 255 diagnostic ultrasound 69–70 twin pregnancy 323 multifetal pregnancy reduction (MPR) folic acid supplements 182 ultrasound 321–322 307, 309 multiple pregnancy 310 variable decelerations 426 multiple pregnancy 304–313 open fetal surgery 436–437 amniocentesis 410, 411 prognosis 70 omega-3 LCP fatty acids 449 anatomic abnormalities 310 screening 67–71 omega-6 LCP fatty acids 449 aneuploidy 310 serum screening 67–69 oocytes 253 antenatal surveillance 311 see also myelomeningocele opioids antepartum management 309–312 neurohypophyseal hormones 83 counseling 307 neutrophils, decidual 335 intrathecal 402 discordant anatomic abnormalities 307 nevirapine 248 regional analgesia 401 fetal complications 306–307 New York Heart Association (NYHA) orange juice, iron absorption 15 fetal lung maturity 93 organ systems, pregnancy effects 38, fetal wastage 306–307 cardiac disease classification genetic counseling 309–310 143–145 39 HELLP syndrome 308, 312–313 nicardipine 357 organic solvents 34 intrapartum monitoring 311–312 nifedipine 211, 212 oxygen deprivation, fetal adaptation maternal nutrition 11 eclampsia 278 neural tube defects 310 preeclampsia post-partum 290, 291 oligohydramnios 323 management 275 oxygenation, fetal markers 105 perinatal outcomes 304–305 preterm labor 357 oxygen-carrying capacity, respiratory polyhydramnios 323 nipple stimulation 98 post-term definition 378 Nitrazine 354 distress syndrome 446 prenatal diagnosis 309–310 non-steroidal anti-inflammatory drugs oxytocin 83 preterm delivery prevention 310– (NSAIDs) 50 311 after cesarean delivery 404 labor augmentation 393 teratogenicity 41 breech delivery 399 non-stress test (NST) 95, 96–97, 99, 101 for labor arrest 385 maternal diabetes 184 uterine contractions 98 oxytocin challenge test 376 oxytocin receptor 334 oxytocin receptor antagonists 359 467

Index pancreas transplantation 171, 172 plasminogen activator inhibitor 2 (PAI-2) evaluation 354 pancreatic hormones 88–89 119, 134 extreme 442 parathyroid hormone (PTH) 16 heart transplantation 172 parvovirus B19 222–224 elevated levels 135 interventions 355–359 patent ductus arteriosus, maternal platelet aggregation 133 management 354–360 platelet count neurodevelopmental sequelae 450 152 outcomes 442–443 patient education, asthma 195–196 fetal 115–116 prognosis 442 patient-controlled analgesia (PCA), HELLP syndrome 277 risk factors 443 thrombocytopenia 114, 116 survival 442 intravenous 404 platelet plug formation 133 syphilis 225 patient-controlled epidural analgesia platelet transfusions 282 transplantation patients 174 thrombocytopenia 114, 116 (PCEA) 402–403, 404 pneumonia see also labor, preterm; preterm penicillamine 47 sickle cell disease 110 delivery; preterm premature penicillin 234, 235 varicella 231 rupture of the membranes polychlorinated biphenyls (PCBs) 34 (PPROM) resistance 234 polycystic ovarian syndrome (PCOS) penicillin G 51, 226 prenatal diagnosis, genetic disease 64 percutaneous balloon mitral 254 preterm delivery polyhydramnios 319–321 valvuloplasty 146 abruption-associated 335 perinatal medicine, advances 3, 4 associations 320–321 bacterial vaginosis 334 perinatal mortality fetal swallowing 318 cervical cerclage 328–329 fetal urinary system malformations decidual-amnion-chorion asthma association 193 epilepsy 203–204 317 inflammation 334–335 underweight women 9–10 management 321 diagnostic accuracy 337–338 uterine rupture 391 multiple pregnancy 323 etiology 333–335 persistent pulmonary hypertension of the uterine mechanical stretching 335 financial costs 326 polyploidy, spontaneous abortion 253 handicap risk 326 newborn (PPHN) 49 polyps, uterine 255 infections 329, 334 pesticides 34 ponderal index 7 maternal body mass index 10 phenobarbital 202, 301 postdate pregnancy see prolonged maternal weight 10 phenytoin, teratogenicity 43 multiple pregnancy 304, 310–311 phosphatidylglycerol assessment 91–92, pregnancy pathway-specific markers 336–337 postpartum care, alcohol/substance prediction 335–337 93 prevention 326–331 phototherapy, neonatal jaundice 448 abuse 29–30 pituitary, fetal Prader–Willi syndrome 416 multiple pregnancy 310–311 prednisone 170 progesterone prophylaxis 329–331 anterior 83–85 recurrent 331 ontogeny 81 thrombocytopenia 114 social phenomenon 326–327 placenta preeclampsia 271–275 spontaneous 263 absorptive capacity 7 confined mosaicism 415–416 asthma association 193 see also labor, preterm disorders 362–369 birth weight 7 preterm premature rupture of the environmental agents 32 etiology 272 famine conditions 10 factor V Leiden mutation 125 membranes (PPROM) 345–351 hormone production 7 heart transplantation 172 abruption-associated 335 malformation 444 hypertension 212–213 cerclage management 267 manual removal 383 inherited thrombophilia 125 cervical cerclage 350 migration 363–364 intrapartum acute myocardial cervical incompetence 267, 268 preferential growth 364 counseling 349–350 separation failure 367–368 infarction 155 deceleration prevention 427–428 teratogenic drugs 39 kidney transplantation 170–171 fetal membrane resealing 350–351 management 272, 274–275 infections 345, 347, 350 see also abruptio placentae mild 272–273, 274 management 347–350 placenta accreta 367–368 multiple pregnancy 308–309 mechanisms 345 pathophysiology 272 oligohydramnios 322 repeat cesarean delivery 384 postpartum management 275 prediction 345–346 placenta previa 362–365 prediction 278–279 prematurity management 354 prevention 278–279 prevention 326, 345–346 clinical presentation 362 renal disease 211 previable 349–350 complications 364 severe 273–275, 279 progesterone in prevention 330 delivery timing 365 systemic lupus erythematosus 217 streptococci group B 235, 236 diagnosis 362–363 thrombocytopenia 114 systemic lupus erythematosus 217 fetal hemorrhage 444 transplantation patients 173 transplantation patients 173 incidence 362 pregnancy, immunosuppressive drugs progesterone management 364 prophylaxis for preterm birth 329–331 repeat cesarean delivery 384 169–170 spontaneous abortion 254–255 risk factors 362 Pregnancy Nutrition Surveillance System progestogens, preterm birth prevention types 363 placental hormones 7 20 329–331 placental sulfatase deficiency 373 pregnancy-associated plasma protein A prolactin 85 plasma products transfusion 282–283 plasma volume 143, 144 (PAPP-A) 73–74, 76 spontaneous abortion 255 plasminogen activator inhibitor 1 (PAI-1) Down syndrome 310 prematurity 119, 134 assessment 354–355 elevated levels 122–123, 135 asthma association 193 468

Index prolonged pregnancy 373–379 hemolysis 109 shock antenatal fetal surveillance 376, 377 mass in pregnancy 143, 144 cardiogenic with amniotic fluid cesarean delivery 377 packed 282 embolism 280 definition 373 prophylactic transfusion 110–111 neonates 444, 445 delivery timing 376–378 transfusion 282, 301 etiology 373–374 reflux, asthma exacerbation 194, 195 shoulder dystocia, gestational diabetes genetic factors 373–374 renal agenesis 317 179 incidence 373 renal blood flow 163 intrapartum management 378 renal disease, maternal 163, 164–167 sickle cell crisis 109, 110 management 376–378 hypertension 211 sickle cell disease 63–64, 109–112 maternal risk 375–376 lupus nephropathy 216–217 multiple pregnancy 378 nephrotic syndrome 164–165 fetal assessment 111 oligohydramnios 322–323 renal failure genetic evaluation 111 prevention 376–378 chronic 168 red blood cell prophylactic transfusion prognosis 378 multiple pregnancy 308 stillbirth 374, 375, 377 renal insufficiency, maternal 110–111 sickle hemoglobin (S) see hemoglobin S proopiomelanocortin (POMC) 84 165–166 sinusitis, asthma exacerbation 194–195 propoxyphene 49–50 renal tubular function, maternal 164 sirolimus 170 propranolol 50 respiratory distress syndrome 91, small for gestational age 287 propylthiouracil (PTU) 87, 88, 89 445–446 see also intrauterine growth restriction hyperthyroidism 188 gestational diabetes 179 (IUGR) thyroid storm 189 risk 92–93 prostaglandins surfactant therapy 446 smoking 27 corticotropin-releasing hormone effects resuscitation, fetal 105–106 sodium retention in pregnancy 163 retinoids 47 solvent abuse 34 333–334 retinol 18 somatostatin 81, 82 delivery 198 rhesus alloimmunization 3, 298–301, sonography see ultrasound final common pathway of delivery 335 sphingomyelin 91 protease inhibitors (PIs) 243, 245–247 302, 448 spina bifida protein, dietary supplementation 14 antibody titers 299 protein C deficiency 121 clinical management 300 antiepileptic drug exposure 202 protein S 121, 134 fetal blood typing 300 open 67 deficiency 121, 126 fetal lung maturation delay 93 pregnancy 119, 135 intrauterine transfusion 300–301 alpha-fetoprotein maternal screening protein Z deficiency 122, 134 prophylaxis 298, 299 68–69 proteinuria, maternal 164–165, 165 surveillance 299–300 hypertension 211, 213 thrombocytopenia 114 ultrasonography 69 prothrombin gene G20210A mutation rhesus antigen (RhD) 298 outcome 70 rhesus immunoglobulin (RhIg) 298, 299, screening 71 121, 125, 126 see also neural tube defect and psychiatric disorders, substance abuse 448 amniocentesis 410 myelomeningocele 26–27 rhesus sensitization, transplantation spinal analgesia 402 pulmonary angiography spinal anesthesia 404 patients 169 spiramycin 227 fetal risk 139–140 rhesus status, blood product replacement splenectomy, thrombocytopenia 114, 115 pulmonary embolism 138 steroidogenesis 88 pulmonary arteriography 137 282, 283 steroids 47–48 pulmonary artery pressure 152 rheumatic heart disease 146, 149 pulmonary edema 158 ritodrine 105, 356–357 see also corticosteroids aortic stenosis 149 rubella 224 stillbirth lung transplantation 173 pulmonary embolism 133, 136–140 sacrococcygeal teratoma 433, 437 epilepsy 203 D-dimer assays 137–138 scalp stimulation 105 post-term pregnancy 374, 375, 377 diagnostic algorithm 139 seizures syphilis 225 diagnostic studies 137 systemic lupus erythematosus 217 patient work-up 139 control 206 streptococci group B (GBS) 234–235, 236 risk assessment 136, 137 during delivery 205–206 antibiotics 234, 235 pulmonary hypertension, persistent of the eclampsia 277, 278 epidemiology 234 during pregnancy 204 isolation 234 newborn (PPHN) 49 selective serotonin reuptake inhibitors prematurity management 354 pulmonary hypoplasia preterm labor 356 (SSRIs) 48–49 prevention 235, 236 congenital diaphragmatic hernia 438 selective termination (ST) 307, 308 stress oligohydramnios 322 selenium toxicity 18 fetal pulmonary maturity tests 91–93 serine protease inhibitors (SERPINs) pulmonary valve lesions, maternal 148 markers 336–337 pyelonephritis, sickle cell disease 110 134 preterm delivery 333–334 sertraline 48–49 maternal 6 rachischisis defect 67 sexually transmitted infections preterm delivery 333–334 radiation exposure, fetal risk 139–140 stroke volume 284 radioidine therapy, ablative 186 premature rupture of the membranes pregnancy 144 red blood cells 345, 347 stuck twin 305–306 substance abuse 24–30 defects 445 prematurity management 354 fetal effects 24, 25, 26 Sheehan syndrome 186 hospital care 29–30 Shirodkar cerclage 264 postpartum care 29–30 pregnancy management 26–27 prenatal care 27, 28–29, 29 469

Index substance abuse (cont.) maternal 113–114 neonatal in vasa previa 367 screening 24 platelet transfusion 282 neonatal jaundice 448 withdrawal 27 thromboembolic disorders 133–140 platelet 114, 116, 282 diagnosis 135–140 red blood cells 282, 301 sulindac 359 pathophysiology 135 sickle cell disease 110–111 surfactant pregnancy 143 transplantation patients 168–174 risk factors 135 antepartum care 168–169 fetal lung 91–92 thrombophilia follow-up of offspring 174 neonatal therapy 3, 4 acquired 123–125 intrapartum management 173 therapy 446 adverse pregnancy outcome prevention pregnancy timing 168 surfactant:albumin ratio 92 prepregnancy assessment/counselling surgery, fetal 433–440 126–127 endoscopic 437–439 inherited 119–123, 125–126 168 open 433–437 urinary tract infections 169 sonography-guided 439–440 recurrent miscarriage 255–256 transposition of the great vessels, swallowing, fetal 317, 318 management 127, 128 syphilis 225–226 pregnancy 143 maternal 153 screening 29 prevention 127 trapped twin syndrome 323 systemic lupus erythematosus (SLE) screening 127 Treponema pallidum (syphilis) 225–226 thromboprophylaxis, cesarean delivery trial of labor 389–395 123–124, 211, 214–220 diagnostic criteria 214, 215 383 birthweight 390 differential diagnosis 216 thyroglobulin 87 candidates 389–390 drug regimens 218 thyroid, fetal 86–88 cervical examination 391 epidemiology 214 counseling 394 etiology 214 dysgenesis 87 interpregnancy interval 392 fetal surveillance 218 thyroid, maternal 87 management 393–394 management 217–218 thyroid disease, maternal 87, 88 oxytocin labor augmentation 393 morbidity/mortality 216 thyroid stimulating hormone (TSH) risks 391–393 pathogenesis 214–216 success rate 390–391 pregnancy effects 216–217 85 uterine rupture risk 391–393 thyroid stimulating hormone (TSH) tricuspid regurgitation tachycardia prevention 147, 148 heart transplantation 172 tachypnea, transient 446–447 receptor 87 sonographic screening 72 tacrolimus 156, 170 thyroid storm 189 tricuspid valve lesions, maternal Tay–Sachs disease 63, 64 thyroidectomy 186 teratogenicity evaluation 41–42 thyroiditis 148 teratogens 38–42 tri-iodothyronine (T3) 87 chronic autoimmune 186 trinucleotide repeats 62 FDA pregnancy safety category postpartum 189 trisomies 253–254 39–41 transient immune 189 trisomy 15 416 thyroperoxidase (TPO) 87 trisomy 18 75 follow-up studies 41 thyrotoxicosis 188 tuberculosis screening 29 identification 41–42 thyrotropin-releasing hormone (TRH) twin pregnancy immunosuppressive drugs 169–170 known 41, 42–47 81, 82, 85 dizygotic 305, 309 neural tube defects 17 thyroxine (T4) 87 fetal lung maturity 93 time of exposure 38 oligohydramnios 323 terbutaline 105, 356–357 gene mutations 87 stuck twin 305–306 testes, fetal 88 hyperthyroidism diagnosis 188 vanishing twin 306 testosterone 88 hypothyroidism diagnosis 186–187 zygosity 305 tetracyclines 51 intra-amniotic administration 88 tetralogy of Fallot, maternal 153 tissue factor 133–134 see also multiple pregnancy thalassemias 63, 64 decidual 336 twin–twin transfusion syndrome 304, hemoglobin S/beta-thalassemia disease tissue factor pathway inhibitor (TFPI) 308, 310 110 134 cordocentesis 420 thalidomide tissue-type plasminogen activator (tPA) fetoscopic surgery 437, 438, 439 management 323 neural tube defects 17 134 oligohydramnios 323 teratogenicity 41, 47 tocolytic therapy 105 polyhydramnios 321 theophylline 197 see also stuck twin thimerosal 33 cervical cerclage 267 thrombin 134, 335 maintenance 359 ultrasound thrombin-activatable fibrinolysis multiple pregnancy 311 amniocentesis 409, 411 preterm birth prevention 327 cervical incompetence 265–266 inhibitor (TAFI) 134 preterm labor 356–359 cervical length 338 thrombin–antithrombin (TAT) complexes primary 359 chorionicity diagnosis 305–306 refractory 359 dating of pregnancy 286–287 336–337 toluene 34 fetal anomaly detection 310 thrombocytopenia 113–117 tonic–clonic seizures 204 fetal growth evaluation 287 labor 205–206 fetal intervention guiding alloimmune 115–116 Toxoplasma gondii (toxoplasmosis) 439–440 neonatal 115, 116–117 fetal weight estimation 273 226–227 fetoscopic surgery 438 autoimmune 113–115 tracheal occlusion 438–439 fetal 114–116, 420 transfusion gestational 113, 116 heparin-induced 128–129 blood product replacement 282–283 intrauterine 223–224, 300–301, 302 maternal in placenta previa 364 470

Index first trimester uterus 383 inherited thrombophilia association combined with serum screens abnormalities 255 120 73–74 closure technique 392, 435 screening 72–73 incisions risk 133 placenta previa 365 thrombophilia 123, 124 gestational age 286–287 previous type 391 venous ultrasonography intrauterine growth restriction repair after cesarean delivery DVT 136 vasa previa 367 pulmonary embolism 138–139 289–293 mechanical stretching 335 ventilation–perfusion (V/Q) scanning multiple pregnancy 311, 312 rupture risk 391–393 fetal risk 139–140 neural tube defects diagnosis 69–70 surgical entry 434, 435, 436 pulmonary embolism 138 oligohydramnios 321–322 ventricular septal defect, maternal 151 placenta accreta diagnosis 367–368 vaginal birth after cesarean delivery 383, ventriculomegaly, fetal 70 placenta previa diagnosis 362–363 389–395 very low birthweight prematurity evaluation 354 multiple pregnancy 304 rhesus alloimmunization surveillance counseling 394 neonatal deaths 442 labor status 391 vibroacoustic stimulation 96, 105 299–300 management 393–394 viral infections, transplantation patients second trimester multiple prior cesarean deliveries 391 oxytocin labor augmentation 393 169 routine 69 previous incision type 391 Virchow triad 135 screening 75 rate 384 vitamin(s) transvaginal 362–363 risks 391–393 vasa previa diagnosis 366 success rate 390–391 prenatal 21 venous thromboembolism 136, trial of labor 389–395 toxicity 18 uterine rupture risk 391–393 vitamin C, iron absorption 15 138–139 vaginal bleeding vitamin D 16, 17 see also Doppler imaging placenta previa 364 supplementation 17 umbilical artery vasa previa 365–366 toxicity 18 circulation 290 vaginal delivery vitamin K neonatal deficiency 205 Doppler imaging 290, 291, 292–293 analgesia/anesthesia 401–403 vitronectin 134 end-diastolic flow 99 breech presentation 397–398, 400 von Willebrand factor 119, 135 umbilical circulation 443 umbilical cord selection criteria 398–399 warfarin 45 blood studies 456 technique 399 mechanical heart valve anticoagulation compression in postdate pregnancy vaginal pessaries 267–268 149–150, 151 vaginal pool collection 91 375, 377 valacyclovir 228–229 weight, fetal cordocentesis 420 valproic acid estimation 287 hematoma 422 neural tube defects 17, 202 mild preeclampsia 273 malformation 444 teratogenicity 43, 203, 207 puncture site bleeding 422 vancomycin 234, 235 weight, maternal 8 umbilical vein vanishing twin 306 energy supplementation 14 cordocentesis 420 variable deceleration relief, excessive gain 20 red cell intravascular transfusion 301 gain in pregnancy 9 underweight women 9–10 amnioinfusion 426 prepregnancy 9, 10–11 weight gain target levels 20 varicella zoster virus 231–232 preterm delivery 10 ureaplasma urealyticum 254 varicella-zoster immunoglobulin (VZIG) protein supplementation 14 urinary tract infections, transplantation retention 11 232 target levels 19, 20 patients 169 vasa previa 365–367 underweight 9–10, 20 urinary tract obstruction, fetoscopic see also obesity diagnosis 366 surgery 437, 439 incidence 365 white American women, weight retention urine, fetal 317 management 366–367 11 urogenital defects outcomes 367 pathophysiology 365 white blood cells 347 antiepileptic drug exposure 202 risk factors 365 Wolff–Parkinson–White syndrome oligohydramnios 322 vasoconstriction 133 uterine activity vaso-occlusion 109 152–153 eclampsia 278 sickling 110 multiple pregnancy 311 vasopressin see antidiuretic hormone X-chromosomes, skewed inactivation 254 uterine contractions, ambulatory X-linked disorders 61, 62, 254 (ADH) xylene 34 monitoring 311 venous thromboembolism 133 uterine rupture zidovudine 244, 247, 248, 249 diagnosis 135–140 zinc toxicity 18 hysterectomy 391, 392, 394 zygosity 305 interpregnancy interval 392 labor induction 393 risk factors 392–393 471