Placental dysfunction, fetal growth retardation. Pathology of infants’ period. Methods of intensive therapy and infant’s reanimation .
Abnormalities of Placentation
Multiple Placentas with a Single Fetus
Prepared by N.Bahnij
Occasionally, the placenta may be separated into lobes. When the division is incomplete and the vessels of fetal origin extend from one lobe to the other before uniting to form the umbilical cord, the condition is termed placenta bipartita or bilobed placenta (Fig. ).
Its reported incidence varies widely, and Fox (1978) cited it at about 1 of 350 deliveries. If the two lobes are separated entirely and the vessels remain distinct, the condition is designated placenta duplex. Occasionally, there is placenta triplex, with three distinct lobes.
An important anomaly is placenta succenturiata, in which one or more small accessory lobes are developed in the membranes at a distance from the periphery of the main placenta, to which they usually have vascular connections of fetal origin . Its incidence is about 3 percent. The accessory lobe may sometimes be retained in the uterus after expulsion of the main placenta, and may subsequently give rise to serious hemorrhage. If, on placental examination, defects are seen in the membranes a short distance from the placental margin, retention of a succenturiate lobe should be suspected. The suspicion is confirmed if vessels extend from the placenta to the margins of the tear.
Ring-shaped Placenta. Ring-shaped placenta is a rare anomaly seen in fewer than 1 in 6000 deliveries. The placenta is annular in shape and sometimes a complete ring of placental tissue is present, but because of atrophy of a portion of the tissue of the ring, a horseshoe shape is more common. These abnormalities appear to be associated with a greater likelihood of antepartum and postpartum bleeding and fetal growth restriction. This anomaly may be a variant of membranaceous placenta (Fox, 1978).
In rare circumstances, all of the fetal membranes are covered by functioning villi, and the placenta develops as a thin membranous structure occupying the entire periphery of the chorion. Placenta membranacea (Fig. )
is also referred to as placenta diffusa. This abnormality may occasionally give rise to serious hemorrhage. Diagnosis can often be made using sonography. After delivery, the placenta may not separate readily. Bleeding resembles that seen in central placenta previa, and it may be necessary to perform a hysterectomy to control bleeding from the large area of implantation.
Fenestrated placenta is a rare anomaly in which the central portion of a discoidal placenta is missing. In some instances, there is an actual hole in the placenta, but more often the defect involves villous tissue only, and the chorionic plate is intact. The clinical significance of this anomaly is that it may be mistakenly considered to represent a missing portion that has been retained in the uterus.
Although the normal-term placenta weighs on average about 500 g, in certain diseases, such as syphilis, the placenta may weigh up to one half as much as the fetus. The largest placentas are usually encountered in cases of erythroblastosis fetalis.
The most common placental lesions, though of diverse origin, are referred to collectively as placental infarcts. The principal histopathological features include fibrinoid degeneration of the trophoblast, calcification, and ischemic infarction from occlusion of spiral arteries. Overclassification of these infarcts has led to unnecessary confusion. Small subchorionic and marginal foci of degeneration are present in almost every term placenta. In simplest terms, degenerative lesions of the placenta have two etiological factors in common: (1) changes associated with aging of the trophoblast and (2) impairment of the uteroplacental circulation causing infarction.
Although the placenta is by no means a dying organ at term, there are morphological indications of aging. During the latter half of pregnancy, syncytial degeneration begins and syncytial knots are formed. The villous stroma usually undergoes hyalinization. The syncytium may then break away, exposing the connective tissue directly to maternal blood. Clotting occurs as a result, and propagation of the clot may result in the incorporation of other villi. Macroscopically, such a focus closely resembles an ordinary blood clot, but if not seen until it has become thoroughly organized, on section a firm, white island of tissue is seen.
Around the edge of nearly every term placenta there is a dense yellowish-white fibrous ring representing a zone of degeneration and necrosis, which usually is termed a marginal infarct. Underneath the chorionic plate, there are nearly always similar lesions, most often pyramidal shaped, ranging from 2 mm to 3 cm across the base, and extending downward with their apices in the intervillous space (subchorionic infarcts). Similar lesions may be noted about the intercotyledonary septa. Occasionally, these lesions meet and form a column of cartilage-like material extending from the maternal surface to the fetal surface. Less frequently, round or oval islands of similar tissue occupy the central portions of the placenta (Fig. ).
Fox (1978) found that about one fourth of placentas from uncomplicated term pregnancies have infarcts, while those pregnancies complicated by severe hypertensive disease are infarcted in about two thirds of cases.
Small calcareous nodules or plaques are frequently observed on the maternal surface of the placenta. An extensive deposition of calcium is shown in Figure 30–5. Placental calcification may be visualized using sonography, and Spirit and colleagues (1982) reported that by 33 weeks more than half of placentas have some degree of calcification, which increases substantively at term. Placental calcification graded ultrasonically has been correlated with fetal lung maturity (Grannum and co-workers, 1979); however, this correlation is not of sufficient strength to justify elective delivery.
Villous (Fetal) Artery Thrombosis
Thrombosis of a fetal villous stem artery produces a sharply demarcated area of avascularity. Fox (1978) found single-artery thrombosis in 4.5 percent of placentas from normal pregnancies and in 10 percent of those involving diabetic women. Benirschke and Driscoll (1974) observed an association between fetal artery thrombosis and antiplatelet antibodies in maternal serum. Fox (1978) estimated that thrombosis of a single fetal stem artery will deprive only 5 percent of the villi of their blood supply. However, he also observed a few placentas from recent stillbirths in which 40 to 50 percent of the villi were so deprived.
In general, placental infarcts caused either by local deposition of fibrin or by the more acute process of intervillous thrombosis, have little clinical significance. Nonetheless, in certain maternal diseases, notably severe hypertension, the reduction in functioning placenta through infarction, coupled with reduced blood flow to the uterus, may be sufficient to cause fetal death.
Villous (fetal) vessels may show endarteritic thickening and obliteration in association with fetal death. When the placental villi are excluded from their supply of maternal blood by fibrin deposits, hematomas, or direct blockage of the decidual circulation, they become infarcted and die. Histologically, the compromised villi are characterized by fibrosis, obliteration of fetal vessels, and gradual disappearance of the syncytium. Shen-Schwarz and associates (1988) described hemorrhagic endovasculitis in less than 1 percent of placentas.
Microscopic Placental Abnormalities. Beginning after 32 weeks, clumps of syncytial nuclei are found to project into the intervillous space, and these are called syncytial knots. By term, up to 30 percent of villi may be involved, however, formation of knots by more than one third of villi is considered abnormal (Fox, 1978). In prolonged pregnancies there are marked increases in syncytial knots and avascular villi as the consequence of fetal artery thrombosis. Generally, increased numbers of syncytial knots are found in placentas in which there may have been reduced uteroplacental blood flow, as with preeclampsia.
It is well recognized that the number of cytotrophoblastic cells becomes progressively reduced as pregnancy advances. In a normal mature placenta, cytotrophoblastic cells are found in about 20 percent of the villi (Fox, 1978). Most often, at this stage of pregnancy such cells are few and inconspicuous. However, numerous cytotrophoblastic cells are found in placentas of pregnant women with diabetes mellitus, erythroblastosis fetalis, and pregnancy-induced hypertension.
Abnormalities of the Umbilical Cord (Funis)
Umbilical cord length varies appreciably, with the mean length being about 55 cm (Rayburn and associates, 1981). Extremes in cord length in abnormal instances range from apparently no cord (achordia) to lengths up to 300 cm. Vascular occlusion by thrombi and true knots are more common in excessively long cords, and they are more likely to prolapse through the cervix. Rarely, excessively short umbilical cords may be instrumental in abruptio placenta and uterine inversion.
Determinants of cord length are intriguing. Studies performed on animals and experiments of nature in human pregnancy support the concept that cord length is positively influenced by the volume of amnionic fluid and by fetal mobility. Miller and associates (1981) identified the human umbilical cord to be shortened appreciably when there had been either chronic fetal constraint from oligohydramnios or decreased fetal movement because of limb dysfunction. Excessive cord length may be the consequence of entanglement of cord and fetus with stretching during fetal movement. Soernes and Bakke (1986) reported that the mean cord length in fetuses with breech presentations was about 5 cm shorter than those with vertex presentations.
In most cases, the umbilical vessels course through the umbilical cord in a spiraled manner. Several authors have observed a significant increase in various indices of adverse perinatal outcome in fetuses with hypocoiled cords, including meconium staining, preterm birth, and operative delivery for fetal distress (Strong and colleagues 1993, 1994). Shen-Schwarz and associates (1996) reported an association between “absent” cord twist and marginal and velamentous cord insertion. Rana and associates (1995) also demonstrated a higher incidence of preterm delivery and cocaine abuse in women with hypercoiled cords.
Marginal Insertion. Cord insertion at the placental margin is sometimes referred to as a battledore placenta. With the exception of the cord being pulled off during delivery of the placenta, it is of little clinical significance.
This is associated with velamentous insertion when some of the fetal vessels in the membranes cross the region of the internal os and occupy a position ahead of the presenting part. At times, the careful examiner will be able to palpate a tubular fetal vessel in the membranes overlying the presenting part. Compression of the vessels between the examining finger and the presenting part is likely to induce changes in the fetal heart rate. At times, the vessels may be visualized directly, or they may be seen on ultrasonic examination Fig..
With vasa previa, there is considerable potential danger to the fetus, for rupture of the membranes may be accompanied by rupture of a fetal vessel, causing exsanguination.
Whenever there is hemorrhage antepartum or intrapartum, the possibility of vasa previa and a ruptured fetal vessel exists. Unfortunately, the amount of fetal blood that can be shed without killing the fetus is relatively small. A quick, readily available approach to detecting fetal blood is to smear the blood on glass slides, stain the smears with Wright stain, and examine for nucleated red cells, which normally are present in cord blood but not maternal blood.
Knots of the Cord
False knots, which result from kinking of the vessels to accommodate to the length of the cord, should be distinguished from true knots, which result from active fetal movements. In nearly 17,000 deliveries in the Collaborative Study on Cerebral Palsy, Spellacy and co-workers (1966) found an incidence of true knots of 1.1 percent. Perinatal loss was 6 percent in the presence of true knots. The incidence of true knots is especially high in monoamnionic twins.
Definition of Fetal Distress
The words fetal distress are too broad and vague to be applied with any precision to clinical situations. For example, some element of fetal distress (danger) is almost universal at some time during normal human parturition. Uncertainty about the diagnosis of fetal distress based upon interpretation of fetal heart rate patterns has given rise to use of descriptions such as reassuring or nonreassuring. “Reassuring” suggests a restoration of confidence by a particular pattern, whereas “nonreassuring” suggests inability to remove doubt. These patterns during labor are dynamic, such that they can rapidly change from reassuring to nonreassuring and vice versa. In this situation, obstetricians essentially experience surges of both confidence and doubt. Put another way, most diagnoses of fetal distress using heart rate patterns occur when obstetricians lose confidence or cannot assuage doubts about fetal condition. These fetal assessments are entirely subjective clinical judgments inevitably subject to imperfection and must be recognized as such.
Why is diagnosis of fetal distress based on heart rate patterns so tenuous? One explanation is that these patterns are more a reflection of fetal physiology than pathology. Physiological control of heart rate includes a variety of interconnected mechanisms that depend on blood flow as well as oxygenation. Moreover, the activity of these control mechanisms is influenced by the preexisting state of fetal oxygenation, as seen, for example, with chronic placental insufficiency. Importantly, the fetus is tethered by an umbilical cord, where blood flow is constantly in jeopardy, which demands that the fetus have a strategy for survival. Moreover, normal labor is a process of increasing acidemia (Dildy and associates, 1994). Thus, normal parturition is a process of repeated fetal hypoxic events resulting in acidemia. Put another way, and assuming that “asphyxia” can be defined as hypoxia leading to acidemia, then normal parturition is an asphyxiating event for the fetus.
Diagnosis of Fetal Distress
Diagnosis of fetal distress based upon fetal heart rate patterns is too often oversimplified. Fetal heart rate decelerations provide clues about in utero events; but do not define fetal damage. A critical dimension—duration of the in utero event—is essentially ignored in deliberations on fetal distress. There have been several research efforts aimed at quantifying the duration of abnormal heart rate patterns necessary to portend significant fetal effects. The most common, due to umbilical cord occlusion, requires considerable time to significantly affect the fetus in experimental animals. Watanabe and associates (1992) showed that sequential complete occlusion of the umbilical cord for 40 seconds followed by 80 seconds of release for 30 minutes in sheep resulted in only moderate fetal acidemia. Similarly, Clapp and colleagues (1988) partially occluded the umbilical cord for 1 minute every 3 minutes in fetal sheep and observed brain damage after 2 hours.
Myers and co-workers (1972) observed that more than 20 late decelerations were necessary in humans for a depressed Apgar score. Low and co-workers (1977), using profound fetal metabolic acidemia as an endpoint, reported that heart rate patterns could only be correlated with outcome during the last 2 hours of labor, and moreover, only in those 2-hour segments showing decelerations with more than 35 percent of uterine contractions. Fleischer and co-workers (1982) observed that abnormal heart rate patterns had to persist for 120 to 140 minutes before fetal acidemia increased significantly.
Significant fetal impact cannot be attributed to severely abnormal fetal heart rate deceleration patterns when these patterns are intermittent and of short duration. The prognostic significance of fetal heart rate changes is further increased by combining several patterns. For example, Gaziano (1979) observed that variable decelerations in conjunction with abnormal baseline rate (either tachycardia or bradycardia) and loss of variability more often predicted poor fetal condition compared with variable decelerations without baseline changes. Nelson and associates (1996) found that although multiple late decelerations and/or decreased beat-to-beat variability were associated with a 4- to 6-fold increased risk for cerebral palsy, these cases accounted for only 0.2 percent of all fetuses with such tracings during labor.
Inevitably, the timing and route of delivery are scrutinized in deliberations about fetal distress. It is generally assumed that cesarean delivery would have improved the infant outcome. Keegan and associates (1985) emphasized that prompt intervention—within 30 minutes of diagnosis of fetal distress—did not prevent newborn seizures. Moreover, Krebs and colleagues (1982b) observed that fetuses with abnormal heart rate patterns in the last portion of labor were in worse metabolic condition when delivered by cesarean delivery compared with those delivered vaginally. The most frequent cause of worrisome patterns is umbilical cord compression. Management of variable fetal heart decelerations, in the absence of baseline changes, is difficult because of the unpredictability of cord occlusion.
Interestingly, cesarean delivery itself, as well as the choice of anesthetic, can affect the fetal heart rate. Prolonged decelerations have been reported during abdominal wall scrubbing in 10 percent of cesarean deliveries (Petrikovsky and co-workers, 1988). Another 10 percent of fetuses exhibited decelerations as a result of the uterine incision provoking excessive contractility.
Meconium in the Amnionic Fluid
Obstetrical teaching throughout this century has included the concept that meconium passage is a potential warning of fetal asphyxia. J. Whitridge Williams, writing in 1903, observed that “a characteristic sign of impending asphyxia is the escape of meconium.” He attributed meconium passage to “relaxation of the sphincter ani muscle induced by faulty aeration of the (fetal) blood.” Obstetricians, however, have also long realized that the detection of meconium during labor is problematic in the prediction of fetal distress or asphyxia. In their review, Katz and Bowes (1992) emphasized the prognostic uncertainty of meconium by referring to the topic as a “murky subject.” Indeed, although 12 to 22 percent of human labors are complicated by meconium, few such labors are linked to infant mortality. In a recent investigation from Parkland Hospital, meconium was found to be a “low-risk” obstetrical hazard because the perinatal mortality attributable to meconium was 1 death per 1000 live births (Nathan and co-workers, 1994).
Three theories have been suggested to explain fetal passage of meconium and may, in part, explain the tenuous connection between the detection of meconium and infant mortality. The pathological explanation proposes that fetuses pass meconium in response to hypoxia, and that meconium therefore signals fetal compromise (Walker, 1953). Alternatively, in utero passage of meconium may represent normal gastrointestinal tract maturation under neural control (Mathews and Warshaw, 1979). Third, meconium passage could also follow vagal stimulation from common but transient umbilical cord entrapment and resultant increased peristalsis (Hon and colleagues, 1961). Thus, fetal release of meconium could also represent physiological processes. Naeye (1995) has postulated that meconium, and perhaps bile acids, can cause constriction of umbilical and placental surface veins.
In a study by
Ramin and co-authors (1996) that included almost 8000 pregnancies delivered at Parkland Hospital with meconium in the amnionic fluid, meconium aspiration syndrome was
significantly associated with fetal acidemia at birth .
Other significant correlates of aspiration included indices of fetal jeopardy such as cesarean delivery, forceps to expedite delivery, and intrapartum heart rate abnormalities. Similarly, indices of condition at birth, to include depressed Apgar scores and need for assisted ventilation in the delivery room, also implicated fetal compromise during labor and/or delivery. Analysis of the type of fetal acidemia based on umbilical blood gases suggested that the fetal compromise associated with meconium aspiration syndrome was an acute event, because most acidemic fetuses had abnormally increased PCO2 rather than the pure metabolic acidemia.
Interestingly, hypercarbia in fetal lambs has been shown to induce fetal gasping and resultant increased amnionic fluid inhalation (Boddy and colleagues, 1974; Dawes and co-workers, 1972). Jovanovic and Nguyen (1989) later observed that meconium gasped into the fetal lungs caused aspiration syndrome only in asphyxiated animals. Ramin and co-authors (1996) hypothesized that the pathophysiology of meconium aspiration syndrome includes, but is not limited to, fetal hypercarbia, which stimulates fetal respiration leading to aspiration of meconium into the alveoli, and lung parenchymal damage secondary to acidemia-induced alveolar cell damage in the presence of meconium. The results of this study could thus be interpreted to implicate meconium as a fetal hazard when acidemia supervenes rather than a result of fetal compromise. In this pathophysiological scenario, meconium in amnionic fluid is a fetal environmental hazard rather than a marker of preexistent compromise.
This proposed pathophysiological sequence is not exclusive, because it does not account for approximately half of cases of meconium aspiration syndrome in which the fetus was not acidemic at birth. It was concluded that the high incidence of meconium observed in the amnionic fluid of women during labor often represents fetal passage of gastrointestinal contents in conjunction with normal physiological processes. Such meconium, however, can become an environmental hazard when fetal acidemia supervenes. Importantly, fetal acidemia occurs acutely, and therefore meconium aspiration is unpredictable and likely unpreventable.
Management of significantly variant fetal heart rate patterns consists of correcting the potential fetal insult, if possible (American College of Obstetricians and Gynecologists, 1995b). Measures may include discontinuing oxytocin, moving the mother to a lateral position, increasing fluid infusions to improve intervillous perfusion, giving oxygen by mask at 8 to 10 L/min, and correcting hypotension associated with regional analgesia. Vaginal examination to rule out prolapsed cord or impending delivery may be helpful. As previously described, amnioinfusion has been used in selected instances of fetal distress due to umbilical cord occlusion fetal heart rate patterns. If these measures are not effective, preparations should be made for prompt delivery by the most expeditious route. Most evidence indicates that even such ideal management of abnormal fetal heart patterns will not always prevent fetal death or brain damage.
Benefits of Electronic Fetal Heart Rate Monitoring
By the end of the 1970s, questions about the efficacy, safety, and costs of electronic monitoring were being voiced from the Office of Technology Assessment, Congress of the United States, and Centers for Disease Control. Banta and Thacker (1979) analyzed 158 reports and concluded that “the technical advances required in the demonstration that reliable recording could be done seems to have blinded most observers to the fact that this additional information will not necessarily produce better outcomes.” They attributed the apparent lack of benefit to the imprecision of electronic monitoring to diagnose fetal distress. Moreover, increased usage was linked to more frequent cesarean delivery. They estimated that additional costs of childbirth in the United States, if half of labors had electronic monitoring, was approximately $400 million per year in 1979 dollars.
The National Institute of Child Health and Human Development appointed a task force that published its consensus report in 1979. After an exhaustive review of electronic monitoring literature, the group concluded that the evidence only suggested a trend toward improved infant outcome in complicated pregnancies. No evidence demonstrated improved outcome in uncomplicated pregnancies. They emphasized that few scientifically conducted investigations had been done to address perinatal benefits.
Importantly, and largely ignored in the current obstetrical litigation crisis, the task force concluded that “courts of law should recognize intrapartum hypoxia as only one of the many potential factors involved in the development of handicaps and perinatal death, and current research and clinical data do not allow comprehensive definition of antepartum or intrapartum risk, nor means to reduce risk of adverse outcome.”
Randomized Electronic Fetal Heart Rate Monitoring Studies
The first five randomized clinical trials of electronic monitoring involved 3100 pregnancies (Haverkamp, 1976, 1979; Kelso, 1978; Renou, 1976; Wood, 1981; and their many colleagues). Only complicated pregnancies were studied in three of these. In four studies, no perinatal benefits of electronic monitoring were found.
The National Maternity Hospital, Dublin, was the site of the largest randomized study of electronic monitoring (MacDonald and co-workers, 1985). Nearly 13,000 pregnancies were included. Most were uncomplicated; however, about one fourth had diabetes, preeclampsia, chronic hypertension, renal and cardiac disease, prior perinatal death, prior neurological abnormality, prior low birthweight, prolonged pregnancy, multiple gestation, breech presentation, or gestation less than 34 weeks. The incidence of forceps delivery was more frequent in the electronically monitored group, but cesarean delivery rates did not differ. No differences were found in the incidence of intrapartum stillbirths or neonatal deaths. Although the number of infants suffering seizures in the auscultation group was increased, there was an equal number of neurologically damaged infants in either group at follow-up.
Luthy and co-workers (1987) studied the effects of electronic monitoring on neurobehavioral development of low-birthweight infants. They studied the neurological outcomes of 212 live-born infants weighing 700 to 1750 g whose intrapartum management had been randomly assigned to either electronic monitoring or periodic fetal heart rate auscultation. Electronic monitoring was not associated with significantly improved neurological outcomes. Cerebral palsy was diagnosed in 13 percent of infants with electronic monitoring compared with 8 percent of those in whom auscultation had been used.
Vintzileos and associates (1993) used coin flipping to randomly assign women to electronic monitoring or to intermittent auscultation in a study performed in Athens, Greece. In contrast to other randomized trials, they showed a significant reduction in “perinatal deaths due to hypoxia.” This study has been severely criticized because of serious flaws in methodology and interpretation (Keirse, 1994). For example, uncontrolled selection of women for subsequent coin flipping to determine study group allocation is a classical example of a “randomization” method that can easily be subverted (Schulz, 1995). Keirse (1994) likened this report to the Trojan horse of the ancient Greeks when he wrote: “The symbolic feature of a Trojan horse, now as in ancient times, is that it encourages the weary and unsuspicious to draw incorrect and misleading inferences.” The Athens study has served as the basis for two other reports claiming the superiority of electronic fetal monitoring (Vintzileos and co-workers, 1995a, 1995b).
Parkland Hospital Experience: Selective versus Universal Monitoring. In July 1982, an investigation began at Parkland Hospital to ascertain whether all women in labor should undergo electronic monitoring (Leveno and co-workers, 1986). In alternating months, universal electronic monitoring was rotated with selective heart rate monitoring, which was the prevailing practice. During the 3-year investigation, 17,410 fetuses were managed with selective monitoring practices. These were compared with 17,641 fetuses managed using universal electronic monitoring. No significant differences were found in any perinatal outcomes. There was a significant small increase in the frequency of cesarean delivery for fetal distress associated with universal electronic monitoring. Thus, increased application of electronic monitoring at Parkland Hospital did not improve perinatal results, but it increased the frequency of cesarean delivery for fetal distress.
Summary of Randomized Studies
Thacker and co-authors (1995) identified 12 published randomized clinical trials of electronic fetal monitoring from 1966 to 1994. Total pregnancies included in these studies was 58,624. They concluded that the benefits once claimed for electronic fetal monitoring are clearly more modest than believed, and appear to be primarily in the prevention of neonatal seizures. Long-term implications of this outcome, however, appear less serious than once believed. Abnormal neurological consequences were not consistently higher among children monitored by auscultation compared with electronic methods. They concurred with the current position of the American College of Obstetricians and Gynecologists (1995b) on intrapartum fetal surveillance.
Why Unfulfilled Expectations? There are several fallacious assumptions behind expectations of improved perinatal outcome with electronic monitoring. One assumption is that fetal distress is a slowly developing phenomenon and that electronic monitoring makes possible early detection of the compromised fetus. This assumption is illogical; how can all fetuses die slowly? Another presumption is that all fetal damage develops in the hospital. Only recently has attention focused on the reality that many damaged fetuses suffered insults before arrival to labor units. The very term “fetal monitor” implies that this inanimate technology in some fashion “monitors.” The assumption is made that if a dead or damaged infant is delivered, the tracing strip must provide some clue, because this device was monitoring fetal condition. Last, and despite contrary evidence, many have hypothesized that fetal distress cannot be detected reliably without electronic instrumentation. All of these assumptions led to great expectations and fostered the belief that all dead or damaged neonates are preventable. These unwarranted expectations have greatly fueled the current litigation crisis in obstetrics. Indeed, Symonds (1994) reported that 70 percent of all liability claims related to fetal brain damage are based on reputed abnormalities in the electronic fetal monitor tracing.
Too many fetuses demonstrate fetal heart rate abnormalities during labor to permit accurate detection of those who are actually compromised. Indeed, most “fetal distress” does not represent an overtly compromised fetus. Fetal heart rate abnormalities are quite common in labor. Importantly, debate continues about interpretation of many heart rate patterns. For example, Keith and co-workers (1995) asked each of 17 experts to review 50 tracings on two occasions, at least 1 month apart. About 20 percent changed their own interpretations, and approximately 25 percent did not agree with the interpretations of their colleagues. Ironically, this state of affairs for electronic monitoring does not differ from that of Benson and co-workers (1968) in their report on auscultation: “Naivete and wishful thinking inspired our hope for a simple rule-of-thumb estimate of fetal distress. Obviously, the problem is much too complex for such an easy appraisal.”
The methods most commonly used for intrapartum fetal heart rate monitoring include auscultation with a fetal stethoscope or a Doppler ultrasound device, or continuous electronic monitoring of the heart rate and uterine contractions. There is no scientific evidence that has identified the most effective method, including frequency or duration of fetal surveillance, that ensures optimum results. Intermittent auscultation or continuous electronic monitoring are considered acceptable methods of intrapartum surveillance in both low- and high-risk pregnancies. The recommended interval between checking the heart rate, however, is longer in the uncomplicated pregnancy. When auscultation is used, it is recommended that it be performed after a contraction and for 60 seconds. It is also recommended that a 1 to 1 nurse–patient ratio be used if auscultation is employed. Thus, the number of nurses available for labor and delivery may preclude use of intermittent auscultation.
Intrapartum Surveillance of Uterine Activity
Analysis of electronically measured uterine activity permits some generalities concerning the relationship of certain patterns of uterine contractions to labor outcome. There is considerable normal variation, however, and caution must be exercised before judging true labor or its absence solely from study of a monitor tracing. Uterine muscle efficiency to effect delivery varies greatly. To use an analogy, 100-meter sprinters all have the same muscle groups yet cross the finish line at different times.
Measurements of intrauterine pressure, that is, amnionic fluid pressure, Internal Uterine Pressure Monitoring
between and during contractions, are made by a fluid-filled plastic catheter positioned so that the distal tip is located in amnionic fluid above the presenting part. First, a plastic catheter guide that contains the distal portion of the catheter is inserted just through the cervical os, and the fluid-filled catheter is then gently pushed beyond the guide into the uterine cavity. To minimize risk to the placenta from the catheter tip, when the site of placental implantation is known, the tip of the catheter inserter should be positioned so that the catheter is likely to be inserted away from the placental site. The opposite end of the catheter, filled with saline, is connected to a strain-gauge pressure sensor adjusted to the same level as the catheter tip in the uterus. The amplified electrical signal produced in the strain gauge by variations in pressure within the fluid system is recorded on a calibrated moving paper strip, simultaneously with the recording of the fetal heart rate. Free communication between amnionic fluid and fluid in the catheter is essential. If the catheter tip becomes obstructed, it can usually be cleared by injecting a small volume of saline through the catheter. Alternatively, intrauterine pressure catheters are now available that have the pressure sensor in the tip of the catheter, which obviates the need for the fluid column.
Uterine contractions can be measured by a displacement transducer placed on the abdomen close to the fundus. The transducer button (“plunger”) is held against the abdominal wall and, as the uterus contracts, the button moves in proportion to the strength of the contraction. This movement is converted into a measurable electrical signal that indicates the relative intensity of the contraction—it does not give an accurate measure of intensity. If carefully supervised, however, external monitoring can give a good indication of the onset, peak, and end of the contraction.
Patterns of Uterine Activity
Caldeyro-Barcia and Poseiro (1960) from Montevideo, Uruguay, were pioneers who have done much to elucidate the patterns of spontaneous uterine activity throughout pregnancy. Their investigations were made possible by the development of electronic means of recording and quantifying uterine contractions before and during labor. Contractile waves of uterine activity were usually measured using intra-amnionic pressure catheters, but early in their studies as many as four simultaneous intramyometrial microballoons were also used to record uterine pressure. They also introduced the concept of Montevideo units to define uterine activity. By this definition, uterine performance is the product of the intensity—increased uterine pressure above baseline tone—of a contraction in mm Hg multiplied by contraction frequency per 10 minutes. For example, three contractions in 10 minutes, each of 50 mm Hg intensity, would equal 150 Montevideo units. Their unique studies provided useful insights for understanding normal labor.
During the first 30 weeks, uterine activity measured in Montevideo units is comparatively quiescent . Uterine contractions are seldom greater than 20 mm Hg, and these have been equated with those first described in 1872 by John Braxton Hicks. Uterine activity increases gradually after 30 weeks, and it is noteworthy that these Braxton Hicks contractions also increase in intensity and frequency. Further increases in uterine activity are typical of the last weeks of pregnancy, termed prelabor. During prelabor, the cervix ripens, presumably as a consequence of increasing uterine contractions .
According to Caldeyro-Barcia and Poseiro (1960), clinical labor usually commences when uterine activity reaches values between 80 and 120 Montevideo units. This translates into approximately three contractions of 40 mm Hg every 10 minutes, or 120 Montevideo units.
Importantly, there is no clear-cut division between prelabor and labor, but rather a gradual and progressive transition.During first-stage labor, uterine contractions increase progressively in intensity from about 25 mm Hg at commencement of labor to 50 mm Hg at the end. At the same time, frequency increases from three to five contractions per 10 minutes, and uterine baseline tone from 8 to 12 mm Hg. Uterine activity further increases during second-stage labor, aided by maternal abdominal muscles during bearing down . Indeed, contractions of 80 to 100 mm Hg are typical, and occur as frequently as five to six per 10 minutes. Interestingly, the duration of uterine contractions (60 to 80 seconds) does not increase appreciably from early active labor (3 to 4 cm dilatation) extending through the second-stage (Pontonnier and colleagues, 1975). Presumably, this constancy of duration serves a fetal respiratory gas-exchange function. That is, functional fetal “breath holding” during a uterine contraction, which results in isolation of the intervillous space where respiratory gas exchange occurs, has a 60- to 80-second limit that remains relatively constant.
Caldeyro-Barcia and Poseiro (1960) also observed empirically that uterine contractions are clinically palpable only after their intensity exceeds 10 mm Hg. Moreover, until their intensity reaches 40 mm Hg, the uterine wall can readily be depressed by the finger. At greater intensity, it then becomes so hard that it resists easy depression. Uterine contractions are usually not associated with pain until their intensity exceeds 15 mm Hg, presumably because this is the minimum pressure required for distending the lower uterine segment and cervix. It follows that Braxton Hicks contractions exceeding 15 mm Hg may be perceived as uncomfortable because distension of the uterus, cervix, and birth canal is generally thought to elicit discomfort.
Hendricks (1968) observed that “the clinician makes great demands upon the uterus. He expects it to remain well relaxed during pregnancy, to contract effectively but intermittently during labor, and then to remain in a state of almost constant contraction for several hours postpartum.” As also described by Caldeyro-Barcia and Poseiro (1960), uterine activity progressively and gradually increases from prelabor through late labor. Indeed, the pattern of uterine activity is one of gradual subsidence or reverse of that leading up to delivery. It is therefore not surprising that the uterus that performs poorly before delivery is also prone to atony and puerperal hemorrhage.
Origin and Propagation of Uterine Contractions
The uterus, unlike the heart, has not been extensively studied in terms of its nonhormonal physiological mechanisms of function. The normal contractile wave of labor originates near the uterine end of one of the fallopian tubes; thus these areas act as “pacemakers” . The right pacemaker usually predominates over the left and starts the great majority of contractile waves. The contraction spreads from the pacemaker area throughout the uterus at 2 cm/sec, depolarizing the whole organ within 15 seconds. This depolarization wave propagates downward toward the cervix. Intensity is greatest in the fundus, and it diminishes in the lower uterus. This phenomenon is thought to reflect reductions of myometrial thickness from the fundus to the cervix. Presumably, this descending gradient of pressure serves to direct fetal descent toward the cervix and efface the cervix. Importantly, all parts of the uterus are synchronized and reach their peak pressure almost simultaneously.
The pacemaker theory also serves to explain the varying intensity of adjacent coupled contractions shown in lines A and B of Figure .
Such coupling is termed incoordination by Caldeyro-Barcia and Poseiro (1960). A contractile wave begins in one cornual-region pacemaker, but does not synchronously depolarize the entire uterus. As a result, another contraction begins in the contralateral pacemaker and produces the second contractile wave of the couplet. These small contractions alternating with larger ones appear to be typical of early labor, and indeed, labor may progress with such uterine activity but at a slower pace. They also observed that labor would progress slowly if regular contractions were hypotonic—that is, contraction intensity less than 25 mm Hg or frequency less than two contractions per 10 minutes. Similar observations were made by Seitchik (1981) in a computer-aided analysis comparing women in active labor with those with arrested labor. Normal labor was characterized by a minimum of three contractions that averaged greater than 25 mm Hg and less than 4-minute intervals between contractions. Less than this amount of uterine activity was associated with arrest of active labor. He cautioned that the prospective diagnosis of hypotonic labor based simply on a few uterine pressures cannot be accomplished reliably. He did report, however, that modest dosages of oxytocin—usually 8 mU/min or less—restored uterine contractions in women with hypocontractile patterns.
Caldeyro-Barcia and Poseiro (1960) attempted to quantify uterine work necessary to dilate the cervix from 2 cm to complete. Labor was induced by infusing oxytocin in parous women, and the total uterine contraction pressure in mm Hg necessary to accomplish complete dilatation was summed. They found that between 4000 and 8000 mm Hg of total pressure was required. If the contractions had an average intensity of 50 mm Hg, then 80 to 160 contractions were necessary. Moreover, if the contraction frequency ranged from four to five per 10 minutes, then the duration of the first stage would be between 3 and 6 hours. Calculations such as these apply to many normal labors and, although applicable to some pregnancies, the extreme biological variation of normal labor defies efforts to mathematically describe it for the purpose of determining departure from normal.
Hauth and co-workers (1986) quantified uterine contraction pressures in 109 women at term who received oxytocin for labor induction or augmentation. Most of these women with successfully stimulated labor achieved 200 to 225 Montevideo units, and 40 percent had up to 300 Montevideo units to effect delivery. They suggested that these levels of uterine activity should be sought before consideration of cesarean delivery for presumed dystocia; a recommendation endorsed by the American College of Obstetricians and Gynecologists (1995a).
Fetal Growth Restriction
Each year in the United States, approximately 250,000 babies are born weighing less than 2500 g and thus classified as low birthweight. Although the majority of these infants are preterm, the National Institutes of Health estimated that approximately 40,000 are at term, having suffered abnormal intrauterine growth (Frigoletto, 1986). In the past, infants of low birthweight who are small for gestational age were designated as suffering from intrauterine growth retardation. To avoid undue alarm in parents, to whom the term “retardation” implies abnormal mental function, the term fetal growth restriction is now preferred. It is estimated that from 3 to 10 percent of infants are growth restricted (Divon and Hsu, 1992).
It was not until about 30 years ago that physicians first recognized that runting—fetal growth restriction—was a human as well as an animal phenomenon. In 1961, Warkany and co-workers reported normal values for infant weights, lengths, and head circumferences and defined fetal growth restriction. Gruenwald (1963) reported that approximately one third of low-birthweight infants were mature and that their small size could be explained by chronic placental insufficiency. These and observations by many others led to development of the concept that birthweight was governed not only by the length of gestation but also by the rate of fetal growth. Of interest is the observation that fetuses who deliver prematurely are smaller compared to their age-matched controls who do not deliver until term, thus implicating growth restriction in some cases of preterm birth (Hediger and colleagues, 1995).
In 1963 Lubchenco and co-workers from Denver published detailed comparisons of gestational ages to birthweights in an effort to derive norms for expected fetal size and, therefore, growth, at a given gestational week. Battaglia and Lubchenco (1967) then classified small-for-gestational-age (SGA) infants as those whose weights were below the 10th percentile for their gestational age. Such infants were shown to be at increased risk for neonatal death. For example, the neonatal mortality rate of a small-for-gestational-age infant born at 38 weeks was 1 percent compared with 0.2 percent in those with appropriate birthweights.
A definition based upon birthweight below the 5th percentile has also been proposed (Seeds, 1984). In addition, Usher and McLean (1969) proposed that fetal growth standards should be based on mean values with normal limits defined by ± 2 standard deviations because this definition would limit small-for-gestational-age infants to 3 percent of births compared with the 10th percentile. From a clinical standpoint, the latter definition appears to be most meaningful, because as shown in Figure 36–1 , most poor outcomes are in those infants with birthweights below the 3rd percentile. Moreover, not all infants with birthweights less than the 10th percentile are pathologically growth restricted; some are small simply because of constitutional factors. Indeed, Manning and Hohler (1991) and Gardosi and colleagues (1992) concluded that 25 to 60 percent of infants conventionally diagnosed to be small for gestational age were in fact appropriately grown when determinants of birthweight such as maternal ethnic group, parity, weight, and height were considered.
Normal Infant Birthweight
Normative data for fetal growth have evolved considerably in the aftermath of the pioneering work done by Lubchenco and co-workers (1963) in Denver. Their data were derived exclusively from white and Hispanic women who resided at high altitude; such infants are smaller than those born at sea level. For example, term infants average 3400 g at sea level, 3200 g at 5000 feet, and 2900 g at 10,000 feet altitude. Several fetal growth curves have been developed from various populations and geographic locations throughout the United States in the more than 30 years since Lubchenko and colleagues first described gestational age-specific birthweights. Brenner and colleagues (1976) used white and black infants delivered in Cleveland and aborted fetuses from North Carolina. Williams (1975) used live births in California to examine fetal growth curves in four ethnic groups. Ott (1993) used postnatal assessments of infants born in St. Louis. Because each of these curves was based on specific ethnic or regional groups, they were not considered to be necessarily representative of the entire population. For these reasons, fetal growth data have been derived on a nationwide basis in both the United States (Alexander and colleagues, 1996) and Canada (Arbuckle and colleagues, 1993).
Symmetrical Versus Asymmetrical Fetal Growth Restriction
Fetal growth has been divided into three phases (Pollack and Divon, 1992; Winick, 1971). The first phase, from conception to the early second trimester, involves cellular hyperplasia—an increase in the number of cells of all organs. This phase is followed by a period of continued hyperplasia and hypertrophy, involving both cell multiplication and organ growth. In the third phase, beyond 32 weeks, cellular hypertrophy is the dominant feature of growth. Cell size increases rapidly, there is fat deposition, and fetal weight may increase by as much as 200 g per week. Given this changing pattern of normal fetal growth, it has long been considered that the head and abdominal proportions in the growth-restricted fetus would reveal both the timing and nature of the insult leading to abnormal growth.
In the example of an early insult due to chemical exposure, viral infection, or an inherent cellular development abnormality caused by aneuploidy could theoretically result in a relative decrease in cell number as well as cell size. The resultant proportionate reduction in both head and body size has been termed symmetrical growth restriction. Conversely, a late pregnancy insult such as placental insufficiency associated with hypertension would affect primarily cell size. Moreover, because placental insufficiency may result in diminished glucose transfer and hepatic storage, fetal abdominal circumference (which reflects liver size) would be reduced. Simultaneously, it is proposed that there is preferential shunting of oxygen and nutrients to the brain, which allows normal brain and head growth. This sequence of events can result in asymmetrical growth restriction with an abnormally increased relative brain size compared with the small liver. Because the fetal brain is normally relatively large and the liver relatively small, the ratio of brain weight to liver weight (usually about 3 to 1) over the last 12 weeks of pregnancy is increased to 5 to 1 or more in many severely growth-restricted infants (Fig. ).
Although these generalizations about the potential pathophysiology of symmetrical versus asymmetrical growth restriction are interesting from a conceptual standpoint, there is considerable evidence that fetal growth patterns are more complex. Nicolaides and co-authors (1991) compared the ratios of fetal head to abdominal circumference in 376 growth-restricted fetuses with and without normal karyotypes. As shown , growth-restricted fetuses with aneuploidy typically had disproportionately large head sizes and were therefore asymmetrically growth restricted rather than the hypothetically expected symmetrical pattern. Similarly, most preterm infants with growth restriction due to preeclampsia and associated uteroplacental insufficiency demonstrate a symmetrical pattern of growth impairment rather than the hypothesized asymmetrical pattern (Salafia and co-authors, 1995).
Recognition of symmetrical and asymmetrical patterns of impaired fetal growth has prompted considerable interest in the antepartum diagnosis of these two forms of compromised growth, because the pattern may potentially reveal the cause. This has been particularly true in the ultrasonic evaluation of fetal growth restriction, where several dimensions of the fetus are now measured and can be related to each other in an attempt to evaluate proportionality of fetal structures. In practice, however, accurate identification of the symmetrical versus asymmetrical fetus has proved difficult. This is probably because the concept of brain sparing in asymmetrical growth restriction is difficult to document in all but the most extreme cases. Crane and Kopta (1980) analyzed several anthropometric measurements in growth-restricted newborns and concluded that the concept of brain sparing was erroneous and could not be used to diagnose the cause of individual fetal growth restriction.
Risk Factors for Fetal Growth Restriction
CONSTITUTIONALLY SMALL MOTHERS. Small women typically have smaller babies. If a woman begins pregnancy weighing less than 100 pounds, the risk of delivering a small-for-gestational-age infant is increased by at least a factor of two (Simpson and colleagues, 1975). Data from a longitudinal study of all births in one week in 1958 in England, Wales, and Scotland indicate that there are intergenerational effects on birthweight that are transmitted through the maternal line (Emanuel and associates, 1992). Thus, there appear to be familial factors that significantly affect birthweight and likely explain why some infants are constitutionally small. In a small woman with a small pelvis, the birth of a small baby whose genetically determined weight is below the average for the entire population is not necessarily an undesirable event nor should it necessarily be considered pathological.
POOR MATERNAL WEIGHT GAIN AND NUTRITION. In the woman of average or low weight, lack of weight gain throughout pregnancy may be associated with fetal growth restriction (Simpson and colleagues, 1975). Lack of weight gain in the second trimester is especially strongly correlated with decreased birthweight (Abrams and Selvin, 1995). If the mother is large and otherwise healthy, however, below-average maternal weight gain without maternal disease is unlikely to be associated with appreciable fetal growth restriction. Marked restriction of weight gain during pregnancy should not be encouraged during the last half of pregnancy. Even so, it appears that caloric restriction to less than 1500 kcal/day adversely affects fetal growth only minimally (Lechtig and co-workers, 1975). The best documented effect of famine on fetal growth was in the winter of 1944 in Holland, when the German Army enforced a restriction of approximately 600 kcal/day for pregnant women. The famine persisted for 28 weeks and there was an average birthweight decrease of 250 g (Stein and colleagues, 1975). Although there was only a small mean decrease in birthweight, fetal mortality rates increased significantly.
SOCIAL DEPRIVATION. The effect of social deprivation on birthweight is interconnected to the effects of associated lifestyle factors such as smoking, alcohol or other substance abuse, and poor nutrition. Wilcox and associates (1995), in a study of 7493 British women, found that the most socially deprived mothers had the smallest babies.
Viral, bacterial, protozoan, and spirochetal infections have been implicated in up to 10 percent of cases of fetal growth restriction (Knox, 1978). The best known of these are infections caused by rubella (Lin and Evans, 1984) and cytomegalovirus (Hanshaw, 1971; Stagno and associates, 1977). Mechanisms affecting fetal growth appear to be different with these two viral infections. Cytomegalovirus is associated with direct cytolysis and loss of functional cells. With rubella, infection causes vascular insufficiency by damaging the endothelium of small vessels. Cell division rate is also reduced in congenital rubella infections (Pollack and Divon, 1992). Hepatitis A and B are associated with preterm delivery but may also adversely affect fetal growth (Waterson, 1979). Listeriosis, tuberculosis, and syphilis have been reported to cause fetal growth restriction. Paradoxically, in cases of syphilis, the placenta is almost always increased in weight and size due to edema and perivascular inflammation (Varner and Galask, 1984). Toxoplasmosis is the protozoan infection most often associated with compromised fetal growth, but congenital malaria may produce the same result (Varner and Galask, 1984).
In a study of over 13,000 infants with major structural anomalies, 22 percent had accompanying growth restriction (Khoury and associates, 1988). In general, the more severe the malformation, the more likely the fetus is to be small for gestational age. This is especially evident in fetuses with chromosomal abnormalities or those with serious cardiovascular malformations . For example, the anencephalic fetus is often growth restricted even when considering the missing brain and cranium (Honnebier and Swaab, 1973). Diminished growth of this degree is not seen in infants with spina bifida, but they are smaller than normal controls (Wald and associates, 1980).
Placentas of fetuses with autosomal trisomies have a reduced number of small muscular arteries in the tertiary stem villi (Rochelson and associates, 1990). Thus, both placental insufficiency and primary abnormal cellular growth and differentiation may contribute to the significant degree of fetal growth restriction often associated with karyotype abnormalities. In a series of 458 fetuses with no sonographically visible structural anomalies, Snijders and co-workers (1993) found karyotype abnormalities in 20 percent. In the presence of growth restriction and fetal anomalies, the prevalence of chromosome abnormalities is even greater.
Although postnatal growth failure is prominent in children with trisomy 21, fetal growth restriction is generally mild (Thelander and Pryor, 1966). The mean birthweight of these infants is 2900 g. A significant first trimester lag in crown–rump length among fetuses with trisomy 21 has been noted by some investigators, but not others (Golbus 1978; Stephens and Shepard, 1980). After the first trimester, the length of all long bones in fetuses with trisomy 21 lags behind those of normal fetuses (Fitzsimmons and colleagues, 1990). Both shortened femur length and hypoplasia of the middle phalanx have been documented with increased frequency in fetuses with trisomy 21.
In contrast to the mild and variable growth restriction that accompanies trisomy 21, fetuses with trisomy 18 are virtually always significantly affected. In one series of newborns with trisomy 18, 10 of 11 weighed less than 2500 g at birth (Moerman and associates, 1982). Growth failure has been noted as early as the first trimester. By the second trimester, long bone measurements typically fall below the 3rd percentile for age and the upper extremity is more severely affected than the lower (Droste and co-workers, 1990). Visceral organ growth is also abnormal in this condition (Droste, 1992). Some degree of growth restriction is also commonly present in fetuses with trisomy 13, but it is generally not as severe as in trisomy 18.
Significant fetal growth restriction is not seen with Turner syndrome (45,X or gonadal dysgenesis) or Klinefelter syndrome (47,XXY) (Droste, 1992).
TRISOMY 16. Trisomy 16 is the most common trisomy in spontaneous abortions and is usually, if not always, lethal to the fetus in the nonmosaic state (Lindor and associates, 1993). It has recently been discovered that spots of trisomy 16 in the placenta—called confined placental mosaicism—lead to placental insufficiency that may account for many cases of previously unexplained fetal growth restriction (Kalousek and colleagues, 1993). In these pregnancies, the chromosome abnormality is confined to the placenta. Wolstenholme (1995) has reviewed the significance of trisomy 16 from gametogenesis to term and onwards.
PLACENTAL AND CORD ABNORMALITIES. Chronic partial placental separation, extensive infarction, or chorioangioma are likely to cause restricted fetal growth. A circumvallate placenta or a placenta previa may impair growth, but usually the fetus is not markedly smaller than normal. Marginal insertion of the cord and especially velamentous insertions are more likely to be accompanied by a growth-restricted fetus (Chap. 30 ).
Many cases of fetal growth restriction are in pregnancies with apparently normal fetuses whose placentas are grossly normal. The cause of growth failure in these cases is often presumed to be uteroplacental insufficiency. Dynamic placental scintigraphy with indium113m has been used in a research setting to study this mechanism of growth restriction (Skjoldebrand and co-workers, 1989). Women with otherwise unexplained fetal growth restriction demonstrated a fourfold reduction in uteroplacental blood flow compared with normally grown fetuses (Lunell and Nylund, 1992). Similar reductions are also seen in growth-restricted fetuses with congenital malformations, suggesting that maternal blood flow may in part be regulated by the fetus (Howard, 1987; Rankin and McLaughlin, 1979). Uteroplacental blood flow is also reduced in women with preeclampsia compared with normotensive women. Interestingly, macrosomic infants do not have increased uteroplacental blood flow (Lunell and Nylund, 1992).
Pregnancy with two or more fetuses is more likely to be complicated by abnormal growth of one or both fetuses compared with normal singletons . Fetal growth restriction has been reported in 10 to 50 percent of twins (Hill and associates, 1994).
Antiphospholipid Antibody Syndrome
. Two classes of antiphospholipid antibodies have been associated with fetal growth restriction—anticardiolipin antibodies and lupus anticoagulant (Lockwood and Rand, 1994). Pregnancy outcome in women with these antibodies is often poor, and may also involve early-onset preeclampsia and second or third trimester fetal demise (Branch and associates, 1992). Maternal morbidity due to vascular thrombotic events is not uncommon. Pathophysiological mechanisms in the fetus appear to be caused by maternal platelet aggregation and placental thrombosis. These antibodies may also be suspected in women demonstrating repetitive second-trimester fetal loss or early-onset fetal growth restriction, especially when accompanied by early, severe hypertensive disease. Diagnosis and management of these syndromes are considered in Chapters 26 and 53.
Screening and Identification of Fetal Growth Restriction
Early establishment of gestational age, attention to maternal weight gain, and careful measurements of uterine height throughout pregnancy will serve to identify many cases of abnormal fetal growth in women without risk factors. Identification of risk factors, including a previously growth-restricted fetus, should raise the possibility of growth restriction during the current pregnancy. In women with significant risk factors, consideration should be given to serial sonography to detect abnormal fetal growth. Although the frequency of such examinations will vary depending upon clinical circumstances, an initial dating examination, followed by a second examination at 32 to 34 weeks, should serve to identify many cases of fetal growth restriction. If clinical findings suggest inadequate fetal growth prior to this time, earlier sonography is necessary. Definitive diagnosis, however, usually cannot be made until delivery.
The identification of the inappropriately growing fetus remains a challenge. This is underscored by the fact that such identification is not always possible even in the nursery. Regardless, there are both simple clinical techniques and more complex technologies that may prove useful in helping to exclude and diagnose fetal growth restriction. Some of the widely used techniques, as well as those of potential use, are described below.
Uterine Fundal Height
Carefully performed serial fundal height measurements throughout gestation are a simple, safe, inexpensive, and reasonably accurate screening method that may be used to detect many small-for-gestational-age fetuses. The principal problem is one of imprecision. For example, Jensen and Larsen (1991) and Walraven and colleagues (1995) found that symphysis to fundus measurements helped to correctly identify only 40 percent of such infants. Thus, small-for-age infants were both overlooked and overdiagnosed. However, these results do not decrease the importance of carefully performed fundal height measurements as a simple screening method.
The method used in most clinics in the United States was reported by Jimenez and colleagues (1983). Briefly this consists of a tape calibrated in centimeters being applied over the abdominal curvature from the top of the symphysis to the top of the uterine fundus, which is identified by palpation or percussion. The tape is applied with the markings away from the examiner to avoid prejudice. Between 18 and 30 weeks, the uterine fundal height in centimeters coincides with weeks of gestation. If the measurement is more than 2 to 3 cm from the expected height, inappropriate fetal growth may be suspected.
Central to the debate over whether all pregnancies should routinely receive ultrasonic evaluations is the potential for diagnosis of fetal growth restriction (Ewigman and colleagues, 1993) (see Chap. 44 , p. 1024). Typically, such routine screening incorporates an ultrasound examination at 16 to 20 weeks to establish gestational age and rule out visible anomalies, and then follow-up imaging at 32 to 34 weeks to evaluate fetal growth.
The optimal ultrasonographic method of estimating fetal size, and therefore fetal growth restriction, has been reviewed by Manning (1995). Combining head, abdomen, and femur dimensions should in theory enhance the accuracy of predictions of fetal size. Unfortunately, any potential improvement is apparently lost by the cumulative error inherent in measurement of each individual fetal dimension. As a result, abdominal circumference measurements have been accepted by experienced ultrasonographers as the most reliable index of fetal size (Manning, 1995; Snijders and Nicolaides, 1994). For example, the estimated fetal weight using sonographic abdominal circumference measurements was almost always within 10 percent of the actual birthweight . Interestingly, abdominal circumference, measured directly in the newborn infant, was also shown to be an important anatomical marker of growth restriction (Deter and colleagues, 1995). Importantly, the elegant observations on the metabolic effects of fetal growth restriction performed at Kings College Hospital and described earlier, all were obtained in fetuses diagnosed to have growth restriction because their ultrasonic abdominal circumference was less than 5th percentile for gestational age (Snijders and Nicolaides, 1994). Such small abdominal circumferences are linked to biochemical abnormalities such as hypoxia and acidemia. Observations such as these serve to emphasize that sonographic measurements of the abdominal circumference can meaningfully signify pathological fetal growth restriction.
Larsen and colleagues (1992) performed ultrasound after 28 weeks and every 3 weeks thereafter in 1000 pregnancies at risk for fetal growth restriction. They randomly withheld the results from clinicians. Revealing the results of ultrasonic estimates of fetal growth during the third trimester significantly increased diagnosis of small-for-gestational-age fetuses. In this same group, elective deliveries also increased, but without overall improvement in neonatal mortality or morbidity. Thus, this method of screening improved the diagnosis, but did not improve fetal outcome. Goldenberg and colleagues (1989) found that as the percentage of pregnancies undergoing ultrasound increased, fetal growth restriction decreased. This was attributed to accurate gestational age information obtained using ultrasound.
An association between oligohydramnios and pathological fetal growth restriction has long been recognized. As shown in Figure 36–7 , the smaller the vertical dimension of sonographically measured pocket of amnionic fluid, the greater the perinatal mortality. The likely explanation for oligohydramnios is diminished fetal urine production due to hypoxia.
Management of Fetal Growth Restriction
Once a small-for-gestational-age fetus is suspected, intensive efforts should be made to determine if growth restriction is present and, if so, its type and the etiology. In the presence of sonographically detectable anomalies, cordocentesis may be performed for rapid karyotyping. The detection of a lethal aneuploidy may obviate cesarean section for fetal indications. Efforts are made to ensure delivery, when possible, of an infant who will subsequently thrive and achieve normal potential.
Growth Restriction Near Term
Prompt delivery is likely to afford the best outcome for the fetus who is considered growth restricted at or near term. In the presence of significant oligohydramnios, most fetuses will be delivered if gestational age has reached 34 weeks or beyond. Assuming that the fetal heart rate pattern is reassuring, vaginal delivery may be attempted. Unfortunately, such fetuses often tolerate labor less well than their appropriately grown counterparts, and cesarean section is indicated for intrapartum fetal compromise. Importantly, uncertainty about the diagnosis of fetal growth restriction should preclude intervention until fetal lung maturity is assured.
Hemolysis from Isoimmunization
In 1892, Ballantyne established clinicopathological criteria for the diagnosis of hydrops fetalis. In 1932, Diamond, Blackfan, and Baty reported that fetal anemia characterized by numerous circulating erythroblasts was associated with this syndrome. Certainly ranking as a major contribution to medicine is the subsequent delineation of the pathogenesis of most cases of hemolytic disease in the fetus and newborn, including the related discovery of the rhesus factor by Landsteiner and Weiner in 1940. In 1941, Levine and associates confirmed that erythroblastosis was due to maternal isoimmunization with paternally inherited fetal factors, and the subsequent development of effective maternal prophylaxis was attributed to Finn and associates (1961) in England, and Freda and co-workers (1963) in the United States.
The CDE antigens are complex, and more than 400 other red cell antigens have been identified. Although some of them are immunologically and genetically important, fortunately many are so rare as to be of little clinical significance.
Individuals who lack a specific red cell antigen can potentially produce an antibody when exposed to that antigen. The antibody may prove harmful to the individual in the case of a blood transfusion or to a fetus during pregnancy. The vast majority of humans have at least one such factor inherited from their father and lacking in their mother. In these cases, the mother could be sensitized if enough erythrocytes from the fetus were to reach her circulation to elicit an immune response. That the disease is identified in very few pregnancies is a result of several circumstances. These include (1) varying rates of occurrence of red cell antigens, (2) their variable antigenicity, (3) insufficient transplacental passage of antigen or antibody across the placenta, (4) the variability of maternal response to the antigen, and (5) protection from isoimmunization by ABO incompatibility of fetus and mother.
A D-negative woman delivered of a D-positive, ABO-compatible infant, has a likelihood of isoimmunization of 16 percent (Bowman, 1985). About 2 percent of such women will be immunized by the time of delivery, another 7 percent will have anti-D antibody by 6 months postpartum, and the remaining 7 percent will demonstrate D-isoimmunization when challenged in a subsequent pregnancy by another D-positive fetus. ABO incompatibility confers some protection against D-isoimmunization because fetal red cells entering the mother usually are rapidly destroyed before they elicit an antigenic response (only a 2 percent chance of D-isoimmunization by 6 months postpartum).
CDE (Rhesus) Blood Group System
CDE (Rhesus) Blood Group System. The CDE, or rhesus, blood group system is of considerable clinical importance because the majority of individuals who lack its major antigenic determinant, D or Rho, become immunized after a single exposure to this erythrocyte antigen. Several nomenclature systems currently are used; however, the CDE grouping system seems easiest to use.
The CDE antigens are inherited independent of other blood group antigens and are located on the short arm of chromosome 1. There is apparently no difference in the distribution of the CDE antigens with regard to sex, however, there are important racial differences. American Indians and Chinese and other Asiatic peoples are almost all D-positive (99 percent). Among African Americans there is a lesser incidence of D-negative individuals (7 to 8 percent) than among white Americans (13 percent). Of all racial and ethnic groups studied thus far, the Basques show the highest incidence of D-negativity (34 percent).
CDE antigens other than D have low immunogenicity but may be significant if the pregnant woman has already formed an antibody to them. All pregnant women should be tested routinely for the presence or absence of D (Rho) antigen on their erythrocytes and for other irregular antibodies in their serum. Barss and colleagues (1988) have argued convincingly that this need be done only once during pregnancy in D-positive women.
ABO Blood Group System
ABO Blood Group System. The major blood group antigens A and B are the most common, but are not the most serious cause of hemolytic disease in the newborn. For example, group O women may from early life have anti-A and anti-B isoagglutinins, which may be augmented by pregnancy. Although about 20 percent of all infants have an ABO maternal blood group incompatibility, only 5 percent of them show overt signs of hemolytic disease. Moreover, when they do, the disease almost always is much milder than that with D-isoimmunization.
Although ABO isoimmunization will cause hemolytic disease of the newborn, it does not cause hydrops fetalis and is a disease of pediatric rather than obstetrical concern. The reasons for this are at least twofold. First, most species of isoantibodies to A and B antigens are immunoglobulin M, and thus not likely to gain access to fetal erythrocytes. Second, fetal red cells have a diminished number of A and B antigenic sites when compared with later in life.
Black infants are more likely to develop ABO disease than are white infants (Kirkman, 1977). Desjardins and co-workers (1979) studied a large number of infants of blood group O mothers to try to identify a relationship between the degree of red cell sensitization by antibody and the cord blood hemoglobin and bilirubin concentrations. They found that when the infant blood type was A or B, the bilirubin was higher and hemoglobin was lower than in cord blood from blood group O infants, even when no antibody was identified on the type A or B red cells. They concluded that ABO incompatibility represents a spectrum of hemolytic disease that ranges from those with little laboratory evidence of red cell sensitization to those with severe disease.
The usual criteria for diagnosis of hemolysis due to ABO incompatibility include the following: (1) the mother is blood group O, with anti-A and anti-B in her serum, while the fetus is group A, B, or AB; (2) there is onset of jaundice within the first 24 hours; (3) there are varying degrees of anemia, reticulocytosis, and erythroblastosis; and (4) there has been careful exclusion of other causes of hemolysis. Unlike the result in CDE hemolytic disease, the Coombs test in ABO incompatibility may be negative, although it is usually positive.
Because there is no adequate method of antenatal diagnosis, careful observation is essential in the neonatal period. Unlike CDE hemolytic disease, ABO disease is frequently seen in first-born infants, and it is likely to recur in subsequent pregnancies. Katz and co-workers (1982) identified a recurrence rate of 87 percent; 62 percent of the affected infants required treatment, but this was most often limited to phototherapy.
The principles of management of the newborn with ABO hemolytic disease are similar to those for the infant born with D-isoimmunization. For simple transfusion or exchange transfusion, group O blood is used. Because the incidence of stillbirths among ABO-incompatible pregnancies is not increased, there is no justification for early labor induction or for performing amniocentesis.
Other Blood Group Incompatibilities
Other Blood Group Incompatibilities. D-antigen incompatibility and ABO heterospecificity account for approximately 98 percent of all cases of hemolytic disease. The possibility of hemolytic disease from rarer blood groups may be suspected from the results of the indirect Coombs test done to screen for abnormal antibodies in maternal serum .
An idea of the frequency of some of these antibodies comes from the report of Bowell and colleagues (1986a), who screened 70,000 pregnant women over a 2-year period. They identified 677 pregnancies with atypical red cell antibodies, for an incidence of nearly 1 percent. One fourth of these were from the Lewis system, which do not cause fetal hemolysis because the antigens do not develop on erythrocytes until a few weeks after birth. Of the remaining 544 antibodies, 72 percent were of the CDE group, and anti-D was most common (158), followed by anti-E (130), anti-c (49), and anti-C (19). Antibodies to the Kell system antigens also were common (76).
In a review by Bowman and colleagues (1992b) of 459 pregnancies from 311 Kell-immunized women, 63 ended in abortion or stillbirth unrelated to anti-Kell sensitization. Of the remaining infants, 376 were unaffected. Of 20 who were affected, 12 newborns required no therapy. There were four perinatal deaths; one from kernicterus and three from hydrops. When the maternal anti-Kell titer is 1:8 or greater, it must be investigated by amniocentesis or fetal blood sampling. Weiner and Widness (1996) recommend the latter because their observations indicate anemia out of proportion to evidence of hemolysis.
The clinical importance of anti-c isoimmunization has been emphasized by Wenk (1986) and Bowell (1986b) and their colleagues. This antibody was the next most common cause of clinically significant isoimmunization following anti-D. Although anti-c isoimmunization most commonly resulted from previous pregnancies, those fetuses whose mothers had been transfused were more likely to have moderate to severe hemolysis.
In a review by Bowman and colleagues (1992a) of 120 pregnancies with either anti-C or anti-Ce alloimmunization, 22 ended in abortion or stillbirth unrelated to isoimmunization. Of 33 affected fetuses, only eight required treatment after birth and none had severe disease.
Mother as Provider of Rare Type Red Cells
Following maternal isoimmunization with a rare blood type, the possibility exists of hemolytic disease in the fetus and neonate. This could create a need for red cells devoid of the antigen or antigens to which the mother is isoimmunized. Moreover, the mother herself may require red cells, for example, because of a complication of hemorrhage at delivery. For such circumstances, even while pregnant, she can successfully donate her own red cells, which are then appropriately frozen for subsequent use, as demonstrated by the following case.
G.D., a 17-year-old gravida 2, P1, lacked immunological evidence of all CDE antigens except D, and had acquired antibodies during the previous pregnancy to C, c, E, and e. Compatible red cells available in the United States were limited to two units frozen in Portland, Oregon. Therefore, repeated phlebotomies were performed during pregnancy and the red cells promptly frozen for possible subsequent use. In spite of her small size—110 pounds nonpregnant—she tolerated quite well the removal of 6 units (3000 mL total) of blood at the rate of 500 mL every 3 to 5 weeks. Iron was provided along with supplementary folic acid. Her measured blood volume of 3800 mL was 47 percent above the nonpregnant state. Repeat cesarean delivery was accomplished without incident. Hemolytic disease in the newborn was treated with exchange transfusions using all of the red cells harvested and stored from the six phlebotomies plus the two frozen units from Portland.
Pathological Changes in Hemolytic Disease
In D-positive fetuses, maternal antibodies are both adsorbed to the D-positive erythrocytes and exist unbound in fetal serum. The adsorbed antibodies act as hemolysins, leading to an accelerated rate of red cell destruction. Maternal antibodies detectable at birth gradually disappear from the infant’s circulation over a period of 1 to 4 months. Their rate of disappearance is influenced to some extent by exchange transfusion. Detection of adsorbed antibodies is best accomplished by the direct Coombs test. If D red cells coated with anti-D antibody are typed with an anti-D saline agglutinin, they may be reported incorrectly as D-negative because of the blocking effect produced by the adsorbed antibody. Therefore, erythrocytes reported to be D-negative from an infant whose mother may be isoimmunized must always be checked by the direct Coombs test.
The pathological changes in the organs of the fetus and newborn infant vary with the severity of the process. The severely affected fetus or infant may show considerable subcutaneous edema as well as effusion into the serous cavities—hydrops fetalis. At times, the edema is so severe that the diagnosis can be easily identified using sonography . In these cases, the placenta is also markedly edematous, appreciably enlarged and boggy, with large, prominent cotyledons and edematous villi. Excessive and prolonged hemolysis serves to stimulate marked erythroid hyperplasia of the bone marrow as well as large areas of extramedullary hematopoiesis, particularly in the spleen and liver, which may in turn cause hepatic dysfunction (Nicolini and associates, 1991). Histological examination of the liver may also disclose fatty degenerative parenchymal changes as well as deposition of hemosiderin and engorgement of hepatic canaliculi with bile. There may be cardiac enlargement and pulmonary hemorrhages. Ascites, hepatomegaly and splenomegaly, may be so massive as to lead to severe dystocia as the consequence of the greatly enlarged abdomen. Hydrothorax may be so severe as to compromise respirations after birth.
The precise pathophysiology of hydrops remains obscure. Theories of its causation include heart failure from profound anemia, capillary leakage caused by hypoxia from severe anemia, portal and umbilical venous hypertension from hepatic parenchymal disruption by extramedullary hematopoiesis, and decreased colloid oncotic pressure from hypoproteinemia caused by liver dysfunction. To study this, Nicolaides and colleagues (1985) performed percutaneous umbilical artery blood sampling in 17 severely D-isoimmunized fetuses at 18 to 25 weeks. All fetuses with hydrops had hemoglobin values of less than 3.8 g/dL as well as plasma protein concentrations less than 2 standard deviations from the mean for normal fetuses of the same age. The hydropic fetuses also had substantive protein concentrations in ascitic fluid collected at fetoscopy. Conversely, all nonhydropic fetuses had hemoglobin values that exceeded 4 g/dL; however, 6 of 10 had hypoproteinemia of the same magnitude as the hydropic fetuses. These investigators concluded that the degree and duration of anemia influence the severity of ascites, and this is made worse by hypoproteinemia. They also hypothesized that severe chronic anemia causes tissue hypoxia with resultant capillary endothelial leakage with protein loss.
Fetuses with hydrops may die in utero from profound anemia and circulatory failure (Fig. ). A sign of severe anemia and impending death is a sinusoidal fetal heart rate pattern . The live-born hydropic infant appears pale, edematous, and limp at birth, often requiring resuscitation. The spleen and liver are enlarged, and there may be widespread ecchymoses or scattered petechiae. Dyspnea and circulatory collapse are common.
Less severely affected infants may appear well at birth, only to become jaundiced within a few hours. Marked hyperbilirubinemia, if untreated, may lead to central nervous system damage, especially to the basal ganglia or kernicterus. Anemia, in part resulting from impaired erythropoiesis, may persist for many weeks to months in the infant who had demonstrated hemolytic disease at birth. In the absence of hypoxia, erythrocyte production normally falls after birth, especially in the preterm infant.
The number of perinatal deaths from hemolytic disease caused by D-isoimmunization has dramatically dropped. The most common reason for this is that the administration of D-immune globulin during or immediately after pregnancy to D-negative women has eradicated most D-isoimmunization. Another reason is that the fetus who is most likely to be seriously affected can be treated by intraperitoneal or direct intravascular transfusions or be delivered preterm. The favorable impact on reducing perinatal mortality as the consequence of these procedures is exemplified by experiences in Manitoba. In that Canadian province, the number of perinatal deaths from hemolytic disease decreased from 29 in 1964 to only 1 in 1975 (Bowman and colleagues, 1977).
Immune Globulin Prophylaxis for the D-Negative, Nonsensitized Mother
Anti-D immune globulin is a 7S immune globulin G extracted by cold alcohol fractionation from plasma containing high-titer D-antibody. Each dose provides not less than 300 mg of D-antibody as determined by radioimmunoassay.
Freda and co-workers (1975) summarized their 10 years of clinical experience with D-immune globulin, confirming their original observations that such globu-lin given to the previously unsensitized D-negative woman within 72 hours of delivery is highly protective. D-negative women undergoing abortion should also be treated, because up to 2 percent having spontaneous abortions and 5 percent having elective terminations become isoimmunized without D-immune globulin. Likewise, women with ectopic pregnancies or hydatidiform moles should be treated. The observation of Blajchman and co-workers (1974) of detectable fetal-maternal hemorrhage after 6 percent of amniocenteses has provided support for a policy that all unsensitized D-negative women suspected of having a D-positive fetus should receive D-immune globulin following such a procedure. For similar reasons, such women should also receive D-immune globulin following external cephalic version (Boucher and associates, 1996).
D-negative women who receive blood or blood fractions are at risk of becoming sensitized. Red cells can supply massive amounts of foreign antigen if the cells are D-positive and their recipient is D-negative. Moreover, platelet transfusions and plasmapheresis can provide sufficient D-antigen to cause sensitization, which can be prevented by an injection of D-antiglobulin. Freda (1973), as well as Bowman (1985), emphasize that when in doubt whether to give anti-D immune globulin, then it should be given.
While adherence to the above guidelines dramatically decreased the risk of maternal isoimmunization, the problem was not eliminated. Bowman and Pollock (1978) identified 1.8 percent of women who became isoimmunized in spite of adherence to the above recommendations. They found that failures were the consequence of spontaneous silent fetal-maternal bleeds before delivery and before the administration postpartum of D-immune globulin. To avoid isoimmunization from fetal-maternal bleeds remote from term, 300 mg of antibody routinely was administered intramuscularly to all nonsensitized D-negative women at 28 weeks, again at 34 weeks, as well as at the time of amniocentesis or uterine bleeding. If the infant was D-positive, a third dose of the immunoglobulin was administered to the mother after delivery. This program was followed by a reduction in the incidence of D-isoimmunization during pregnancy from 1.8 percent to 0.07 percent. A single dose at about 28 weeks proved to be almost as effective as were the two doses antepartum, and only 2 of 1799 D-negative women developed D-isoimmunization despite antenatal prophylaxis. The small amount of antibody that crosses the placenta results at times in a weakly positive direct Coombs test in cord and infant blood; however, none of the infants showed evidence of anemia or exaggerated hyperbilirubinemia.
Chavez and associates (1991), in a review of the epidemiology of CDE hemolytic disease in the United States, estimated an incidence of 10.6 per 10,000 live births. They concluded that CDE hemolytic disease still contributed significantly to both neonatal morbidity and mortality.
Appropriate concern has been raised for the possibility that the human immunodeficiency virus or other viruses may be transmitted by plasma-derived products such as D-immunoglobulin. Exclusion of individuals who are antibody or antigen positive for various hepatitis viruses should significantly reduce the risk of the spread of these infections by various immunoglobulin preparations. The human immunodeficiency virus should be inactivated by the manufacturing process itself .
A single intramuscular dose of 300 mg of D-immunoglobulin is administered routinely to all D-negative, nonimmunized women at 28 to 32 weeks, and again within 72 hours of the birth of a D-positive infant. A similar dose is also given at the time of amniocentesis and whenever there is uterine bleeding, unless the routine dose at 28 to 32 weeks had been given very recently. If a massive fetal–maternal hemorrhage is recognized, more immune globulin should be given, as described below. One dose of 300 mg will protect the mother against a bleed of up to 15 mL of D-positive red cells, or 30 mL of fetal blood.
Ness and colleagues (1987) provided data for the incidence of excessive fetal–maternal hemorrhage that may cause isoimmunization despite postpartum immune globulin administration. Using the enzyme-linked antiglobulin test, they studied almost 800 D-negative mothers giving birth to D-positive infants, and found evidence in 1 percent of the mothers for fetal bleeding in excess of 30 mL. Another 5.6 percent of these pregnancies had fetal-maternal bleeds of between 11 and 30 mL. Thus, at least 1 percent, and perhaps more, of susceptible mothers would have been given insufficient immune globulin if not tested. Importantly, they identified no risk factors that predicted excess bleeding, and recommended that all women be tested at delivery. Stedman and co-workers (1986), utilizing the erythrocyte rosette test, reported similar results.
In most institutions the rosette or similar test is routinely performed on postpartum maternal blood samples of D-negative women delivering D-positive infants to identify those women requiring more than the standard dose of D-immunoglobulin. In women who potentially require repeated injections of D-immunoglobulin—for example, repeated, unexplained uterine bleeding in the first or second trimester—an indirect Coombs test will, if positive, allow the confirmation of antibody excess from the last immunoglobulin injection and avoid the need for additional prophylaxis.
Whether to provide routinely D-antiglobulin prophylaxis for Du-positive women is controversial. Bowman (1985) cites five instances in 750,000 pregnancies in which a Du-positive mother produced anti-D antibody. Fortunately, in none of these was the fetus severely affected. If there is any doubt about D-antigen status, then globulin should be given.
Large Fetal to Maternal Bleed
In the case of a larger fetal–maternal hemorrhage, the D-positive erythrocytes may, by careful examination, be identified at times as clumps in the crossmatch of the erythrocytes from maternal blood and the D-immune globulin. However, the acid-elution technique for identifying erythrocytes that contain appreciable hemoglobin is best used to identify a major bleed and to approximate its magnitude.
When the acid-elution test is performed, red cells rich in fetal hemoglobin are easy to identify . A careful differential count will serve to approximate closely the percentage of fetal cells in the maternal blood. From this value, as described on page 982, an estimate of the volume of fetal red cells in the maternal circulation can be made. The volume of fetal red cells calculated is then divided by 15 (volume of red cells effectively neutralized by 300 mg of antibody), and this provides a reasonable estimate of the number of 300 mg ampules of D-immune globulin required for protection. In practice, in cases of fetal-maternal hemorrhage, sensitization of the mother can be prevented by injecting sufficient D-immune globulin intramuscularly to provide demonstrable free antibody in the maternal serum.
Rarely, the D-negative woman will have been exposed in utero to D-antigen from her mother and become sensitized as the consequence. As with fetal–maternal bleeds, a major blood group (ABO) incompatibility offers appreciable protection against D-sensitization. Jennings and Clauss (1978), in a study of 105 D-negative infants born to D-positive mothers, identified a maternal–fetal bleed in only two instances. Jennings and Clauss (1978) and Bowman (1985), on the basis of their extensive studies, do not believe that D-immune globulin prophylaxis is warranted for D-negative babies born to D-positive mothers.
The management of isoimmunization, except for ABO incompatibility, is similar regardless of the inciting antigen. Because D-isoimmunization is most common, general management for this clinical situation is discussed.
The mother who is sufficiently immunized to produce enough antibody to cause overt hemolytic disease in the fetus and newborn will have detectable D-antibody in her serum by 36 weeks. From early studies, if no treatment was given for the sensitized D-negative woman with a D-positive fetus, the perinatal mortality rate was about 30 percent . With aggressive management, including diagnostic amniocenteses or studies performed on fetal blood obtained by cordocentesis, repeated ultrasound examinations, intrauterine transfusions in selected cases, and early delivery in most cases, the perinatal mortality rate can be lowered remarkably. For optimal outcome, management is individualized and aided by the following information:
1. Past obstetrical history, with emphasis on fetal outcome and how that outcome was achieved.
2. Accurate knowledge of fetal age.
3. The paternal D-antigen status, because if he is negative, then the fetus cannot be affected.
4. Maternal antibody determinations repeated throughout pregnancy.
5. Spectrophotometric analyses of amnionic fluid, or sonographically-directed fetal blood sampling.
An antibody titer, performed using the indirect Coombs test, that is no higher than 1:16 almost always means that the fetus will not die in utero from hemolytic disease. A titer higher than this indicates the possibility of severe hemolytic disease. It is emphasized that the titer in the previously sensitized woman may, during a subsequent pregnancy, rise infrequently to high levels even though her fetus is D-negative—the so-called amnestic response. Whenever the antibody titer is sufficiently elevated to be clinically significant, fetal evaluation is warranted. In most institutions this critical titer is considered to be 1:16 or greater; however, in some centers, if the titer remains below 1:32, then a good fetal outcome is anticipated.
Prior to the mid-1980s, indirect evaluation of fetal hemolytic disease was almost always accomplished by determining the amount of bilirubin pigment in amnionic fluid by spectrophotometric analysis. There is now reasonable experience with sonographically-directed fetal blood sampling to warrant, in some cases, direct assessment of the degree of hemolysis and anemia, as well as identifying the presence or absence of the suspected antigen.
The absorbance of breakdown pigments, mostly bilirubin, in the supernatant of amnionic fluid, when measured in a continuously recording spectrophotometer, is demonstrable as a hump with maximum absorbance at 450 nm wavelength, as shown in Figure 42–10. Because the change in optical density is measured, this is referred to as DOD450. The magnitude of the increase in optical density above baseline at 450 nm most often, but not always, correlates well for any gestational age with the intensity of the hemolytic disease.
Liley (1964) constructed a graph that provides for reasonably precise prediction of the severity of hemolysis, a modification of which is demonstrated in Figure 42–11. Depending on the severity of disease, amniocenteses are repeated at 1- to 3-week intervals (American College of Obstetricians and Gynecologists, 1990). In general such amniocenteses are initiated at 24 to 26 weeks. Prior to this time, there is limited data regarding normal values for amnionic fluid optical density readings (Queenan and co-workers, 1993). Thus, in mothers with a history of early fetal hydrops or death from isoimmunization, cordocentesis and direct fetal blood analysis is often appropriate. Although some clinicians with extensive experience in cordocentesis have abandoned amnionic fluid analysis altogether in favor of serial cordocentesis, such an approach has not been demonstrated to be superior and its routine use remains controversial. Not only do risks of cordocentesis exceed those of amniocentesis, but the degree of isoimmunization may increase following this procedure .
Optical density values in zone 1 generally indicate an unaffected fetus, one who will only have mild disease, or a D-negative fetus. Values in zone 3 indicate a severely affected fetus, and death within 7 to 10 days may be expected. Transfusion or delivery is indicated. In zone 2, the prognosis is less accurate, but the fetus is at moderate to severe risk and repeated amniocentesis or fetal blood sampling may be required to establish the actual condition of the fetus. In lower zone 2, the expected fetal hemoglobin concentration is between 11.0 and 13.9 g/dL, whereas in upper zone 2, the anticipated hemoglobin level ranges from 8.0 to 10.9 g/dL.
Ananth and Queenan (1989), in a study of 32 women with D-isoimmunized pregnancies at 16 to 20 weeks, reported that amnionic fluid DOD450 values greater than 0.15 were predictive of severe fetal hemolysis, while those less than 0.09 had mild or no disease. Values between these two were not predictive and require further evaluation.
Fetal Blood Sampling
Nicolaides and colleagues (1986) studied 59 D-isoimmunized pregnancies at 18 to 25 weeks, and reported poor correlation in nonhydropic fetuses between the degree of fetal anemia and the trend in amnionic fluid analysis using the Liley graph. Nicolaides and Snijders (1992) concluded that the only reliable method to determine severity in the second trimester is direct measurement of fetal hemoglobin. Nicolaides and co-workers (1988) recommend that transfusions be commenced when the hemoglobin deficit exceeds 2 g/dL from the mean for normal fetuses of corresponding gestational age . Despite these concerns, amnionic fluid analysis remains an important and accepted means of managing the isoimmunized woman. Queenan and associates (1993) provided data regarding the utility of amnionic fluid analysis as early as 14 weeks.
Intraperitoneal Fetal Transfusions
The refinement in prognostic precision furnished by amnionic fluid analysis led Liley (1963) to try, in apparently hopeless cases, intrauterine blood transfusion into the fetal peritoneal cavity. With such transfusions, the overall survival rate in more recent years was probably about 50 percent. The team in Winnipeg, however, has been much more successful. They reported 100 percent survival of nonhydropic fetuses and 75 percent survival of hydropic fetuses when treated with intrauterine transfusion, or an overall survival rate of 92 percent (Harman and co-workers, 1983). Watts and colleagues (1988) reported similar results. Both groups emphasized improved fetal evaluation through the use of real-time sonography before, during, and after fetal transfusion.
At Winnipeg Center, 731 fetal transfusions have been carried out on 302 fetuses since the first transfusion was attempted in 1964. Mortality has decreased progressively as follows: 1964 to 1968, 55 percent; 1968 to 1972, 34 percent; 1972 to 1976, 34 percent; 1976 to 1980, 29 percent; and the recent study cited earlier, 8 percent. Importantly, the publicly funded anti-D prophylaxis program in Manitoba has lowered the risk of sensitization of mothers in that province from 13 percent to 0.18 percent, and in turn the frequency of intrauterine transfusions.
In a comparison of 44 intraperitoneal versus 44 intravascular transfusions, Harman and colleagues (1990) reported that the intravascular approach resulted in significantly more surviving infants (91 versus 66 percent), fewer infants with Apgar scores of less than 7 at 5 minutes (14 versus 38 percent), and increased frequency of vaginal delivery (83 versus 50 percent). They concluded that although intraperitoneal transfusion should not be abandoned, it was relegated a second-choice procedure for very limited circumstances (Harman and colleagues, 1990).
Intravascular Fetal Transfusions
In 1981, the group from Lewisham Hospital in London described a technique for direct intravascular blood transfusion using fetoscopy (Rodeck and colleagues, 1981). Subsequent to this (1984), they reported results from 25 severely D-isoimmunized fetuses, including 15 with hydrops, who were given intravascular transfusions between 19 and 32 weeks. They again used fetoscopy, but some of these transfusions were now accomplished using sonographically-directed needle placements. Those fetuses in whom treatment was begun before 25 weeks had a remarkable 84 percent survival. Since this time, investigators from Yale (Grannum and colleagues, 1986) and Mount Sinai in New York (Berkowitz and co-workers, 1988) have also reported their successes with the method, which is shown in Figure 42–13. In many centers, this procedure has largely replaced the intraperitoneal technique for transfusion.
Ney and co-workers (1991) reported an overall survival of 85 percent with intravascular transfusion in severely isoimmunized fetuses. Survival was not significantly different comparing hydropic fetuses with non-hydropic fetuses in their study. Weiner and colleagues (1991a) reported an overall survival rate of 96 percent when intravascular transfusion was given for severe fetal anemia defined as a hematocrit of 30 percent or less.
Nicolini and associates (1990) described fetal blood sampling and intravascular transfusion utilizing the fetal intrahepatic vein. A fetal blood sample was successfully obtained in 91 percent of attempts, and the fetal hematocrit was raised to satisfactory levels in approximately 90 percent of the transfusions. The survival rate in 42 fetuses who were transfused was 86 percent.
Although intravascular transfusion is a relatively safe procedure, it is not without risk. In a review of 594 diagnostic cordocenteses and 156 intravascular transfusions, Weiner and associates (1991b) reported that duration of bleeding was greater with arterial than venous puncture and with intravascular transfusions compared with diagnostic venipuncture. Preterm prematurely ruptured membranes and amnionitis developed overall in 0.4 percent and 0.5 percent of procedures, respectively. Fetal bradycardia was identified in 7 percent of all cases, and the perinatal loss rate as 0.8 percent. Other complications include hyperkalemia (Thorp and associates, 1990), development of a porencephalic cyst (Dildy and colleagues, 1991), and depressed neonatal erythropoiesis (Millard and co-workers, 1990; Thorp and collaborators, 1991). Radunovic and co-workers (1992) have reported increased mortality in hydropic fetuses who had acute hematocrit increases associated with intravascular transfusions. Schumacher and Moise (1996) recently reviewed fetal transfusions for red cell alloimmunization.
Molecular Genetics and Isoimmunization
Molecular Genetics and Isoimmunization. Work by Dildy (1996), Fisk (1994), Rossiter (1994), and van den Veyer (1996) and their colleagues demonstrates the feasibility of fetal D-antigen typing from amniocytes or chorionic villi, using polymerase chain reaction. Such techniques will most likely allow women whose partners are heterozygous for the D antigen to determine fetal blood type without cordocentesis, and potentially avoid unnecessary invasive procedures.
Subsequent Child Development
In Bowman’s experience (1978), the great majority of fetal transfusion survivors developed normally; 74 of 89 tested when 18 months of age or older were completely normal, four were abnormal, whereas development in 11 appeared somewhat delayed, perhaps because of preterm birth.
Other Methods to Try to Minimize Fetal Hemolysis
In an attempt to prevent D-antibody formation, to remove antibody already formed, or to block antibody action on the red cell, a number of techniques have been tried without consistent success. Plasmapheresis does not appear to provide benefits that outweigh the risks and the costs. Promethazine in large doses has been cited by some as being beneficial (Charles and Blumenthal, 1982); however, this is unproven. D-positive erythrocyte membrane in enteric coated capsules has been administered orally to sensitized women throughout pregnancy on the basis that such treatment might induce T-suppressor cell formation that would in turn reduce antibody response to challenges by the antigen. This also does not appear to provide any benefit (Gold and co-workers, 1983). Attempts at immunosuppression with corticosteroids have proven to be of no benefit.
Method of Delivery
The fetus who is to be delivered remote from term because of evidence of hemolytic disease will sometimes benefit from cesarean section. By doing so, the time of birth is set and the most experienced personnel can be assembled to provide for optimal treatment.
Exchange Transfusion in the Newborn
Cord blood analysis should be carried out immediately for any pregnancy in which the D-negative mother is known to be sensitized. Cord blood hemoglobin concentration and direct Coombs test are of considerable importance when the infant is D-positive. If the infant is overtly anemic, it is often best to carry out the initial exchange promptly to correct anemia. Type O, D-negative red cells, recently collected, are used. For infants who are not overtly anemic, the need for exchange transfusion is determined by the rate of increase in bilirubin concentration, the maturity of the infant, and the presence or absence of other complications.
Disposal of Bilirubin
Before birth, unconjugated or free bilirubin is readily transferred across the placenta from fetal to maternal circulation—and vice versa, if the maternal plasma level of unconjugated bilirubin is high. Whereas bilirubin glucuronide is water soluble and normally is excreted into the bile by the liver and into the urine by the kidney when the plasma level is elevated, unconjugated bilirubin is not excreted in the urine or to any extent in the bile.
The great concern over unconjugated hyperbilirubinemia in the newborn, especially the premature, is its association with kernicterus. The yellow staining of the basal ganglia and hippocampus is indicative of profound degeneration in these regions. Surviving infants show spasticity, muscular incoordination, and varying degrees of mental retardation. There is a positive correlation between kernicterus and unconjugated bilirubin levels above 18 to 20 mg/dL, although kernicterus may develop at much lower concentrations, especially in very preterm infants.
Factors other than the serum bilirubin concentration contribute to the development of kernicterus. Hypoxia and acidosis enhance bilirubin toxicity. Both hypothermia and hypoglycemia predispose the infant to kernicterus by raising the level of nonesterified fatty acids, which compete with bilirubin for the binding sites on albumin and inhibit bilirubin conjugation. Sepsis contributes to kernicterus, although the mechanism is not clear. Although it is extremely unlikely that they lead to kernicterus, sulfonamides and salicylates may increase the level of bilirubin because they compete with unconjugated bilirubin for protein-binding sites. Sodium benzoate, in injectable diazepam, furosemide, and gentamicin, displaces bilirubin from albumin. Excessive doses of vitamin K analogues may be associated with hyperbilirubinemia. The importance of the serum albumin concentration and the binding sites so provided is obvious.
Breast Milk Jaundice
Breast milk jaundice has been attributed to the excretion of pregnane-3a,20b-diol into breast milk by some mothers. This steroid was reported by Arias and colleagues (1964) to block bilirubin conjugation by inhibiting glucuronyl transferase activity. Breast milk samples from mothers of infants with hyperbilirubinemia have been described to have an unusually high lipolytic activity and liberate large quantities of fatty acids that inhibit bilirubin conjugation (Foliot and co-workers, 1976). Another explanation is that bilirubin is broken down in the intestine to form free bilirubin, which can be reabsorbed. Usually, bovine milk and human milk appear to block the reabsorption of free bilirubin, whereas the milk of mothers with jaundiced offspring does not, and may even enhance its reabsorption. With breast milk jaundice, the serum bilirubin level rises from about the fourth day after birth to a maximum by 15 days. If breast feeding is continued, the high levels persist for another 10 to 14 days and slowly decline over the next several weeks. No cases of overt bilirubin encephalopathy have been reported caused by this phenomenon (Maisels, 1979).
By far the most common form of unconjugated nonhemolytic jaundice is so-called physiological jaundice. In the mature infant, the serum bilirubin increases for 3 to 4 days to achieve serum levels up to 10 mg/dL or so and then falls rapidly. In preterm infants, the rise is more prolonged and may be more intense. Jaundice in the newborn should not be ignored as being physiological in the following circumstances:
1. The infant is visibly jaundiced in the first 24 hours after birth.
2. The total bilirubin concentration in serum is increasing daily by more than 5 mg/dL.
3. The total bilirubin concentration is above 15 mg/dL.
4. Jaundice is visible for more than 1 week in a term infant or 2 weeks in a preterm infant.
Exchange transfusion for severe hyperbilirubinemia is not associated with a mortality rate of less than 1 percent when moribund, hydropic, and kernicteric infants are excluded from analysis.
Phototherapy is now widely used to treat hyperbilirubinemia. In most instances, its use leads to a lower bilirubin level from its oxidation. Light that penetrates the skin also increases peripheral blood flow, which enhances photo-oxidation. By some unknown mechanism, light seems to promote hepatic excretion of unconjugated bilirubin. As much surface area as possible should be exposed, and the infant should be turned every 2 hours with close temperature monitoring to prevent dehydration. The fluorescent bulbs must be appropriate wavelength and the eyelids should be closed and completely shielded from light. Serum bilirubin should be monitored for at least 24 hours after discontinuance of phototherapy.
Much attention has focused on the immune system as important in recurrent pregnancy loss. Two primary pathophysiological models that have evolved are the autoimmune theory (immunity against self) and the alloimmune theory (immunity against another person).
AUTOIMMUNE FACTORS. It has been determined from compiled studies that approximately 15 percent of over 1000 recurrent pregnancy loss patients have recognized autoimmune factors (Kutteh and Pasquarette, 1995). The most significant antibodies have specificity against negatively charged phospholipids and are most commonly detected by testing for lupus anticoagulant (LAC) and anticardiolipin antibody (ACA). Women with both a history of early fetal loss and high levels of antibodies may suffer a 70 percent miscarriage recurrence (Dudley and Branch, 1991). Pooling studies totaling 1500 women with recurrent loss yields an average incidence of 17 percent for anticardiolipin antibody and 7 percent for lupus anticoagulant. In contrast, only 1 to 3 percent of normal obstetrical patients are found to have either of these (Harris and Spinnato, 1991; Lockwood and colleagues, 1989). In a prospective study of 860 women screened for anticardiolipin antibody in the first trimester, Yasuda and colleagues (1995) reported that 60 (7 percent) were positive. Spontaneous abortion occurred in 25 percent of the antibody-positive group compared with 10 percent of the negative group.
Lupus anticoagulant is an immunoglobulin (IgG, IgM, or both) that interferes with one or more of the phospholipid-dependent tests of in vitro coagulation. The term is a misnomer because it is associated with clinically important increases in thromboembolic events. Second, lupus anticoagulant is most often diagnosed in patients who do not meet the diagnostic criteria for lupus .
Antiphospholipid antibodies are acquired antibodies targeted against a phospholipid. They can be of the IgG, IgA, or IgM isotope. The mechanism of pregnancy loss in these women is thought to involve placental thrombosis and infarction. One mechanism may involve the inhibition of prostacyclin release (Fig. 26–5 ). This product of endothelial cells is a potent vasodilator and inhibitor of platelet aggregation. On the other hand, platelets produce thromboxane A2, a vasoconstrictor and platelet aggregator. These antibodies therefore may reduce prostacyclin production, facilitating a thromboxane dominant milieu that leads to thrombosis. In addition, they have been shown to inhibit protein C activation.
Investigators have proposed various treatments for the antiphospholipid antibody syndrome including low-dose aspirin, prednisone, heparin, and intravenous immunoglobulin (Coulam, 1995). These treatments are thought to counteract the adverse action of antibodies by affecting both the immune and coagulation systems. Cowchock and colleagues (1992) performed a randomized trial comparing prednisone to low-dose heparin therapy in 20 women with antibodies and recurrent pregnancy loss. Live-birth rates were equal (75 percent) for both groups. However, those women receiving a glucocorticoid demonstrated a significantly greater incidence of maternal and fetal morbidity. Kutteh (1996) described 50 such women who were treated with either heparin and low-dose aspirin or aspirin alone. Heparin was initiated at 5000 u subcutaneously twice daily with a positive pregnancy test and titrated according to the partial thromboplastin time and platelet count. Although 76 percent of women in the heparin plus aspirin group delivered viable infants, only 44 percent of those treated with aspirin alone had a live birth. Maternal and obstetrical complications were low in both groups. Recent data indicate that antibodies bind directly to heparin in vitro and function in a similar way in vivo, thereby decreasing the adverse effects of the antibodies by increasing their clearance (Ermel and associates, 1995).
ALLOIMMUNE FACTORS. A number of women with recurrent pregnancy loss have been diagnosed as having an alloimmune cause. They have received a variety of therapies targeted at stimulating maternal immune tolerance of fetal material. Diagnosis of an alloimmune factor has centered on several tests: (1) maternal and paternal HLA comparison, (2) assessment of maternal serum for the presence of cytotoxic antibodies to paternal leukocytes, and (3) maternal serum testing for blocking factors for maternal–paternal mixed lymphocyte reactions. In essence, those couples determined to have significant HLA-type homology, or in which the women were found to have minimal antipaternal antibodies, were judged to represent an alloimmune disorder.
Some physicians have infused pooled human immunoglobulin as an alternative to paternal lymphocyte therapy. A recent prospective, double-blind, placebo-controlled trial using intravenous gamma globulin to treat women with recurrent loss demonstrated an improvement in women receiving this treatment versus placebo (Coulam, 1995).
Guerrero and Rojas (1975) noted an increased incidence of abortion relative to successful pregnancies when insemination occurred 4 days before or 3 days after the time of shift in basal body temperature. They concluded, therefore, that aging of the gametes within the female genital tract before fertilization increased the chance of abortion. Dickey and colleagues (1992) reported that in infertility patients over 35 there was a higher incidence of small amnionic sac syndrome and an increased incidence of euploidic abortion. Whether ovulation induction or in vitro fertilization result in aging of gametes prior to implantation is not known.
Disorders of Amnionic Fluid Volume
Normally, amnionic fluid volume increases to about 1 L, or somewhat more by 36 weeks, but decreases thereafter . Postterm, there may be only a few hundred mL or less. Diminished fluid volume is termed oligohydramnios. Somewhat arbitrarily, more than 2000 mL of amnionic fluid is considered excessive and is termed hydramnios and sometimes called polyhydramnios. In rare instances, the uterus may contain an enormous quantity of fluid, with reports of as much as 15 L. In most instances, chronic hydramnios develops, which is the gradual increase of amnionic fluid. In acute hydramnios, the uterus may become markedly distended within a few days.
Measurement of Amnionic Fluid
Over the past two decades, a number of ultrasonic methods have been used to measure the amount of amnionic fluid. Limitations of using a single pocket of amnionic fluid to determine accurate quantification of fluid were obvious. Accordingly, Phelan and colleagues (1987) described the clinical utility of quantification using the amnionic fluid index. This is calculated by adding the vertical depths of the largest pocket in each of four equal uterine quadrants. According to their calculations, significant hydramnios is defined by an index greater than 24 cm. Moore and Cayle (1990) reported normal values for the index for 791 normal pregnancies from 16 to 42 weeks (Table 29–3 ). Hallak and colleagues (1993) studied 892 normal pregnancies and reported similar trends, but lower absolute numbers (Fig. 29–2 ). Porter and associates (1996) have provided normal values for 282 twin pregnancies.
Magann and associates (1992) used the dye-dilution technique to measure amnionic fluid in 40 women undergoing amniocentesis in late pregnancy. They found that the amnionic fluid index was reasonably reliable in determining normal or increased amnionic fluid, but was inaccurate to diagnosis oligohydramnios. Williams (1993) reviewed techniques and concluded that there is good inter- and intra-observer variability. In a preliminary study, Bootstaylor and associates (1996) found that assessment of the index with the woman in the lateral decubitus position correlated well with supine values. Peedicayil and colleagues (1994) emphasized that borderline values should be repeated before interventions are undertaken.
Importantly, several factors may modulate the amnionic fluid index. Yancey and Richards (1994) reported that high altitude (6000 ft) was associated with an increased index. Kilpatrick and Safford (1993), but not Kerr and associates (1996), showed that maternal oral hydration increased the index consistently. Conversely, fluid restriction may lower the index.
Minor to moderate degrees of hydramnios—2 to 3 L—are rather common. Because of the difficulty of complete collection and measurement of fluid, the diagnosis is usually based on clinical impression (Fig. 29–3 ) confirmed by sonographic estimation. The frequency of the diagnosis varies appreciably with different observers, and it is not surprising that published data on its incidence have varied from 1 in about 60 deliveries to 1 in 750.
Hill and associates (1987) from the Mayo Clinic provide a reasonably accurate incidence of hydramnios using ultrasonic measurements. More than 9000 prenatal patients underwent routine ultrasonic evaluation near the end of the second or the beginning of the third trimester. The overall incidence of hydramnios was 0.9 percent. Mild hydramnios—defined as pockets measuring 8 to 11 cm in vertical dimension—were present in 80 percent of cases with excessive fluid. Moderate hydramnios—defined as a pocket containing only small parts measured 12 to 15 cm deep—was found in 15 percent. Finally, 5 percent had severe hydramnios defined by a free-floating fetus found in pockets of fluid of 16 cm or greater. Although two thirds of all cases were idiopathic, the other third were associated with fetal anomalies, maternal diabetes, or multifetal gestation. Golan and co-workers (1993) reported remarkably similar findings in nearly 14,000 women.
Causes of Hydramnios
Significant hydramnios is frequently associated with fetal malformations, especially of the central nervous system or gastrointestinal tract. For example, hydramnios accompanies about half of cases of anencephaly and esophageal atresia. In the Mayo Clinic study, which dealt exclusively with their own population, the cause of mild hydramnios was identified in only about 15 percent of cases, whereas in cases with moderately or severely increased amnionic fluid, the cause was identified in more than 90 percent. In almost half of cases with moderate and severe hydramnios, a fetal anomaly was identified.
Mild midtrimester hydramnios does not have a bleak prognosis. Glantz and co-workers (1994) studied 47 consecutive singleton pregnancies with a single deepest pocket of 6 to 10 cm at 14 to 27 weeks. This resolved spontaneously in three fourths and perinatal outcomes were similar to matched controls without hydramnios. In the group in which hydramnios persisted, 2 of 10 had fetal aneuploidy.
By contrast, Damato and colleagues (1993) reported results from 105 referred women sent to their prenatal diagnostic center for evaluation of excessive fluid. Using definitions similar to those described by Hill and associates (1987), these investigators observed that almost 65 percent of the 105 pregnancies were anomalous (Table 29–4 ). There were 47 singletons with one or more anomalies: gastrointestinal (15), nonimmune hydrops (12), central nervous system (12), thoracic (9), skeletal (8), chromosomal (7), and cardiac (4). Among 19 twin pregnancies, only two were normal. Twelve of the remaining 17 had twin–twin transfusion.
Using an index of 24 cm to define hydramnios, some studies indicate that perinatal mortality is increased substantively. In a report by Carlson and associates (1990), of 49 women with an amnionic fluid index of 24 cm or more, 22 (44 percent) had a recognized fetal malformation and six of these fetuses had aneuploidy. Moreover, there were 14 perinatal deaths among these 49 women. Brady and colleagues (1992) described findings with unexplained or idiopathic hydramnios in 125 cases found in over 5000 nonreferred pregnant women. They used a definition of an index of 25 cm or greater, and reported two fetuses with trisomy 18 and two with trisomy 21. Zahn and co-workers (1993) described outcomes in 45 referred women. A third had major structural malformations and 10 percent of the 45 had chromosomal anomalies.
Smith and colleagues (1992) reported no increase in adverse pregnancy outcomes in 97 women with mild, unexplained hydramnios defined by an amnionic fluid index of 24 to 40 cm (mean 28.3 cm). Perhaps this should not be surprising; Moise (1991) emphasized that the normal range for the amnionic fluid index exceeds 24 cm between 26 and 39 weeks. He recommended that the best criterion for hydramnios is an index greater than three standard deviations, or the 97.5 percentile for gestational age .
Early in pregnancy, the amnionic cavity is filled with fluid very similar in composition to extracellular fluid. During the first half of pregnancy, transfer of water and other small molecules takes place not only across the amnion but through the fetal skin. During the second trimester, the fetus begins to urinate, swallow, and inspire amnionic fluid (Abramovich and colleagues, 1979; Duenhoelter and Pritchard, 1976). These processes almost certainly have a significant modulating role in the control of fluid volume. Although the major source of amnionic fluid in hydramnios has most often been assumed to be the amnionic epithelium, no histological changes in amnion or chemical changes in amnionic fluid have been found.
Because the fetus normally swallows amnionic fluid, it has been assumed that this mechanism is one of the ways by which the volume is controlled. The theory gains validity by the nearly constant presence of hydramnios when swallowing is inhibited as in cases of esophageal atresia. Fetal swallowing is by no means the only mechanism for preventing hydramnios. Both Pritchard (1966) and Abramovich (1970) quantified this and found in some instances of gross hydramnios that appreciable volumes of fluid were swallowed.
In cases of anencephaly and spina bifida, increased transudation of fluid from the exposed meninges into the amnionic cavity may be an etiological factor. Another possible explanation in anencephaly, when swallowing is not impaired, is excessive urination caused either by stimulation of cerebrospinal centers deprived of their protective coverings, or lack of antidiuretic effects of impaired arginine vasopressin secretion. The converse is well established—that fetal defects that cause anuria are nearly always associated with oligohydramnios.
In hydramnios associated with monozygotic twin pregnancy, the hypothesis has been advanced that one fetus usurps the greater part of the circulation common to both twins and develops cardiac hypertrophy, which in turn results in increased urine output (Chap. 38 ). Naeye and Blanc (1972) identified dilated renal tubules, enlarged bladder, and an increased urinary output in the early neonatal period, suggesting that increased fetal urine production is responsible for hydramnios. Conversely, donor members of parabiotic transplacental transfusion pairs had contracted renal tubules with oligohydramnios.
Hydramnios that rather commonly develops with maternal diabetes during the third trimester remains unexplained. One explanation is that maternal hyperglycemia causes fetal hyperglycemia that results in osmotic diuresis. Bar-Hava and associates (1994) have provided evidence that third-trimester amnionic fluid volume in 399 gestational diabetes reflected recent glycemic status. Yasuhi and co-workers (1994) reported increased fetal urine production in fasted diabetic women compared with nondiabetic controls. Of interest, fetal urine production increased in nondiabetic women after eating, but this was not observed in the diabetic woman.
Major symptoms accompanying hydramnios arise from purely mechanical causes and result principally from pressure exerted within and around the overdistended uterus upon adjacent organs. When distension is excessive, the mother may suffer from severe dyspnea and, in extreme cases, she may be able to breathe only when upright. Edema, the consequence of compression of major venous systems by the very large uterus, is common, especially in the lower extremities, the vulva, and the abdominal wall. Rarely, severe oliguria may result from ureteral obstruction by the very large uterus .
With chronic hydramnios, the accumulation of fluid takes place gradually and the woman may tolerate the excessive abdominal distension with relatively little discomfort. In acute hydramnios, however, distension may lead to disturbances sufficiently serious to be threatening. Acute hydramnios tends to develop earlier in pregnancy than does the chronic form—often as early as 16 to 20 weeks—and it may rapidly expand the hypertonic uterus to enormous size. As a rule, acute hydramnios leads to labor before 28 weeks, or the symptoms become so severe that intervention is mandatory. In the majority of cases of chronic hydramnios, and thus differing from acute hydramnios, the amnionic fluid pressure is not appreciably higher than in normal pregnancy.
The primary clinical finding with hydramnios is uterine enlargement in association with difficulty in palpating fetal small parts and in hearing fetal heart tones. In severe cases, the uterine wall may be so tense that it is impossible to palpate any fetal parts (Fig ).
The differentiation among hydramnios, ascites, and a large ovarian cyst can usually be made without difficulty by ultrasonic evaluation. Large amounts of amnionic fluid can nearly always be readily demonstrated as an abnormally large echo-free space between the fetus and the uterine wall or placenta . At times, a fetal abnormality such as anencephaly or other neural-tube defects, or a gastrointestinal tract anomaly, may be seen.
In general, the more severe the degree of hydramnios, the higher the perinatal mortality rate. The outlook for the infant in pregnancies with marked hydramnios is poor. Even when sonography and x-ray show an apparently normal fetus, the prognosis is still guarded, because fetal malformations and chromosomal abnormalities are common. Perinatal mortality is increased further by preterm delivery, even with a normal fetus. Many and colleagues (1995) reported that 19 percent of 275 women with an index of at least 25 cm delivered preterm. Preterm delivery was more common with an anomalous fetus (39 percent). Erythroblastosis, difficulties encountered by infants of diabetic mothers, prolapse of the umbilical cord when the membranes rupture, and placental abruption as the uterus rapidly decreases in size, add still further to bad outcomes.
The most frequent maternal complications associated with hydramnios are placental abruption, uterine dysfunction, and postpartum hemorrhage. Extensive premature separation of the placenta sometimes follows escape of massive quantities of amnionic fluid because of the decrease in the area of the emptying uterus beneath the placenta (Chap. 32 ). Uterine dysfunction and postpartum hemorrhage result from uterine atony consequent to overdistention. Abnormal presentations and operative intervention are also more common.
Minor degrees of hydramnios rarely require treatment. Even moderate degrees with some discomfort can usually be managed without intervention until labor ensues or until the membranes rupture spontaneously. If there is dyspnea or abdominal pain, or if ambulation is difficult, hospitalization becomes necessary. Bed rest rarely has any effect, and diuretics and water and salt restriction are likewise ineffective. Recently, indomethacin therapy has been used for symptomatic hydramnios.
The principal purpose of amniocentesis is to relieve maternal distress, and to that end it is transiently successful. At times, amniocentesis appears to initiate labor even though only a part of the fluid is removed; hence, relief of distress may not allow continuation of pregnancy. Elliott and associates (1994) reported results from 200 therapeutic amniocenteses in 94 women with hydramnios. Common causes included twin–twin transfusion (38 percent), idiopathic (26 percent), fetal or chromosomal anomalies (17 percent), and diabetes (12 percent). They removed a mean of 1650 mL of fluid at each procedure and gained an average duration of 7 weeks to delivery. Only three procedures were complicated: one woman had ruptured membranes, one developed chorioamnionitis, and another suffered placental abruption after 10 L of fluid was removed.
To remove amnionic fluid, a commercially available plastic catheter that tightly covers an 18-gauge needle is inserted through the locally anesthetized abdominal wall into the amnionic sac, the needle is withdrawn, and an intravenous infusion set is connected to the catheter hub. The opposite end of the tubing is dropped into a graduated cylinder placed at floor level, and the rate of flow of amnionic fluid is controlled with the screw clamp so that about 500 mL/hr is withdrawn. After about 1500 to 2000 mL have been collected, the uterus has usually decreased in size sufficiently so that the catheter may be withdrawn from the amnionic sac. At the same time, maternal relief is dramatic and the danger of placental separation from decompression is very slight. Using strict aseptic technique, this procedure can be repeated as necessary to make the woman comfortable. Elliott and colleagues (1994) used wall suction and removed 1000 mL over 20 minutes (50 mL/min); however, we prefer more gradual removal.
The disadvantages inherent in rupture of the membranes through the cervix is the possibility of cord prolapse and especially of placental abruption. Slow removal of the fluid by amniocentesis helps to obviate these dangers.
In their review of several studies, Kramer and colleagues (1994) concluded that indomethacin impairs lung liquid production or enhances absorption, decreases fetal urine production, and increases fluid movement across fetal membranes. Doses employed by most investigators range from 1.5 to 3 mg/kg per day.
Cabrol and associates (1987) treated eight women with idiopathic hydramnios from 24 to 35 weeks with indomethacin for 2 to 11 weeks. Hydramnios, defined by at least one 8-cm fluid pocket, improved in all cases. There were no serious adverse effects and the outcome was good in all cases. Kirshon and associates (1990) treated eight women (three sets of twins) with hydramnios from 21 to 35 weeks. In all of these, two therapeutic amniocenteses had been done before indomethacin was given. Of 11 fetuses, three were stillborn associated with twin–twin transfusion syndrome and one newborn died at 3 months of age. The remaining seven infants did well. Mamopoulos and colleagues (1990) treated 15 women—11 were diabetic—who had hydramnios at 25 to 32 weeks. Indomethacin was given and amnionic fluid volume decreased in all women, from a mean of 10.7 cm at 27 weeks to 5.9 cm after therapy. The outcome was good in all 15 newborns.
A major concern for the use of indomethacin is the potential for closure of the fetal ductus arteriosus . Moise and colleagues (1988) reported that 50 percent of 14 fetuses whose mothers received indomethacin had ductal constriction detected by Doppler ultrasound. Persistent constriction was not demonstrated in the studies described earlier, nor has it been described in studies in which indomethacin was given for tocolysis (Kramer and colleagues, 1994).
In rare instances, the volume of amnionic fluid may fall far below the normal limits and occasionally be reduced to only a few mL of viscid fluid. The cause of this condition is not completely understood. In general, oligohydramnios developing early in pregnancy is less common and frequently has a bad prognosis. By contrast, diminished fluid volume may be found relatively often with pregnancies that continue beyond term. Marks and Divon (1992) found oligohydramnios—defined as an amnionic fluid index of 5 cm or less—in 12 percent of 511 pregnancies 41 weeks or greater. In 121 women who they studied longitudinally, there was a mean decrease in the amnionic fluid index of 25 percent per week beyond 41 weeks. The risk of cord compression, and in turn fetal distress, is increased as the consequence of diminished fluid in all labors, but especially in postterm pregnancy (Grubb and Paul, 1992; Leveno and colleagues, 1984).
A number of conditions have been associated with diminished fluid. Oligohydramnios is almost always evident when there is either obstruction of the fetal urinary tract or renal agenesis. Therefore, anuria almost certainly has an etiological role in such cases. A chronic leak from a defect in the membranes may reduce the volume of fluid appreciably, but most often labor soon ensues. Exposure to angiotensin-converting enzyme inhibitors has been associated with oligohydramnios . Anywhere from 15 to 25 percent of cases are associated with the fetal anomalies .
Fetal prognosis is poor with early-onset oligohydramnios. Shenker and colleagues (1991) described 80 such pregnancies and only half of these fetuses survived. Mercer and Brown (1986) described 34 midtrimester pregnancies complicated by oligohydramnios diagnosed ultrasonically by the absence of amnionic-fluid pockets greater than 1 cm in any vertical plane. Nine of these fetuses (26 percent) had anomalies, and 10 of the 25 who were phenotypically normal either aborted spontaneously or were stillborn because of severe maternal hypertension, restricted fetal growth, or placental abruption. Of the 14 live-born infants, eight were preterm and seven died. The six infants who were delivered at term did well.
Newbould and colleagues (1994) described autopsy findings in 89 infants with the oligohydramnios sequence. Only 3 percent had a normal renal tract; 34 percent had bilateral renal agenesis; 34 percent bilateral cystic dysplasia, 9 percent unilateral agenesis with dysplasia, and 10 percent minor urinary abnormalities.
Otherwise normal infants may suffer the consequences of early-onset severely diminished amnionic fluid. Adhesions between the amnion and fetal parts may cause serious deformities including amputation. Moreover, subjected to pressure from all sides, the fetus assumes a peculiar appearance, and musculoskeletal deformities such as clubfoot are observed frequently.
PULMONARY HYPOPLASIA. The incidence of pulmonary hypoplasia at birth has been unchanged and ranges from 1.1 to 1.4 per 1000 infants (Moessinger and colleagues, 1989). When amnionic fluid is scant, pulmonary hypoplasia is common (Fig. 29–5 ). According to Fox and Badalian (1994) and Lauria and colleagues (1995), there are three possibilities that account for pulmonary hypoplasia. First, thoracic compression may prevent chest wall excursion and lung expansion. Second, lack of fetal breathing movements decrease lung inflow. The third and most widely accepted model is there is a failure to retain amnionic fluid or increased outflow with impaired lung growth and development.
The appreciable volume of amnionic fluid demonstrated by Duenhoelter and Pritchard (1976) to be inhaled by the normal fetus is suggestive of a role for the inspired fluid in expansion, and in turn growth, of the lung. Fisk and colleagues (1992), however, concluded that fetal breathing impairment does not cause pulmonary hypoplasia with oligohydramnios. In a unique experiment, McNamara and associates (1995) described findings from two sets of monoamnionic twins with discordant renal anomalies. They provided evidence that normal amnionic fluid volume in the presence of fetal renal obstruction allows normal lung development.
Oligohydramnios in Late Pregnancy
Oligohydramnios and decreased fetal urine production prior to labor may also be a marker for infants who may not tolerate labor well (Groome and associates, 1991). Significant oligohydramnios, defined by an amnionic fluid index of 5 cm or less, appears to be associated with an increased risk of adverse perinatal outcomes. Sarno and co-workers (1989, 1990) reported that an index of 5 cm or less was associated with a fivefold increased cesarean delivery rate. Baron and colleagues (1995) reported a 50 percent increase in variable decelerations during labor and a sevenfold increased cesarean delivery rate in these women. Divon and associates (1995) studied 638 postterm pregnancies in labor and observed that only women whose amnionic fluid index was 5 cm or less had fetal heart rate decelerations and meconium. Reporting preliminary data, Bush and colleagues (1996) found that a 500 mL saline bolus given intravenously to the mother increased amnionic fluid index in most cases of oligohydramnios. Interestingly, Chauhan and collaborators (1995) showed that diminished amnionic fluid index increased the cesarean delivery rate only in women whose labor attendants were made aware of the findings!
Infusion of crystalloid to replace pathologically diminished amnionic fluid has most often been used during labor to prevent umbilical cord compression . It was not found effective to decrease the incidence of meconium aspiration syndrome (Usta and colleagues, 1995). As reviewed by Lameier and Katz (1993), infusion of isotonic fluid by amniocentesis has been used to provide better contrast for ultrasonic fetal evaluation. Dye can also be instilled to document membrane rupture. Wenstrom and associates (1995) surveyed academic obstetrical departments and reported that amnioinfusion is widely performed with relatively few complications.