Ashley S. Roman, MD, MPH
PRETERM LABOR
ESSENTIALS OF DIAGNOSIS
Estimated gestational age of greater than 20 0/7 weeks and less than 37 0/7 weeks
Regular uterine contractions at frequent intervals
Documented cervical change or appreciable cervical dilatation or effacement
Pathogenesis
Labor is the process of coordinated uterine contractions leading to progressive cervical effacement and dilatation by which the fetus and placenta are expelled. Preterm labor is defined as labor occurring after 20 weeks’ but before 37 weeks’ gestation. Although there is no strict definition in the literature regarding the amount of uterine contractions required for preterm labor, there is consensus that contractions need to be regular and at frequent intervals. Generally, more than 4 contractions per hour are needed to cause cervical change. The uterine contractions need not be painful to cause cervical change and may manifest themselves as abdominal tightening, lower back pain, or pelvic pressure. In addition, there must be demonstrated cervical effacement or dilatation to meet a diagnosis of preterm labor.
It is important to distinguish preterm labor from other similar clinical entities, such as cervical incompetence (cervical change in the absence of uterine contractions) and preterm uterine contractions (regular contractions in the absence of cervical change) because the treatment for these situations differs. Cervical incompetence may require cerclage placement, and preterm uterine contractions without cervical change is generally a self-limited phenomenon that resolves spontaneously and requires no intervention. If ruptured membranes accompany preterm labor, these cases are classified as preterm premature rupture of membranes (for discussion of diagnosis see Premature Rupture of Membranes).
Preterm birth complicates approximately 12% of all pregnancies in the United States. It is the number one cause of neonatal morbidity and mortality and causes 75% of neonatal deaths that are not due to congenital anomalies.
Thirteen percent of all infants are classified as low birth weight (<2500 g), of whom 25% are mature low-birth-weight infants and approximately 75% are truly premature. The latter group accounts for nearly two-thirds of infant deaths (approximately 25,000 annually in the United States). Approximately 30% of premature births are due to miscalculation of gestational age or to medical intervention required by the mother or fetus.
The care of premature infants is costly. Compared with term infants, those born prematurely suffer greatly increased morbidity and mortality (eg, functional disorders, abnormalities of growth and development). Thus every effort is made to prevent or inhibit preterm labor. If preterm labor cannot be inhibited or is best allowed to continue, it should be conducted with the least possible trauma to the mother and infant.
Many obstetric, medical, and anatomic disorders are associated with preterm labor. Some of the risk factors are listed in Table 14–1. Detailed discussions of these conditions are given in other chapters. The cause of preterm labor in 50% of pregnancies, however, is idiopathic. Although several prospective risk-scoring tools are in use, they have not been convincingly demonstrated to be of value.
Table 14–1. Risk factors associated with preterm labor.
Prevention
Unfortunately, there are few interventions known to prevent preterm labor. For women with a history of a prior spontaneous preterm birth, there is evidence indicating that progestin administered via either vaginal suppositories of progesterone or weekly intramuscular injections of 17-α hydroxyprogesterone caproate starting at 16–20 weeks until approximately 36–37 weeks reduces the risk of recurrent preterm birth by approximately 30%. Furthermore, vaginal progesterone may also reduce the risk of preterm birth in women found to have a short cervix on transvaginal ultrasound in the midtrimester. But, aside from these specific interventions, there is little we can do to prevent preterm labor.
Clinical Findings
A. Symptoms and Signs
1. Uterine contractions—Regular uterine contractions at frequent intervals as documented by tocometer or uterine palpation, generally more than 2 in one-half hour.
2. Dilation and effacement of cervix—This can be established by clinical examination or by transvaginal ultrasound. Documented cervical change in dilation or effacement of at least 1 cm or a cervix that is well effaced and dilated (at least 2 cm) on admission is considered diagnostic. On transvaginal ultrasound, a cervical length less than the 10th percentile (generally ≤2.5 cm) is also suggestive of cervical effacement.
3. Other signs—Many patients present with bloody mucous vaginal discharge, or “bloody show.” More significant vaginal bleeding should be evaluated for abruptio placentae or placenta previa. Additionally, patients may report an increase in vaginal discharge or passage of their mucus plug.
B. Evaluation
Evaluation should include determination of the following:
1. Gestational age—Gestational age must be between 20 0/7 and 37 0/7 weeks’ estimated gestational age (EGA), which should be calculated based on the patient’s last menstrual period (LMP) or date of conception, if known, or the previous sonographic estimation if these dates are uncertain.
2. Fetal weight—Care must be taken to determine fetal size by ultrasonography.
3. Presenting part—The presenting part must be noted because abnormal presentation is more common in earlier stages of gestation.
4. Fetal monitoring—Continuous fetal monitoring should be performed to ascertain fetal well-being.
5. Tocodynamometry—Tocodynamometry should be performed to confirm the presence and frequency of contractions.
6. Physical examination—Physical examination should be performed to assess for cervical dilation, ruptured membranes (see section on Premature Rupture of Membranes), fundal tenderness, vaginal bleeding, and fever.
C. Laboratory Studies
1. Complete blood count with differential.
2. Urine obtained by catheter for urinalysis, culture, and sensitivity testing.
3. Ultrasound examination for fetal size, position, and placental location.
4. Amniocentesis may be useful to ascertain fetal lung maturity in instances in which EGA is uncertain, the size of the fetus is in conflict with the estimated date of conception (too small, suggesting intrauterine growth restriction, or too large, suggesting more advanced EGA), or the fetus is more than 34 weeks’ EGA. Specifically, the amniotic fluid can be tested for lecithin/sphingomyelin (L/S) ratio, the presence of phosphatidylglycerol, fluorescence polarization assay, or lamellar body count. Amniocentesis should also be performed in instances in which chorioamnionitis is suspected; the fluid should be tested for Gram’s stain, bacterial culture, glucose levels, cell count, and, if available, interleukin-6 level.
5. Speculum examination should be performed. Cervical cultures should be sent for gonorrhea and chlamydia. A wet mount should be performed to look for signs of bacterial vaginosis. Group B streptococcus (GBS) cultures should be taken from the vaginal and rectal mucosa. A swab may also be used to test any fluid in the vaginal to see if it is amniotic fluid (see section on Premature Rupture of Membranes).
6. Hematologic workup in cases associated with vaginal bleeding (see Chapter 18).
7. Fetal fibronectin testing kits have been approved by the Food and Drug Administration (FDA) as a means to assess the risk of preterm birth in patients with preterm labor. A cervicovaginal swab is taken to look for the presence of fetal fibronectin. A negative test is effective at identifying women at low risk of imminent delivery (within 2 weeks). A positive test result, however, is less sensitive at predicting preterm birth. The test may be helpful in identifying patients at low risk of preterm birth who can be managed on an outpatient basis.
Differential Diagnosis
The differential diagnosis includes preterm contractions without labor (ie, without cervical change) and cervical insufficiency (ie, cervical dilation without uterine contractions). However, clinical examination and signs can help distinguish among these entities.
Complications
The primary complication of preterm labor is preterm birth and the resulting prematurity of the infant. Treatment is directed toward reducing the likelihood of preterm birth and reducing the risk of prematurity-related complications in the infant, such as respiratory distress syndrome and neurologic injury.
Treatment
Decisions regarding management are made based on EGA, estimated weight of the fetus, and existence of contraindications to suppressing preterm labor. Table 14–2 lists factors indicating that preterm labor should be allowed to continue. Once the patient is determined to not have any of these contraindications, the management of preterm labor depends on fetal gestational age. Generally, management falls into 1 of 2 categories: expectant management (observation) or intervention. For pregnancies between 24 0/7 and 34 0/7 weeks’ EGA, intervention with corticosteroids has been shown to be of benefit in reducing neonatal morbidity and mortality rates. Although the efficacy of tocolysis has been much debated, it is generally accepted that a delay in delivery of 48 hours may be achieved at a minimum. Because this window can be used for corticosteroid administration, tocolysis is favored in many centers.
Table 14–2. Some cases in which preterm labor should not be suppressed.
Extremes of preterm gestational age pose special problems. Fetuses of very preterm pregnancies (20–23 weeks; EGA or estimated fetal weight [EFW] less than 550 g) are generally not considered to be viable. If these pregnancies can be continued for several more weeks, the fetuses will become viable, but have a high risk for significant morbidity if they are born in this periviable period and survive. Furthermore, intervention carries significant risks to the mother, including the risks of prolonged bed rest and side effects of tocolysis. Given these risks, expectant management is an acceptable and, in certain instances, preferable alternative to intervention. Mothers who choose intervention as opposed to expectant management should be extensively counseled by a multidisciplinary team, including the neonatologist, obstetrician, and social worker.
Conversely, once a pregnancy has continued beyond 34–37 weeks’ EGA or EFW greater than 2500 g, the fetal survival rate is within 1% of the survival rate at 37 weeks. Fetal morbidity is less severe and is rarely a cause of long-term sequelae. Furthermore, corticosteroids have not been shown to be of benefit in fetuses of this age or size. Therefore, expectant management is usually the recommended course of action. Several factors should be considered when deciding between intervention and expectant management, including the certainty of the patient’s dates, EFW, presence of maternal problems that could delay fetal lung maturity such as diabetes mellitus, and family history of late-onset respiratory distress syndrome (RDS).
There are other cases in which maternal or fetal factors indicate that preterm labor should be allowed to continue regardless of gestational age. Table 14–2 lists cases in detail.
The following is a protocol for management of pregnancies with preterm labor between 24 and 34 weeks’ gestation.
A. Bed Rest
The role of bed rest in the management of preterm labor is controversial. Meta-analyses have failed to demonstrate prolongation of pregnancy. Bed rest is associated with an increased risk of maternal thromboembolism. At minimum, bed rest may be advised particularly during the initial evaluation of an episode of preterm labor to allow for close fetal and maternal monitoring.
B. Corticosteroids
The administration of corticosteroids to accelerate fetal lung maturity has become the standard of care in the United States for all women between 24 and 34 weeks’ EGA at risk of preterm delivery within the following 7 days. It has been shown to decrease the incidence of neonatal respiratory distress, intraventricular hemorrhage, and neonatal mortality. Steroids can be given according to 1 of 2 protocols: (1) betamethasone 12 mg intramuscularly (IM) every 24 hours for a total of 2 doses; or (2) dexamethasone 6 mg IM every 12 hours for a total of 4 doses.
The optimal benefits of antenatal corticosteroids are seen 24 hours after administration, peak at 48 hours, and continue for at least 7 days. If therapy for preterm labor is successful and the pregnancy continues beyond 2 weeks, there are data suggesting that a single repeat course of steroids may be beneficial if the risk of preterm birth remains high and the patient is <33 weeks. More than 2 courses, however, may be associated with fetal growth abnormalities and delayed psychomotor development in the infant. In terms of safety of 1 or 2 courses of antenatal steroids, there does not appear to be an increased risk of infection or suppression of the fetal adrenal glands with steroid administration, and long-term follow-up of fetuses who received 1 or 2 courses of antenatal steroids shows no sequelae that can be attributed directly to steroid administration.
C. Tocolysis
If the patient continues to contract and falls into a high-risk group based on a history of preterm birth, positive fibronectin, short cervix on transvaginal sonography, or changing dilatation on cervical examination, tocolytic therapy may be initiated. When using tocolysis to treat preterm labor, it is important to keep the following goals in mind. The short-term goal is to continue the pregnancy for 48 hours after steroid administration, after which the maximum effect of the steroids can be achieved. The long-term goal is to continue the pregnancy beyond 34–36 weeks (depending on the institution), at which point fetal morbidity and mortality are dramatically reduced, and tocolysis can be discontinued.
Tocolytic therapy should be considered in the patient with cervical dilatation less than 5 cm. Successful tocolysis is generally considered fewer than 4–6 uterine contractions per hour without further cervical change.
The beta-mimetics and nifedipine are the most commonly used tocolytic agents. The decision to use a specific tocolytic should be carefully considered because of contraindications and side effects associated with each agent (Table 14–3).
Table 14–3. Side effects and complications of common tocolytics.
1. Beta-mimetic adrenergic agents—Beta-mimetic adrenergic agents act directly on beta receptors (β2) to relax the uterus. Their use is limited by dose-related cardiovascular side effects, including pulmonary edema, adult RDS, elevated systolic blood pressure and reduced diastolic blood pressure, and both maternal and fetal tachycardia. Other dose-related effects are decreased serum potassium level and increased blood glucose and plasma insulin levels and lactic acidosis. Maternal medical contraindications to the use of β-adrenergic agents include cardiac disease, hyperthyroidism, uncontrolled hypertension or pulmonary hypertension, asthma requiring sympathomimetic drugs or corticosteroids for relief, uncontrolled diabetes, and chronic hepatic or renal disease. Commonly observed effects during intravenous administration are palpitations, tremors, nervousness, and restlessness. The beta-mimetic in common use is terbuta-line. Although it has been used in the past, ritodrine is no longer commercially available. Because of the side effects, beta-mimetic tocolysis in the United States is now limited almost exclusively to subcutaneous intermittent injections as a method of temporizing and triaging patients before definitive therapy with other agents.
Although not approved by the FDA for use as a tocolytic, terbutaline has been studied in the United States and is used widely as a tocolytic agent. For tocolysis, it is administered via subcutaneous boluses. Given the potential for maternal cardiac toxicity, terbutaline should only be used for a maximum of 48–72 hours and should only be used in an inpatient setting.
2. Magnesium sulfate—Although its exact mechanism of action is unknown, magnesium sulfate appears to inhibit calcium uptake into smooth muscle cells, reducing uterine contractility. The efficacy of magnesium is debated, but several small studies have shown an effect comparable to that of beta-mimetics, and it may be better tolerated than beta-mimetics. Magnesium sulfate may appear less likely to cause serious side effects than the beta-mimetics, but its therapeutic range is close to the range at which it will cause respiratory and cardiac depression. Therefore, patients receiving magnesium sulfate should be monitored closely for signs of toxicity, with frequent checks of deep tendon reflexes, pulmonary examinations, and strict calculations of the patient’s fluid balance. These effects may be reversed by calcium gluconate (10 mL of a 10% solution given intravenously), and this antidote should be kept at the bedside when magnesium sulfate is used.
3. Calcium channel blockers—Calcium channel blockers such as nifedipine work as tocolytics by inhibiting calcium uptake into uterine smooth muscle cells via voltage-dependent channels, thereby reducing uterine contractility. Several studies have shown nifedipine to be equally or more efficacious than beta-mimetics in preterm labor. Other advantages are its low incidence of maternal side effects and ease of administration. Nifedipine can be given by mouth. A common regimen for tocolysis is nifedipine 20 mg by mouth, then 10–20 mg by mouth every 6 hours until contractions diminish sufficiently.
4. Prostaglandin synthase inhibitors—Prostaglandin synthase inhibitors such as indomethacin have been shown to be as effective as ritodrine for tocolysis, but their use has been limited by potentially serious fetal effects. Indomethacin works as a tocolytic by inhibiting prostaglandin synthesis, an important mediator in uterine smooth muscle contractility. The advantages of indomethacin are its ease of administration (it can be given by rectum or by mouth) and its potent tocolytic activity. However, it has been associated with oligohydramnios and premature closure of the ductus arteriosus. In preterm infants delivered before 30 weeks’ EGA, some studies have demonstrated an increased risk of intracranial hemorrhage, necrotizing enterocolitis, and patent ductus arteriosus after birth. A common regimen for tocolysis is indomethacin 100 mg per rectum loading dose (or 50 mg by mouth), then 25–50 mg by mouth or rectum every 4–6 hours. Ultrasound should be performed every 48–72 hours to check for oligohydramnios. Because of the potentially serious fetal effects, many centers limit its use to infants less than 32 weeks’ EGA and its duration of use to less than 48 hours.
5. Treatment with multiple tocolytics—All tocolytics have significant failure rates; therefore, if 1 tocolytic appears to be failing, that agent should be stopped and another agent should be tried. The use of multiple tocolytics at the same time appears to have an additive tocolytic effect, but also appears to increase the risk of serious side effects. For example, magnesium sulfate used in combination with nifedipine theoretically can cause serious maternal hypotension. Likewise, magnesium sulfate supplemented by 1–2 doses of subcutaneous terbutaline may be safe and effective, but sustained treatment with the 2 can increase the patient’s risk of pulmonary edema. It should be remembered that the patient who is difficult to tocolyze may have an unrecognized chorioamnionitis or placental abruption, conditions that may be contraindications to use of any tocolysis at all.
6. Results of tocolytic therapy—With all tocolytics, a point may be reached where further therapy is not indicated. This may be due to adverse maternal or fetal response to the progress of labor. Thus, if cervical dilatation reaches 5 cm, the treatment should be considered a failure and abandoned. Conversely, if labor resumes after a period of quiescence, treatment should be carefully considered because the recrudescence of contractions may be a sign of intrauterine infection. In some cases, therapy may be reinstituted using the same or a different drug.
D. Antibiotics
Antibiotic therapy as a treatment of preterm labor and a means of prolonging pregnancy has been studied and has shown no benefit in delaying preterm birth in this population of patients. Patients with preterm labor should be started on antibiotics for prevention of neonatal GBS infection if the patient’s GBS status is positive or unknown. Penicillin or ampicillin is used as first-line agents; cefazolin, clindamycin, erythromycin, or vancomycin can be used if the patient is allergic to penicillin. If the patient is successfully tocolyzed and there is no sign of imminent delivery or if the patient’s most recent rectovaginal GBS culture (within 5 weeks) is negative, GBS prophylaxis can be discontinued.
E. Magnesium Sulfate for Fetal/Neonatal Neuroprotection
Several recent large trials have shown a reduced risk of cerebral palsy in fetuses exposed to magnesium sulfate in utero. The largest trial from the United States demonstrated a significant reduction in moderate to severe cerebral palsy in children at or beyond 2 years of age who received magnesium sulfate immediately before delivery. The optimal candidates for magnesium for this indication are not well defined, but it is reasonable to offer magnesium sulfate to any woman between 24 0/7 and 32 0/7 weeks of gestation immediately before delivery to reduce the risk of adverse neurologic outcomes (Table 14–4).
Table 14–4. Protocol for use of magnesium sulfate for fetal neuroprotection.
F. Conduct of Labor and Delivery
Premature infants younger than 34 weeks should be delivered in a hospital equipped for neonatal intensive care whenever possible, because inter-hospital transfer after birth is more hazardous. Although the route of delivery for very-low-birth-weight infants has been hotly debated, there is no conclusive evidence of a benefit to routine caesarean delivery. Indications for caesarean are the usual obstetrical indications, including nonreassuring fetal status, malpresentation, and history of prior caesarean.
If caesarean delivery is indicated, the decision to operate is based on maturity of the fetus and prognosis for survival. In borderline cases (23–24 weeks’ gestation and 500–600 g EFW), the wishes of the parents with regard to intervention assume an important place. When performing a caesarean delivery, it is important to ascertain that the uterine incision is adequate for extraction of the fetus without delay or unnecessary trauma. This may require a vertical incision when the lower uterine segment is incompletely developed. Trauma to the newborn may be minimized by en caul delivery.
When birth follows the unsuccessful use of parenteral tocolytic agents, keep in mind the potential residual adverse effects of these drugs. β-Adrenergic agents may cause neonatal hypotension, hypoglycemia, hypocalcemia, and ileus. Magnesium sulfate may be responsible for respiratory and cardiac depression.
G. Cord pH & Blood Gases
Apgar scores are often low in low-birth-weight babies. This finding does not indicate asphyxia or compromised status but merely reflects the immaturity of the physiologic systems. Therefore, it is crucial to obtain cord pH and blood gas measurements for premature (and other high-risk) infants in order to document the status at birth. Cord pH and blood gas measurements may also be helpful in reconstructing intrapartum events, clarifying resuscitative measures, and determining the need for more intensive neonatal care.
Prognosis
Excellent neonatal care in the delivery room and nursery will do much to ensure a good prognosis for the preterm infant (see Chapter 22). Lower-birth-weight babies have a lesser chance of survival and a greater chance of permanent sequelae in direct relationship to size. Making generalizations regarding survival rates and sequelae is difficult because of the many causes of preterm delivery, the different levels of perinatal care, and the institutional differences in reported series. However, general figures for survival and morbidity have been reported and are helpful in counseling patients (Table 14–5).
Table 14–5. Approximate neonatal survival of preterm infants.1
Rouse DJ, Hirtz DG, Thom E, et al. A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008:359:895–905. PMID: 18753646.
American College of Obstetricians and Gynecologists. Assessment of Risk Factors for Preterm Birth. Clinical Management Guidelines for Obstetrician-Gynecologists. ACOG Practice Bulletin No. 31. Washington, DC: American College of Obstetricians and Gynecologists; 2001.
American College of Obstetricians and Gynecologists. Use of Progesterone to Reduce Preterm Birth. ACOG Committee Opinion No. 419. Washington, DC: American College of Obstetricians and Gynecologists; 2008.
American College of Obstetricians and Gynecologists. Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection. ACOG Committee Opinion No. 455. Washington, DC: American College of Obstetricians and Gynecologists; 2010.
American College of Obstetricians and Gynecologists. Antenatal Corticosteroid Therapy for Fetal Maturation. ACOG Committee Opinion No. 475. Washington, DC: American College of Obstetricians and Gynecologists; 2011.
Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. JAMA 2001;286:1581–1587. PMID: 11585480.
Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labour: The ORACLE II randomised trial. Lancet 2001;357: 989–994. PMID: 11293641.
PREMATURE RUPTURE OF MEMBRANES
ESSENTIALS OF DIAGNOSIS
History of a gush of fluid from the vagina or watery vaginal discharge
Demonstration of amniotic fluid in the vagina on physical exam
Absence of active labor
Pathogenesis
Rupture of the membranes may occur at any time during pregnancy. Premature rupture of the membranes (PROM) is defined as rupture of membranes before the onset of active labor. It becomes a particular problem if the fetus is preterm (preterm premature rupture of membranes [PPROM]) or, in the case of a term fetus, if the period of time between rupture of the membranes and the onset of labor is prolonged. If 24 hours elapse between rupture of the membranes and the onset of labor, the problem is one of prolonged PROM.
The exact cause of rupture is not known, although many conditions are associated with PROM (Table 14–6). PROM occurs in approximately 10.7% of all pregnancies. In approximately 94% of cases, this occurs at term or ≥37 weeks (approximately 20% of these are cases of prolonged rupture). Preterm fetuses (<37 weeks) account for approximately 5% of the total number of cases of PROM.
Table 14–6. Diseases and disorders associated with premature rupture of the membranes.
The pathophysiology of PROM is poorly understood. Risk factors include decidual hemorrhage, a history of spontaneous preterm birth in a prior pregnancy, bacterial colonization of the membranes, and invasive procedures such as amniocentesis. PROM is an important cause of preterm labor, prolapse of the cord, placental abruption, and intrauterine infection. Chorioamnionitis is an important sequela of PROM and may precede endomyometritis or sepsis of the newborn.
In extremely prolonged rupture of the membranes, the fetus may have an appearance similar to that of Potter’s syndrome (ie, flattened facial features, wrinkling of the skin). If rupture of membranes with subsequent oligohydramnios occurs early in pregnancy at less than 26 weeks’ EGA, it can cause pulmonary hypoplasia and limb positioning defects in the newborn.
Prevention
As with preterm labor, there are few interventions known to prevent PPROM. For women with a history of a prior spontaneous preterm birth, there is evidence indicating that progestin administered via either vaginal suppositories of progesterone or weekly intramuscular injections of 17-α hydroxyprogesterone caproate from 16 weeks until approximately 36–37 weeks reduces the risk of recurrent preterm birth by approximately 30%. Furthermore, vaginal progesterone may also reduce the risk of preterm birth in women found to have a short cervix on transvaginal ultrasound in the midtrimester. But, aside from these specific interventions, there is little we can do to prevent PPROM.
Clinical Findings
A. Symptoms
The diagnostic evaluation must be efficient and impeccably conducted to minimize the number of vaginal examinations and the risk of chorioamnionitis. Symptoms are the key to diagnosis; the patient usually reports a sudden gush of fluid or continued leakage. Additional symptoms that may be useful include the color and consistency of the fluid and the presence of flecks of vernix or meconium, reduced size of the uterus, and increased prominence of the fetus to palpation.
B. Sterile Speculum Examination
A most important step in accurate diagnosis is examination with a sterile speculum. This examination is the key to differentiating PROM from hydrorrhea gravidarum, vaginitis, increased vaginal secretions, and urinary incontinence. The examiner should look for the 3 hallmark confirmatory findings associated with PROM:
1. Pooling—the collection of amniotic fluid in the posterior fornix.
2. Nitrazine test—a sterile cotton-tipped swab should be used to collect fluid from the posterior fornix and apply it to Nitrazine (phenaphthazine) paper. In the presence of amniotic fluid, the Nitrazine paper turns blue, demonstrating an alkaline pH (7.0–7.25).
3. Ferning—Fluid from the posterior fornix is placed on a slide and allowed to air-dry. Amniotic fluid will form a fernlike pattern of crystallization.
Together, these 3 findings confirm ruptured membranes, although several factors may produce false-positive results. Alkaline pH on Nitrazine test can also be caused by vaginal infections or the presence of blood or semen in the sample. Cervical mucus can cause ferning, but usually patchy and less extensive than with PROM. During the speculum examination, the patient’s cervix should be visually inspected to determine the degree of dilatation and effacement and the presence of cord prolapse. If vaginal pool is significant, the pool can be collected and sent for fetal lung maturity determination if the gestational age is greater than 32 weeks. Cervical secretions should also be sent for culture, and a wet mount should be performed.
If no free fluid is found, a dry pad should be placed under the patient’s perineum and observed for leakage. Other confirmatory tests for PROM include observed loss of fluid from the cervical os when the patient coughs or performs a Valsalva maneuver during speculum examination and oligohydramnios on ultrasound examination. If the examiner still cannot confirm rupture of membranes and the patient’s history is highly suspicious for PROM, it may be necessary to perform amniocentesis and inject a dilute solution of indigo carmine dye. This can be done after removal of amniotic fluid for pulmonary maturity testing, analysis for evidence of subacute intra-amniotic infection, and possible culture and sensitivity testing. After 15–30 minutes, examination of the patient’s perineal pad will reveal blue dye if the membranes are ruptured.
C. Physical Examination
Once PROM is confirmed, a careful physical examination is necessary to search for other signs of infection. Given the risk of infection, there is no indication for digital cervical examination if the patient is in early labor. The sterile speculum examination is sufficient to distinguish between early and advanced labor.
D. Laboratory Studies
Initial laboratory studies should include a complete blood count with differential. In preterm pregnancies, evaluation should also include urine collected by catheterization for urinalysis, culture, and sensitivity testing and ultrasound examination for fetal size and amniotic fluid index. For patients between 32 and 34 weeks, a specimen of amniotic fluid collected from the vaginal pool or via amniocentesis can be sent for fetal lung maturity studies. Furthermore, many centers perform amniocentesis in all women with PPROM before 34 weeks to test for evidence of intra-amniotic infection.
E. Chorioamnionitis
In all cases of chorioamnionitis, it is safer for the fetus to be delivered than to be retained in utero. The most common organisms causing chorioamnionitis are those that ascend from the vagina (eg, Escherichia coli, Bacteroides, GBS, group D streptococcus, and other anaerobes). The most reliable signs of infection include the following: (1) Fever—the temperature should be checked every 4 hours. (2) Maternal leukocytosis—a daily leukocyte count and differential can be obtained. An increase in the white blood cell count or neutrophil count may indicate the presence of intra-amniotic infection. (3) Uterine tenderness—check every 4 hours. (4) Tachycardia—either maternal pulse >100 beats/min or fetal heart rate >160 beats/min—is suspicious. (5) Foul-smelling amniotic fluid.
A number of confounding factors may complicate the diagnosis of chorioamnionitis. For example, corticosteroid administration may cause mild leukocytosis (increase of 20–25%), and labor is associated with leukocytosis. If the diagnosis of chorioamnionitis is equivocal, amniocentesis can be performed to evaluate for evidence of infection, as described earlier in this chapter.
Differential Diagnosis
The differential diagnosis includes the increased physiologic vaginal discharge associated with pregnancy, vaginal infections such as bacterial vaginosis, and passage of a woman’s mucus plug. Physical examination with testing of any vaginal discharge or pool can distinguish among these entities.
Complications
Complications associated with PROM are primarily associated with duration of membrane rupture and the development of chorioamnionitis. Treatment outlined below is directed toward expediting delivery and preventing chorioamnionitis and fetal/neonatal infection. Complications with PPROM are primarily related to prematurity and the risk of fetal/neonatal infection. As in patients with preterm labor, treatment is directed toward reducing the likelihood of pre-term birth and reducing the risk of prematurity-related complications in the infant such as RDS and neurologic injury.
Treatment
The management of PROM depends on several factors, including gestational age and the presence or absence of chorioamnionitis.
A. Chorioamnionitis
If chorioamnionitis is present in the patient with PROM, the patient should be actively delivered regardless of gestational age. Broad-spectrum antibiotics should be started to treat the chorioamnionitis. If the patient is not in labor, labor should be induced to expedite delivery. Caesarean delivery should be reserved for the usual obstetric indications (eg, fetal malpresentation, nonreassuring fetal status).
B. Term Pregnancy Without Chorioamnionitis
The term pregnancy (EGA ≥37 weeks) with PROM in the absence of infection can be managed expectantly or actively. One large study found that starting induction of labor at presentation as opposed to expectant management reduced the time interval between PROM and delivery and the frequency of chorioamnionitis and postpartum febrile morbidity and neonatal antibiotic treatment. Therefore, active management with induction of labor at time of presentation for the woman with PROM at term is the preferred management strategy.
C. Preterm Pregnancy Without Chorioamnionitis
The principles of managing the preterm PROM patient are similar to those for managing the preterm labor patient. The key difference is the much increased risk of developing chorioamnionitis associated with preterm PROM. Pregnancies beyond 34 weeks’ EGA can be managed as a term pregnancy with induction of labor or delivery via caesarean delivery (if indicated) because there is no evidence that antibiotics, corticosteroids, or tocolytics improve outcome in these patients.
Rupture of membranes before viability (ie, before 22–24 weeks of gestation) can be managed in one of several ways. One option is termination of pregnancy, given the high risk of adverse pregnancy outcome and prematurity. However, in the patient without evidence of chorioamnionitis, expectant management may be considered. Several case series have documented substantial survival rates (15–50%) with PPROM at 18–22 weeks. Although many patients may be unwilling to accept the risk of chorioamnionitis (30%) and even sepsis, they should be informed of the option of expectant management with antibiotic therapy.
For pregnancies with PROM between 24 and 34 weeks’ EGA, several interventions have been shown to prolong pregnancy and improve outcome. After chorioamnionitis has been ruled out and a specimen of amniotic fluid from vaginal pool collection or amniocentesis sent for determination of fetal lung maturity, management should consist of the following interventions.
1. Antibiotics—Antibiotics have emerged as an important treatment for preterm PROM. In contrast to preterm labor, where antibiotics have shown no benefit in prolonging pregnancy, antibiotics appear to be effective in prolonging the latency period from rupture of membranes to delivery in patients with preterm PROM. They have also been shown to decrease the infection rate in these patients. A number of well-designed studies have shown improved neonatal outcomes with antibiotics alone and with antibiotics combined with corticosteroid therapy. Table 14–7 provides 1 recommended protocol for antibiotic use in preterm PROM.
Table 14–7. Antibiotic therapy for preterm premature rupture of membranes.
2. Corticosteroids—The National Institutes of Health (NIH) consensus development panel recommends the use of steroids in PROM patients before 32 weeks’ EGA in the absence of intra-amniotic infection. In this patient population, corticosteroids have been shown to decrease the rate of RDS, necrotizing enterocolitis, and intraventricular hemorrhage. The benefit of steroids at 32–33 weeks in women with PPROM is unclear. However, steroids may also be considered in patients with PPROM between 32 and 33 6/7 weeks, especially if pulmonary immaturity has been documented via testing of amniotic fluid.
3. Tocolytics—No study has shown that tocolytics alone improve fetal outcome in women with PPROM. In general, the use of tocolytics in the PPROM patient should be either avoided entirely or limited to 48 hours’ duration to permit administration of corticosteroids and antibiotics.
4. Magnesium sulfate for fetal neuroprotection—As with the management of preterm labor, consideration should be given to administering magnesium sulfate for fetal neuroprotection if delivery is felt to be imminent in the PPROM patient between 24 and 32 weeks of gestation. See Table 14–4 for a suggested protocol.
If after starting these interventions the fetal lung profile from testing of amniotic fluid returns as mature, the fetus should be delivered. Again, if at any time the patient shows signs of chorioamnionitis, the fetus should be delivered.
D. Role of Outpatient Management
In rare selected cases, patients who remain undelivered may be candidates for outpatient management. If leakage of fluid stops, the amniotic fluid volume normalizes, and the patient remains afebrile without evidence of increasing uterine irritability, she can be discharged home. These patients should be monitored very closely on an outpatient basis. They must be reliable and compliant with follow-up appointments. They also must take their temperature 4 times per day and be counseled on the warning signs of chorioamnionitis. These patients should also be monitored with frequent biophysical profiles; some sources recommend daily testing.
Seaward PG, Hannah ME, Myhr TL, et al. International multicentre term prelabor rupture of membranes study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term. Am J Obstet Gynecol 1997;177:1024–1029. PMID: 9396886.
Mercer BM, Miodovnik M, Thurnau GR, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: A randomized controlled trial. JAMA 1997;278:989–995. PMID: 9307346.
Rouse DJ, Hirtz DG, Thom E, et al. A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008:359:895–905. PMID: 18753646.
American College of Obstetricians and Gynecologists. Premature Rupture of Membranes. ACOG Practice Bulletin No. 80. Washington, DC: American College of Obstetricians and Gynecologists; 2007.
How HY, Cook CR, Cook VD, Miles DE, Spinnato JA. Preterm premature rupture of membranes: Aggressive tocolysis versus expectant management. J Matern Fetal Med 1998;7:8–12. PMID: 9502662.
Kenyon SL, Taylor DJ, Tarnow-Mordi W. ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: The ORACLE I randomised trial. Lancet2001;357:979–994. PMID: 11293641.
PROLONGED OR POSTTERM PREGNANCY
ESSENTIALS OF DIAGNOSIS
Confirmation of gestational age greater than 42 completed weeks
Pathogenesis
The prolonged or postterm pregnancy is defined as pregnancy that has reached 42 weeks of gestation from the first day of the LMP or 40 weeks’ gestation from the time of conception. Most fetuses will show effects of impaired nutritional supply (weight loss, reduced subcutaneous tissue, scaling, parchment-like skin). This condition is referred to as dysmaturity. The most common cause of prolonged pregnancy is incorrect dating due to variable length of the menstrual cycle. This has been reduced in recent years with widespread use of first-trimester ultrasound for dating. The cause of most cases of true prolonged pregnancy remains unknown. Experiments of nature, such as anencephalic fetuses and those with placental sulfatase deficiency, suggest that changes in placental steroid metabolism due to fetal hormonal signaling play a central role in the timing of delivery. At least 3% of infants are born after 42 completed weeks’ gestation (in some series, as many as 12%). Because of the potential risks of dysmaturity, these infants deserve particular attention.
The maternal risks usually relate to large fetal size (ie, dysfunctional labor, arrested progress of labor, fetopelvic disproportion). Large fetal size may result in birth injury (eg, shoulder dystocia). Placental insufficiency is thought to be associated with aging of the placenta and is the basis for another group of fetal problems. Oligohydramnios, which is more common in postterm gestation, may lead to cord compromise.
Complications resulting from prolonged pregnancy result in a sharp rise in perinatal mortality and morbidity rates (2–3 times those of infants born at 37–42 weeks). Complications in the survivors increase the chance of neurologic sequelae.
Prevention
The most common cause of an apparent postterm pregnancy is an error in pregnancy dating. First-trimester ultrasound is an accurate way to confirm a patient’s estimated date of delivery and has been shown to reduce the incidence of pregnancies diagnosed as postterm.
Clinical Findings
The diagnosis of prolonged pregnancy is made by confirmation of the gestational age by referring to records of early pregnancy tests and ultrasound examinations, the exact time of conception (if known), and clinical parameters (eg, LMP, quickening, detection of fetal heart tones).
Differential Diagnosis
The most likely differential diagnosis of the suspected post-term pregnancy is incorrect pregnancy dating, which may be determined via a careful review of the patient’s dating criteria. However, it may be difficult to ascertain the correct due date in a patient who presents for prenatal care late in pregnancy or has not had any early ultrasounds in pregnancy.
Treatment
The principal risk of labor induction has been thought to be an increased rate of caesarean birth. It has now been conclusively demonstrated, however, that induction of labor at 41 weeks does not increase the caesarean rate compared with expectant management with antepartum testing. Therefore, many authorities offer induction of labor at 41 completed weeks, reserving expectant management for those patients who refuse induction.
To adequately assess the risk of fetal compromise, the following is a useful protocol for pregnancies beyond 41 weeks’ gestation:
1. Some form of fetal surveillance is advised, either with nonstress testing and measurement of amniotic fluid volume twice per week or with biophysical profiles twice per week.
2. Perform ultrasonic monitoring at least twice weekly to assess amniotic fluid volume (biophysical profiles may be obtained at the same time).
3. Have the mother count fetal movements each day.
The following additional precautions should be taken:
1. Decreased fetal movement warrants an immediate biophysical profile evaluation.
2. Abnormalities in the nonstress test mandate induction or a backup test such as the full biophysical profile.
3. An abnormal contraction stress test, decreased amniotic fluid volume, abnormal biophysical profile, or other signs of fetal distress require delivery.
4. A large or compromised fetus may require caesarean delivery (see discussion of macrosomia in Chapter 16).
5. In the absence of fetopelvic disproportion or fetal distress, labor can be induced. Fetal monitoring should be continuous.
American College of Obstetricians and Gynecologists. Management of postterm pregnancy. ACOG Practice Bulletin No. 55. Washington, DC: American College of Obstetricians and Gynecologists; 2004.
American College of Obstetricians and Gynecologists. Assessment of Risk Factors for Preterm Birth. Clinical Management Guidelines for Obstetrician-Gynecologists. ACOG Practice Bulletin No. 31. Washington, DC: American College of Obstetricians and Gynecologists; 2001.
American College of Obstetricians and Gynecologists. Use of Progesterone to Reduce Preterm Birth. ACOG Committee Opinion No. 419. Washington, DC: American College of Obstetricians and Gynecologists; 2008.
American College of Obstetricians and Gynecologists. Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection. ACOG Committee Opinion No. 455. Washington, DC: American College of Obstetricians and Gynecologists; 2010.
American College of Obstetricians and Gynecologists. Antenatal Corticosteroid Therapy for Fetal Maturation. ACOG Committee Opinion No. 475. Washington, DC: American College of Obstetricians and Gynecologists; 2011.
RH ALLOIMMUNIZATION & OTHER BLOOD GROUP INCOMPATIBILITIES
ESSENTIALS OF DIAGNOSIS
Maternal Rh-negativity and presence of antibody on indirect Coombs’ test
Rh or other antibody titer posing fetal risk
May have a previous infant with hemolytic disease of the newborn
Postnatal fetal cord blood findings of Rh-positivity and anemia (hemoglobin <10 g)
Pathogenesis
A fetus receives half of its genetic components from its mother and half from its father; therefore, the fetus may have red blood cell (RBC) antigens different from those of its mother. Some blood groups may act as antigens in individuals not possessing those blood groups. The antigens reside on red blood cells. If enough fetal cells cross into the maternal blood, a maternal antibody response may be provoked. If these maternal antibodies cross the placenta, they then can enter the fetal circulation and destroy the fetal erythrocytes, causing hemolytic anemia. This leads to fetal responses to meet the challenge of enhanced blood cell breakdown. These changes in the fetus and newborn are called erythroblastosis fetalis or fetal hydrops. Several blood groups are capable of producing fetal risk, but those in the Rh group have caused the overwhelming majority of cases of erythroblastosis fetalis, so the Rh group is used as the example.
The Rh blood group is the most complex human blood group. Rh antigens are lipoproteins that are confined to the red cell membrane. The Rh antigens are D, C, c, E, e, and G. The major antigen in this group, Rh (D), or Rh factor, is of particular concern. A woman who is lacking Rh(D) (otherwise known as Rh-negative) may carry an Rh-positive fetus if the fetus inherited the D antigen from the father. If fetal red blood cells pass into the mother’s circulation in sufficient numbers, maternal IgG antibodies to the D antigen may develop and cross the placenta, causing hemolysis of fetal blood cells (Fig. 14–1). Hemolytic disease of the newborn may occur, and severe disease may cause fetal death.
Figure 14–1. A: Rh-negative woman before pregnancy. B: Pregnancy occurs. The fetus is Rh-positive. C: Separation of the placenta. D: After delivery, Rh alloimmunization occurs in the mother, and she develops antibodies (S) to the Rh-positive antigen. E: The next pregnancy with an Rh-positive fetus. Maternal antibodies cross the placenta, enter the fetal bloodstream, and attach to Rh-positive red cells, causing hemolysis.
In standard testing when the father is Rh-positive, 2 possibilities exist: he is either homozygous or heterozygous. Forty-five percent of Rh-positive persons are homozygous for D and 55% are heterozygous. If the father is homozygous, all of his children will be Rh-positive; if he is heterozygous, his children will have a 50% chance of being Rh-positive. By way of contrast, the Rh-negative individual is always homozygous.
Basque populations have the highest incidence of Rh negativity (30–35%). White populations in general have a higher incidence than other ethnic groups (15–16%). African Americans have a rate of 8%, African blacks 4%, Indoeurasians 2%, and North American Indians 1%.
In mothers who do not receive prophylaxis with anti-D immunoglobulin, the overall risk of alloimmunization for an Rh-positive ABO-compatible infant with an Rh-negative mother is approximately 16% after 2 deliveries of Rh-positive infants. Of these, 1.5–2% of reactions will occur antepartum and 7% within 6 months of delivery; the remainder (7%) manifest early in the second pregnancy, most likely as the result of an amnestic response. ABO incompatibility between an Rh-positive fetus and an Rh-negative mother provides some protection against Rh alloimmunization; in these cases the overall incidence is 1.5–2%. In mothers who receive prophylaxis with anti-D immunoglobulin administered both antepartum and postpartum, the risk of alloimmunization is reduced to 0.1%.
A. Maternal Rh Alloimmunization
Rh alloimmunization generally occurs by 1 of 2 mechanisms: (1) after incompatible blood transfusion or (2) after fetomaternal hemorrhage between a mother and an incompatible fetus. Fetomaternal hemorrhage may occur during pregnancy or at delivery. With no apparent predisposing factors, fetal red cells have been detected in maternal blood in 6.7% of women during the first trimester, 15.9% during the second trimester, and 28.9% during the third trimester. Predispositions to fetomaternal hemorrhage include spontaneous or induced abortion, amniocentesis, chorionic villus sampling, abdominal trauma (eg, due to motor vehicle accidents or external version), placenta previa, abruptio placentae, fetal death, multiple pregnancy, manual removal of the placenta, and caesarean section.
Although the exact number of Rh-positive cells necessary to cause alloimmunization of the Rh-negative pregnant woman is unknown, as little as 0.1 mL of Rh-positive cells can cause sensitization. Even with delivery, this amount occurs in less than half of cases.
Fortunately, there are other mitigating factors to Rh alloimmunization. A very important factor is that approximately 30% of Rh-negative persons never become sensitized (non-responders) when given Rh-positive blood. ABO incompatibility also confers a protective effect (see Incidence).
The initial maternal immune response to Rh sensitization is low levels of immunoglobulin (Ig) M. Within 6 weeks to 6 months, IgG antibodies become detectable. In contrast to IgM, IgG is capable of crossing the placenta and destroying fetal Rh-positive cells.
B. Other Blood Group Alloimmunization
Of the other blood groups that may evoke an immunoglobulin capable of crossing the placenta (often called atypical or irregular immunizing antibodies), those that may cause severe fetal hemolysis (listed in descending order of occurrence) are Kell, Duffy, Kidd, MNSs, and Diego. P, Lutheran, and Xg groups may also cause fetal hemolysis, but it usually is less severe.
Prevention
Prevention of Rh (D) alloimmunization is possible by identifying women known to be negative for the Rh (D) antigen and administering anti-D immunoglobulin to prevent sensitization.
A. Prepregnancy or First Prenatal Visit
On the first prenatal visit, all pregnant women should be screened for the ABO blood group and the Rh(D) antigen. They should also undergo antibody screening (indirect Coombs’ test). All Rh-negative mothers should receive prophylaxis according to the following protocol.
B. Visit at 28 Weeks
Antibody screening is performed. If negative, 300 μg of anti-D immunoglobulin (RhIgG) is given. If positive, the patient should be managed as Rh-sensitized.
C. Visit at 40 Weeks
If more than 12 weeks have elapsed since anti-D immunoglobulin administration, consideration should be given to administering 300 μg of anti-D immunoglobulin at 40 weeks of gestation.
D. Postpartum
If the infant is Rh(D)-positive, 300 μg of RhIgG is administered to the mother (provided maternal antibody screening is negative). Although RhIgG should generally be given within 72 hours after delivery, it has been shown to be effective in preventing alloimmunization if given up to 28 days after delivery. If the antibody screen is positive, the patient is managed as if she will be Rh-sensitized during the next pregnancy.
E. Special Fetomaternal Risk States
Several circumstances may occur during pregnancy that mandate administration of RhIgG to the unsensitized patient outside the management protocol described.
1. Abortion—Sensitization will occur in 2% of spontaneous abortions and 4–5% of induced abortions. In the first trimester, because of the small amount of fetal blood, 50 μg of RhIgG apparently is sufficient to prevent sensitization. However, because the cost of RhIgG has dropped, a full 300-μg dose is usually given. The same dose is recommended for exposure after the first trimester. The risk of Rh alloimmunization after threatened abortion is less well understood, but many experts agree that RhIgG should also be given to these patients.
2. Amniocentesis, Chorionic Villus Sampling, and Cord Blood Sampling—If the placenta is traversed by the needle, there is up to an 11% chance of sensitization. Therefore, administration of 300 μg of RhIgG is recommended when these procedures are performed in the unsensitized patient.
3. Antepartum Bleeding—In cases of antepartum vaginal bleeding or when there is evidence of a subchorionic hematoma or placenta abruption on ultrasound, administration of 300 μg of RhIgG is recommended. If the pregnancy is carried more than 12 weeks from the time of RhIgG administration, a repeat prophylactic dose is recommended.
4. External cephalic version—Fetomaternal hemorrhage occurs in 2–6% of patients who undergo external cephalic version, whether failed or successful; therefore, these patients should receive 300 μg of RhIgG.
F. Delivery With Fetomaternal Hemorrhage
Fetomaternal hemorrhage so extensive that it cannot be managed with 300 μg of RhIgG occurs in only approximately 0.4% of patients. The amount of hemorrhage can be quantified by the Kleihauer-Bethke test and additional doses of RhIgG given according to the amount of fetomaternal hemorrhage.
Clinical Findings
Hemolytic disease of the newborn occurs when the maternal antibodies cross the placenta and destroy the Rh-positive fetal red blood cells. Fetal anemia results, stimulating extramedullary erythropoietic sites to produce high levels of nucleated red cell elements. Immature erythrocytes are present in the fetal blood because of poor maturation control. Hemolysis produces heme, which is converted to bilirubin; both of these substances are neurotoxic. However, although the fetus is in utero, heme and bilirubin are effectively removed by the placenta and metabolized by the mother.
When fetal red blood cell destruction far exceeds production and severe anemia occurs, erythroblastosis fetalis may result. This is characterized by extramedullary hematopoiesis, heart failure, edema, ascites, and pericardial effusion. Tissue hypoxia and acidosis may result. Normal hepatic architecture and function may be disturbed by extensive liver erythropoiesis, which may lead to decreased protein production, portal hypertension, and ascites. On ultrasound, fetal hydrops may be visualized, which is defined as the presence of any 2 of the following: pleural effusion, ascites, pericardial effusion, increased skin thickness, polyhydramnios, or increased placental thickness.
In the immediate neonatal interval, the primary problem may relate to anemia and the sequelae mentioned previously. However, hyperbilirubinemia may also pose an immediate risk and certainly poses a risk as further red cell breakdown occurs. The immature (and often compromised) liver, with its low levels of glucuronyl transferase, is unable to conjugate the large amounts of bilirubin. This results in a high serum bilirubin level, with resultant kernicterus (bilirubin deposition in the basal ganglia).
Treatment
A. Management of the Unsensitized Rh-Negative Patient
Management of the pregnancy complicated by alloimmunization is guided by 2 factors: whether the patient has a history of an affected fetus in a previous pregnancy (ie, fetus with severe anemia or hydrops) and maternal antibody titers.
1. No history of previous fetus affected by rh alloimmunization—Once the antibody screen is positive for alloimmunization, these patients should be followed up with antibody titers at intake, 20 weeks’ EGA, and then every 2–4 weeks. As long as antibody titers remain below the critical titer (<1:32 in our laboratory, but each laboratory must establish its own norms), there is no indication for further intervention. Once antibody titers reach 1:32, additional surveillance should be performed because a titer of 1:32 places the fetus at significant risk of hydrops and demise before 37 weeks. Ultrasound assessment of blood flow in the fetal middle cerebral artery (MCA) by Doppler has been shown to be a reliable and noninvasive screening tool for detecting moderate to severe fetal anemia. It is based on the concept that the fetus preserves oxygen delivery to the brain in the setting of anemia by increasing flow to the brain of the low viscosity blood. Ultrasound is performed to identify the circle of Willis, and blood flow in the proximal third of the MCA can be estimated using Doppler. High peak velocity blood flow in this area (>1.5 multiples of the median) correlates well with severe fetal anemia. This test can be performed at 2-week intervals in these patients, so more invasive diagnostic interventions can be avoided until evidence of severe anemia is observed.
In the past, amniocentesis has been used to determine amniotic fluid bilirubin levels and identify fetuses at risk of severe anemia; however, given the invasive nature of repeated amniocenteses, ultrasound for MCA Dopplers has widely replaced amniocentesis for this indication.
2. History of a prior fetus affected by rh alloimmunization—Antibody titers need not be followed in these pregnancies because amniocentesis is indicated by the history of prior affected fetus. Amniocentesis may be performed to determine the fetal genotype if the father of the fetus is determined to be heterozygous for D. If the fetus is determined to have the D antigen, that fetus is considered to be at risk of hemolytic disease and severe anemia regardless of maternal antibody titers. In general, after a first affected pregnancy, future pregnancies tend to manifest with more severe disease and at an earlier gestational age. For this reason, MCA Doppler surveillance should be initiated at 18 weeks and repeated every 1–2 weeks. Treatment of these patients is dictated by MCA Doppler.
3. Results of MCA Dopplers—Once it is determined that a patient should be followed with MCA Dopplers, the results of the MCA Dopplers will place the fetus into one of three categories:
A. UNAFFECTED OR MILDLY AFFECTED FETUS—The fetus that has normal MCA Doppler studies is considered to be unaffected or mildly affected. Testing should be repeated every 2–3 weeks, and delivery should be entertained at term or near term and after the fetus has achieved pulmonary maturity.
B. MODERATELY AFFECTED FETUS—The fetus that has MCA Doppler studies nearing 1.5 multiples of the median should be tested more frequently, every 1–2 weeks. Delivery may be required before term, and the fetus is delivered as soon as pulmonary maturity is reached. In some cases, enhancement of pulmonary maturity by use of corticosteroids may be necessary.
C. SEVERELY AFFECTED FETUS—The severely affected fetus has MCA Doppler studies >1.55 multiples of the median or has frank evidence of hydrops (eg, ascites, pleural or pericardial effusion, subcutaneous edema). Intervention usually is needed to allow the fetus to reach a gestational age at which delivery and neonatal risks are fewer than the risks of in utero therapy.
If the fetus is preterm, cordocentesis or percutaneous umbilical cord blood sampling is recommended at this stage to directly assess the fetal hematocrit. Intrauterine transfusions are generally performed between 18 and 35 weeks of gestation. Before 18 weeks, access to the umbilical vein is limited due to the small caliber of the vessel. After 35 weeks, the risk/benefit ratio favors delivery of a fetus with evidence of severe anemia. Once severe anemia is confirmed, intrauterine transfusion can be performed directly into the umbilical vein. The transfusion is performed using O-negative, cytomegalovirus-negative, washed, leukocyte-depleted, irradiated packed red cells. The intraperitoneal technique was used in years past but has largely been replaced by intravascular fetal transfusion secondary to its more predictable absorption.
After transfusion, repeat transfusions or delivery usually will be necessary, as production of fetal blood markedly decreases or ceases. Timing of these transfusions may be assisted by ultrasonic determination of MCA Doppler studies. Delivery should take place when the fetus has documented pulmonary maturity.
American College of Obstetricians and Gynecologists. Prevention of Rh D Alloimmunization. ACOG Practice Bulletin No. 4. Washington, DC: American College of Obstetricians and Gynecologists; 1999.
Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9–14. PMID: 10620643.
Saade GR. Noninvasive testing for fetal anemia. N Engl J Med 2000;342:52–53. PMID: 10620651.
STILLBIRTH
ESSENTIALS OF DIAGNOSIS
Intrauterine fetal death at or beyond 20 weeks’ gestation
Pathogenesis
Stillbirth affects <1% of pregnancies, with an incidence of approximately 6 per 1000 pregnancies in the United States. There are a number of known risk factors for stillbirth, which are presented in Table 14–8.
Table 14–8. Risk factors and etiologies for stillbirth.
In the past, cord accident was thought to be the cause of many stillbirths. However, more recent data suggest that a nuchal cord is found in approximately 30% of normal births and is most likely an incidental finding when a stillbirth is diagnosed. In order for a stillbirth to be attributed to cord accident, evidence of cord obstruction or compromise (ie, thrombosis) should be seen on pathologic examination, and other causes of stillbirth should be excluded.
In many cases, up to 50% of stillbirths, it is difficult to elucidate a cause of the stillbirth. In some cases, this may be attributable to incomplete workup. However, in many cases, the stillbirth may be unexplained despite a thorough evaluation.
Prevention
Compliance with prenatal care is an important strategy that may prevent stillbirth. The early diagnosis of fetal abnormalities and obstetrical complications such as preeclampsia may allow for the initiation of an appropriate surveillance strategy or timely delivery in order to avoid stillbirth.
Clinical Findings
Stillbirth is diagnosed with the absence of cardiac activity in a fetus at or beyond 20 weeks of gestational age on ultrasound or at birth. Some women with stillbirth may report decreased or absent fetal movement, vaginal bleeding, or abdominal pain.
However, in many cases, the patient may be asymptomatic for the stillbirth and may even report what she thought was normal fetal movement.
Treatment
Once a stillbirth is diagnosed, it is important to initiate an evaluation to determine the cause. A complete history and physical is the first step to look for findings suggestive of a possible cause. For instance, vaginal bleeding may be suggestive of placental abruption, and maternal fever and abdominal pain may indicate congenital fetal infection.
A. Evaluation
Ultrasound examination should be performed to confirm the fetal demise and the gestational age and to evaluate for any signs of fetal abnormality. Further testing can be divided into maternal and fetal testing (Table 14–9). The role of investigation for maternal inherited thrombophilia is controversial. Testing for maternal inherited thrombophilia should be considered if the fetus is severely growth restricted, if there is evidence of thrombosis on placental pathology, or if there is a personal or family history of deepvenous thrombosis. Maternal toxicology screen should be considered if there is a suspicion for maternal drug abuse. Testing for diabetes should be performed if the patient was not screened during the pregnancy or if the fetus is large for gestational age. Placental pathology will test for evidence of abruption, thrombosis, or infarction. Additionally, placental pathology can evaluate for signs of viral or bacterial infection. Fetal autopsy is recommended for all stillbirths. However, the patient may decline, in which case external fetal evaluation and x-rays are recommended. Fetal karyo-type may be obtained by testing amniotic fluid obtained via amniocentesis before delivery of the fetus or evaluation of fetal or placental tissue. One limitation to testing karyotype from any of these tissues is culture failure. Amniocentesis appears to have the highest yield in terms of success in determining fetal karyotype.
Table 14–9. Evaluation of stillbirth.
B. Delivery
Depending on the gestational age of the pregnancy, the pregnancy can be delivered by either induction of labor or dilation and evacuation. Some centers with expertise in late second-trimester dilation and evacuation may offer the procedure up to 26–28 weeks. With adequate cervical preparation before the procedure, an intact specimen can be obtained in many cases to allow for autopsy. Alternatively, labor induction can be performed regardless of gestational age. Hysterotomy or caesarean delivery is generally reserved for patients who fail induction of labor.
Prognosis
The prognosis for future pregnancies depends on the underlying cause of the stillbirth. For women in whom no etiology for stillbirth is found despite a thorough evaluation, the risk of recurrent stillbirth after 20 weeks is approximately 1–2%.
American College of Obstetricians and Gynecologists. Management of Stillbirth. ACOG Practice Bulletin No. 102. Washington, DC: American College of Obstetricians and Gynecologists; 2009.