Ultrasonography of the fetus, a common obstetric procedure, is both safe and accurate. Indications for antenatal ultrasonography include estimation of gestational age (unknown dates, discrepancy between uterine size and dates or suspected growth restriction), assessment of amniotic fluid volume, estimation of fetal weight, determination of the location of the placenta and the number and position of fetuses, and identification of congenital anomalies.

Fetal growth can be assessed by ultrasonography as early as 6-8 wk. The most accurate assessment of gestational age is by 1st-trimester ultrasound measurement of crown-rump length. The biparietal diameter is used to assess gestational age beginning in the 2nd trimester. Through 30 weeks the biparietal diameter accurately estimates gestation to within ± 10 days. Later in gestation, accuracy falls to ± 3 wk. Methods used to assess gestational age at term include measurement of abdominal circumference and femoral length. If a single ultrasound examination is performed, the most information can be obtained with a scan at 18-20 wk, when both gestational age and fetal anatomy can be evaluated. Serial scans may be useful in assessing fetal growth. Two patterns of fetal growth restriction have been identified: continuous fetal growth 2 standard deviations (SD) below the mean for gestational age or a normal fetal growth curve that abruptly slows or flattens later in gestation (Fig. 90-1).

Figure 90-1 A, Example of a “low-profile” growth retardation pattern in an uneventful pregnancy and labor. The baby cried at 1 min and hypoglycemia did not develop. Birthweight was below the 5th percentile for gestational age. B, Example of a “late-flattening” growth retardation pattern. The mother had a typical history of preeclampsia, and the infant had intrapartum fetal distress, a low Apgar score, and postnatal hypoglycemia. Birthweight was below the 5th percentile for gestational age.

(From Campbell S: Fetal growth, Clin Obstet Gynecol 1:41–65, 1974.)

Fetal maturity and dating are usually assessed by history (last menstrual period), physical examination, auscultation of fetal heart sounds at 16-18 wk, maternal perception of fetal movements at 18-20 wk, fundal height, and ultrasound (growth). Lung maturation may be estimated by determining the surfactant content of amniotic fluid (Chapter 95.3).

Fetal compromise may occur during the antepartum or intrapartum period; it may be asymptomatic in the antenatal period. Antepartum fetal surveillance is warranted for women at increased risk for fetal death, including those with a history of stillbirth, intrauterine growth restriction (IUGR), oligohydramnios or polyhydramnios, multiple gestation, rhesus sensitization, hypertensive disorders, diabetes mellitus or other chronic maternal disease, decreased fetal movement, and post-term pregnancy. The predominant cause of antepartum fetal distress is uteroplacental insufficiency, which may manifest clinically as IUGR, fetal hypoxia, increased vascular resistance in fetal blood vessels (Figs. 90-2 and 90-3), and, when severe, mixed respiratory and metabolic (lactic) acidosis. The goals of antepartum fetal surveillance are to prevent intrauterine fetal demise, to prevent hypoxic brain injury, and to either prolong gestation in women at risk for preterm delivery when such prolongation is safe or deliver a fetus when it is in jeopardy. Methods for assessing fetal well-being are listed in Table 90-1.

Figure 90-2 Normal Doppler velocity in sequential studies of fetal umbilical artery flow velocity waveforms from one normal pregnancy. Note the systolic peak flow with lower but constant heart flow during diastole. The systolic : diastolic ratio can be determined and, in normal pregnancies, is less than 3 after the 30th wk of gestation. The numbers indicate the weeks of gestation.

(From Trudinger B: Doppler ultrasound assessment of blood flow. In Creasy RK, Resnik R, editors: Maternal-fetal medicine: principles and practice, ed 5, Philadelphia, 2004, WB Saunders.)

Figure 90-3 Abnormal umbilical artery Doppler in which the diastolic component shows flow in a reverse direction. This finding occurs in severe intrauterine hypoxia and intrauterine growth restriction.

(From Trudinger C: Doppler ultrasound assessment of blood flow. In Creasy RK, Resnik R, editors: Maternal-fetal medicine: principles and practice, ed 5, Philadelphia, 2004, WB Saunders.)

Table 90-1 FETAL DIAGNOSIS AND ASSESSMENT

* DNA genetic analysis on chorionic villus samples, amniocytes from amniocentesis, or fetal cells recovered from the maternal circulation may obviate the need for direct fetal tissue biopsy if the gene or genetic marker is available (e.g., the gene for Duchenne muscular dystrophy).

The most commonly used noninvasive tests are the nonstress test (NST), the full and modified biophysical profile (BPP), and less commonly, the contraction stress test (CST). The NST monitors the presence of fetal heart rate accelerations that follow fetal movement. A reactive (normal) NST result demonstrates two fetal heart rate accelerations of at least 15 beats/min lasting 15 sec. A nonreactive NST result suggests fetal compromise and requires further assessment with a CST or the BPP. A CST observes the fetal heart rate response to spontaneous, nipple-stimulated, or oxytocin-stimulated uterine contractions. Fetal compromise is suggested when the majority of contractions in 10 min are followed by late decelerations. A CST is relatively contraindicated in women with preterm premature rupture of membranes, a previous uterine scar from a classic cesarean section, multiple gestations, incompetent cervix, and placenta previa. The goals of fetal monitoring are to prevent intrauterine fetal demise and hypoxic brain injury. Although the CST and NST have low false-negative rates, both have high false-positive rates. The full BPP assesses fetal breathing, body movement, tone, heart rate, and amniotic fluid volume, and it is used to improve the accurate and safe identification of fetal compromise (Table 90-2). A score of 2 is given for each observation present. A total score of 8-10 is reassuring; a score of 6 is equivocal, and retesting should be done in 12-24 hr; and a score of 4 or less warrants immediate evaluation and possible delivery. The BPP has good negative predictive value. The modified BPP consists of the combination of an ultrasound estimate of amniotic fluid volume (the amniotic fluid index) and the NST. When results of both are normal, fetal compromise is very unlikely. Signs of progressive compromise seen on Doppler ultrasonography include reduced, absent, or reversed diastolic waveform velocity in the fetal aorta or umbilical artery (see Fig. 90-3 and Table 90-1). High-risk fetuses often have combinations of abnormalities, such as oligohydramnios, reversed diastolic Doppler umbilical artery blood flow velocity, and a low BPP.

Table 90-2 BIOPHYSICAL PROFILE SCORING: TECHNIQUE AND INTERPRETATION

* Modification of the criteria for reduced amniotic fluid from less than 1 cm to less than 2 cm would seem reasonable. Ultrasound is used for biophysical assessment of the fetus.

From Creasy RK, Resnik R, Iams JD, editors: Maternal-fetal medicine: principles and practice, ed 5, Philadelphia, 2004, Saunders.

Fetal compromise during labor may be detected by monitoring the fetal heart rate, uterine pressure, and fetal scalp blood pH (Fig. 90-4). Continuous fetal heart rate monitoring detects abnormal cardiac patterns by instruments that compute the beat-to-beat fetal heart rate from a fetal electrocardiographic signal. Signals are derived from an electrode attached to the fetal presenting part, from an ultrasonic transducer placed on the maternal abdominal wall to detect continuous ultrasonic waves reflected from the contractions of the fetal heart, or from a phonotransducer placed on the mother’s abdomen. Uterine contractions are simultaneously recorded from an amniotic fluid catheter and pressure transducer or from a tocotransducer applied to the maternal abdominal wall overlying the uterus. Fetal heart rate patterns show various characteristics, some of which suggest fetal compromise. The baseline fetal heart rate is the average rate between uterine contractions, which gradually decreases from about 155 beats/min in early pregnancy to about 135 beats/min at term; the normal range at term is 110-160 beats/min. Tachycardia (>160 beats/min) is associated with early fetal hypoxia, maternal fever, maternal hyperthyroidism, maternal β-sympathomimetic drug or atropine therapy, fetal anemia, infection, and some fetal arrhythmias. The last do not generally occur with congenital heart disease and may resolve spontaneously at birth. Fetal bradycardia (<110 beats/min) may be normal (e.g., 105-110 beats/min) but may occur with fetal hypoxia, placental transfer of local anesthetic agents and β-adrenergic blocking agents, and, occasionally, heart block with or without congenital heart disease.

Figure 90-4 Patterns of periodic fetal heart rate (FHR) deceleration. The tracing in A shows early deceleration occurring during the peak of uterine contractions as a result of pressure on the fetal head. B, Late deceleration caused by uteroplacental insufficiency. C, Variable deceleration as a result of umbilical cold compression. Arrows denote the time relationship between the onset of FHR changes and uterine contractions.

(From Hon EH: An atlas of fetal heart rate patterns, New Haven, CT, 1968, Harty Press.)

Normally, the baseline fetal heart rate is variable. Variability is classified as follows: absence of variability, if an amplitude change is undetectable; minimal variability if amplitude range is ≤ 5 beats/min (beats/min); moderate variability if amplitude range is 6-25 beats/min; marked variability if amplitude range is > 25 beats/min. Variability may be decreased or lost with fetal hypoxemia or the placental transfer of drugs such as atropine, diazepam, promethazine, magnesium sulfate, and most sedative and narcotic agents. Prematurity, the sleep state, and fetal tachycardia may also diminish beat-to-beat variability.

Periodic accelerations or decelerations of the fetal heart rate in response to uterine contractions may also be monitored (see Fig. 90-4). An acceleration is an abrupt increase in fetal heart rate of ≥15 beats/min in ≥15 sec. The presence of accelerations or moderate variability reliably predicts the absence of fetal metabolic acidemia. However, their absence does not reliably predict fetal acidemia or hypoxemia. Early deceleration associated with head compression is a repetitive pattern of gradual decrease and return of the fetal heart rate that is coincidental with the uterine contraction (Table 90-3). Variable deceleration (associated with cord compression) is characterized by variable shape, abrupt onset and occurrence with consecutive contractions, and return to baseline at or after the conclusion of the contraction. Late deceleration, associated with fetal hypoxemia, occurs repetitively after a uterine contraction is well established and persists into the interval following contractions. The late deceleration pattern is usually associated with maternal hypotension or excessive uterine activity, but it may be a response to any maternal, placental, umbilical cord, or fetal factor that limits effective oxygenation of the fetus. Reflex late decelerations with normal beat-to-beat variability are associated with chronic compensated fetal hypoxia, and they occur during uterine contractions that temporarily impede oxygen transport to the heart. Nonreflex late decelerations are more ominous and indicate severe hypoxic depression of myocardial function.

If late decelerations are unresponsive to oxygen supplementation, hydration, discontinuation of labor stimulation, and position changes, prompt delivery is indicated. A three-tier system has been developed by a panel of experts for interpretation of fetal heart rate tracings (Table 90-4). Category I tracings are normal and are strongly predictive of normal fetal acid-base status at the time of the observation. Category II tracings are not predictive of abnormal fetal status, but there is insufficient evidence to categorize them as category I or III; further evaluation, surveillance, and reevaluation are indicated. Category III tracings are abnormal and predictive of abnormal fetal acid-base status at the time of observation. Category III tracings require prompt evaluation and efforts to expeditiously resolve the abnormal fetal heart rate as previously discussed for late decelerations.

Fetal scalp blood sampling during labor through a slightly dilated cervix may aid in confirming fetal distress suspected on the basis of variations in fetal heart rate or the presence of meconium in amniotic fluid. The proper use of this technique may result in earlier delivery of depressed infants, who thus have a better chance of successful resuscitation, increased survival, and less morbidity. Alternatively, when continuous fetal heart rate monitoring or general clinical evaluation suggests that a fetus is at risk, a normal fetal scalp blood sample may help avert obstetric intervention.

Fetal scalp blood pH in normal labor decreases from about 7.33 early in labor to approximately 7.25 at the time of vaginal delivery; the base deficit is about 4-6 mEq/L. Changes in the buffer base may be particularly helpful in assessing fetal status, because they correspond to the accumulation of fetal lactic acid. A pH <7.25 suggests fetal distress, and a pH <7.20 is an indication for further assessment and intervention. Determination of the lactate concentration in fetal scalp blood is another tool for monitoring the condition of the fetus.

Umbilical cord blood samples obtained at the time of delivery are useful to document fetal acid-base status. Although the exact cord blood pH value that defines significant fetal acidemia is unknown, an umbilical artery pH <7.0 has been associated with greater need for resuscitation and a higher incidence of respiratory, gastrointestinal, cardiovascular, and neurologic complications. Nonetheless, in many cases, even when a low pH is detected, newborn infants are neurologically normal.

Intrapartum fetal pulse oximetry is another measure of fetal status. Even though initial data suggested that intrapartum fetal pulse oximetry could help identify fetuses with a nonreassuring status, a large randomized controlled trial showed that intrapartum fetal pulse oximetry does not lead to a reduction in cesarean section rates or improvement in the condition of newborns at birth.

The use of medications or herbal remedies during pregnancy is potentially harmful to the fetus. Consumption of medications occurs during the majority of pregnancies. The average mother has taken 4 drugs other than vitamins or iron during pregnancy. Almost 40% of pregnant women receive a drug for which human safety during pregnancy has not been established (category C pregnancy risk; see later). Moreover, many women are exposed to potential reproductive toxins, such as occupational, environmental, or household chemicals, including solvents, pesticides, and hair products. The effects of drugs taken by the mother vary considerably, especially in relation to the time in pregnancy when they are taken and the fetal genotype for drug-metabolizing enzymes. Miscarriage or congenital malformations result from the maternal ingestion of teratogenic drugs during the period of organogenesis. Maternal medications taken later, particularly during the last few weeks of gestation or during labor, tend to affect the function of specific organs or enzyme systems, and they adversely affect the neonate rather than the fetus (Tables 90-5 and 90-6).

Table 90-5 AGENTS ACTING ON PREGNANT WOMEN THAT MAY ADVERSELY AFFECT THE STRUCTURE OR FUNCTION OF THE FETUS AND NEWBORN

CNS, central nervous system; IUGR, intrauterine growth restriction; LBW, low birthweight. VACTERAL, vertebral, anal, cardiac, tracheoesophagcal fistula, renal, arterial, limb.

The effects of drugs may be evident immediately in the delivery room or later in the neonatal period, or they may be delayed even longer. The administration of diethylstilbestrol during pregnancy, for instance, resulted in vaginal adenocarcinoma in the female offspring in the 2nd or 3rd decade of life.

Evidence has confirmed an interaction between genetic factors and susceptibility to certain drugs or environmental toxins. Phenytoin teratogenesis may be mediated by genetic differences in the enzymatic production of epoxide metabolites; specific genes may influence the adverse effects of benzene exposure during pregnancy. Polymorphisms of genes encoding enzymes that metabolize the polycyclic aromatic hydrocarbons in cigarette smoke influence the growth-restricting effects of smoking on the fetus.

Often the risk of controlling maternal disease must be balanced with the risk of possible complications in the fetus. The majority of women with epilepsy have normal fetuses. Nonetheless, several commonly used antiepileptic drugs are associated with congenital malformations. Infants exposed to valproic acid may have multiple anomalies, including NTDs, hypospadias, facial anomalies, cardiac anomalies, and limb defects. In addition, they have lower developmental index scores than unexposed infants and infants exposed to other commonly used antiepileptic drugs.

Methotrexate is used for medical termination of pregnancy; surviving exposed infants may be at higher risk for congenital anomalies, IUGR, hypotonia, and developmental delay.

Moderate or high alcohol intake (≥7 drinks per week or ≥3 drinks on multiple occasions) is a risk for fetal alcohol syndrome. The exposed fetuses are at risk for growth failure, central nervous system abnormalities, cognitive defects, and behavioral problems. Smoking during pregnancy is associated with IUGR and facial clefts.

In view of the limits of current knowledge about the fetal effects of maternal medication, drugs and herbal agents should not be prescribed during pregnancy without weighing of maternal need against the risk of fetal damage. All women should be specifically counseled to abstain from the use of alcohol, tobacco, and illicit drugs during pregnancy.

When an infant or child has a congenital malformation or is developmentally delayed, the parents often wrongly blame themselves and attribute the child’s problems to events that occurred during pregnancy. Because benign infections occur and several nonteratogenic drugs are often taken during many pregnancies, the pediatrician must evaluate the presumed viral infections and the drugs ingested to help parents understand their child’s birth defect. The causes of approximately 40% of congenital malformations are unknown. Although only a relatively few agents are recognized to be teratogenic in humans (see Tables 90-5 and 90-6), new agents continue to be identified. Overall, only 10% of anomalies are due to recognizable teratogens (Chapter 102). The time of exposure is usually at less than 60 days of gestation during organogenesis. Specific agents produce predictable lesions. Some agents have a dose or threshold effect; below the threshold, no alterations in growth, function, or structure occur. Genetic variables such as the presence of specific enzymes may metabolize a benign agent into a more toxic-teratogenic form (e.g., phenytoin conversion to its epoxide). In many circumstances, the same agent and dose may not consistently produce the lesion.

Reduced enzyme activity of the folate methylation pathway, particularly the formation of 5-methyltetrahydrofolate, may be responsible for neural tube or other birth defects. The common thermolabile mutation of 5,10-methylene tetrahydrofolate reductase may be one of the enzymes responsible. Folate supplementation for all pregnant women (by direct fortification of cereal grains, mandatory in the USA), and oral folic acid tablets taken during organogenesis may overcome this genetic enzyme defect, thus reducing the incidence of neural tube and perhaps other birth defects.

The U.S. Food and Drug Administration (FDA) classifies drugs into five pregnancy risk categories. Category A drugs pose no risk on the basis of evidence from controlled human studies. For category B drugs, either no risk has been shown in animal studies but no adequate studies in humans or some risk has been shown in animal studies but these results are not confirmed by human studies. For category C drugs, either definite risk has been shown in animal studies but no adequate human studies have been performed or no data is available from either animal or human studies. Category D includes drugs with some risk but with a benefit that may exceed that risk for the treated life-threatening condition, such as streptomycin for tuberculosis. Category X is for drugs that are contraindicated in pregnancy on the basis of animal and human evidence and for which the risk exceeds the benefits.

The specific mechanism of action is known or postulated for very few teratogens. Warfarin, an anticoagulant because it is a vitamin K antagonist, prevents the carboxylation of γ-carboxyglutamic acid, which is a component of osteocalcin and other vitamin K–dependent bone proteins. The teratogenic effect of warfarin on developing cartilage, especially nasal cartilage, appears to be avoided if the pregnant woman’s anticoagulation treatment is switched from warfarin to heparin for the period between weeks 6 and 12 of gestation. Hypothyroidism in the fetus may be caused by the maternal ingestion of an excessive amount of iodides or propylthiouracil; each interferes with the conversion of inorganic to organic iodides. Phenytoin may be teratogenic because of the accumulation of a metabolite as a result of deficiency of epoxide hydrolase.

Recognition of teratogens offers the opportunity to prevent related birth defects. If a pregnant woman is informed of the potentially harmful effects of alcohol on her unborn infant, she may be motivated to avoid alcohol consumption during pregnancy. A woman with insulin-dependent diabetes mellitus may significantly decrease her risk for having a child with birth defects by achieving good control of her disease before conception.

90.6 Radiation (See Also Chapter 699)

Accidental exposure of a pregnant woman to radiation is a common cause for anxiety about whether her fetus will have genetic abnormalities or birth defects. It is unlikely that exposure to diagnostic radiation will cause gene mutations; no increase in genetic abnormalities has been identified in the offspring exposed as unborn fetuses to the atomic bomb explosions in Japan in 1945.

A more realistic concern is whether the exposed human fetus will show birth defects or a higher incidence of malignancy. The estimated radiation dose for most radiographs is less than 0.1 rad, and for most CT scans it is less than 5 rad. Imaging studies with high radiation exposure (such as CT scans) can be modified to ensure that radiation doses are kept as low as possible. Thus, single diagnostic studies do not result in radiation doses high enough to affect the embryo or fetus. Therapeutic abortion should not be recommended, given the low likelihood for high radiation exposure. Most of the evidence suggests that usual fetal radiation exposure does not increase the risk of childhood leukemia and other cancers. The limited data on human fetuses show that large doses of radiation (20-50 rad) may cause fetal death (the most sensitive period is the 3rd and 4th post-conception wk) as well as microcephaly, severe mental retardation, and growth retardation (the most sensitive period is 4th to 15th wk). The available data suggest no harmful fetal effect of diagnostic MRI or ultrasonography.

90.7 Intrauterine Diagnosis of Fetal Disease (See Table 90-1 and Chapter 90.2)

Diagnostic procedures are used to identify fetal diseases when abortion is being considered, when direct fetal treatment is possible, or when a decision is made to deliver a viable but premature infant to avoid intrauterine fetal demise. Fetal assessment is also indicated in a broader context when the family, medical, or reproductive history of the mother suggests the presence of a high-risk pregnancy or a high-risk fetus (Chapters 89 and 90.3).

Various methods are used for identifying fetal disease (see Table 90-1). Fetal ultrasonographic imaging may detect fetal growth abnormalities (by biometric measurements of biparietal diameter, femoral length, or head or abdominal circumference) or fetal malformations (Fig. 90-5). Although 89% of fetuses whose biparietal diameter is 9.5 cm or more are at least in the 37th wk of gestation, the lungs of these fetuses may not be mature. Serial determinations of growth velocity and the head-to-abdomen circumference ratio enhance the ability to detect IUGR. Real-time ultrasonography may identify placental abnormalities (abruptio placentae, placenta previa) and fetal anomalies such as hydrocephalus, NTDs, duodenal atresia, diaphragmatic hernia, renal agenesis, bladder outlet obstruction, congenital heart disease, limb abnormalities, sacrococcygeal teratoma, cystic hygroma, omphalocele, gastroschisis, and hydrops (Table 90-7).

Figure 90-5 Assessment of fetal anatomy. A, Overall view of the uterus at 24 wk showing a longitudinal section of the fetus and an anterior placenta. B, Transverse section at the level of the lateral ventricle at 18 wk showing (on the right) prominent anterior horns of the lateral ventricles on either side of the midline echo of the falx. C, Cross section of the umbilical cord showing that the lumen of the umbilical vein is much wider than that of the two umbilical arteries. D, Four-chambered view of the heart at 18 wk with equal-sized atria. E(i), normal male genitals near term. E(ii), Hydrocele outlining a testicle within the scrotum projecting into a normal-sized pocket of amniotic fluid at 38 wk. Approximately 2% of male infants after birth have clinical evidence of a hydrocele that is often bilateral, not to be confused with subcutaneous edema occurring during vaginal breech birth. F, Section of a thigh near term showing thick subcutaneous tissue (4.6 mm between markers) above the femur of a fetus with macrosomia. G, Fetal face viewed from below, showing (from right to left) the nose, alveolar margin, and chin at 20 wk.

(From Special investigative procedures. In Beischer NA, Mackay EV, Colditz PB, editors: Obstetrics and the newborn, ed 3, Philadelphia, 1997, WB Saunders.)

Real-time ultrasonography also facilitates performance of cordocentesis and the BPP by imaging fetal breathing, body movements, tone, and amniotic fluid volume (see Table 90-2). Doppler velocimetry assesses fetal arterial blood flow (vascular resistance) (see Figs. 90-2 and 90-3). Roentgenographic examination of the fetus has been replaced by real-time ultrasonography, MRI, and fetoscopy.

Amniocentesis, the transabdominal withdrawal of amniotic fluid during pregnancy for diagnostic purposes (see Table 90-1), is frequently performed to determine the timing of delivery of fetuses with erythroblastosis fetalis or the need for fetal transfusion. It is also done for genetic indications, usually between the 15th and 16th wk of gestation, with results available within 1-2 wk. The most common indication for genetic amniocentesis is advanced maternal age (the risk for chromosome abnormality at age 21 years is 1 : 526, vs 1 : 8 at age 49). The amniotic fluid may be directly analyzed for amino acids, enzymes, hormones, and abnormal metabolic products, and amniotic fluid cells may be cultivated to permit detailed cytologic analysis for prenatal detection of chromosomal abnormalities and DNA-gene or enzymatic analysis for the detection of inborn metabolic errors. Analysis of amniotic fluid may also help in identifying NTDs (elevation of α-fetoprotein), adrenogenital syndrome (elevation of 17-ketosteroids and pregnanetriol), and thyroid dysfunction. Chorionic villus biopsy (transvaginal or transabdominal) performed in the 1st trimester also provides fetal cells but may pose a slightly increased risk for fetal loss and limb reduction defects. Fetal cells circulating in maternal blood and fetal DNA in maternal plasma are potential noninvasive sources of material for prenatal diagnosis. This technology may eliminate the need for amniocentesis or chorionic villus sampling.

The best available chemical indices of fetal maturity are provided by determination of amniotic fluid creatinine and lecithin levels, which reflect the maturity of the fetal kidneys and lungs, respectively. Lecithin is produced in the lungs by type II alveolar cells and eventually reaches the amniotic fluid via the effluent from the trachea. Until the middle of the 3rd trimester, its concentration nearly equals that of sphingomyelin; thereafter, the sphingomyelin concentration remains constant in amniotic fluid while the lecithin concentration increases. By 35 wk, the lecithin : sphingomyelin (L : S) ratio averages about 2 : 1, indicative of lung maturity.

Earlier lung maturation may occur in the presence of severe premature separation of the placenta, premature rupture of the fetal membranes, narcotic addiction, or maternal hypertensive and renal vascular disease. A delay in pulmonary maturation may be associated with hydrops fetalis or maternal diabetes without vascular disease. The likelihood of hyaline membrane disease is greatly reduced with L : S ratios of 2 : 1 or more, although hypoxia, acidosis, and hypothermia may increase the risk despite this “mature” L : S ratio. Maternal and fetal blood have an L : S ratio of about 1 : 4; thus, contamination will not alter the significance of a ratio of 2 : 1 or more. Meconium contamination, sample storage, and sample centrifugation may reduce the reliability of the L : S ratio.

Saturated phosphatidylcholine or phosphatidylglycerol concentrations in amniotic fluid may be more specific and sensitive predictors of pulmonary maturity, especially in high-risk pregnancies such as those occurring in women with diabetes (Chapters 89 and 101.1).

Amniocentesis can be carried out with little discomfort to the mother, but even in experienced hands, the procedure entails some small risk, such as direct damage to the fetus, placental puncture and bleeding with secondary damage to the fetus, stimulation of uterine contraction and premature labor, amnionitis, and maternal sensitization to fetal blood. The earlier in gestation that amniotic puncture is done, the greater the risk to the fetus. Using ultrasound for placental and fetal localization can reduce the risk of complications. The procedure should be limited to cases in which the potential benefits of the findings will outweigh the risk.

Cordocentesis, or percutaneous umbilical blood sampling, is used to diagnose fetal hematologic abnormalities, genetic disorders, infections, and fetal acidosis (see Table 90-1). Under direct ultrasonographic visualization, a long needle is passed into the umbilical vein at its entrance to the placenta or fetal abdominal wall. Umbilical blood may be withdrawn to determine fetal hemoglobin, platelet concentration, lymphocyte DNA, the presence of infection, or PaO₂, pH, PCO₂, and lactate levels.

Transfusion or administration of drugs can be performed through the umbilical vein (Table 90-8). Serum screening is offered to pregnant women at midgestation to evaluate the risk for Down syndrome (trisomy 21) and congenital malformations known to cause elevations of various markers, including abdominal wall and NTDs. A combination of these biochemical markers (including α-fetoprotein, inhibin A, estriol, pregnancy-associated plasma protein A, and β-HCG [human chorionic gonadotropin]) and ultrasound increases the positive predictive value of these screening tests. Additionally, families with a known genetic syndrome may be offered prenatal genetic testing from amniotic fluid or amniocytes obtained via amniocentesis or chorionic villus sampling.

Table 90-8 FETAL THERAPY

EXIT, Ex utero intrapartum treatment; IVIG, intravenous immunoglobulin; (?), possible but not proved efficacy.

* Drug of choice (may require percutaneous umbilical cord sampling and umbilical vein administration if hydrops is present). Most drug therapy is given to the mother, with subsequent placental passage to the fetus.

^† Detailed fetal ultrasonography is needed to detect other anomalies; karyotype is also indicated.

^‡ EXIT permits surgery and other procedures.

Management of a fetal disease depends on coordinated advances in diagnostic accuracy and knowledge of the disease’s natural history; an understanding of fetal nutrition, pharmacology, immunology, and pathophysiology; the availability of specific active drugs that cross the placenta; and therapeutic procedures. Progress in providing specific treatments for accurately diagnosed diseases has improved with the advent of real-time ultrasonography and cordocentesis (see Tables 90-1 and 90-8).

The incidence of sensitization of Rh-negative women by Rh-positive fetuses has been reduced by prophylactic administration of Rh(D) immunoglobulin to mothers early in pregnancy and after each delivery or abortion, thus reducing the frequency of hemolytic disease in their subsequent offspring. Fetal erythroblastosis (Chapter 97.2) may be accurately diagnosed by amniotic fluid analysis and treated with intrauterine intraperitoneal or, more often, intraumbilical vein transfusions of packed Rh-negative blood cells to maintain the fetus until it is mature enough to have a reasonable chance of survival.

Fetal hypoxia or distress may be diagnosed with moderate success. Treatment, however, remains limited to supplying the mother with high concentrations of oxygen, positioning the uterus to avoid vascular compression, and initiating operative delivery before severe fetal injury occurs.

Pharmacologic approaches to fetal immaturity (e.g., administration of steroids to the mother to accelerate fetal lung maturation and decrease the incidence of respiratory distress syndrome [Chapter 95.3] in prematurely delivered infants) are successful. Inhibiting labor with tocolytic agents is unfortunately not successful in most patients with premature labor. Management of definitively diagnosed fetal genetic disease or congenital anomalies consists of parental counseling or abortion; rarely, high-dose vitamin therapy for a responsive inborn error of metabolism (biotin-dependent disorders) or fetal transfusion (with red blood cells or platelets) may be indicated. Fetal surgery (see Table 90-8) remains an experimental approach to therapy and is available only in a few highly specialized perinatal centers. The nature of the defect and its consequences, as well as ethical implications for the fetus and the parents, must be considered.

Folic acid supplementation decreases the incidence and recurrence of (NTDs). Because the neural tube closes within the 1st 28 days of conception, periconceptional supplementation is needed for prevention. It is recommended that women without a prior history of a NTD ingest 400 µg/day of folic acid throughout their reproductive years. Women with a history of a prior pregnancy complicated by an NTD or a 1st-degree relative with an NTD should have preconceptional counseling and should ingest 4 mg/day of supplemental folic acid beginning at least 1 mo before conception. Fortification of cereal grain flour with folic acid is established policy in the USA and some other countries. The optimal concentration of folic acid in enriched grains is somewhat controversial. The incidence of NTD in the USA and other countries has decreased significantly since these public health initiatives were implemented. Use of some antiepileptic drugs (valproate, carbamazepine) during pregnancy is associated with an increased risk of NTD. Women taking these medications should ingest 1-5 mg of folic acid/day in the preconception period.