PRETERM LABOR, PROM, IUGR, POSTTERM PREGNANCY, AND IUFD
Calvin J. Hobel
Worldwide, preterm labor and delivery are major causes of perinatal morbidity and mortality. Although fewer than 12% of all infants born in the United States are preterm, their contribution to neonatal morbidity and mortality ranges from 50% to 70%. The medical and economic impact of preterm delivery is significant, and major goals of obstetric care are to reduce the incidence of the condition and to increase the gestational age of infants whose preterm births are unavoidable.
DEFINITION AND INCIDENCE
Preterm birth is usually defined as one occurring after 20 weeks and before 37 completed weeks of gestation. Labor that occurs between these gestational ages is defined as preterm labor. Internationally, the lower boundary defining preterm birth varies between 20 and 24 weeks.
Preterm births in the United States have increased from 9.8% in 1981 to 12.7% in 2005. Between 1988 and 2004, the mortality rate for white infants declined by 55% to 5.7 infant deaths per 1000 live births, and the mortality rate for black infants declined by 45% to 13.6. In the past 10 years, the decline in infant mortality for both races has been less than anticipated. Because prematurity is the leading cause of infant mortality, the prevention of prematurity has become a high priority.
ETIOLOGY AND RISK FACTORS
The estimated causes of preterm birth are listed in Table 12-1. Private patients have a much higher proportion of spontaneous preterm labor, whereas black patients in public institutions have a higher proportion of deliveries due to PPROM.
TABLE 12-1 ETIOLOGY OF PRETERM BIRTH
Estimated Percentage of Preterm Births
Spontaneous preterm labor
Preterm premature rupture of membranes (PPROM)
Cervical incompetence or uterine anomalies
Intrauterine growth restriction (IUGR)
∗ Increasing proportion due to advancing maternal age and assisted reproductive technologies (ART).
Attempts have been made to define further the spontaneous preterm labor subgroup. Some experts now believe this may be caused by undiagnosed conditions of placental, infectious, immunologic, uterine, or cervical origin. Recently, genetic thrombophilias have been shown to account for a significant proportion of the uteroplacental problems leading to intrauterine growth restriction (IUGR) and preeclampsia, the two major reasons for the early induction of labor to avoid fetal death. In the past 10 years, closer surveillance of high-risk pregnancies has led to earlier delivery and an increase in late preterm deliveries (between 34 and 37 weeks), a major contribution to the increasing preterm birth rate.
Another reason for the increasing incidence of preterm birth is that more women are postponing childbirth as a lifestyle choice. This is associated with a greater risk for infertility and therefore greater use of assisted reproductive technologies (ART), which are associated with multiple gestations and increased risk for preterm birth. A variety of socioeconomic, psychosocial, and medical conditions have been found to carry an increased risk for preterm delivery in these women who postpone childbearing.
In the United States, the incidence of preterm deliveries in the black population is twice as high as that in the white population. This factor cannot be viewed as a single entity but probably encompasses other characteristics of the population, such as poor access to and procurement of antenatal care, high stress levels, poor nutritional status, and the possibility of genetic differences.
Medical and Obstetric Factors
When one preterm birth has occurred, the relative risk for preterm delivery in the next pregnancy is 3.9, and the risk increases to 6.5 with two previous preterm deliveries.
Second-trimester abortions seem to carry an increased risk for subsequent preterm delivery, especially if a previous preterm birth has also occurred. The risk associated with induced first-trimester abortions is controversial. Repeated spontaneous first-trimester abortions, however, do increase the risk.
Other medical and obstetrical factors include bleeding in the first trimester, urinary tract infections, multiple gestation, uterine anomalies, polyhydramnios, and incompetent cervix.
Recently, attention has been directed toward maternal employment, physical activity, nutritional status, genital tract infections, stress, and anxiety as major risk factors for preterm birth.
“Group education” has been shown to decrease preterm birth. All at-risk patients, together with a healthcare provider, should discuss how to adjust personal behaviors and lifestyles to decrease the risk.
Four potential pathways leading to preterm delivery have been identified:
1. Infection (cervical)
3. Psychosocial stress and work strain (fatigue)
4. Uterine stretch (multiple gestations)
Bacterial vaginosis has been shown to be associated with preterm delivery, independent of other recognized risk factors. Treatment of bacterial vaginosis has reduced the incidence of preterm delivery. In addition, treating women in preterm labor with antibiotics significantly prolongs the time from the onset of treatment to delivery, compared with that in patients who do not receive antibiotics. Thus, addressing the issue of these relatively asymptomatic infections is an important strategy for preventing preterm birth.
There is a link between vaginal-cervical infections and progressive changes in the cervical length, as measured by vaginal ultrasonography. The relative risk for preterm birth increases significantly from 2.4 for a cervical length of 3.5 cm (50th percentile) to 6.2 for a length of 2.5 cm (10th percentile). Short cervices appear to be more common in women who have had prior preterm births and pregnancy terminations.
The most recent test to be developed is cervical and vaginal fetal fibronectin. This substance is a basement membrane protein produced by the fetal membranes. When the fetal membranes are disrupted, as with repetitive uterine activity, shortening of the cervix, and in the presence of infection, fibronectin is secreted into the vagina and can be tested. A positive fetal fibronectin test at 22 to 24 weeks predicts more than half of the spontaneous preterm births that occur before 28 weeks. A positive test for fetal fibronectin is significantly associated with a short cervix, vaginal infections, and uterine activity. A negative test is the best predictor of a low risk for preterm delivery.
The placental-vascular pathway begins early in pregnancy at the time of implantation, when there are important changes taking place at the placental-decidual-myometrial interface. First, there are important immunologic changes, with a switch from a TH1 type of immunity, which may be embryotoxic, to TH2 antibody profile, in which blocking antibody production is thought to prevent rejection. At the same time, the trophoblasts are invading the spiral arteries of the decidua and myometrium, thus assuring that a low-resistance vascular connection is established. Alterations in both of these early changes are thought to play an important role in the pathophysiology of poor fetal growth, an important component of preterm birth (indicated and spontaneous), fetal growth restriction, and preeclampsia.
Both mental (cognitive) and work-related stress and strain are postulated to initiate a stress response that increases release of cortisol and catecholamines. Cortisol from the adrenal gland initiates early placental corticotrophin-releasing hormone (CRH) gene expression, and elevated levels of CRH are known to initiate labor at term. Catecholamines released during the stress response not only affect blood flow to the uteroplacental unit but also cause uterine contractions (norepinephrine). Poor nutrition in the form of reduced calories or abnormal patterns of intake (fasting) are known stressors and have been associated with a significantly increased risk for preterm birth. In support of the stress pathway are the studies that have shown that the rate of change of CRH, a mediator of the stress response, increases significantly in the weeks before the onset of preterm labor. Stress reduction and improved nutrition are the only current interventions that can be applied to this pathway.
Uterine Stretch Pathway
Uterine stretch as a result of increasing volume during normal and abnormal gestations is an important physiologic mechanism that facilitates the process of emptying the uterus. This pathway is common in patients with polyhydramnios and those with multiple gestations, both of which have an increased risk for preterm birth.
The diagnosis of preterm labor occurring between 20 and 37 weeks is based on the following criteria in patients with ruptured or intact membranes: (1) documented uterine contractions (four per 20 minutes) and (2) documented cervical change (cervical effacement of 80% or cervical dilation of 2 cm or more). Uterine contractions are not a good predictor of preterm labor, but cervical changes are.
Provided that membranes are not ruptured and there is no contraindication to a vaginal examination (e.g., placenta previa), an initial assessment must be done to ascertain cervical length and dilation and the station and nature of the presenting part. The patient should also be evaluated for the presence of any underlying correctable problem, such as a urinary tract or vaginal infection. She should be placed in the lateral decubitus position (taking the weight of the uterus off the great vessels and improving blood flow to the uterus), monitored for the presence and frequency of uterine activity, and reexamined for evidence of cervical change after an appropriate interval, unless she already meets the preceding criteria for preterm labor. During the period of observation, either oral or parenteral hydration should be initiated.
With adequate hydration and bed rest, uterine contractions cease in about 20% of patients. These patients, however, remain at high risk for recurrent preterm labor.
Because of the role of cervical colonization and vaginal infection in the etiology of preterm labor and premature rupture of membranes, cultures should be taken for group B streptococcus. Other organisms that may be important are Ureaplasma, Mycoplasma, and Gardnerella vaginalis. The latter is associated with bacterial vaginosis, a diagnosis that can be made by the presence of three of four clinical signs (vaginal pH > 4.5, amine odor after addition of 10% potassium hydroxide [KOH], and presence of clue cells or milky discharge).
Antibiotics should be administered to patients who are in preterm labor. For patients who are not allergic to penicillin, a 7-day course of ampicillin, erythromycin, or both can be given. Those allergic to penicillin can be given clindamycin.
Once the diagnosis of preterm labor has been made, the following laboratory tests should be obtained: complete blood cell count, random blood glucose level, serum electrolyte levels, urinalysis, and urine culture and sensitivity. An ultrasonic examination of the fetus should be performed to assess fetal weight, document presentation, assess cervical length, and rule out the presence of any accompanying congenital malformation. The test may also detect an underlying etiologic factor, such as twins or a uterine anomaly.
If the patient does not respond to bed rest and hydration, tocolytic therapy is instituted, provided there are no contraindications. Measures implemented at 28 weeks should be more aggressive than those initiated at 35 weeks. Similarly, a patient with advanced cervical dilation on admission requires more aggressive management than one whose cervix is closed and minimally effaced.
UTERINE TOCOLYTIC THERAPY
It is assumed that physiologic events leading to the initiation of labor also occur in preterm labor. The pharmacologic agents presently being used all seem to inhibit the availability of calcium ions, but they may also exert a number of other effects. The agents currently used and their dosages are presented in Box 12-1.
BOX 12-1 Uterine Tocolytic Agents
Solution: Initial solution contains 6 g (12 mL of 50% MgSO4) in 100 mL of 5% dextrose. Maintenance solution contains 10 g (20 mL of 50% MgSO4) in 500 mL of 5% dextrose
Initial dose: 6 g over 15-20 min, parenterally
Titrating dose: 2 g/hr until contractions cease; follow serum levels (5-7 mg/dL); maximal dose, 4 g/hr
Maintenance dose: Maintain dose for 12 hr, then 1 g/hr for 24-48 hr
Preparation: Oral gelatin capsules of 10 or 20 mg
Loading dose: 30 mg; if contractions persist after 90 min, give an additional 20 mg (second dose); if labor is suppressed, a maintenance dose of 20 mg is given orally every 6 hr for 24 hr and then every 8 hr for another 24 hr.
Failure: If contractions persist 60 min after the second dose, treatment should be considered a failure.
Prostaglandin Synthetase Inhibitors
Short-term use only
In the United States, magnesium sulfate is frequently the drug of choice for initiating tocolytic therapy. Magnesium acts at the cellular level by competing with calcium for entry into the cell at the time of depolarization. Successful competition results in an effective decrease of intracellular calcium ions, resulting in myometrial relaxation.
Although magnesium levels required for tocolysis have not been critically evaluated, it appears that the levels needed may be higher than those required for prevention of eclampsia. Levels from 5.5 to 7.0 mg/dL appear to be appropriate. These can be achieved using the dosage regimen outlined in Box 12-1. After the loading dose is given, a continuous infusion is maintained, and plasma levels should be determined until therapeutic levels are reached. The drug should be continued at therapeutic levels until contractions cease unless the labor progresses. Because magnesium is excreted by the kidneys, adjustments must be made in patients with an abnormal creatinine clearance. Once successful tocolysis has been achieved, the infusion is continued for at least 12 hours, and then the infusion rate is weaned over 2 to 4 hours and then discontinued. In high-risk patients (advanced cervical dilation or continued labor in very-low-birth-weight cases), the infusion can be continued until the fetus has been exposed to glucocorticoids to enhance lung maturity.
A common minor side effect of magnesium therapy is a feeling of warmth and flushing on first administration. Respiratory depression is seen at magnesium levels of 12 to 15 mg/dL, and cardiac conduction defects and arrest are seen at higher levels.
In the fetus, plasma magnesium levels approach those of the mother, and a low plasma calcium level may also be demonstrated. The neonate may show some loss of muscle tone and drowsiness, resulting in a lower Apgar score. These effects are prolonged in the preterm neonate because of the decrease in renal clearance.
Long-term parenteral magnesium therapy has been used for control of preterm labor in selected patients. An important side effect seems to be loss of calcium, and it may be important in such patients to institute calcium therapy on a prophylactic basis.
Nifedipine as an oral agent is very effective in suppressing preterm labor with minimal maternal and fetal side effects. It works by inhibiting the slow, inward current of calcium ions during the second phase of the action potential of uterine smooth muscle cells and may gradually replace intravenous magnesium sulfate. The only side effects are headache, cutaneous flushing, hypotension, and tachycardia. The latter two side effects can be partially avoided by making certain the patient is well hydrated and by the use of support stockings, such as TED (antiembolism) hose.
Prostaglandin Synthetase Inhibitors
Prostaglandins induce myometrial contractions at all stages of gestation, both in vivo and in vitro. Because prostaglandins are locally synthesized and possess a relatively short half-life, prevention of their synthesis within the uterus could abort labor. These agents are used on a short-term basis in special circumstances when prostaglandin production may be the inciting factor in preterm labor, such as with the presence of uterine fibroids. In the United States, indomethacin is the most commonly used prostaglandin inhibitor; it can be administered both orally and rectally, with some slight delay in absorption from rectal administration as compared with the oral route. Peak serum levels of indomethacin occur 1.5 to 2 hours after oral administration. Excretion of the intact drug occurs in maternal urine. It can result in oligohydramnios and premature closure of the fetal ductus arteriosus, which in turn may lead to neonatal pulmonary hypertension and cardiac failure. In addition, indomethacin decreases fetal renal function, and indomethacin-exposed infants have a greater risk for necrotizing enterocolitis, intracranial hemorrhage, and patent ductus arteriosus. Short-term use may be acceptable, but if patients are given indomethacin, the fetus should be evaluated with ultrasonography for ductus arteriosus flow.
Oxytocin Receptor Antagonists
Atosiban was the first oxytocin receptor antagonist developed. It binds to receptors in the myometrium and other gestational tissues, preventing the oxytocin-induced increase in inositol triphosphate, the messenger that increases intracellular calcium and causes myometrial contractions and upregulation of prostaglandin production. These agents are not approved for use in the United States.
Combined therapy, using a combination of nifedipine and prostaglandin synthetase inhibitors, is being explored in countries such as Australia, Canada, and Europe.
Efficacy of Tocolytic Therapy
Although the advent of tocolytic agents has failed to decrease preterm births in large population studies, their use has improved neonatal survival, decreased respiratory distress syndrome (RDS), and increased the birth weight of infants. The benefit of measures to postpone delivery beyond 34 weeks’ gestational age is under investigation.
A number of studies have advocated the use of antibiotic prophylaxis in patients with preterm labor. Such patients may have a higher incidence of subclinical chorioamnionitis than previously thought.
Diagnostic amniocentesis in patients with idiopathic preterm labor has identified about 15% whose amniotic cavity is colonized with pathogens. It is reasonable to assume that a proportion of the remaining cases will have bacteria in the decidual cell space between the chorion and the myometrium. Thus the use of prophylactic antibiotics in women with preterm labor may prevent the progression of a subclinical infection to clinical amnionitis.
Contraindications to Tocolytic Therapy
Contraindications include severe preeclampsia, severe bleeding from placenta previa or abruptio placentae, chorioamnionitis, intrauterine growth restriction, fetal anomalies incompatible with life, and fetal demise. Because of the low success rate, advanced cervical dilation may also preclude tocolytic therapy, although therapy may delay delivery sufficiently for glucocorticoid administration to accelerate fetal lung maturity. Management of patients should be individualized, and even if the patient’s cervix is dilated 6 cm and she is having infrequent contractions, it is advisable to employ tocolysis and administer glucocorticoid therapy.
USE OF GLUCOCORTICOIDS FOR FETAL PULMONARY MATURATION
Antenatal corticosteroid therapy for fetal pulmonary maturation reduces mortality and the incidence of RDS and intraventricular hemorrhage (IVH) in preterm infants. These benefits extend to a broad range of gestational ages (24 to 34 weeks) and are not limited by gender or race. Treatment consists of 2 doses of 12 mg of betamethasone, given intramuscularly 24 hours apart, or 4 doses of 6 mg of dexamethasone, given intramuscularly 12 hours apart. Optimal benefit begins 24 hours after initiation of therapy and lasts 7 days. Because treatment with corticosteroids for less than 24 hours is still associated with significant reductions in neonatal mortality, RDS, and IVH, antenatal corticosteroids should be given unless immediate delivery is anticipated.
LABOR AND DELIVERY OF THE PRETERM INFANT
A certain number of patients will not respond to tocolytic therapy. The goal in these patients is to conduct both labor and delivery in an optimal manner so as not to contribute to the morbidity or mortality of the preterm infant. All parameters for assessing gestational age and fetal weight must be considered. With modern neonatal care, the lower limit of potential viability is 24 weeks or 500 g, although these limits vary with the expertise of the neonatal intensive care unit.
Fetal heart rate patterns that are relatively innocuous in the term fetus may indicate a more ominous outcome for the preterm fetus. Continuous fetal heart monitoring and prompt attention to abnormal fetal heart rate patterns are extremely important. Acidosis at birth adversely affects respiratory function by destroying surfactant and delaying its release.
With a vertex presentation, vaginal delivery is preferred, independent of gestational age, provided that fetal acidosis and delivery trauma are avoided. Use of outlet forceps and an episiotomy to shorten the second stage are advocated. Some reports recommend cesarean delivery of the very-low-birth-weight baby.
About 23% of infants present as a breech at 28 weeks, compared with about 4% at term. This presentation carries an increased risk for cord prolapse or compression. In addition, cervical entrapment of the aftercoming fetal head may occur at delivery because, before term, the head is proportionally larger than the buttocks. For the breech fetus estimated at less than 1500 g, neonatal outcome is improved by cesarean birth.
Premature Rupture of the Membranes
DEFINITION AND INCIDENCE
Premature rupture of the membranes (PROM) is defined as amniorrhexis (spontaneous rupture of membranes as opposed to amniotomy) before the onset of labor at any stage of gestation.PPROM should be used to define those patients who are preterm with ruptured membranes, whether or not they have contractions.
ETIOLOGY AND RISK FACTORS
The etiology of PROM remains unclear, but a variety of factors are purported to contribute to its occurrence, including vaginal and cervical infections, abnormal membrane physiology, incompetent cervix, and nutritional deficiencies.
Diagnosis of PROM is based on the history of vaginal loss of fluid and confirmation of amniotic fluid in the vagina. Episodic urinary incontinence, leukorrhea, or loss of the mucous plug must be ruled out. Management of the patient presenting with this history depends on the gestational age. Because of the risk for introducing infection and the usually long latency period from the time of examination until delivery, the examiner’s hands should not be inserted into the vagina of a patient who is not in labor, whether preterm or term. A sterile vaginal speculum examination should be performed to confirm the diagnosis, to assess cervical dilation and length, and if the patient is preterm, to obtain cervical cultures and amniotic fluid samples for pulmonary maturation tests.
On examination, pooling of amniotic fluid in the posterior vaginal fornix can usually be seen. A Valsalva maneuver or slight fundal pressure may expel fluid from the cervical os, which is diagnostic of PROM. Confirmation of the diagnosis can be made by (1) testing the fluid with Nitrazine paper, which will turn blue in the presence of the alkaline amniotic fluid, and (2) placing a sample on a microscopic slide, air drying, and examining for ferning. False-positive Nitrazine test results occur in the presence of alkaline urine, blood, or cervical mucus. In the presence of blood, which is usually seen in patients who are also in early labor, the pattern may appear to be skeletonized, and a distinct ferning may not be seen. As in the case of preterm labor with intact membranes, a complete ultrasonic examination should be carried out to rule out fetal anomalies and to assess gestational age and amniotic fluid volume.
An intact amniotic sac serves as a mechanical barrier to infection, but in addition, amniotic fluid has some bacteriostatic properties that may play a role in preventing chorioamnionitis and fetal infections. Intact membranes are not an absolute barrier to infection because bacterial colonization still occurs in the decidual space and membrane interface in 10% of patients in term labor and in up to 25% of patients in preterm labor.
For preterm fetuses with PPROM, the risks associated with preterm delivery must be balanced against the risks for infection and sepsis that may make in utero existence even more problematic. For the mother, the risks include not only the development of chorioamnionitis but also the possibility of failed induction in the presence of an unfavorable cervix, resulting in subsequent cesarean birth.
Management is dictated to a large extent by the gestational age at the time of membrane rupture, although the quantity of amniotic fluid remaining after PPROM may be as important as gestational age in determining pregnancy outcome.
Ultrasonic definition of oligohydramnios has been standardized. Objective criteria include measurement of the vertical axis of amniotic fluid present in four quadrants, the total being called the amniotic fluid index (AFI). A value of less than 5 cm is considered abnormal.
Oligohydramnios associated with PROM in the fetus at less than 24 weeks’ gestation may lead to the development of pulmonary hypoplasia. Factors that may be responsible include fetal crowding with thoracic compression, restriction of fetal breathing, and disturbances of pulmonary fluid production and flow. The duration of membrane rupture is an important consideration. Constraints placed on fetal movements in utero can also result in a variety of positional skeletal abnormalities, such as talipes equinovarus.
If PROM occurs at 36 weeks or later and the condition of the cervix is favorable, labor should be induced after 6 to 12 hours if no spontaneous contractions occur. In the presence of an unfavorable cervical condition with no evidence of infection, it is reasonable to wait 24 hours before induction of labor to decrease the risk for failed induction and maternal febrile morbidity. The following discussion applies when premature membrane rupture occurs before 36 weeks’ gestational age.
In addition to the laboratory tests obtained for the patient in preterm labor, sufficient amniotic fluid can usually be obtained from the vaginal pool for pulmonary maturation studies. Because of the higher incidence of chorioamnionitis in association with PROM, amniotic fluid should also be examined with Gram stain and culture.
Conservative Expectant Management
Conservative management applies to the care of patients with PPROM who are observed with the expectation of prolonging gestation. Because the risk for infection appears to increase with the duration of membrane rupture, the goal of expectant management is to continue the pregnancy until the lung profile is mature. Careful surveillance must be maintained to diagnose chorioamnionitis at an early enough stage to minimize fetal and maternal risks. In its fulminant state, chorioamnionitis is associated with a high maternal temperature and a tender, sometimes irritable, uterus.
In cases of subclinical infection, diagnosis and treatment may be delayed. A combination of factors should alert the clinician to the possibility of chorioamnionitis, including maternal temperature greater than 100.4°F (38°C) in the absence of any other site of infection, fetal tachycardia, a tender uterus, and uterine irritability on nonstress testing.
The presence of bacteria by Gram stain or culture of amniotic fluid obtained at amniocentesis correlates with subsequent maternal infection in about 50% of cases and with neonatal sepsis in about 25%. The presence of white blood cells alone in amniotic fluid is less predictive of infection. The decision to perform amniocentesis is based on the gestational age, the presence of early signs of infection, and the AFI as measured by real-time ultrasonography. Recently investigators have described elevation of inflammatory cytokines in the amniotic fluid and fetal circulation in preterm infants who subsequently developed chronic lung disease during the neonatal period. A similar response may be associated with a greater risk for damage to the preterm baby’s brain, thus increasing the risk for cerebral palsy. Thus the management of patients with PROM is critical for the prevention of neonatal morbidity.
Ampicillin or erythromycin significantly prolongs the interval to delivery in patients with PPROM. The neonates delivered from patients receiving prophylaxis also have less morbidity.
Management of Chorioamnionitis
Once chorioamnionitis is diagnosed, antibiotic therapy should be delayed only until appropriate cultures have been taken. Ampicillin and gentamycin in combination are the drugs of choice. In the penicillin-sensitive patient, cephalosporins may be indicated, noting the 12% incidence of crossover sensitivity. Once antibiotics have been started, labor should be induced. If the condition of the cervix is unfavorable and there is evidence of fetal involvement, it may be necessary to perform a cesarean delivery.
The presence of active genital herpes is an important concern in the presence of ruptured membranes. Herpes infection at a site remote from the cervix and vagina is probably not associated with an increased risk for fetal infection, so the site of infection should be taken into consideration before recommending immediate cesarean delivery.
The use of tocolytics to control preterm labor in patients with PROM is controversial. The arguments against their use are that they may mask evidence of maternal infection (e.g., tachycardia) and that contractions associated with the membrane rupture may be indicative of uterine infection. Arguments for their use are that PROM is sometimes initially associated with evidence of uterine contractions, and time is gained for pulmonary maturation. In the presence of infection, tocolysis is usually unsuccessful.
Use of Corticosteroids
There is a decreased incidence of RDS in infants who are born with PPROM 16 to 72 hours after membrane rupture, presumably owing to the endogenous release of corticosteroids from the stress of decreased amniotic fluid. Perhaps for this reason, the National Institutes of Health (NIH) guidelines for glucocorticoid therapy recommend they be given to patients with PPROM only up to 32 weeks’ gestation, rather than up to 34 weeks’ gestation, when membranes are intact.
After inpatient observation for 2 to 3 days without any evidence of infection, outpatient management can be considered in an attempt to reduce the incidence of late preterm births (34 to 37 weeks). To be eligible for such management, the patient should be reliable, fully informed regarding the risks involved, and prepared to participate in her own care. The fetus should be presenting as a vertex, and the cervix should be closed to minimize the chance of cord prolapse. At home, restricted physical activity is advised, no coital activity should occur, and the patient must monitor her temperature at least 4 times per day. Instructions should be given to return immediately if the temperature exceeds 100°F (37.8°C).
The patient should be seen weekly, at which time her temperature should be taken, nonstress testing performed after 28 weeks, and the baseline fetal heart rate and AFI evaluated. Ultrasonic evaluation of fetal growth should also be carried out every 2 weeks. Any patient with oligohydramnios is not a candidate for outpatient management.
Labor and Delivery
The same considerations discussed under preterm labor apply to patients with PROM. The decrease in amniotic fluid that is sometimes seen can result in early cord compression and the presence of variable fetal heart decelerations. This is true of both vertex and breech presentations; therefore, there is a necessity for abdominal delivery in a large number of cases unless fluid replacement can be instituted by amnioinfusion.
Tests of Pulmonary Maturity
By far, the major determinant of successful extrauterine existence is the ability of the neonate to maintain successful oxygenation. Pulmonary maturation involves changes in pulmonary anatomy in addition to alterations of physiologic and biochemical parameters. Beginning at about 24 weeks, the terminal bronchioles divide into three or four respiratory bronchioles. Type II pneumocytes, which are important in surfactant synthesis, begin to proliferate during this phase.
Surfactant is required for successful lung function in the fetus and is a complex mixture of phospholipids, neutral lipids, proteins, carbohydrates, and salts. It is important in decreasing alveolar surface tension, maintaining alveoli in an open position at a low internal alveolar diameter, and decreasing intraalveolar lung fluid. Synthesis takes place in the type II pneumocytes by incorporation of choline, and significant recycling seems to occur by resorption and secretion.
Initially, the important phospholipid was thought to be phosphatidylcholine (lecithin), but it is apparent that other components, such as phosphatidylinositol (PI) and phosphatidylglycerol (PG), are also important.These substances are produced and secreted in increasing amounts as gestation advances, and the continued egress of tracheal fluid into the amniotic fluid results in their increasing presence near term.
Measurement of these substances in the amniotic fluid obtained by amniocentesis allows prediction of the risk for development of RDS in the neonate. Lecithin (L) levels increase rapidly after 35 weeks’ gestation, whereas sphingomyelin (S) levels remain relatively constant after this gestational age. The lecithin and sphingomyelin concentrations are measured by thin-layer chromatography and are expressed as the L/S ratio. The presence of blood or meconium in the amniotic fluid will affect the L/S ratio; meconium will decrease it, and blood will normalize it to a value of 1.4.
Using two-dimensional thin-layer chromatography, both PG and PI can be measured. Along with the L/S ratio, these make up the lung profile. RDS is rare when the L/S ratio is greater than 2 and PG is present, whereas when the L/S ratio is less than 2 and no PG is present, more than 90% of infants develop RDS. When the L/S ratio indicates pulmonary immaturity (L/S < 2), but PG is present, fewer than 5% of infants develop RDS. The lung profile offers a more reliable predictor of pulmonary maturity, especially in infants of diabetic mothers. Other advantages of using PG are that contamination with vaginal secretions or blood, as occurs in cases of ruptured membranes and vaginal pool sampling, does not interfere with the detection of PG.
RAPID TESTS FOR FETAL LUNG MATURITY
A rapid test to assess fetal lung maturity, which could then be followed up with the more standard tests, provides a very useful clinical tool. One such test is the lamellar body number density (LBND) assessment, performed using an electronic cell counter (Coulter), which is gaining increased interest and use. This test can be completed within 2 hours by any hospital clinical laboratory. Normal ranges have been developed and depend on the individual laboratory (maturity ≥ 46,000 μL LBND), and the sensitivity and predictive value are as good as if not better than the standard L/S ratio.
RDS in preterm infants is caused by a lack of surfactant. Production of surfactant by type II pneumocytes may be induced by corticosteroids and thyroid-releasing hormone, but many premature infants still develop RDS. Several human studies using instillation of surfactant into the pulmonary tree immediately after delivery have shown dramatic improvements in lung mechanics and the survival of infants. A wide variety of surfactant preparations are now available, including synthetic surfactants and surfactants derived from animal sources.
Intrauterine Growth Restriction
Intrauterine growth restriction (IUGR) by definition occurs when the birth weight of a newborn infant is below the 10th percentile for a given gestational age. The terms small for gestational age (SGA) and IUGR, should not be used synonymously. SGA merely indicates that a fetus or neonate is below a defined reference range of weight for a gestational age, whereas IUGR refers to a small group of fetuses or neonates whose growth potential has been limited by pathologic processes in utero, with resultant increased perinatal morbidity and mortality. Growth-restricted fetuses are particularly prone to problems such as meconium aspiration, asphyxia, polycythemia, hypoglycemia, and mental retardation, and they are at greater risk for developing adult-onset conditions such as hypertension, diabetes. and atherosclerosis.
The causes of IUGR can be grouped into three main categories: maternal, placental, and fetal. Combinations of these are frequently found in pregnancies with IUGR.
Maternal causes include poor nutritional intake, cigarette smoking, drug abuse, alcoholism, cyanotic heart disease, and pulmonary insufficiency. In recent years, the antiphospholipid syndrome(autoantibody production) has been identified as a cause of IUGR in some women, both with and without hypertension. Antiphospholipid antibodies such as lupus-like anticoagulant and anticardiolipin antibodies are autoimmune (acquired) conditions, which contribute to the formation of vascular lesions in both the uterine and the placental vasculature that may result in impaired fetal growth and demise. Recently, several hereditary thrombophilias have been identified, which have been associated with a greater risk for IUGR, abruption, and preeclampsia. These conditions result in vascular lesions within the spinal arteries supplying the placenta. Identification and treatment with low-dose heparin and low-dose aspirin have been shown to reduce the risk for IUGR.
This category is representative of circumstances in which there is inadequate substrate transfer because of placental insufficiency. Conditions that lead to this state include essential hypertension, chronic renal disease, and pregnancy-induced hypertension. If the latter occurs late in pregnancy and is not accompanied by chronic vascular or renal disease, significant IUGR is unlikely to occur. A small fraction of IUGR cases may be attributed to placental or cord abnormalities (e.g., velamentous cord insertion).
In this case, inadequate or altered substrate is present. Examples of fetal causes include intrauterine infection (listeriosis and TORCH [toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex] agents) and congenital anomalies.
Two types of fetal growth restriction have been described: symmetrical and asymmetrical. In fetuses with symmetrical growth restriction, growth of both the head and the body is inadequate. The head-to-abdominal circumference ratio may be normal, but the absolute growth rate is decreased. Symmetrical growth restriction is most commonly seen in association with intrauterine infections or congenital fetal anomalies. When asymmetrical growth restriction occurs, usually late in pregnancy, the brain is preferentially spared at the expense of abdominal viscera. As a result, the head size is proportionally larger than the abdominal size. The liver and fetal pancreas undergo the most dramatic anatomic and biochemical changes, and these changes are now thought to play an important role in programming the fetus for a greater risk for obesity and diabetes later in life (see Chapter 1).
Growth restriction may go undiagnosed unless the obstetrician establishes the correct gestational age of the fetus (Box 12-2), identifies high-risk factors from the obstetric database, and serially assesses fetal growth by fundal height or ultrasonography. Fetal or neonatal IUGR is usually defined as weight at or below the 10th percentile for gestational age.
BOX 12-2 Factors Evaluated in Dating a Pregnancy
• Accuracy of the date of the last normal menstrual period
• Evaluation of uterine size on pelvic examination in the first trimester
• Evaluation of uterine size in relation to gestational age during subsequent antenatal visits (concordance or size-for-dates discrepancy)
• Gestational age when fetal heart tones were first heard using a Doppler ultrasonic device (usually at 12-14 wk)
• Date of quickening (usually 18-20 wk in a primigravida and 16-18 wk in a multigravida)
• Sonographic measurement of fetal length (crown-rump) in first trimester (most accurate)
Serial uterine fundal height measurements should serve as the primary screening tool for IUGR. A more thorough sonographic assessment should be undertaken when (1) the fundal height lags more than 3 cm behind a well-established gestational age or (2) the mother has a high-risk condition such as preexisting hypertension; chronic renal disease; advanced diabetes with vascular involvement; preeclampsia; viral disease; addiction to nicotine, alcohol, or hard drugs; or the presence of serum lupus anticoagulant or antiphospholipid antibodies.
Recently, interest has focused on the prediction of patients at risk for IUGR at mid-pregnancy. Patients with abnormal triple screens (alpha-fetoprotein, human chorionic gonadotropin [hCG], and estriol [E3]) who do not have abnormal fetuses by ultrasound and amniocentesis may be at risk for IUGR. In addition, elevations of umbilical artery and uterine artery Doppler assessments (increased resistance) as early as mid-pregnancy are associated with a greater risk for IUGR as pregnancy progresses.
At present, a number of sonographic parameters are used to diagnose IUGR: (1) biparietal diameter (BPD), (2) head circumference, (3) abdominal circumference (Figure 12-1), (4) head-to-abdominal circumference ratio, (5) femoral length, (6) femoral length–to–abdominal circumference ratio, (7) amniotic fluid volume, (8) calculated fetal weight, and (9) umbilical and uterine artery Doppler. Of these, the abdominal circumference is the single most effective parameter for predicting fetal weight because it is reduced in both symmetrical and asymmetrical IUGR. Most formulas for estimating fetal weight incorporate two or more parameters to reduce the variance of measurements.
FIGURE 12-1 Mean head and abdominal circumferences (green) with 5th (red) and 95th (blue) percentile confidence limits between 16 and 40 weeks’ menstrual age.
(Adapted from Campbell S, Griffin D, Roberts A, et al: Early prenatal diagnosis of abnormalities of the fetal head, spine, limbs, and abdominal organs. In Orlandi C, Polani PE, Bovicelli L [eds]: Recent Advances in Prenatal Diagnosis: Proceedings of the First International Symposium on Recent Advances in Prenatal Diagnosis, Bologna, September 15-16, 1980. New York, John Wiley & Sons, 1980.)
During advancing gestation, the head circumference remains greater than the abdominal circumference until about 34 weeks, at which point the ratio approaches 1 (Figure 12-2). After 34 weeks, the normal pregnancy is associated with an abdominal circumference that is greater than the head circumference. When asymmetrical growth restriction occurs, usually in the third trimester, the BPD is essentially normal, whereas the ratio of head to abdominal circumference is abnormal. With symmetrical growth restriction, the head-to-abdominal circumference ratio may be normal, but the absolute growth rate is decreased, and estimated fetal weight is reduced.
FIGURE 12-2 Graphic representation of the mean head-to-abdominal (H/A) circumference ratios (green) with 5th (red) and 95th (blue) percentile confidence limits from 17 to 42 weeks’ menstrual age.
(From Campbell S, Thomas A: Ultrasound measurement of the fetal head to abdominal circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol 84:165, 1977.)
From 50% to 90% of infants with manifestations of IUGR at birth can be identified with serial prenatal ultrasonography. The accuracy depends on the quality of the assessments, the criteria used for diagnosis, and the effect of interventions applied when this diagnosis is made. For example, it is not unusual to observe an improvement in fetal growth after interventions such as work stoppage, bed rest, dietary modification, and curtailment of the use of tobacco, hard drugs, and alcohol.
It is worthwhile to plot out each serial measurement on a standard growth curve. For example, a fetus measuring near the 10th percentile in mid-gestation may continue to grow along that curve (SGA) or, conversely, may fall well below the 10th percentile (IUGR) later in pregnancy.
An important part of preventive medicine is to anticipate risks that can be modified before a woman becomes pregnant. Improving nutrition and stopping smoking are two approaches that should improve fetal growth in women who are underweight, who smoke, or both. For women with antiphospholipid antibodies associated with the delivery of a prior IUGR infant, low-dose aspirin (81 mg/day) in early pregnancy may reduce the likelihood of recurrent IUGR. For patients with one of the hereditary thrombophilias, low-dose heparin (5000 U twice daily) with or without low-dose aspirin has also been shown to reduce the risk for recurrent IUGR.
Once a fetus has been identified as having decreased growth, attention should be directed toward modifying any associated factors that can be changed. Because poor nutrition and smoking exert their main effects on birth weight in the latter half of pregnancy, cessation of smoking and improved nutrition can have a positive impact. The working woman who becomes fatigued is more likely to have a low-birth-weight infant. Work leave, or in some cases of maternal disease, hospitalization, will increase uterine blood flow and may improve the nutrition of the fetus at risk.
The objective of clinical management is to expedite delivery before the occurrence of fetal compromise, but after fetal lung maturation has been achieved. This requires regular fetal monitoring with a twice-weekly nonstress test (NST) and biophysical profile. Most institutions use a modified biophysical profile that includes an NST and AFI. The oxytocin challenge test (OCT) is rarely used because its false-positive rate approaches 50%.
Fetuses clinically suspected of IUGR could be approached as follows:
1. For cases in which results of fetal monitoring are normal and ultrasonic findings strongly suggest normal growth, no clinical intervention is warranted.
2. For cases in which ultrasonic findings strongly suggest IUGR, with or without abnormal fetal surveillance, delivery is indicated at gestational ages of 34 weeks or later, or at any reasonable gestational age if pulmonary maturity is documented. In the presence of severe oligohydramnios, amniocentesis may not be safe or feasible. Delivery should be strongly considered without assessing lung maturity because these fetuses are at great risk for asphyxia, and the stress associated with IUGR usually accelerates fetal pulmonary maturity.
3. For those cases in which ultrasonic findings are equivocal for IUGR, bed rest, fetal surveillance, and serial ultrasonic measurements at 3-week intervals are indicated.
A simple technique is available whereby a pregnant woman can help in the assessment of fetal well-being. She assesses fetal movement (kick counts) each evening while resting comfortably on her left side. If she does not perceive 10 movements in 1 hour, she is instructed to call her healthcare provider to schedule a biophysical assessment. Some providers instruct their patients, irrespective of their risk, to begin a fetal kick count chart during the last trimester of pregnancy.
Doppler-derived umbilical artery systolic-to-diastolic ratios are abnormal in IUGR fetuses. Fetuses with growth restriction tend to have increased resistance to flow and to demonstrate low, absent, or reversed diastolic flow This noninvasive technique can be used to evaluate high-risk patients and may help in the timing of delivery when used in conjunction with the modified biophysical profile (see Chapter 7 for more information about Doppler assessment of fetal well-being).
LABOR AND DELIVERY
IUGR per se is not a contraindication for induction of labor, but there should be a low threshold to perform a cesarean birth because of the poor capacity of the IUGR fetus to tolerate asphyxia. As a result, during labor, these high-risk patients must be electronically monitored to detect the earliest evidence of fetal distress.
A combined obstetric-neonatal team approach to delivery is mandatory because of the likelihood of neonatal asphyxia.
After birth, the infant should be carefully examined to rule out the possibility of congenital anomalies and infections. The monitoring of blood glucose levels is important because the fetuses do not have adequate hepatic glycogen stores, and hypoglycemia is a common finding. Furthermore, hypothermia is not uncommon in these infants. Respiratory distress syndrome is more common in the presence of fetal distress because fetal acidosis reduces surfactant synthesis and release.
The long-term prognosis for infants with IUGR must be assessed according to the varied etiologies of the growth restriction. If infants with chromosomal abnormalities, autoimmune disease, congenital anomalies, and infection are excluded, the outlook for these newborns is generally good. However, the IUGR infant is at greater risk for adult-onset diseases such as hypertension, diabetes, and atherosclerosis (see Chapter 1).
The prolonged or postterm pregnancy is one that persists beyond 42 weeks (294 days) from the onset of the last normal menstrual period. Estimates of the incidence of postterm pregnancy range from 6% to 12% of all pregnancies.
Perinatal mortality is 2 to 3 times higher in these prolonged gestations. Much of the increased risk to the fetus and neonate can be attributed to development of the fetal postmaturity (dysmaturity) syndrome, which occurs when a growth-restricted fetus remains in utero beyond term. Occurring in 20% to 30% of postterm pregnancies, this syndrome is related to the aging and infarction of the placenta, resulting in placental insufficiency with impaired oxygen diffusion and decreased transfer of nutrients to the fetus. Some of these fetuses meet the criteria for having IUGR and should not have been allowed to advance to term. If evidence of intrauterine hypoxia is present (such as meconium staining of the umbilical cord, fetal membranes, skin, and nails), perinatal mortality is even further increased.
The fetus with postmaturity syndrome typically has loss of subcutaneous fat, long fingernails, dry and peeling skin, and abundant hair. The 70% to 80% of postdate fetuses not affected by placental insufficiency continue to grow in utero, many to the point of macrosomia (birth weight greater than 4000 g). This macrosomia often results in abnormal labor, shoulder dystocia, birth trauma, and an increased incidence of cesarean birth.
The cause of postdate pregnancy is unknown in most instances. Prolonged gestation is common in association with an anencephalic fetus and is probably linked to the lack of a fetal labor-initiating factor from the fetal adrenals, which are hypoplastic in anencephalic fetuses. Prolonged gestation may also be associated rarely with placental sulfatase deficiency and extrauterine pregnancy. Paternal genes, as expressed by the fetus, play a role in the timing of birth and the risk for repeating a prolonged pregnancy.
The diagnosis of postterm pregnancy is often difficult. The key to appropriate classification and subsequent successful perinatal management is the accurate dating of gestation. It is estimated that uncertain dates are present in 20% to 30% of all pregnancies; hence, the importance of early and accurate assessment of gestational age cannot be overemphasized.
The appropriate management of prolonged pregnancy revolves around identification of the low percentage of fetuses with postmaturity syndrome who are truly at risk for intrauterine hypoxia and fetal demise. When biophysical tests of fetal well-being are available, the time of delivery for each patient should be individualized. However, if the gestational age is firmly established at 42 weeks, the fetal head is well fixed in the pelvis, and the condition of the cervix is favorable, labor usually should be induced.
The two clinical problems that remain are (1) patients with good dates at 42 weeks’ gestation with an unripe cervix, and (2) patients with uncertain gestational age seen for the first time with a possible or probable diagnosis of prolonged pregnancy.
In the first group of patients, a twice-weekly NST and biophysical profile should be performed. The AFI is an important ultrasonic measurement that should also be used in the management of these patients. The AFI is the sum of the vertical dimensions (in centimeters) of amniotic fluid pockets in each of the four quadrants of the gestational sac. Delivery is indicated if there is any indication of oligohydramnios (AFI ≤ 5) or if spontaneous fetal heart rate decelerations are found on the NST. So long as these parameters of fetal well-being are reassuring, labor need not be induced unless the cervical condition becomes favorable, the fetus is judged to be macrosomic, or there are other obstetric indications for delivery.
Some institutions begin weekly testing at 41 weeks to avoid missing the few fetuses who are stressed before 42 weeks. At 42 weeks’ gestation with firm dates, delivery is initiated by the appropriate route, regardless of other factors, in view of the increasing potential for perinatal morbidity and mortality.
When the patient presents very late in gestation for initial assessment of prolonged pregnancy, but the gestational age is in question and fetal assessment is normal, an expectant approach is often acceptable. The risk of intervention with the delivery of a preterm infant must be considered. The woman herself can participate in the fetal assessment by doing fetal kick counts during the postterm period.
Continuous electronic fetal monitoring must be employed during the induction of labor. The patient should be encouraged to lie on her left side. The fetal membranes should be ruptured as early as is feasible in the intrapartum period so that internal electrodes can be applied and the color of the amniotic fluid assessed. Cesarean birth is indicated for fetal distress. It should not be delayed because of the decreased capacity of the postterm fetus to tolerate asphyxia and the increased risk for meconium aspiration. If meconium is present, neonatal asphyxia should be anticipated, and a neonatal resuscitative team should be present at delivery.
Intrauterine Fetal Demise
Intrauterine fetal demise (IUFD) is fetal death after 20 weeks’ gestation but before the onset of labor. It complicates about 1% of pregnancies. With the development of newer diagnostic and therapeutic modalities over the past two decades, the management of IUFD has shifted from watchful expectancy to more active intervention.
In more than 50% of cases, the etiology of antepartum fetal death is not known or cannot be determined. Associated causes include hypertensive diseases of pregnancy, diabetes mellitus, erythroblastosis fetalis, umbilical cord accidents, fetal congenital anomalies, fetal or maternal infections, fetomaternal hemorrhage, antiphospholipid antibodies, and hereditary thrombophilias.
Clinically, fetal death should be suspected when the patient reports the absence of fetal movements, particularly if the uterus is small for date or if the fetal heart tones are not detected using a Doppler device. Because the placenta may continue to produce hCG, a positive pregnancy test does not exclude an IUFD.
Diagnostic confirmation has been greatly facilitated since the advent of ultrasonography. Real-time ultrasonography confirms the lack of fetal movement and absence of fetal cardiac activity.
Fetal demise between 14 and 28 weeks allows for two different approaches: watchful expectancy and induction of labor.
About 80% of patients experience the spontaneous onset of labor within 2 to 3 weeks of fetal demise. The patient’s feeling of personal loss and guilt may create such anxiety, however, that this conservative approach may prove unacceptable. Thus, in general, the management of women who fail to go into labor spontaneously is active intervention by induction of labor or dilation and evacuation (D&E).
Induction of Labor
Justifications for such intervention include the emotional burden on the patient associated with carrying a dead fetus, the slight possibility of chorioamnionitis, and the 10% risk for disseminated intravascular coagulationwhen a dead fetus is retained for more than 5 weeks in the second or third trimester.
Vaginal suppositories of prostaglandin E2 (dinoprostone [Prostin E2]) can be used from the 12th to the 28th week of gestation. Dinoprostone is an effective drug with an overall success rate approaching 97%. Although at least 50% of patients receiving dinoprostone experience nausea and vomiting or diarrhea with temperature elevations, these side effects are transient and can be minimized with premedication (i.e., prochlorperazine [Compazine]). There have been reported cases of uterine rupture and cervical lacerations, but with properly selected patients, the drug is safe. The maximal recommended dose is a 20-mg suppository every 3 hours until delivery. Dinoprostone use in this range is contraindicated in patients with prior uterine incisions (e.g., cesarean, myomectomy) because of the unacceptable risk for uterine rupture. Furthermore, prostaglandins are contraindicated in patients with a history of bronchial asthma or active pulmonary disease, although the E series drugs act primarily as bronchodilators. Misoprostol (Cytotec, a synthetic prostaglandin E1 analogue) vaginal tablets have been found to be quite effective with little or no gastrointestinal side effects, and they are less expensive than dinoprostone.
After 28 weeks’ gestation, if the condition of the cervix is favorable for induction and there are no contraindications, misoprostol followed by oxytocin is the treatment of choice.
Monitoring of Coagulopathy
Regardless of the mode of therapy chosen, weekly fibrinogen levels should be monitored during the period of expectant management, along with a hematocrit and platelet count. If the fibrinogen level is decreasing, even a “normal” fibrinogen level of 300 mg/dL may be an early sign of consumptive coagulopathy in cases of fetal demise. An elevated prothrombin and partial thromboplastin time, the presence of fibrinogen-fibrin degradation products, and a decreased platelet count may clarify the diagnosis.
If laboratory evidence of mild disseminated intravascular coagulation is noted in the absence of bleeding, delivery by the most appropriate means is recommended. If the clotting defect is more severe or if there is evidence of bleeding, blood volume support or use of component therapy (fresh-frozen plasma) should be given before intervention.
A search should be undertaken to determine the cause of the intrauterine death. TORCH (see Table 7-1) and parvovirus studies and cultures for Listeria are indicated. In addition, all women with a fetal demise should be tested for the presence of anticardiolipin antibodies. Testing for the hereditary thrombophilias should also be considered. If congenital abnormalities are detected, fetal chromosomal studies and total body radiographs should be done, in addition to a complete autopsy. The autopsy report, when available, must be discussed in detail with both parents. In a stillborn fetus, the best tissue for a chromosomal analysis is the fascia lata, obtained from the lateral aspect of the thigh. The tissue can be stored in saline or Hanks’ solution. A significant number of cases of IUFD are the result of fetomaternal hemorrhage, which can be detected by identifying fetal erythrocytes in maternal blood (Kleihauer-Betke test).
The parents may experience feelings of guilt or anger, which may be magnified when there is an abnormal fetus or genetic defect. Referral to a bereavement support group for counseling is advisable.
Subsequent pregnancies in a woman with a history of IUFD must be managed as high-risk cases.
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