The overall approach to management of PROM takes into consideration neonatal survival at the gestational age when rupture occurs. Management may be divided into four different phases of pregnancy. During the second trimester, neonatal survival is nil, leading numerous investigators to adopt a policy of expectant management or induction. Early in the third trimester, neonatal survival rises markedly, but there is still considerable morbidity associated with delivery at this gestational age. In the mid-third trimester, neonatal survival is high, but there is still considerable morbidity, whereas in the late third trimester (at or near term) neonatal mortality and morbidity are low. Neonatal outcome is one of the driving features in determining clinical management.
Diagnosis of Infection After PROM
Both invasive and noninvasive tests have been assessed. As shown in Table 11.1, none of these tests is ideal, particularly because of their low positive predictive values.
Use of Steroids
Clinicians remain unable to agree on the risks and benefits of steroids in preterm PROM. The first meta-analysis in 1989 concluded that the use of steroids “increases the incidence of endometritis and may increase neonatal infections.” The 1994 National Institutes of Health (NIH) Consensus Conference concluded that the risk of maternal and infant infection may be increased with corticosteroid use after PROM but that the magnitude of this risk was small. The NIH recommendations are summarized in Table 11.2. The benefits of steroids with PPROM before 28 weeks, however, have not been firmly established.
TABLE 11.2. Corticosteroid use in PPROM a
Effect of Latent Period and Vaginal Examination upon Incidence of Amnionitis
In earlier studies, the incidence of amnionitis rose with increasing length of the latent period, but other investigators have found no increase in the incidence of amnionitis among preterm pregnancies with increasing latent periods. In a comparison of outcomes, women with digital examination after PROM had a significantly shorter latent period (2.1 ± 4.0 vs. 11.3 ± 13.4 days; P < .001), more maternal infection (44% vs. 33%; P = .09), and more positive amniotic fluid cultures (11/25 [44%]
vs. 10/63 [16%]; P < .05). Thus, routine vaginal examination should be avoided until labor develops in patients with preterm PROM.
Use of Prophylactic Antibiotics
In patients with PROM prior to term, there are two rationales for prophylactic antibiotics. The first is a clear one; namely, for prevention of perinatal GBS infection.
A second rationale for antibiotic prophylaxis has been based upon the hypothesis that infection is either the triggering cause of preterm PROM or that infection ensuing after preterm PROM triggers the labor. Accordingly, this rationale for prophylactic antibiotics has been to delay delivery after preterm PROM rather than to prevent clinically evident infection. We believe that good evidence has been provided to favor use of broad-spectrum antibiotics in selected cases of preterm PROM. This support was provided in a meta-analysis and in prospective randomized trials. In the meta-analysis, 24 trials were identified and 13 were included, containing 1,594 women. However, only 6 of the trials were placebo-controlled, and the trials were heterogeneous with regard to antibiotics used. In addition, there was no standard use of steroids, tocolytics, or prophylaxis for GBS. Nevertheless, benefits were demonstrated in favor of women receiving antibiotics. These benefits included a significant delay in delivery within 7 days, a reduction in chorioamnionitis, and a reduction in neonatal sepsis. There were also reductions (that did not achieve statistical
significance) in postpartum infection, neonatal death, neonatal pneumonia, and neonatal bacteremia.
In the large MFM trial, patients were enrolled if they had preterm PROM for less than 72 hours at 24 to 32 weeks gestation. Patients were excluded if there was
chorioamnionitis, labor, or fetal distress. Patients were then randomized to a course of ampicillin plus erythromycin (each for 2 days i.v. followed by up to 7 days orally) vs. placebo. Patients with GBS were given treatment during the latent period and no tocolytics were used. However, at the time the study was designed, it was decided not to use corticosteroids in any patients. The primary end point was a prospectively defined composite of neonatal death, neonatal RDS, grade III or IV intraventricular hemorrhage, grade II or III necrotizing enterocolitis, or neonatal sepsis. Patients randomized to antibiotic therapy had a significantly greater likelihood of remaining undelivered when assessed at 2 days, 7 days, 14 days, and 21 days ( Fig. 11.2). In addition, the primary composite outcome was significantly reduced in the total population and in the GBS-negative cohort. Individual adverse outcomes significantly reduced in the antibiotic group included RDS, chorioamnionitis, neonatal sepsis, and neonatal pneumonia. Table 11.3 summarizes the benefits of antibiotics in patients with preterm PROM and stratifies the results by total population versus the GBS-negative cohort.
FIG. 11.2. Prolongation of pregnancy in group B streptococci-negative cohort. Antibiotic group shown in open circles; placebo in solid circles. (From Sweet RL, Gibbs RS. Infectious diseases of the female genital tract, fourth ed. Philadelphia: Lippincott Williams & Wilkins, 2002; with permission.)
TABLE 11.3. Maternal–Fetal Medicine network trial of antibiotics after PPROM: summary of benefits
Subsequent to this trial, others have appeared assessing antibiotics in conjunction with antenatal corticosteroid therapy for patients with preterm premature rupture of the membranes. One study assessed 112 women with PROM from 25 to 35 weeks and randomized them to ampicillin sulbactam/amoxicillin clavulanate versus
ampicillin/amoxicillin versus placebo. Tocolytics were used in this trial and betamethasone was used weekly up to 32 weeks. Patients receiving the antibiotics had less serious neonatal complications including neonatal death, RDS, and neonatal sepsis (P < .05) and they also had significantly higher mean birth weight (P = .03). Lewis and colleagues reported a randomized clinical trial of corticosteroids in patients with preterm PROM after treating these patients for a minimum of 12 hours with
ampicillin/sulbactam. Antibiotics were continued for 7 days and steroids were repeated weekly. No tocolytics were used. The authors defined the primary outcome as the incidence of RDS, whereas secondary outcome measures included latency and neonatal or maternal infections. In this study of 77 patients, no statistically
significant difference in latency was noted comparing the steroid versus no steroid group, and both neonatal and maternal infections were similar. However, there was a significant reduction in the incidence of RDS, 18.4% in the steroid group compared with 43.6% in the no steroid group. The authors concluded that treating preterm PROM with a broad-spectrum antibiotic before corticosteroids decreased RDS without apparent adverse effect. In 1998, a meta-analysis of five trials on antibiotic and glucocorticoid treatment reportedly did not show a significant effect on outcomes including maternal infection, neonatal sepsis, RDS, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal morbidity. In contrast, the authors note “antibiotic therapy without concomitant use of glucocorticoids significantly reduced the odds of maternal infection, neonatal sepsis, and intraventricular hemorrhage substantially.” However, this meta-analysis did not include some of the more recent studies noted immediately above.
In a very large (nearly 5,000 patients) international trial (ORACLE I), patients with PPROM were randomized to one of four courses: oral erythromycin, oral
amoxicillin-clavulanic acid, both antibiotics, or oral placebo. Each regimen was taken four times a day for 10 days or until delivery. The primary outcome measure used was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasound. Erythromycin was associated with several benefits to the
neonate (fewer cases with the composite outcome, prolongation of pregnancy, and fewer positive blood cultures). Amoxicillin-clavulanic acid—with or without erythromycin—was associated with prolongation of pregnancy, but it was also associated with a significant increase in neonatal necrotizing enterocolitis. The
applicability of this study to contemporary U.S. practice is limited, however, because the authors made no provision for GBS prophylaxis. Other features of the study to emphasize are that antibiotics were used orally, enrollment was permitted up to 37 weeks (only 50% of cases were less than 32 weeks), and there was no standard approach for use of steroids or tocolytics. (Steroids were used in 75% of cases and tocolytics in <15%.)
Widespread use of antibiotics in this situation has raised concern about selection pressure toward resistant organisms, but in the MFM trial, there was no significant increase in maternal yeast infection or neonatal Candida sepsis, nor were there any cases of pseudomembranous colitis, maternal sepsis, or maternal death.
Determination of Fetal Lung Maturity
Because RDS is the single greatest threat to infants with PROM, some investigators have determined the status of fetal pulmonary maturity and proceeded with
delivery when there was lung maturity. One study used amniocentesis and obtained fluid in about half of the cases. Others have attempted to collect amniotic fluid from the vagina and have had success rates of 80% to 94%. Presence of either PG or an L/S R of more than two in amniotic fluid collected vaginally has been reported to be a good predictor of pulmonary maturity.
In a larger series of patients with PROM before 36 weeks, investigators determined whether PG was present in the vaginal pool and delivered patients when there was presence of PG, spontaneous labor, or evidence of sepsis. PG in amniotic fluid from the vagina reliably predicted fetal lung maturity. However, absence of PG did not necessarily mean that RDS would develop. Of the 131 patients who did not show PG in the vaginal pool in any sample, 82 (62%) were delivered of infants who had no RDS. Thus, even with PROM, delivery of a premature infant simply because its lungs showed biochemical maturity may be questioned in view of other potential
hazards of prematurity and the difficulty of the induction. Of note, some genital tract bacteria have been found to yield a false-positive test for PG.
MANAGEMENT
PROM at or Near Term ( Table 11.4)
TABLE 11.4. Summary of management: PROM at or near term (= 35 wks)
In the last few years, new studies have influenced changes in management of PROM at term. Previously, induction of labor (with oxytocin) within 12 to 24 hours after PROM at term was a practice followed by most U.S. obstetricians. Studies in the United States and in Scandinavia supported the safety of this approach and reported shorter maternal hospital stays with less clinically evident neonatal infection. Although expectant management with inpatient observation had been shown to be safe in most patient populations, this approach has become less popular because of the inconvenience and expense of the hospitalizations. Several studies have reported the safety and benefits of prostaglandins and have supported the increased popularity of induction with these preparations. In comparison to patients managed
expectantly, those given intravaginal prostaglandin E 2 (PGE 2) shortly after admission had significantly less likelihood of a need for oxytocin and a significantly shorter time to delivery. There was no significant difference in cesarean section rate or in maternal or neonatal infection rates. In the largest trial of management of PROM at term, patients were studied in a four-arm trial with approximately 1,250 patients in each arm. These arms were as follows: Expectant management plus oxytocin for induction as needed; induction with i.v. oxytocin shortly after admission; induction with PGE 2 gel in a dose of only 1 to 2 mg shortly after admission; and expectant management followed by PGE 2 induction as needed. One methodological concern regarding this study is the low dose of PGE 2 gel used vaginally. With most patients receiving less than 2 mg, the dose was smaller than used in most U.S. trials. As shown in Figure 11.3, patients randomized to expectant management initially had significantly longer times to delivery than patients randomized to either of the induction arms ( P < .001). In addition, the rate of clinically diagnosed chorioamnionitis was less in the patients randomized to induction initially (with significance achieved at P < .01 comparing arms 1 vs. 2). The distribution of postpartum infection was similar to that of chorioamnionitis. In addition, there was no significant difference in rates of neonatal infection or cesarean section. Of note, patient satisfaction was significantly higher in the induction arms.
FIG. 11.3. Selected outcomes in an international term PROM trial. (From Sweet RL, Gibbs RS. Infectious diseases of the female genital tract, fourth ed. Philadelphia:
Lippincott Williams & Wilkins, 2002; with permission.)
A large meta-analysis involving 23 studies and including nearly 7,500 patients concluded that conservative management may result in more maternal infections than immediate induction with either oxytocin or prostaglandins. This meta-analysis also showed that the rate of chorioamnionitis was higher in patients induced with
prostaglandin versus those induced with oxytocin. However, this meta-analysis was heavily influenced by the large international trial, and as noted previously, this trial used a very low dose of prostaglandin.
Within the last few years, intravaginal misoprostol (a PGE 1 analog) has assumed marked popularity for induction because of its efficacy and low cost. Intravaginal misoprostol (50 µg every 4 hours for a maximum of 12 tablets) was compared with oxytocin in women with single pregnancies and an unfavorable cervix (<2 cm dilated and <80% effaced). The results of this trial are presented in Table 11.5. Overall, patients randomized to misoprostol had a shorter induction time, by approximately 2 hours, but they had significantly more uterine tachysystole. Of note, over 85% of patients required only one dose of misoprostol. Compared to other trials evaluating misoprostol in patients at term with intact membranes, the dose used in this trial is relatively high.
TABLE 11.5. Misoprostol vs. oxytocin in PROM
A 1998 American College of Obstetricians and Gynecologists' (ACOG) Practice Bulletin concluded that with term PROM, labor may be induced at the time of admission or that patients may be observed for up to 24 to 72 hours after PROM. In sum, while a range of practices is available and supported in the literature, the decision
regarding delivery after PROM at term must take into account fetal presentation, fetal status, cervical ripeness, presence of infection, and patient desires. For patients with a breech (or other malpresentation) infant or an infant with evidence of intolerance of labor, prompt cesarean delivery is most appropriate. If there is clinically evident infection and no contradiction to vaginal delivery, then immediate induction and antibiotic therapy are indicated. If the cervix is ripe, then a short period of observation is reasonable, but induction with oxytocin resolves the situation. When the cervix is unripe, induction with either prostaglandins or oxytocin shortens the time to delivery, decreases risk of infection, and does not appear to increase cesarean section rate. The epidemiologic data linking chorioamnionitis with cerebral palsy provide additional impetus to move toward delivery after PROM at term.
PROM at 32 to 34 Weeks ( Table 11.6)
TABLE 11.6. Summary of management: PROM at 32–34 wks
Management in this gestational age category remains controversial. When there is evidence of fetal lung maturity, two trials have reported benefits to induction versus continued expectancy. In one trial, induction had several benefits, including a shorter time to delivery (14 vs. 36 hours; P < .001), shorter maternal hospital stay (2.3 vs.
3.5 days; P < .001), and less chorioamnionitis (11 vs. 28%; P = .06). Neonatal hospital stay was also shorter (6.3 vs. 7.3 days), but this difference was not significant.
Although the authors found less clinically diagnosed neonatal sepsis in the induction group (28 vs. 60%; P < .003), there was no difference in confirmed sepsis (7 cases in induction group vs. 4 in expectant). There were no significant differences in the rates for cesarean delivery, postpartum infection, or neonatal survival. The other trial also found advantages to induction versus expectancy. Despite the reasons advanced by these authors, there is not yet compelling evidence to induce all pregnancies with PROM at 32 to 34 weeks simply because there is evidence of lung maturity. There is no improvement in perinatal mortality (PNM), and in other populations, induction in the presence of an unripe cervix at 32 to 34 weeks might result in higher infection rates or cesarean delivery rates. However, the evolving concern of intrauterine infection causing cerebral palsy adds strength to arguments for induction in the presence of lung maturity.
For pregnancies with PROM at 32 to 34 weeks, we have generally used expectant management. We do not routinely perform amniocentesis, but use this selectively when we suspect infection or growth restriction. We assess fetal status during expectant management with usual testing, mainly daily nonstress tests with biophysical profiles as needed for backup. In selected pregnancies at 32 to 34 weeks, we induce labor in the presence of lung maturity. Such situations include development of a favorable cervix (noted on a speculum examination) or poor patient compliance. We, of course, proceed with delivery when there are maternal or fetal indications including evidence of infection. For pregnancies with PROM at 32 to 34 weeks, we give intrapartum prophylaxis per the Centers for Disease Control and Prevention (CDC)/ACOG guidelines. We also obtain an appropriate rectovaginal culture for GBS at the time of admission, unless delivery is imminent. We then begin empirical intravenous prophylaxis until the culture result is available and is negative. If at 33 to 34 weeks the culture is positive, we will continue intravenous penicillin for 48 hours, then stop and re-culture.
PROM at 25 to 31 Weeks ( Table 11.7)
TABLE 11.7. Summary of management: PROM at 25–32 wks
Management in the gestational age category also remains especially controversial. For management of PROM after viability but before 32 weeks, our practice is to generally follow expectant management and proceed with delivery where there is spontaneous onset of labor or clinical evidence of infection. We follow national guidelines for intrapartum prophylaxis for prevention of GBS neonatal sepsis. For patients in whom delivery is not imminent, we also obtain an appropriate culture for GBS from the rectovaginal area. We do administer corticosteroids in a standard regimen. We also apply broad-spectrum antibiotic therapy, usually following the
ampicillin/amoxicillin plus erythromycin regimen of the MFM trial. This regimen is limited to 7 days. When the patient goes into labor, we begin GBS prophylaxis unless the GBS culture was negative on admission, as recommended by the CDC. Use of tocolytics during this gestational age in patients with preterm premature rupture of the membranes remains controversial.
PROM at Less Than 25 Weeks ( Table 11.8)
TABLE 11.8. Summary of management: PROM <25 wks
For PROM before viability (approximately 24 weeks), several descriptive reports have demonstrated a highly variable latent period, high maternal infection rates (but with little serious morbidity), and an appreciable survival rate, especially when delivery occurs after week 24 ( Table 11.9). Outcome data with expectant management of PROM in the second trimester showed perinatal survival and “intact” neurologic survival stratified by the gestational age at the time of PROM ( Fig. 11.4). In sum, when gestational age occurred from weeks 14 to 19, overall survival was only 40% whereas when PROM occurred at 20 to 25 weeks, overall survival was nearly 90%.
The alternative to expectant management is induction. In the patient with PROM this early in pregnancy, we individualize the decision, involving the family fully. In the proper setting, we offer expectant management.
TABLE 11.9. Summary of management: PROM at =24 wks
FIG. 11.4. Outcome with expected management of second trimester PROM. (From Sweet RL, Gibbs RS. Infectious diseases of the female genital tract, fourth ed.
Philadelphia: Lippincott Williams & Wilkins, 2002; with permission.)
Chorioamnionitis Complicating PROM at Any Gestational Age ( Table 11.10)
TABLE 11.10. Management of clinically evident chorioamnionitis
When clinically evident chorioamnionitis is diagnosed at any gestational age, broad-spectrum antibiotics, appropriate for the array of suspected aerobes and
anaerobes, should be initiated intravenously. There is no place for expectancy when intrauterine infection becomes clinically overt and preparation should be made for delivery.
SUMMARY POINTS
Management of PROM
At or near term (35 weeks) induction is usually preferred; GBS prophylaxis is given with a positive screening culture at 35 to 37 weeks or with rupture of membranes greater than 18 hours plus an unknown culture status.
At 32 to 34 weeks, manage by either expectancy or by induction (especially with evidence of lung maturity). Give GBS prophylaxis. Do not use tocolytics or corticosteroids.
At 25 to 32 weeks, manage by expectancy. Give GBS prophylaxis and give corticosteroids. We give antibiotics for 7 days to prolong pregnancy. No standard
At 25 to 32 weeks, manage by expectancy. Give GBS prophylaxis and give corticosteroids. We give antibiotics for 7 days to prolong pregnancy. No standard