Review of Critical Care Medicine

1. Actions of CRH on the Fetal Adrenal Gland

As discussed in Chapter 3 (see Fetal Adrenal Glands), the human fetal adrenal glands are morphologically, functionally, and physiologically remarkable organs. At term, the fetal adrenal glands weigh the same as those in the adult and are similar in size to the adjacent fetal kidney. The daily production of steroids by the fetal adrenal glands near term is estimated to be 100 to 200 mg/day, which is higher than the 30 to 40 mg/day seen in adult adrenals at rest. Within the fetal adrenal gland, steroidogenic function and zonation are different from the adult. For example, significant amounts of cortisol are not produced in the fetal adrenal gland until the last trimester. As a result, fetal cortisol levels increase during the last weeks of gestation (Murphy, 1982). During this same period, levels of dehydroepiandrosterone sulfate (DHEA-S) production also are increasing significantly, leading to increases in maternal estrogens, particularly estriol. The increase in adrenal activity occurs in contrast to fetal adrenocorticotropic hormone (ACTH) levels which do not increase until the stress of actual labor.

This substantial growth and increased steroid synthesis during latter gestation is at a time when fetal plasma ACTH levels appear to decline (Winters and co-workers, 1974). Thus, many investigators have surmised that there must be growth and steroidogenesis stimuli for these glands in addition to ACTH. Two observations have made it extremely likely that factors secreted by the placenta play a key role in the regulation of steroidogenesis during late gestation. First, the fact that ACTH levels do not increase significantly during the last part of gestation makes it likely that growth and differentiation of the fetal adrenal glands are influenced by factors secreted by the placenta. Second, the fetal zone of the adrenal gland undergoes rapid involution immediately after birth when placenta-derived factors are no longer available. Many believe that CRH of placental origin is one of the critical components that facilitates fetal adrenal hypertrophy and increased steroidogenesis late in gestation. Indeed, in vitro studies have shown that CRH is able to stimulate fetal adrenal DHEA-S and cortisol biosynthesis (Parker and associates, 1999; Smith and co-workers, 1998). The ability of CRH to regulate the adrenal glands and of the adrenals to regulate placental production of CRH has led to the idea of a feed-forward endocrine cascade that occurs late in gestation (Fig. 6–19).

Placental CRH has been proposed to play several roles in the regulation of parturition. First, placental CRH may enhance fetal cortisol production, which would provide positive feedback on the placenta to produce more CRH. The resulting high level of CRH may modulate myometrial contractility. Second, cortisol has been proposed to affect the myometrium indirectly by stimulating the membranes to increase prostaglandin synthesis. Third, CRH has been shown to stimulate fetal adrenal C₁₉-steroid synthesis, leading to increased substrate for placental aromatization. The resulting elevation in estrogens would shift the estrogen-to-progesterone ratio and promote the expression of a series of contractile proteins in the myometrium, leading to a loss of myometrial quiescence.

Ref:- Williams

2.Prolactin

Maternal plasma levels of prolactin increase markedly during the course of normal pregnancy. Serum concentration levels are usually 10-fold greater at term—about 150 ng/mL—compared with normal nonpregnant women. Paradoxically, after delivery, the plasma prolactin concentration decreases even in women who are breast feeding. During early lactation, pulsatile bursts of prolactin secretion occur apparently in response to suckling. The physiological cause of the marked increase in prolactin prior to parturition is not entirely certain. It is known, however, that estrogen stimulation increases the number of anterior pituitary lactotrophs and may stimulate the release of prolactin from these cells (Andersen, 1982). Thyroid-releasing hormone also acts to cause an increased prolactin level in pregnant compared with nonpregnant women, but the response decreases as pregnancy advances (Andersen, 1982; Miyamoto, 1984). Serotonin also is believed to increase prolactin, and prolactin-inhibiting factor (dopamine) inhibits its secretion.

The principal function of maternal serum prolactin is to ensure lactation. Early in pregnancy, prolactin acts to initiate DNA synthesis and mitosis of glandular epithelial cells and the presecretory alveolar cells of the breast. Prolactin also increases the number of estrogen and prolactin receptors in these same cells. Finally, prolactin promotes mammary alveolar cell RNA synthesis, galactopoiesis, and production of casein and lactalbumin, lactose, and lipids (Andersen, 1982). Kauppila and co-workers (1987) found that a woman with an isolated prolactin deficiency failed to lactate after two pregnancies, establishing the absolute necessity of prolactin for lactation but not for successful pregnancy outcome.

Prolactin is present in amnionic fluid in high concentrations. Levels of up to 10,000 ng/mL are found at 20 to 26 weeks, thereafter, levels decrease and reach a nadir after 34 weeks. Several investigators have presented convincing evidence that the uterine decidua is the site of prolactin synthesis in amnionic fluid (see Chap. 3, Decidual Prolactin Production). Although the exact function of amnionic fluid prolactin is not known, it has been suggested that amnionic fluid prolactin impairs the transfer of water from the fetus into the maternal compartment, thus preventing fetal dehydration during late pregnancy when amnionic fluid is normally hypotonic.

3.Fetal Heart Rate Patterns   ;-It is now generally accepted that interpretation of fetal heart rate patterns can be problematic because of the lack of agreement on definitions and nomenclature (Freeman, 2002). The National Institute of Child Health and Human Development Research Planning Workshop (1997) brought together investigators with expertise in the field to propose standardized, unambiguous definitions for interpretation of fetal heart rate patterns during labor. The definitions proposed as a result of this workshop will be used in this chapter. It is important to recognize that interpretation of electronic fetal heart rate data is based on the visual pattern of the heart rate as portrayed on chart recorder graph paper. Thus, the choice of vertical and horizontal scaling greatly affects the appearance of the fetal heart rate. Scaling factors recommended by the workshop are 30 beats per minute (beats/min or bpm) per vertical cm (range, 30 to 240 beats/min) and 3 cm/min chart recorder paper speed. Fetal heart rate variation is falsely displayed at the slower 1 cm/min paper speed when compared with that of the smoother baseline recorded at 3 cm/min (Fig. 18–6). Thus, pattern recognition can be considerably distorted depending on the scaling factors used.

Fetal heart rate obtained by scalp electrode and recorded at 1 cm/min compared with that of 3 cm/min chart recorder paper speed.

Baseline Fetal Heart Activity

Baseline fetal heart activity refers to the modal characteristics that prevail apart from periodic accelerations or decelerations associated with uterine contractions. Descriptive characteristics of baseline fetal heart activity include rate, beat-to-beat variability, fetal arrhythmia, and distinct patterns such as sinusoidal or saltatory fetal heart rates.

Rate

With increasing fetal maturation, the heart rate decreases. This continues postnatally such that the average rate is 90 beats/min by age 8 (Behrman, 1992). Pillai and James (1990) longitudinally studied fetal heart rate characteristics in 43 normal pregnancies. The baseline fetal heart rate decreased an average of 24 beats/min between 16 weeks and term, or approximately 1 beat/min per week. It is postulated that this normal gradual slowing of the fetal heart rate corresponds to maturation of parasympathetic (vagal) heart control (Renou and co-workers, 1969).

The baseline fetal heart rate is the approximate mean rate rounded to increments of 5 beats/min during a 10-minute tracing segment. In any 10-minute window, the minimum interpretable baseline duration must be at least 2 minutes. If the baseline fetal heart rate is less than 110 beats/min, it is termed bradycardia; if the baseline rate is greater than 160 beats/min, it is termed tachycardia. The average fetal heart rate is considered to be the result of tonic balance between accelerator and decelerator influences on pacemaker cells. In this concept, the sympathetic system is the accelerator influence, and the parasympathetic system is the decelerator factor mediated via vagal slowing of heart rate (Dawes, 1985). Heart rate also is under the control of arterial chemoreceptors such that both hypoxia and hypercapnia can modulate rate. More severe and prolonged hypoxia, with a rising blood lactate level and severe metabolic acidemia, induces a prolonged fall of heart rate due to direct effects on the myocardium.

Bradycardia

During the third trimester, the normal mean baseline fetal heart rate has generally been accepted to be between 120 and 160 beats/min. The lower normal limit is disputed internationally with some investigators recommending 110 beats/min (Manassiev, 1996). Pragmatically, a rate between 100 and 119 beats/min, in the absence of other changes, usually is not considered to represent fetal compromise. Such low but potentially normal baseline heart rates also have been attributed to head compression from occiput posterior or transverse positions, particularly during second-stage labor (Young and Weinstein, 1976). Such mild bradycardias were observed in 2 percent of monitored pregnancies and averaged about 50 minutes in duration. Freeman and colleagues (2003) have concluded that bradycardia within the range of 80 to 120 beats/min with good variability is reassuring. Interpretation of rates less than 80 beats/min is problematic, and such rates generally are considered nonreassuring.

Some causes of fetal bradycardia include congenital heart block and serious fetal compromise. Figure 18–7 shows bradycardia in a fetus dying from placental abruption. Maternal hypothermia under general anesthesia for repair of a cerebral aneurysm or during maternal cardiopulmonary bypass for open-heart surgery also can cause fetal bradycardia (see Chap. 44, Valve Replacement During Pregnancy). Sustained fetal bradycardia in the setting of severe pyelonephritis and maternal hypothermia also has been reported (Hankins and co-workers, 1997). These infants apparently are not harmed by several hours of such bradycardia.

Fetal bradycardia measured with a scalp electrode in a pregnancy complicated by placental abruption and subsequent fetal death.

Tachycardia

Fetal tachycardia is defined as a baseline heart rate in excess of 160 beats/min. The most common explanation for fetal tachycardia is maternal fever from amnionitis, although fever from any source can increase baseline fetal heart rate. Such infections also have been observed to induce fetal tachycardia before overt maternal fever is diagnosed (Gilstrap and associates, 1987). Fetal tachycardia caused by maternal infection typically is not associated with fetal compromise unless there are associated periodic heart rate changes or fetal sepsis.

Other causes of fetal tachycardia include fetal compromise, cardiac arrhythmias, and maternal administration of parasympathetic (atropine) or sympathomimetic (terbutaline) drugs. The key feature to distinguish fetal compromise in association with tachycardia seems to be concomitant heart rate decelerations. Prompt relief of the compromising event, such as correction of maternal hypotension caused by epidural analgesia, can result in fetal recovery.

Wandering Baseline

This baseline rate is unsteady and “wanders” between 120 and 160 beats/min (Freeman and colleagues, 2003). This rare finding is suggestive of a neurologically abnormal fetus and may occur as a preterminal event.

Beat-to-Beat Variability

Baseline variability is an important index of cardiovascular function and appears to be regulated largely by the autonomic nervous system (Kozuma and colleagues, 1997). That is, sympathetic and parasympathetic “push-pull,” mediated via the sinoatrial node, produces moment-to-moment or beat-to-beat oscillation of the baseline heart rate. Such irregularity of the heart rate is defined as baseline variability. Variability is further divided into short term and long term.

Short-term variability reflects the instantaneous change in fetal heart rate from one beat—or R wave—to the next. This variability is a measure of the time interval between cardiac systoles (Fig. 18–8). Short-term variability can most reliably be determined to be normally present only when electrocardiac cycles are measured directly with a scalp electrode. Long-term variability is used to describe the oscillatory changes that occur during the course of 1 minute and result in the waviness of the baseline (Fig. 18–9). The normal frequency of such waves is three to five cycles per minute (Freeman and co-authors, 2003).

It should be recognized that precise quantitative analysis of both short- and long-term variability presents a number of frustrating problems due to technical and scaling factors. For example, Parer and co-workers (1985) evaluated 22 mathematical formulas designed to quantify heart rate variability and most were unsatisfactory. Consequently, most clinical interpretation is based on visual analysis with subjective judgment of the smoothness or flatness of the baseline. According to Freeman and colleagues (2003), there is no current evidence that the distinction between short- and long-term variability has any clinical relevance. Similarly, the NICHD Workshop (1997) did not recommend differentiating short- and long-term variability because in actual practice they are visually determined as a unit. The workshop panel defined baseline variability as those baseline fluctuations of two cycles per minute or greater. They recommended the criteria shown in Figure 18–10 for quantification of variability. Normal beat-to-beat variability was accepted to be 6 to 25 beats/min.

Grades of baseline fetal heart rate variability (irregular fluctuations in the baseline of 2 cycles per minute or greater) together with a sinusoidal pattern. The sinusoidal pattern differs from variability in that it has a smooth, sinelike pattern of regular fluctuation and is excluded in the definition of fetal heart rate variability. (1) Undetectable, absent variability; (2) minimal  5 beats/min variability; (3) moderate (normal), 6 to 25 beats/min variability; (4) marked, > 25 beats/min variability; (5) sinusoidal pattern. (From National Institute of Child Health and Human Development Research Planning Workshop, 1997.)

Several physiological and pathological processes can affect or interfere with beat-to-beat variability. Dawes and co-workers (1981) described increased variability during fetal breathing. In healthy infants, short-term variability is attributable to respiratory sinus arrhythmia (Divon and co-workers, 1986). Fetal body movements also affect variability (Van Geijn and co-workers, 1980). Pillai and James (1990) reported increased baseline variability with advancing gestation. Up to 30 weeks, baseline characteristics were similar during both fetal rest and activity. After 30 weeks, fetal inactivity was associated with diminished baseline variability and conversely, variability was increased during fetal activity. Fetal gender does not affect heart rate variability (Ogueh and Steer, 1998).

It is important to recognize that the baseline fetal heart rate becomes more physiologically fixed (less variable) as the rate increases. Conversely, there is more instability or variability of the baseline at lower heart rates. This phenomenon presumably reflects less cardiovascular physiological wandering as beat-to-beat intervals shorten due to increasing heart rate.

Diminished beat-to-beat variability can be an ominous sign indicating a seriously compromised fetus. Paul and co-workers (1975) reported that loss of variability in combination with decelerations was associated with fetal acidemia. They analyzed variability in the 20 minutes preceding delivery in 194 pregnancies. Decreased variability was defined as 5 or fewer beats/min excursion of the baseline (see Fig. 18–10), whereas acceptable variability exceeded this range. Fetal scalp pH was measured 1119 times in these pregnancies, and mean values were found to be increasingly more acidemic when decreased variability was added to progressively intense heart rate decelerations. For example, mean fetal scalp pH of about 7.10 was found when severe decelerations were combined with 5 beats/min or less variability compared with a pH about 7.20 when greater variability was associated with similarly severe decelerations.

Severe maternal acidemia also can cause decreased fetal beat-to-beat variability, as shown in Figure 18–11 in a mother with diabetic ketoacidosis. The precise pathological mechanisms by which fetal hypoxemia results in diminished beat-to-beat variability are not totally understood.

Interestingly, mild degrees of fetal hypoxemia have been reported actually to increase variability, at least at the outset of the hypoxic episode (Murotsuki and co-authors, 1997). According to Dawes (1985), it seems probable that the loss of variability is a result of metabolic acidemia that causes depression of the fetal brainstem or the heart itself. Thus, diminished beat-to-beat variability, when a reflection of compromised fetal condition, likely reflects acidemia rather than hypoxia.

A common cause of diminished beat-to-beat variability is analgesic drugs given during labor (see Chap. 19, Parenteral Agents). A large variety of central nervous system depressant drugs can cause transient diminished beat-to-beat variability. Included are narcotics, barbiturates, phenothiazines, tranquilizers, and general anesthetics. Diminished variability occurs regularly within 5 to 10 minutes following intravenous meperidine administration, and the effects may last up to 60 minutes or longer depending on the dosage given (Petrie, 1993). Butorphanol given intravenously diminishes fetal heart rate reactivity (Schucker and colleagues, 1996). Hill and colleagues (2003), in a study performed at Parkland Hospital, found that 5 beats/min or less variability occurred in 30 percent of women given continuous intravenous meperidine compared with 7 percent in those given continuous labor epidural analgesia using 0.0625-percent bupivacaine and 2 g/mL of fentanyl.

Magnesium sulfate, widely used in the United States for tocolysis as well as management of hypertensive women, has been arguably associated with diminished beat-to-beat variability. Hallak and colleagues (1999) randomly assigned 34 normal, nonlaboring women to standard magnesium sulfate infusion versus isotonic saline. Magnesium sulfate was associated with statistically decreased variability only in the third hour of the infusion. However, the average decrease in variability was deemed clinically insignificant because the mean variability was 2.7 beats/min in the third hour of magnesium infusion compared with 2.8 beats/min at baseline. Magnesium sulfate also blunted the frequency of accelerations.

It is generally believed that reduced baseline heart rate variability is the single most reliable sign of fetal compromise. For example, Smith and co-workers (1988) performed a computerized analysis of beat-to-beat variability in growth-restricted fetuses before labor. They observed that diminished variability (4.2 beats/min or less) that was maintained for 1 hour was diagnostic of developing acidemia and imminent fetal death. By contrast, Samueloff and associates (1994) evaluated variability as a predictor of fetal outcome during labor in 2200 consecutive deliveries. They concluded that variability by itself cannot be used as the only indicator of fetal well-being. Conversely, they also concluded that good variability should not be interpreted as necessarily reassuring.

In summary, beat-to-beat variability is affected by a variety of pathological and physiological mechanisms. Variability has considerably different meaning depending on the clinical setting. The development of decreased variability in the absence of decelerations is unlikely to be due to fetal hypoxia (Davidson and co-workers, 1992). A persistently flat fetal heart rate baseline—absent variability—within the normal baseline rate range and without decelerations may reflect a previous insult to the fetus that has resulted in neurological damage (Freeman and colleagues, 2003).

Periodic Fetal Heart Rate Changes

The periodic fetal heart rate refers to deviations from baseline that are related to uterine contractions. Acceleration refers to an increase in fetal heart rate above baseline and deceleration to a decrease below baseline rate. The nomenclature most commonly used in the United States is based upon the timing of the deceleration in relation to contractions—thus, early, late, or variable in onset related to the corresponding uterine contraction. The waveform of these decelerations is also significant for pattern recognition. In early and late decelerations, the slope of fetal heart rate change is gradual, resulting in a curvilinear and uniform or symmetrical waveform. With variable decelerations, the slope of fetal heart rate change is abrupt and erratic, giving the waveform a jagged appearance. It has been proposed that decelerations be defined as recurrent if they occur with 50 percent or more of contractions in any 20-minute period (NICHD Research Planning Workshop, 1997).

Another system now used less often for description of decelerations is based on the pathophysiological events considered most likely to cause the pattern. In this system, early decelerations are termed head compression, late decelerations are termed uteroplacental insufficiency, and variable decelerations become cord compression patterns. The nomenclature of type I (early), type II (late), and type III (variable) “dips” proposed by Caldeyro-Barcia and co-workers (1973) is not used in the United States.

Accelerations

An acceleration is a visually apparent abrupt increase—defined as onset of acceleration to a peak in less than 30 seconds—in the fetal heart rate baseline (NICHD Research Planning Workshop, 1997). According to Freeman and co-authors (2003), accelerations most often occur antepartum, in early labor, and in association with variable decelerations. Proposed mechanisms for intrapartum accelerations include fetal movement, stimulation by uterine contractions, umbilical cord occlusion, and fetal stimulation during pelvic examination. Fetal scalp blood sampling and acoustic stimulation also incite fetal heart rate acceleration (Clark and co-workers, 1982). Finally, acceleration can occur during labor without any apparent stimulus. Indeed, accelerations are common in labor and nearly always associated with fetal movement. These accelerations are virtually always reassuring and almost always confirm that the fetus is not acidemic at that time.

Accelerations seem to have the same physiological explanations as beat-to-beat variability in that they represent intact neurohormonal cardiovascular control mechanisms linked to fetal behavioral states. Krebs and co-workers (1982) analyzed electronic heart rate tracings in nearly 2000 fetuses and found sporadic accelerations during labor in 99.8 percent. The presence of fetal heart accelerations during the first or last 30 minutes, or both, was a favorable sign for fetal well-being. The absence of such accelerations during labor, however, is not necessarily an unfavorable sign unless coincidental with other nonreassuring changes. There is about a 50-percent chance of acidemia in the fetus who fails to respond to stimulation in the presence of an otherwise nonreassuring pattern (Clark and colleagues, 1984; Smith and colleagues, 1986).

Early Deceleration

Early deceleration of the fetal heart rate consists of a gradual decrease and return to baseline associated with a contraction (Fig. 18–14). Such early deceleration was first described by Hon (1958). He observed that there was a drop in heart rate with uterine contractions and that this was related to cervical dilatation. He considered these findings to be physiological.

Figure 18–14.

Feature s of early fetal heart rate deceleration. Characteristics include gradual decrease in the heart rate with both onset and recovery coincident with the onset and recovery of the contraction. The nadir of the deceleration is 30 seconds or more after the onset of the deceleration.

Freeman and co-authors (2003) defined early decelerations as those generally seen in active labor between 4 and 7 cm dilatation. In their definition, the degree of deceleration is generally proportional to the contraction strength and rarely falls below 100 to 110 beats/min or 20 to 30 beats/min below baseline. Such decelerations are uncommon during active labor and are not associated with tachycardia, loss of variability, or other fetal heart rate changes. Importantly, early decelerations are not associated with fetal hypoxia, acidemia, or low Apgar scores.

Head compression probably causes vagal nerve activation as a result of dural stimulation and that mediates the heart rate deceleration (Paul and co-workers, 1964). Ball and Parer (1992) concluded that fetal head compression is a likely cause not only of the deceleration shown in Figure 18–14 but also of those shown in Figure 18–15, which typically occur during second-stage labor. Indeed, they observed that head compression is the likely cause of many variable decelerations classically attributed to cord compression.

Figure 18–15.

Two different fetal heart rate patterns during second-stage labor that are likely both due to head compression. Maternal bearing-down efforts correspond to the spikes with uterine contractions. Fetal heart rate deceleration C is consistent with the pattern of head compression shown in Figure 18–12. Deceleration B, however, is “variable” in appearance because of its jagged configuration and may also represent cord occlusion.

Late Deceleration

The fetal heart rate response to uterine contractions can be an index of either uterine perfusion or placental function. A late deceleration is a smooth, gradual, symmetrical decrease in fetal heart rate beginning at or after the peak of the contraction and returning to baseline only after the contraction has ended (American College of Obstetricians and Gynecologists, 1995b). In most cases, the onset, nadir, and recovery of the deceleration occur after the beginning, peak, and ending of the contraction, respectively (Fig. 18–16). The magnitude of late decelerations is rarely more than 30 to 40 beats/min below baseline and typically not more than 10 to 20 beats/min. Late decelerations usually are not accompanied by accelerations.

Figure 18–16.

Features of late feta l heart rate deceleration. Characteristics include gradual decrease in the heart rate with the nadir and recovery occurring after the end of the contraction. The nadir of the deceleration occurs 30 seconds or more after the onset of the deceleration.

Myers and associates (1973) studied monkeys in which they compromised uteroplacental perfusion by lowering maternal aortic blood pressure. The time interval, or lag period, from the onset of a contraction to the onset of a late deceleration was directly related to basal fetal oxygenation. They demonstrated that the length of the lag phase was predictive of the fetal PO₂ but not fetal pH. The lower the fetal PO₂ prior to contractions, the shorter the lag phase to onset of late decelerations. This lag period reflected the time necessary for the fetal PO₂ to fall below a critical level necessary to stimulate arterial chemoreceptors, which mediated decelerations.

Murata and co-workers (1982) also showed that a late deceleration was the first fetal heart rate consequence of uteroplacental-induced hypoxia. During the course of progressive hypoxia that led to death over 2 to 13 days, the monkey fetuses invariably exhibited late decelerations before the development of acidemia. Variability of the baseline heart rate disappeared as acidemia developed.

A large number of clinical circumstances can result in late decelerations. Generally, any process that causes maternal hypotension, excessive uterine activity, or placental dysfunction can induce late decelerations. The two most common causes are hypotension from epidural analgesia and uterine hyperactivity caused by oxytocin stimulation. Maternal diseases such as hypertension, diabetes, and collagen-vascular disorders can cause chronic placental dysfunction. A rare cause is severe chronic maternal anemia without hypovolemia. Placental abruption can cause acute late decelerations (Fig. 18–17).

Figure 18–17.

Late decelerations due to uteroplacental insufficiency resulting from placental abruption. Immediate cesarean delivery was performed. Umbilical artery pH was 7.05 and the PO₂ was 11 mm Hg.

Variable Decelerations

The most common deceleration patterns encountered during labor are variable decelerations attributed to umbilical cord occlusion. Melchior and Bernard (1985) identified variable decelerations in 40 percent of over 7000 monitor tracings when labor had progressed to 5 cm dilatation and in 83 percent by the end of the first stage. Variable deceleration of the fetal heart rate is defined as a visually apparent abrupt decrease in rate. The onset of deceleration commonly varies with successive contractions (Fig. 18–18). The duration is less than 2 minutes.

Figure 18–18.

Features of variable fetal heart rate decelerations. Characteristics include abrupt decrease in the heart rate with onset commonly varying with successive contractions. The decelerations measure  15 beats/min for 15 seconds or longer with an onset to nadir phase of less than 30 seconds. Total duration is less than 2 minutes.

Very early in the development of electronic monitoring, Hon (1959) tested the effects of umbilical cord compression on fetal heart rate (Fig. 18–19). Similar complete occlusion of the umbilical cord in experimental animals produces abrupt, jagged-appearing deceleration of the fetal heart rate (Fig. 18–20). Concomitantly, fetal aortic pressure increases. Itskovitz and co-workers (1983) observed that variable decelerations in fetal lambs occurred only after umbilical blood flow was reduced by at least 50 percent.

Figure 18–19.

Fetal heart rate effects of compression of a prolapsed umbilical cord in a 25-week footling breech. Panel A shows the effects of 25-second compression compared with those of 40 seconds in panel B. (Redrawn from Hon, 1959, with permission.)

Figure 18–20.

Total umbilical cord occlusion (arrow) in the sheep fetus is accompanied by increase in fetal aortic blood pressure. Blood pressure changes in the umbilical vessels are also shown. (From Kunzel, 1985, with permission.)

Two types of variable decelerations are shown in Figure 18–21. The deceleration denoted by A is very much like that seen with complete umbilical cord occlusion in experimental animals (see Fig. 18–20). Deceleration B, however, has a different configuration because of the “shoulders” of acceleration before and after the deceleration component. Lee and co-workers (1975) proposed that this variation of variable decelerations was caused by differing degrees of partial cord occlusion. In this physiological scheme, occlusion of only the vein reduces fetal blood return, thereby triggering a baroreceptor-mediated acceleration. Subsequent complete occlusion results in fetal systemic hypertension due to obstruction of umbilical artery flow. This stimulates a baroreceptor-mediated deceleration. Presumably, the aftercoming shoulder of acceleration represents the same events occurring in reverse (Fig. 18–22).

Figure 18–21

Varying (variable) fetal heart rate decelerations. Deceleration B exhibits “shoulders” of acceleration compared with deceleration A.

Figure 18–22.

Schematic representation of the fetal heart rate (FHR) effects of partial occlusion (PO) and complete occlusion (CO) of the umbilical cord. (FSBP = fetal systemic blood pressure; UA = umbilical artery; UC = uterine contraction; UV = umbilical vein.) (From Lee and co-authors, 1975, with permission.)

Ball and Parer (1992) concluded that variable decelerations are mediated vagally and that the vagal response may be due to chemoreceptor or baroreceptor activity, or both. Partial or complete cord occlusion produces an increase in afterload (baroreceptor) and a decrease in fetal arterial oxygen content (chemoreceptor). These both result in vagal activity leading to deceleration. In fetal monkeys the baroreceptor reflexes appear to be operative during the first 15 to 20 seconds of umbilical cord occlusion followed by decline in PO₂ at approximately 30 seconds, which then serves as a chemoreceptor stimulus (Mueller-Heubach and Battelli, 1982).

Thus, variable decelerations represent fetal heart rate reflexes that reflect either blood pressure changes due to interruption of umbilical flow or changes in oxygenation. It is likely that most fetuses have experienced brief but recurrent periods of hypoxia due to umbilical cord compression during gestation. The frequency and inevitability of cord occlusion undoubtedly has provided the fetus with these physiological mechanisms as a means of coping. The great dilemma for the obstetrician in managing variable fetal heart rate decelerations is determining when variable decelerations are pathological. The American College of Obstetricians and Gynecologists (1995b) has defined significant variable decelerations as those decreasing to less than 70 beats/min and lasting more than 60 seconds.

Other fetal heart rate patterns have been associated with umbilical cord compression. Saltatory baseline heart rate (Fig. 18–23) was first described by Hammacher and co-workers (1968) and linked to umbilical cord complications during labor. Saltatory derives from the Latin and French words meaning “to leap.” The pattern consists of rapidly recurring couplets of acceleration and deceleration causing relatively large oscillations of the baseline fetal heart rate. We also observed a relationship between cord occlusion and the saltatory pattern (Leveno and associates, 1984). In the absence of other fetal heart rate findings, these do not signal fetal compromise. Lambda is a pattern involving an acceleration followed by a variable deceleration with no acceleration at the end of the deceleration. This pattern typically is seen in early labor and is not ominous (Freeman and colleagues, 2003). This lambda pattern may result from mild cord compression or stretch. Overshoot is a variable deceleration followed by acceleration. The clinical significance of this pattern is controversial (Westgate and colleagues, 2001).

Figure 18–23.

Saltatory baseline fetal heart rate showing rapidly recurring couplets of acceleration combined with deceleration.

Prolonged Deceleration

Shown in Figure 18–24, this pattern is defined as an isolated deceleration lasting 2 minutes or longer but less than 10 minutes from onset to return to baseline (NICHD Research Planning Workshop, 1997). Prolonged decelerations are difficult to interpret because they are seen in many different clinical situations. Some of the more common causes include cervical examination, uterine hyperactivity, cord entanglement, and maternal supine hypotension.

Figure 18–24.

Prolonged fetal heart rate deceleration due to uterine hyperactivity. Approximately 3 minutes of the tracing are shown, but the fetal heart rate returned to normal after uterine hypertonus resolved. Vaginal delivery later ensued.

Epidural, spinal, or paracervical analgesia may induce prolonged deceleration of the fetal heart rate. For example, Eberle and colleagues (1998) reported that prolonged decelerations occurred in 4 percent of normal parturients given either epidural or intrathecal labor analgesia. Hill and colleagues (2003) observed prolonged deceleration in 1 percent of women given epidural analgesia during labor at Parkland Hospital. Other causes of prolonged deceleration include maternal hypoperfusion or hypoxia from any cause, placental abruption, umbilical cord knots or prolapse, maternal seizures including eclampsia and epilepsy, application of a fetal scalp electrode, impending birth, or even maternal Valsalva maneuver.

The placenta is very effective in resuscitating the fetus if the original insult does not recur immediately. Occasionally, such self-limited prolonged decelerations are followed by loss of beat-to-beat variability, baseline tachycardia, and even a period of late decelerations, all of which resolve as the fetus recovers. Freeman and co-authors (2003) emphasize rightfully that the fetus may die during prolonged decelerations. Thus, management of prolonged decelerations can be extremely tenuous. Management of isolated prolonged decelerations is based upon bedside clinical judgment, which inevitably will sometimes be imperfect given the unpredictability of these decelerations.

^aFollowing a uterine contraction.

^bIncludes tracing evaluation and charting when continuous electronic monitoring is used.

Adapted from the American College of Obstetricians and Gynecologists (1995b).

4. Doppler Velocimetry

The Doppler shift is a phenomenon that occurs when a source of light or sound waves is moving relative to an observer; the observer detects a shift in the wave frequency. Similarly, when sound waves strike a moving target, the frequency of the sound waves reflected back is shifted proportionate to the velocity and direction of the moving target. Because the magnitude and direction of the frequency shift depend on the relative motion of the moving target, the velocity and direction of the target can be determined.

Important to obstetrics, Doppler may be used to determine the volume and rate of blood flow through maternal and fetal vessels. In this situation, the sound source is the ultrasound transducer, the moving target is the column of red blood cells flowing through the circulation, and the reflected sound waves are observed by the ultrasound transducer. Two types—continuous and pulse wave Doppler—are used in medicine.

Continuous wave Doppler equipment has separate crystals: one that transmits a high-frequency sound wave, and another that continuously receives signals. It can record high frequencies using low power output and is easy to use. Unfortunately, it is nonselective, recognizing all signals along its path, and does not allow visualization of the blood vessel(s). In m-mode echocardiography, continuous wave Doppler is used to evaluate motion through time. It defines blood flow through the heart, but because the cardiac structures are not visualized, it requires the correlation of the sequence of waveforms produced with the sequence of structures interrogated by the sound wave.

Pulse wave Doppler has equipment that uses only one crystal, which transmits the signal and then waits until the returning signal is received before transmitting another one. It is more expensive and requires higher power, but allows precise targeting and visualization of the vessel of interest. Pulse wave Doppler also can be configured to allow color-flow mapping, in which computer software displays blood flowing away from the transducer as blue and blood flowing toward the transducer as red.

Various combinations of continuous wave Doppler, pulse wave Doppler, color-flow Doppler, and real-time ultrasound are commercially available and are loosely referred to as duplex Doppler.

Clinical Applications

The Doppler equation shown in Figure 16–17 contains the variables that affect the Doppler shift. An important source of error when calculating flow or velocity is the angle between sound waves from the transducer and flow within the vessel—termed the angle of insonation and abbreviated as theta (). Because cosine  is a component of the equation, measurement error becomes large when the angle of insonation is not close to zero. The practical solution to this problem has been the use of ratios to compare different waveform components—allowing cosine  to cancel out of the equation. Figure 16–18 is a schematic of the Doppler waveform and describes the three ratios commonly used. The simplest is the systolic–diastolic ratio (S/D ratio), which compares maximum (peak) systolic flow with end-diastolic flow, thereby evaluating downstream impedance to flow.

Doppler waveforms from normal pregnancy. Shown clockwise are normal waveforms from the maternal arcuate, uterine, and external iliac arteries, and from the fetal umbilical artery and descending aorta. Reversed end-diastolic flow velocity is apparent in the external iliac artery, whereas continuous diastolic flow characterizes the uterine and arcuate vessels. Finally, note the greatly diminished end-diastolic flow in the fetal descending aorta. (From Copel and colleagues, 1988.)

Umbilical Artery

This vessel normally has forward flow throughout the cardiac cycle, and the amount of flow during diastole increases as gestation advances. Thus the S/D ratio decreases, from about 4.0 at 20 weeks to 2.0 at term. The S/D ratio is generally less than 3.0 after 30 weeks (Fleischer and associates, 1986). Umbilical artery Doppler may be a useful adjunct in the management of pregnancies complicated by fetal growth restriction. As presented in Chapter 15 (see Umbilical Artery Doppler Velocimetry), umbilical artery velocimetry has been subjected to more rigorous assessment than has any previous test of fetal health (Alfirevic and Neilson, 1995). It is, however, not recommended for screening of low-risk pregnancies or for complications other than growth restriction.

Umbilical artery Doppler is considered abnormal if the S/D ratio is above the 95th percentile for gestational age. In extreme cases of growth restriction, end-diastolic flow may become absent or even reversed (Fig. 16–20). These are ominous findings and should prompt a complete fetal evaluation—almost half of cases are due to fetal aneuploidy or a major anomaly (Wenstrom and associates, 1991). In the absence of a reversible maternal complication or a fetal anomaly, reversed end-diastolic flow suggests severe fetal circulatory compromise and usually prompts immediate delivery. Sezik and colleagues (2004) recently reported that fetuses of preeclamptic women who had absent or reversed end-diastolic flow were more likely to have hypoglycemia and polycythemia.

Umbilical artery Doppler waveforms. A. Normal diastolic flow. B. Absence of end-diastolic flow. C. Reversed end-diastolic flow. (Courtesy of Dr. Diane Twickler.)

Ductus Arteriosus

Doppler evaluation of the ductus arteriosus has been used primarily to monitor fetuses exposed to indomethacin and other nonsteroidal anti-inflammatory agents. Indomethacin, which is used for tocolysis, causes constriction of the ductus in sheep and human fetuses (Huhta and colleagues (1987). The resulting increased pulmonary flow may cause reactive hypertrophy of the pulmonary arterioles, and eventually pulmonary hypertension develops (see Chap. 36, Prostaglandin Inhibitors). In a study of 61 indomethacin-treated pregnant women, Vermillion and colleagues (1997) reported that half of exposed fetuses developed ductal constriction. Fortunately, this complication is largely reversible if medication is discontinued before 32 weeks (Moise, 1993).

Middle Cerebral Artery

Peak systolic velocity in the middle cerebral artery is increased with fetal anemia because of increased cardiac output and decreased blood viscosity (Segata and Mari, 2004). Velocity measurements are generally problematic because a high insonating angle introduces considerable error. Middle cerebral artery measurements are an exception, however, because the path of the artery often presents a very low angle of insonation.

Mari and colleagues (1995) performed velocity studies in 135 normal fetuses and 39 with alloimmunization. They reported that all anemic fetuses had peak systolic velocity above the normal mean. This prompted a collaborative study of 376 pregnancies by Mari and colleagues (2000). Using a threshold of 1.50 multiples of the median (MoM), they correctly identified all fetuses with moderate or severe anemia with a false-positive rate of 12 percent. Other investigators have since reported similar results (Abdel-Fattah, 2002; Bahado-Singh, 2000; Cosmi, 2002; Deren and Onderoglu, 2002, and all their associates).

It also has been hypothesized that Doppler evaluation of blood flow through cerebral vessels might be used to detect altered cerebral circulation before there is hypoxemia significant enough to alter the fetal heart rate pattern. The cerebroplacental ratio has been introduced as an indicator of brain sparing in fetuses with growth restriction and as a predictor of adverse perinatal outcome (Bahado-Singh and colleagues, 1999; Gramellini and associates, 1992). Currently, the American College of Obstetricians and Gynecologists (1999) considers antepartum surveillance with cerebral artery Doppler velocimetry to be investigational.

Uterine Artery

Uterine blood flow increases from 50 mL/min early in gestation to 500 to 750 mL/min by term. The uterine artery Doppler waveform is unique and characterized by high diastolic flow velocities similar to those in systole, and by highly turbulent flow, which displays a spectrum of many different velocities (Fig. 16–21). Increased resistance to flow and development of a diastolic notch have been associated with pregnancy-induced hypertension (Arduini, 1987; Fleischer, 1986; Harrington, 1996; North, 1994, and all their colleagues). In a recent study, Zeeman and co-authors (2003) confirmed that increased impedance of uterine artery velocimetry at 16 to 20 weeks was predictive of superimposed preeclampsia developing in women with chronic hypertension. Whether it will be clinically helpful to predict preeclampsia in this manner is yet unclear.

5. Screening for Common Congenital Abnormalities

The vast majority of cases of NTDs, Down syndrome, and many other fetal abnormalities are found in families with no prior history of birth defects. Prenatal evaluation of only women at high risk for these complications would thus fail to identify most affected pregnancies. Couples with no family history of genetic abnormalities can now be offered prenatal screening tests for certain fetal disorders. Screening tests by design do not provide a diagnosis, but rather identify individuals with risk high enough to benefit from a definitive diagnostic test. According to Wald and associates (1997), genetic screening tests should meet criteria generally accepted for other types of screening tests:

1. The disorder is well defined and serious.
2. Treatment or prevention is available but not possible without the screening test.
3. The screening test is cost effective and reliable.
4. The subsequent diagnostic test is reliable.

That said, Caughey and collaborators (2004) interviewed 447 women of all ages with undetermined genetic risk. They reported that half were willing to undergo invasive prenatal diagnostic testing. One third of women aged 35 years or older expressed a willingness to pay partially or completely for such testing. Such requests present a conundrum for prenatal diagnostic centers and each should have a protocol to cover these exigencies.

Neural-Tube Defects (NTDs)

At least 95 percent of children with NTDs are born into families with no prior history. Prior to the late 1970s, identification of affected pregnancies was not possible. At that time, Brock and associates (1972, 1973) reported that both amnionic fluid and maternal serum alpha-fetoprotein (AFP) levels were much higher in pregnancies complicated by fetal anencephaly and other NTDs. The first large prospective trial of maternal serum screening was the UK Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube Defects (1977). The utility of maternal serum AFP screening for NTDs was subsequently confirmed by others and adopted in the United States and Europe (Burton and associates, 1983; Haddow and colleagues, 1983; Milunsky and co-workers, 1980).

Alpha-Fetoprotein (AFP)

This glycoprotein is synthesized early in gestation by the fetal yolk sac and later by the fetal gastrointestinal tract and liver (see Chap. 4). It normally circulates in fetal serum and passes into fetal urine and thus into amnionic fluid. Although its function is unknown, AFP is the major serum protein in the embryo-fetus, analogous to albumin. Its concentration increases steadily in both fetal serum and amnionic fluid until 13 weeks, after which these levels rapidly decrease (Burton, 1988). AFP passes into the maternal circulation by diffusion across the placental membranes and also may be transported via the placental circulation (Brumfield and colleagues, 1990). AFP is found in steadily increasing quantities in maternal serum after 12 weeks (Fig. 13–2). Open fetal body wall defects uncovered by integument permit additional AFP to leak into the amnionic fluid, and maternal serum AFP levels are increased.

Maternal Serum AFP Screening

Maternal screening is offered between 14 and 22 weeks. Maternal serum AFP is measured in nanograms per milliliter and reported as a multiple of the median (MoM) of the unaffected population. Converting the results to MoM normalizes the distribution of AFP levels and permits comparison of results from different laboratories and populations. Factors that influence the maternal serum AFP level include weight, race, and diabetic status, as well as the gestational age and number of fetuses. Using a maternal serum AFP level of 2.0 or 2.5 MoM as the upper limit of normal, most laboratories report a screen-positive rate of 3 to 5 percent, a sensitivity of at least 90 percent, and a positive-predictive value of 2 to 6 percent (Milunsky and associates, 1989).

Evaluation of an elevated maternal serum AFP begins with a basic ultrasonographic examination to determine fetal age and viability and the number of fetuses (Fig. 13–3). Underestimating gestational age accounts for a large proportion of abnormal test results. In such cases, the laboratory can usually generate a corrected report when given accurate pregnancy dating criteria. If the initial specimen was obtained prior to 14 weeks, a repeated specimen is necessary. The distributions of maternal serum AFP levels in affected and unaffected pregnancies overlap considerably (Fig. 13–4). If the level falls within the range of the overlap—the indiscriminate zone of 2.5 to 3.5 MoM—then repeating the measurement may determine whether the pregnancy is really at risk. Because repeated measurements tend to regress toward the mean of the population to which they belong, a truly elevated maternal serum AFP level will remain so in the repeated sample, whereas levels from an unaffected pregnancy have a tendency to normalize .

Maternal serum AFP levels greater than 3.5 MoM need not be repeated, because levels this high are outside the AFP distribution of unaffected pregnancies and clearly indicate increased fetal risk. In general, the likelihood that the fetus is affected increases in proportion to the AFP level. In a study of 773 women with elevated serum AFP levels, Reichler and colleagues (1994) reported that there was a progressive increase in the frequency of NTDs, ventral wall defects, and other anomalies as maternal serum AFP levels rose (Fig. 13–5). About 40 percent of pregnancies were abnormal when the AFP level was greater than 7 MoM.

Other causes of elevated levels that can be determined by ultrasonography include fetal death, multiple gestations, structural defects, and placental abnormalities

Table 13–7. Conditions Associated with Abnormal Maternal Serum Alpha-Fetoprotein Concentrations

Elevated Levels

Neural-tube defects

Pilonidal cysts

Esophageal or intestinal obstruction

Liver necrosis

Cystic hygroma

Sacrococcygeal teratoma

Abdominal wall defects—omphalocele, gastroschisis

Urinary obstruction

Renal anomalies—polycystic or absent kidneys

Congenital nephrosis

Osteogenesis imperfecta

Congenital skin defects

Cloacal exstrophy

Chorioangioma of placenta

Placental abruption

Placenta accreta

Oligohydramnios

Preeclampsia

  Multifetal gestation

Low birthweight

  Fetal death

Improper adjustment for low maternal weight

Underestimated gestational age

Maternal hepatoma or teratoma

Low Levels

Chromosomal trisomies

Gestational trophoblastic disease

Fetal death

Improper adjustment for high maternal weight

Overestimated gestational age

Recommendations for Screening

The American College of Obstetricians and Gynecologists (2003) recommends that all pregnant women be offered second-trimester maternal serum AFP screening. It should be performed within a protocol that includes quality control, counseling, follow-up, and high-resolution ultrasonography. Because only 1 in 16 to 1 in 33 women with an elevated serum AFP level actually has an affected fetus, women should be counseled regarding the high false-positive rates, the risks of amniocentesis, and the rationale for the screening program.

Ultrasonographic Examination

After confirming the gestational age and establishing fetal number and viability, the fetus is evaluated by targeted ultrasonography. Anencephaly, other major cranial defects, and most spine defects can be readily identified (Figs. 13–6 and 13–7). In 99 percent of cases, open spine lesions are associated with one or more of five specific cranial anomalies detected by ultrasonography (Watson and associates, 1991). As detailed in Chapter 16 (see Neural-Tube Defects), these include frontal notching, also called the lemon sign; small biparietal diameter; ventriculomegaly; obliteration of the cisterna magna; and elongated cerebellum, the banana sign (Fig. 13–8). These cranial anomalies are most clearly visible in the second trimester, and some, such as the lemon sign, may resolve later in pregnancy.

Cranial ultrasound in a fetus with Arnold–Chiari malformation showing frontal scalloping (lemon sign) on the left and effacement of the cisterna magna (banana sign) on the right. (Courtesy of Dr. Jodi Dashe.)

In the early days of AFP screening, an elevated maternal serum AFP level prompted amniocentesis to determine the amnionic fluid AFP level. If the AFP level was elevated, then an assay for acetylcholinesterase was done. These tests were considered diagnostic for fetal NTD. Today, however, nearly 100 percent of NTDs are identified by ultrasonography used alone (Nadel and colleagues, 1990; Sepulveda and associates, 1995). Citing this high detection rate, several authorities conclude that a woman with an elevated maternal serum AFP level and a normal ultrasonographic examination need not undergo amniocentesis for amnionic fluid AFP measurement. Instead, she could be counseled that the risk of an NTD is reduced by 95 percent when no spine defects or cranial findings are seen ultrasonographically (Hogge, 1989; Morrow, 1991; Van den Hof, 1990, and their colleagues).

By contrast, a number of other studies report considerably less than a 100-percent ultrasonographic detection rate for structural fetal anomalies, especially before 22 weeks. For example, only 17 percent of all fetal anomalies were identified in the Routine Antenatal Diagnostic Imaging with Ultrasound (RADIUS) trial (Chap. 16, Clinical Applications). VanDorsten and colleagues (1998) reported only a 48-percent ultrasonographic detection rate for all fetal anomalies diagnosed. Platt and co-workers (1992) reported that 6 of 161 cases of open spina bifida were not recognized in a screening program. Accordingly, many recommend that an amniocentesis for amnionic fluid AFP be offered to all women with elevated maternal serum AFP levels. Women considering amniocentesis should be informed that amnionic fluid AFP measurement will detect only open spine defects, and not the 3 to 5 percent of defects that are covered by skin (Crandall and Matsumoto, 1984).

Amniocentesis

Amnionic fluid AFP levels are measured if an NTD is suspected, if the maternal serum AFP is elevated and the ultrasonographic examination is nondiagnostic, or simply because the maternal serum AFP is elevated, as discussed previously. An elevated amnionic fluid AFP level prompts assay of the same sample for acetylcholinesterase. After ruling out blood contamination, the presence of this enzyme verifies that exposed neural tissue or another open fetal defect is present.

Because NTDs carry a small associated risk of aneuploidy, and aneuploidy would change the prognosis and likely pregnancy management, ultrasonographic identification of a fetal NTD should prompt fetal karyotyping. In a review of more than 17,000 prenatal diagnosis cases, Hume and associates (1996) observed a 2-percent rate of aneuploidy in the 106 fetuses with an isolated NTD. Harmon and colleagues (1995) found that 7 of 43 fetuses with isolated NTDs were aneuploid.

Some clinicians determine the fetal karyotype whenever both maternal serum and amnionic fluid AFP levels are elevated, even if the amnionic fluid acetylcholinesterase assay is negative and an open NTD has thus been ruled out. Gonzalez and associates (1996) reported that in women with elevated serum and amnionic fluid AFP levels and normal ultrasonographic examinations, the incidence of chromosomal abnormalities was elevated fivefold above background risk.

Incidental Fetal Karyotype

If a woman with a normal targeted ultrasonographic examination has undergone amniocentesis for amnionic fluid AFP just because her maternal serum AFP level was elevated, and the amnionic fluid AFP level is normal, fetal karyotyping is controversial. Thiagarajah and colleagues (1995) studied 658 such women and concluded that there was no justification for routine fetal karyotyping. In contrast, Feuchtbaum and associates (1995) reviewed 8097 pregnancies complicated by elevated maternal serum AFP levels. In the pregnancies in which the elevated maternal serum AFP level was “unexplained” because there was no fetal NTD or ventral wall defect and the amnionic fluid AFP level was normal, the rate of chromosomal anomalies was 1.1 percent, or twice as high as that of the general population.

Incidental Amnionic Fluid AFP Measurement

When amniocentesis is performed primarily for genetic analysis, amnionic fluid AFP is often routinely measured. This practice may not be cost-effective. Shields and colleagues (1996) reviewed almost 7000 women who underwent second-trimester amniocentesis for fetal karyotyping. They reported that measurement of amnionic fluid AFP did not increase the detection of anomalies. Similarly, Silver and associates (2001) performed a retrospective analysis of 2769 amnionic fluid specimens and reported that incidental amnionic fluid AFP measurement identified only one NTD not detected by ultrasonography. They estimated that routine amnionic fluid AFP measurement cost $219,000 per informative case.

Unexplained Elevated Abnormal Maternal Serum AFP Levels

Even if there are no obvious fetal abnormalities, several large studies have shown that unexplained high maternal serum AFP levels often forecast a poor pregnancy outcome. These outcomes include low birthweight, oligohydramnios, placental abruption, and fetal death (Katz, 1990; Simpson, 1991; Waller, 1991, each with their associates). According to Wenstrom and co-workers (1992), the first maternal serum AFP level is the most predictive, and serial measurements are not helpful. Simpson and colleagues (1991) reported that second-trimester, but not third-trimester, maternal serum AFP elevation levels were associated with preterm ruptured membranes, preterm birth, and low-birthweight infants. Ramus and associates (1996) studied 241 women with unexplained serum AFP elevations and reported that they had a higher incidence of preterm delivery than women who had normal levels—22 versus 11 percent. The incidence of preterm delivery was highest (47 percent) in the 38 women who had both unexplained elevated serum levels and placental sonolucencies on ultrasonographic examination.

Although elevated maternal serum AFP levels in these cases are assumed to result from placental damage or dysfunction, neither the etiology of the elevated maternal serum values nor the most appropriate management for these women is clear. In these cases, no specific program of maternal or fetal surveillance favorably affects pregnancy outcomes (American College of Obstetricians and Gynecologists, 1996; Cunningham and Gilstrap, 1991).

Management of the Fetus with an NTD

Other than termination of pregnancy, options for pregnancies complicated by an NTD have traditionally been limited. Anencephaly, exencephaly, and iniencephaly are lethal, but some women elect to continue these pregnancies. Routine prenatal care is given, but interventions for fetal indications are not recommended as they will not change fetal outcome.

Counseling and decision making in the case of an isolated fetal spine defect are more difficult. Such women may benefit from counseling by a pediatric neurosurgeon, neurologist, or other specialists in pediatric development. The fully informed couple is more likely to make their best decision and to be prepared for the range of possible pregnancy outcomes. With continued pregnancy, antenatal care is designed to detect changes in fetal status that might alter the timing or route of delivery. Generally, the goal is delivery at term, but rapidly increasing ventriculomegaly may prompt delivery before term so that a shunt can be placed. Fetal heart rate testing is problematic because heart rate patterns in anomalous fetuses can be difficult to interpret (Vindla and associates, 1997).

The optimal timing and method of delivery remain controversial. All studies of delivery methods for fetuses with NTDs are retrospective and suffer from various biases. That said, an equal number of reports support cesarean versus vaginal delivery (Bensen and co-workers, 1988; Luthy and colleagues, 1991; Sakala and Andree, 1990). Theoretically, cesarean delivery might reduce the risk of mechanical trauma and infection of the fetal spine and also allow precise timing of delivery so that appropriate consultants can be available. Optimally, the delivery time and method should be determined on a case-by-case basis by the team that ultimately will care for the woman and her neonate. Team members should include maternal–fetal medicine specialists, neonatologists, neurosurgeons, and others. Fetal surgical repair of meningomyelocele is discussed later (see Neural-Tube Defects).

Down Syndrome

Before the mid-1980s, amniocentesis for fetal karyotyping was generally offered only to women aged 35 years and older. After Merkatz and colleagues (1984) reported that pregnancies with fetal Down syndrome were characterized by low maternal serum AFP levels, prenatal NTD screening was expanded to include Down syndrome screening in women aged younger than 35 years. Cuckle (1984) and Haddow (1983) and their associates confirmed this finding, and most NTD screening programs now include Down syndrome screening.

Screening program results show that detection rates are highest when maternal age-related risk is incorporated because it is the most powerful predictor of aneuploidy. Ultimately, the Down syndrome risk for each woman is estimated by multiplying her maternal age-related risk by a likelihood ratio determined by her serum AFP level (New England Regional Genetics Group, 1989). Women with a calculated Down syndrome risk greater than a predetermined threshold are offered amniocentesis for fetal karyotyping. This screening threshold is typically equal to the midtrimester or term Down syndrome risk of a 35-year-old woman.

Multiple-Marker Screening

Fetal aneuploidy alters serum analytes other than AFP. If a fetus has Down syndrome, second-trimester serum levels of chorionic gonadotropin (hCG) are usually higher and those of unconjugated estriol are lower than expected (Bogart and colleagues, 1987; Wald and associates, 1988a, 1988b). The individual predictive values of hCG, estriol, and AFP for detecting Down syndrome are low, but when combined they can frequently distinguish euploid fetuses from those with Down syndrome.

The most common second-trimester screening protocol in current use, variously called the expanded AFP test, AFP plus, triple screen, or multiple-marker screening test, is based on a composite likelihood ratio determined by levels of all three analytes. The maternal age-related risk is then multiplied by this ratio. The screening threshold chosen may be the midtrimester risk of a 35-year-old woman. More frequently, a threshold is chosen because it results in the optimal combination of a high detection rate with a low screen-positive rate. The risk threshold of about 1:200 is selected most often because, at a 5-percent screen-positive rate, the Down syndrome detection rate is 60 percent in women younger than 35 years. In women older than 35 years, the multiple-marker test detects more than 75 percent of fetuses with Down syndrome and a portion of other aneuploidies as well, although at a detection rate close to 25 percent (Haddow and co-workers, 1994). The multiple-marker test has been validated and has become the preferred second-trimester Down syndrome screening test in most centers (Burton, 1993; Cheng, 1993; Wenstrom, 1993, and their colleagues).

There are several permutations of the multiple-marker test in current use. Some centers offer AFP and hCG testing alone, and others use estriol measurement as a third marker. Some prefer to measure the free -subunit of hCG (-hCG) instead of the intact hCG molecule, and others add inhibin as a fourth analyte (Wald and colleagues, 1996; Wenstrom and associates, 1999b). Other multiple-marker screening tests have been used that combine maternal serum analytes, ultrasonographic measurement of the nuchal fold, long bone measurements, and other parameters (Bahado-Singh and colleagues, 2001; Morris and co-workers, 2001). Several investigative protocols are subsequently discussed.

In most series, only 6 percent of all screen-positive samples are associated with an affected fetus. Thus, a positive screening test indicates increased risk but not necessarily fetal Down syndrome. Conversely, a negative screening test indicates no increased risk, but does not mean that the fetus is normal. Once gestational age is confirmed by ultrasonography, women with a positive screening test should be offered amniocentesis for karyotyping (American College of Obstetricians and Gynecologists, 1996).

Serum Screening in Women Older Than 35 Years

The basis of any multiple-marker algorithm is the maternal age-related risk. Thus, the multiple-marker screening test identifies a higher proportion of fetal Down syndrome cases—at least 80 percent—in women aged 35 years and older than in younger women (Haddow and co-workers, 1994). Although the detection rate increases along with maternal age, so does the screen-positive rate. For example, about 25 percent of women aged 35 years and older will have a test result indicating increased risk. Although some older women will opt for empirical amniocentesis regardless of screening results, others find that serum screening facilitates the decision to undergo invasive testing.

First-Trimester Down Syndrome Screening

Early identification of fetal aneuploidy is desirable for many reasons, including the availability of more options for pregnancy termination. First-trimester screening protocols in current use include maternal serum analyte screening, ultrasonographic evaluation, or a combination of both. Urinary screening has been studied, but the results were disappointing. The most discriminatory first-trimester maternal serum analytes appear to be free -hCG and pregnancy-associated plasma protein A (PAPP-A) (Haddow and associates, 1998; Wald and colleagues, 1998). Measurement of the nuchal translucency (NT), an echolucent area seen in longitudinal views of the back of the neck, is also highly discriminatory (Snijders and colleagues, 1998). If the NT measurement is expressed as an MoM, it can be combined with serum analytes to calculate a composite risk.

Two large trials of combined first-trimester ultrasonographic and serum screening have documented its efficacy. First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Study, referred to as the “BUN study,” reported by Wapner and co-workers (2003) was a multicenter trial that enrolled 8514 women who underwent screening between 74 and 97 days of gestation. Individual risks of fetal Down syndrome and trisomy 18 were calculated based on age, first-trimester levels of free -hCG and PAPP-A, and NT measurement. Women determined to be screen positive were offered fetal karyotyping. Using a Down syndrome risk cutoff of 1:270, 85 percent of Down syndrome cases were identified at a false-positive rate of 9.4 percent. When the false-positive rate was held at 5 percent, the detection rate was 79 percent. Importantly, 91 percent of trisomy 18 cases were identified at a false-positive rate of 2 percent. Because of the high incidence of spontaneous pregnancy loss in aneuploid pregnancies, performing fetal karyotyping after first-trimester screening likely resulted in the identification of some aneuploid pregnancies that would otherwise have been lost spontaneously. This outcome can be viewed either positively or negatively.

The FASTER (First- and Second-Trimester Evaluation of Risk) trial was reported by Malone and colleagues (2003a, 2003b). This multicenter trial included 33,557 women, and it took a slightly different approach. All women participating in the trial underwent both first-trimester screening—which included free -hCG, PAPP-A, NT measurement, and maternal age—and second-trimester screening with hCG, AFP, estriol, and inhibin, along with maternal age. If either test was positive, fetal karyotyping was offered. The investigators then evaluated the screen-positive and detection rates for first-, second-, and combined first- and second-trimester screening. They found that the best results were obtained when women had combined both first- and second-trimester screening—the Fully Integrated Test—and then underwent definitive testing if its result was positive. The integrated test yielded a Down syndrome detection rate of 90 percent at a screen-positive rate of 5.4 percent. Importantly, the investigators determined that NT measurement was difficult to do accurately and reproducibly (D’Alton and associates, 2003). Further, not only did NT measurement medians vary from center to center and operator to operator, but NT medians obtained by a single operator varied over time. The authors therefore concluded that NT measurement should be performed only by operators with specific training and that measurement medians for individual operators should be monitored carefully and adjusted as necessary.

In addition to drifting NT medians, problems with first-trimester screening include a relatively narrow gestational age window for screening—approximately 10 to 13 weeks—and variability in NT measurement resulting from poor visibility, suboptimal fetal position, or inconsistent measurement technique. Accurate assessment of gestational age is essential. The American College Obstetricians (2004) emphasizes that appropriate training, monitoring systems, and counseling must be provided.

Elective Genetic Amniocentesis in Women Younger Than 35 Years

Some women younger than 35 years may request amniocentesis for fetal karyotyping despite reassuring maternal serum screening and ultrasonographic findings. Caughey and colleagues (2004) interviewed 447 women of all ages with undetermined genetic risk and reported that half were willing to undergo invasive prenatal diagnostic testing. One third of women aged 35 years or older expressed a willingness to pay partially or completely for such testing. These investigators concluded that guidelines should be expanded to offer testing for a genetic diagnosis, not only for screening. Others believe that each case must be evaluated individually, and each center must develop its own protocol to handle such requests (Pauker and Pauker, 1994).