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~1 Physiologic Assessment of Fetal Compromise This chapter discusses several clinical and laboratory procedures that have made the measurement of potential biologic markers of fetal development possible. Most of these assessments are performed during the organogenesis (beginning 14 days post-conception) and fetal growth periods. Despite technologic and methodologic achievements, no specific biologic mark- ers are available to indicate that exposure to a xenobiotic is associated with specific cellular, subcellular, or phar- macodynamic events. This chapter consid- ers the general roles that various diagnos- tic methods and biologic markers could have in understanding regulation of fetal growth and differentiation and the way xenobiotic agents affect normal events. Understanding the physiologic and en- docrinologic bases of fetal development is a major goal of perinatal biology. Dur- ing the last decade, many technologic de- velopments have allowed precise evalua- tion of the fetus in utero and diagnosis of abnormalities. The following are ex- amples of important contributions to bio- logic markers of pregnancy: Concentration of phospholipids, e.g., lecithin:sphingomyelin ratio and phosphatidylglycerol in amniotic fluid as related to fetal lung maturity. 241 . Genetic screening of amniotic cells. Concentration of estriol in maternal urine and serum. Direct measures of growth including femur length and biparietal diameters. These clinical assessments have been most helpful in modifying clinical care and ascertaining appropriate in utero development. Maternal serum alpha-feto- protein (AFP) screening is a test to assess fetal well-being. High concentrations of maternal AFP are found when fetuses have open neural tube defects (see Appendix). Increases in maternal serum AFP with no detectable amniotic fluid AFP and normal anatomic features as assessed with ultra- sonography suggest that a pregnancy is at high risk for preterm labor, low birth- weight, and fetal wastage. Developing and using biologic markers of fetal growth and development are dif- ficult. ~ . . l he t~etus is not easily acces- slble, and obtaining fetal cells, tissue, or amniotic fluid for marker determination can be burdensome. Several fetal physio- logic variables can be measured, but most are nonspecific, imprecise, and insensi- tive as markers of toxicity. Major hor- monal and metabolic differences between the fetus and the adult hamper comparisons. Furthermore, fetal responses vary widely among species; a marker in one species

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242 might not be informative in another. The fetus consists of cells of numerous types, each with unique responses to various agon- ists; the reactions of cells and tissues vary with maturity and stage of develop- ment; and fetal maturity at birth differs among species. Many studies have been conducted on prenatal exposure to toxi- cants, such as methyl mercury (Koos and Longo, 1976; Clarkson, 1987), lead (Hoffer et al., 1984), alcohol (Jones et al., 1973), and tobacco (Longo, 1982~. Despite knowledge of these and other chemical and toxicant effects, little is known of criti- cal doses or exposures, critical periods during development, or how biologic varia- tion produces response variation. A1- though one can observe and measure gross effects, few indexes detail more subtle cellular and subcellular changes. Before 1960, most birth defects were considered to be genetic in origin. The fetus was believed to occupy a privileged site within the uterus, protected from the effects of environmental agents to which the mother might be exposed. Associ- ation between maternal rubella infection and abnormal fetal development was recog- nized in the early 194Os, but adverse ef- fects of prenatal exposure to a drug were not reported until 20 years later, when . TOXICI7~YDURING PREGNrANCY thalidomide was determined to be the cause of serious developmental defects. A host of chemicals, drugs, and environmental agents have since been implicated as tera- togens, and most drugs and chemicals are suspected of being able to cause a congeni- tal malformation. Chemical teratogens have been classified by their relationship to fetal abnormalities (Simpson et al., 1982; Jones and Chernoff, 1984; Sever and Brent, 1986~. Some drugs have potential adverse effects on the fetus (Table 21- 1~; others have a questionable relation- ship to fetal anomalies; still others, ~nc~uc~ng several classed as "litogens~- drugs that have been mentioned in legal actions (Mills and Alexander, 1986-seem to have no relationship to fetal abnor- malities. Most pregnant women are exposed to a variety of agents. The National Institutes of Health found that the average pregnant woman takes five drugs (including nutri- tional supplements) during the course of her pregnancy, and about half the total drug consumption occurs during organogen- esis, i.e., during the first trimester (Sever and Brent, 1986; Shepard, 1986~. Some 2-3% of developmental defects are known to be due to drugs and chemicals, and 65% are of unknown origin; the size of the TABLE 21-1 Some Drugs with Potential Adverse Effects on the Neonate Drub Potential Adverse Effect v Azathioprine Cannabis Chl oramp h en i co l Cocaine Diazepam Ethanol Heroin/narcotics Lithium O~ocin Phenobarbital Propranolol Reserpine Salicylates Thiazides Tobacco Warfarin Decreased immunologic competence (Lower et al., 1971; DeWitte et al., 1984) Neurobehavioral abnormalities (Fried, 1980) Gray syndrome (Sutherland, 1959) Neonate withdrawal; cerebral infarction (Chasnoff, 1985) Floppy baby syndrome (Owen et al., 1972; Cree et al., 1973; Gillberg, 1977; Speight, 1977) Cardiac malformations; mental retardation (Mulvihill, 1976) Prenatal and postnatal growth retardation, neonate withdrawal; microcephaly (Stone et al., 1971; Zelson et al., 1971; Naeye et al., 1973; Rothstein and Gould, 1974; Fricker and Segal, 1978) Cardiac malformations (Schou et al., 1973) Hyperbilirubinemia (Sim.c and Neliann ~ 97S Ch~w ~n`1 .Cw~n ~ Q77 R'.~71~, 1984) ~ ~ D^-~ ~ ~ ~ ~''~'~ -' ' ~ ~~ Neonatal bleeding (Desmond et al., 1972) Hypoglycemia and bradycardia (Cotrill et al., 1977) Nasal congestion (Budnick et al., 1955) Platelet dysfunction (Rumack et al., 1982) Thrombocytopenia, electrolyte imbalance (Trimble et al., 1964; Alstatt, 1965; An- derson and Hanson, 1974) Intrauterine growth retardation (Werler et al., 1985) Bleeding disorders (Warkany, 1976; Hall et al., 1980)

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ASSESSMENT OF FETAL COMPROMISE latter category might reflect lack of knowledge and shows the need for markers to identify specific chemicals and their relation to defects. Table 21-1 lists potential adverse effects of several com- monly used drugs. Some environmental chemicals can harm the fetus and be particularly troublesome, because they can be pervasive and unsus- pected, such as chlorbiphenyls, labora- tory solvents, naphthalene, and organic mercury. The effects of exposure to poly- brominated biphenyls are discussed in Chapter 24. This chapter focuses on as- sessment procedures. The need for biologic markers of exposure to and effects of these and other chemicals is enormous. ULTRASONOGRAPHY Of the tools used successfully for fetal diagnosis, few have attracted as much attention as ultrasonography (ultra- sound). During the last decade, antenatal ultrasonographic resolution has increased dramatically, from detection of such gross defects as anencephaly to detection of subtle abnormalities of the brain, car- diovascular system, kidneys, and other organs (Table 21-2) (Caller, 1983~. A1- though instrument resolution and operator skill have improved, few studies have rig- orously examined diagnostic accuracy for specific anomalies. The accuracy of high-resolution ultrasonography is of critical importance. Anencephaly can be diagnosed ultrasonographically with 100% certainty (Chervenak et al., 1984~. Anomalies manifested by two or more embryo- logically related markers, each detec- table ultrasonographically (such as al- lobar holoprosencephaly) can be diagnosed reliably (Chervenak et al., 1985~. Ultra- sonography is less accurate for single abnormalities of dimension (such as micro- cephaly) or those in which the structure of interest cannot be clearly distin- guished. Use of ultrasonography has advanced rapidly for diagnosis of fetal size and, to a lesser extent, maturity. Some struc- tural measurements are useful in these diagnoses, including biparietal diameter and head circumference, abdominal circum- 243 TABLE 21-2 Diagnostic Ultrasound and Biologic Indicators MATUR\TIONAL OR MORPHOMUlKIC BIOLOGICAL INDICATORS Fetus Gross malformations Estimated fetal weight Head: bipanetal diameter circumference Abdomen: circumference Head/abdomen: circumference Femur: length Heart: nght/left ventricle malformations Placenta Size Matun~ FUNCTIONAL OR PHYSIOLOGICAL BIOLOGICAL INDICATORS Fetus Brain: cerebral blood flow velocity Cardiovascular: heart rate; cardiac output; umbilical blood flow velocity, umbilical pystolic/diastolic Respiratory: breathing movements; somatic movements Placenta Blood flow: uterine; umbilical ference, and length of the femur and other long bones. Ultrasonography also is valuable to diagnose fetal heart defects and cardio- vascular function (Knochel et al., 1983~. Combining real-time and static techniques has enabled practitioners to monitor car- diac structure, rhythm, chamber size, and pericardial effusion (Knochel et al., 1983~. Measurement of vessel diameter using ultrasonography in conjunction with pulsed-doppler technology that meas- ures blood-flow velocity through cardiac valves and in major vessels makes calcula- tion of cardiac output and blood-flow rate possible. More than 100 major malfunctions and malformations, including those of the genitourinary tract, abdominal wall, and other systems, can be diagnosed with these techniques (Allen et al., 1984; Weaver, 1988~. Doppler profiles of the arcuate artery at midgestation might identify fetuses at risk for death and intrauterine growth retardation and doppler studies during the third trimester could be used to assess the umbilical vessel to judge fetal well-being.

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244 Ultrasonography increases the safety and effectiveness of other diagnostic methods, such as amniocentesis, chorionic villus sampling, fetoscopy, and fetal blood sampling (Ward et al., 1983; DeVore and Hobbins, 1984; Hobbins et al., 1985; Katayama and Roesler, 1986~. AMNIOCENTESIS The ability to enter the amniotic cavity to sample amniotic fluid without appreciable risk to mother or fetus allows several diagnostic tests to be performed that are indicative of fetal well-being. Amniocentesis initially was used to es- timate concentrations of bilirubin and related pigments in amniotic fluid and thereby identify hemolytic disease. Am- niocentesis performed later in gestation is now used primarily to determine the relative concentration of surfactant- active phospholipids released from the fetal lung (i.e., measure the lecithin- to-sphingomyelin ratio), in an effort to assess the risk of respiratory distress syndrome in a premature infant. Amniocen- tesis is also used to measure individual phospholipids, such as phosphatidylgly- cerol; it is increasingly useful for iden- tifying hereditary disorders (O'Brien, 1984; Johnson and Godmilow, 1988~. Meas- urement of abnormal biochemical processes is useful in antenatal diagnosis of about 100 inborn errors of metabolism. All chro- mosomal anomalies-i.e., trisomy 21, 13, and 18 and triploidy-are potentially diag- nosable from amniotic fluid samples (Rob- erts et al., 1983; McDonough, 1985~. In addition, measurement of AFP in amniotic fluid can suggest the presence of neural tube defects, congenital nephrosis, or trisomy 21. Techniques of molecular biol- ogy can be applied to cell analyses for antenatal diagnosis of chromosomal abnor- malities, genetic enzymatic defects, and DNA adducts. Amniotic cells and fluids obtained through amniocentesis are among the best markers of development available and are now available at less than 14 weeks of ges- tation (Johnson and Godmilow, 1988~. Com- bined ultrasound, amniocentesis, alpha- fetoprotein analysis, and other methods can detect prenatally more than 700 fetal TOXIC17YDURING PREGNANCY disorders (Weaver, 1988~. The success of these genetic markers and markers of specific organ function demonstrates the potential for developing markers for toxi- city screening. Fetal lung maturity mark- ers can be modified with drug therapy; that demonstrates that lung maturation is sen- sitive to xenobiotic intervention. New applications or screens for embryonic tissues might provide similar specificity and sensitivity necessary to examine the ability of a conceptus to respond to se- lected xenobiotics. A similar clinical application likely to be more widely avail- able is umbilical blood sampling with cor- docentesis (see below) (Daffos et al., 1985~. Blood samples would make it pos- sible to diagnose fetal conditions, such as hypothyroidism, in utero and permit appropriate therapy to be initiated. CHORIONIC VILLUS SAMPLING Chorionic villus sampling (CVS) allows cells to be obtained that reflect the ge- netic constitution of the conceptus (Green et al., 1988~. Used during weeks 10-12 of the first trimester, CVS provides diagnos- t~c resu~ts w~th~n a few days to 2 weeks. A small sample of chorionic villi is aspir- ated through a flexible catheter that is passed through the cervix under sono- graphic guidance; alternatively, an as- piration needle can be passed transabdom- inally (Smidt-Jensen and Hahnemann, 1984~. As with cells obtained through amniocentesis, heritable disorders can be diagnosed with enzyme assays, by chromo- somal number or abnormality, and with DNA analysis (Jackson, 1985; Green et al., 1988; Rhoads et al., 1989~. However, villi can be contaminated with maternal decidua, and chromosomal mosaicism (i.e., the in- complete expression of genes on all chromo- somes) appears to be more common than in amniotic fluid cells. Additional screening of genetic infor- mation, as well as enzymes and cDNA probes or DNA adducts, provides an important tool to assess risk associated with exposure to toxic substances. CVS is a valuable technique to assess the effects of xeno- biotics during early organogenesis, when critical periods of structural organ de- velopment occur. As microanalytic methods

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ASSESSMENT OF FETAL COMPROMISE are developed, xenobiotic concentrations in trophoblast tissue might also be deter- mined. FETOSCOPY Fetoscopy to allow direct visualization of the fetus and placenta without disrupt- ing pregnancy (Rodeck and tTicolaides, 1983a) would permit external fetal anoma- lies to be detected and allow fetal tissues and blood vessels to be sampled directly from the umbilical cord or placenta. Fetal well-being in Rh isoimmunization can be assessed by measuring fetal and maternal antibody changes. Fetoscopy holds great promise for the detection of biologic markers; however, it is a research procedure carried out in few academic in- stitutions. Until the risks of spontaneous abortion associated with fetoscopy are reduced, the general applicability of this technique for toxicity screening is lim- ited. FETAL BLOOD AND TISSUE SAMPLING Fetal blood obtained in utero can be used for antenatal diagnosis of hemoglo- binopathies, coagulation defects, meta- bolic and cytogenetic disorders, immuno- deficiencies, and infections (Rodeck and Nicolaides, 1983b; Daffos et al., 1985~. Originally, blood specimens were col- lected directly from umbilical or placen- tal vessels with a fetoscope. More recent- ly, percutaneous sampling of fetal cord blood with a needle and sonographic guid- ance (cordocentesis) has allowed fetal blood sampling with less risk to the fetus (Daffos et al., 1985~. Analysis of fetal blood permits many conditions to be diag- nosed and various biologic markers to be detected(Hobbinset al., 1985~. Fetal skin and liver have been sampled successfully and used for histologic and biochemical studies when amniocentesis or fetal blood sampling could not provide the necessary information. Biopsy instru- ments introduced under fetoscopic and ultrasonographic guidance have been used to collect samples for detection of ge- netic disorders, such as epidermolysis and ichthyosis, glycogen storage disease, 245 and ornithine transcarbamylase deficien- cy of the liver. The same tissues might be used to study more subtle markers, such as DNA probes. MEASURING FETAL BODY AND BREATHING MOVEMENTS In normal pregnancies, fetal movements increase from about 30 per 12 hours at 24 weeks of gestation to about 130 at 32 weeks and then decrease to about 100 at term; however, these values vary considerably (EhrstrDm, 1987~. The fetus that is felt by the mother to move consistently is usu- ally healthy. A sudden decrease in fetal activity suggests fetal compromise (Sa- dovsky and Polishuk, 1977~. Fetal breathing activity can be detected with ultrasonography and other techniques by 11 weeks. By 16 weeks, breathing move- ments are sufficiently intense to move small amounts of amniotic fluid in and out of the respiratory tract. During the third trimester, breathing movements average about 50 per minute and are episod- ic. In sheep, much of the activity occurs in association with periods of rapid eye movements and high-frequency, low-vol- tage, electrocortical activity (Koos, 1985~. The frequency of fetal breathing movements decreases in association with hypoxemia, asphyxia, hypoglycemia, ma- ternal smoking, ethanol ingestion, and other stresses. Although breathing and body movements are indexes of fetal well- being, changes in these movements are nonspecific and thus are crude biologic markers. ELECTRONIC FETAL HEART-RATE MONITORING Antepartum and intrapartum surveil- lance of fetal well-being with early de- tection of fetal distress is most commonly accomplished by monitoring the fetal heart rate. During uterine contractions, utero- placental blood flow temporarily de- creases. Antepartum electronic fetal heart rate monitoring is associated with a high specificity 99% but sensitivity of 40-50% (Lavery, 1982~. The normal fetal heart rate is 120-160 beats per minute. Rates higher than 160

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246 beats per minute are recognized as tachycardia and lower than 120 beats per minute as bradycardia. Fetal heart rate variability is divided into short-term or beat-to-beat variability and long- term variability, which consists of regu- lar crude sine waves with a cycle of ap- proximately 6 beats per minute or greater. Periodic changes in the fetal heart rate are evident. Early decelerations occur with uterine contraction and are thought to represent a vagal reflex due to mild transient hypoxia not associated with fetal compromise. Late decelerations are thought to be caused by myocardial hypoxia for the period of a contraction, when the deoxygenated bolus of blood from the pla- centa insufficient to support myocardial action. Variable decelerations differ in duration and timing as related to a uterine and are thought to represent um- bilical cord compression. There are vari- able degrees of variable decelerations. A reactive, reassuring nonstress test is one in which at least two fetal movements occur within 20 minutes with accelerations of fetal heart rate above baseline by 15 beats per minute, with long-term variabil- ity greater than 10 beats per minute and a baseline between 120 and 160 beats per minute (Keegan and Paul, 1980~. A contraction stress test can be per- formed by nipple simulation or intravenous infusion of oxytocin. An adequate test is achieved when three contractions are obtained within 10 minutes. A positive result demonstrates persistent late de- celerations associated with more than 50% of the uterine contractions in 10 min- utes. A negative result is a normal base- line fetal heart rate with no late deceler- ations. A negative result is associated with fetal survival for 1 week or more for more than 99% of patients (Collect and Holls, 1982). Fetal heart-rate monitoring has been the subject of many reports. Unfortunate- ly, empirical observations and associa- TOXICITYDURING PREGNANCY tions have not been matched by deep under- standing of the physiologic bases of the phenomena observed. Although of proven usefulness in the detection of fetal dis- tress, changes in heart rate and in beat- to - beat variability are sufficiently nonspecific to restrict their role as markers. BIOPHYSICAL PROFILE Evaluation of several factors of fetal well-being have been combined into the biophysical profile. Heart-rate reac- tivity is determined with electronic moni- toring and diagnostic ultrasonography is used to assess gross body movements, muscle tone, breathing activity, and am- niotic fluid volume. These factors are evaluated on an Apgar-like scale (Platt et al., 1985~. Again, although apparently of empirical value, each factor is nonspe- cific and of only limited diagnostic value. MAGNETIC RESONANCE IMAGING Several reports of organ and tissue imag- ing with magnetic resonance imaging (MRI) during pregnancy have suggested the use- fulness of MRI (F.W. Smith et al., 1983; I.R. Johnson et al., 1984; Kay and Matti- son, 1986; McCarthy and Haseltine, 1987; Mattison and Angtuaco, 1988; Mattison et al., 1099~; however, its safety during gestation has not been established. The high magnetic fields required might affect embryonic and fetal development, particu- larly in pregnant women who work with the instrument over a long term. In experimen- tal animals, use of 3iP-MRI has great poten- tial to determine functional metabolic correlates, temporal relationships, and intracellular actions of chemicals in the heart, liver, and placenta. Use of para- magnetic ions also might be applicable for specific visualization of the placenta and conceptus.