Preterm premature rupture of membranes (PROM) complicates approximately 120,000 pregnancies in the United States annually.1 The optimal management of pregnancies complicated by preterm PROM remains largely undefined and is an area of great controversy in obstetrics.1–4 Issues such as the use of prophylactic antibiotics, tocolytic therapy, or corticosteroids, the role of fetal lung maturity testing, optimal antenatal surveillance strategy, and immediate delivery compared with expectant management are undefined aspects of management.1–4 Of these issues, the issue of immediate delivery compared with expectant management is of particular interest and clinical importance. Although those pregnancies when preterm PROM occurs less than 30 weeks of gestation are generally expectantly managed, given the inherent risks of extreme prematurity, management beyond 30 weeks is highly variable among obstetric centers in the United States.2
During the past decade a growing body of evidence has emerged associating upper genital tract infection with both spontaneous preterm delivery and preterm PROM.5–8 A number of studies have demonstrated that this occult intrauterine infection as well as clinical chorioamnionitis may be associated with the subsequent development of adverse neonatal outcomes such as neonatal death, periventricular leukomalacia, intraventricular hemorrhage, cerebral palsy, and bronchopulmonary dysplasia.9–22 Upper genital tract infection may result in an indolent inflammatory response, eliciting the production of a wide array of proinflammatory mediators that can lead to injury to the fetal central nervous system and lung.17 Thus, the development of occult or clinically evident intrauterine infection may pose significant neonatal risks. Given that expectant management of preterm PROM entails close surveillance for the development of chorioamnionitis, with delivery implemented when it is diagnosed, the fetus is inherently exposed to an environment in which an array of inflammation and proinflammatory cytokines are present.
The decision to abandon further expectant management of women with preterm PROM in favor of delivery requires a close assessment of the potential risks related to the development of intrauterine infection in those pregnancies expectantly managed compared with the gestational age–related risks for neonatal morbidity and mortality related to intentional delivery. To address this important issue, we conducted a comprehensive review of neonatal and maternal outcomes of all pregnancies complicated by preterm PROM that were recently managed at our institution, using a standardized management protocol. These data were sought to provide important information regarding neonatal and maternal morbidity and mortality rates in pregnancies complicated by preterm PROM and determine whether there is an optimal delivery gestational age.
MATERIALS AND METHODS
With approval from the University of Alabama at Birmingham Institutional Review Board, we conducted a review of the University of Alabama at Birmingham Obstetric Antenatal Record and Neonatal Database to identify all women presenting to our institution for obstetric care and subsequent delivery after confirmed preterm premature rupture of membranes 24 weeks or more that resulted in delivery at less than 37 weeks at our institution between August 1, 1998, and August 1, 2000. This period was selected because it marked initiation of a standard management protocol for the management of preterm PROM at our institution. Pregnancies complicated by multifetal gestation, fetal anomalies, and chronic hypertension were excluded from analysis. Similarly, outborn infants who were transferred to our neonatal intensive care unit after delivery were also excluded given nonstandardized antepartum management.
All women in this investigation were managed under a standardized protocol that included inpatient expectant management for all cases of preterm PROM less than 34 weeks of gestation (in the absence of active labor, chorioamnionitis, and fetal compromise), administration of prophylactic antibiotics (azithromycin 1 g on presentation, with repeated dosing once on day 5; ampicillin and amoxicillin—initially, intravenous ampicillin 2 g every 6 hours for 12–24 hours followed by amoxicillin 250 mg orally every 8 hours for 10 days), and administration of betamethasone 12 mg intramuscularly (2 doses 24 hours apart) for those pregnancies less than 32 weeks. Maternal and fetal status was closely monitored for development of chorioamnionitis, labor, or fetal compromise. Vaginal amniotic fluid pool specimens were collected for the determination of the presence of phosphatidylglycerol on all women beginning at 32 weeks of gestation and repeated weekly if immature until delivery. Expectant management was abandoned and delivery expedited if any of the following criteria were noted: 1) chorioamnionitis, 2) active labor, 3) fetal compromise, 4) presence of phosphatidylglycerol in vaginal pool amniotic fluid specimen, or 5) gestational age 34 weeks or more. Pregnancy dating was established according to standardized institutional guidelines.
All maternal and neonatal medical records were reviewed and outcome data collected using standardized definitions. Specific outcomes evaluated included neonatal mortality, composite major and minor neonatal morbidity (defined below), individual major and minor neonatal morbidity rates, maternal infection morbidity (endometritis or chorioamnionitis), and maternal and neonatal length of stay. Composite neonatal major morbidity was defined as the presence of any of the following: intraventricular hemorrhage, respiratory distress syndrome, intubation, bronchopulmonary dysplasia, sepsis, seizure, necrotizing enterocolitis, bowel perforation, retinopathy of prematurity, meningitis, pneumonia or primary pulmonary hypertension, patent ductus arteriosis, or retinopathy of prematurity). Composite neonatal minor morbidity was defined as the presence of any of the following: hyperbilirubinemia, transient tachypnea of the newborn, or metabolic disturbances (hyper- or hypoglycemia or hyper- or hyponatremia).
Outcome data for each gestational age were statistically compared with the respective outcome for those preterm PROM pregnancies that delivered at 36 0/7 to 36 6/7 weeks of gestation. Statistical analyses included the Student t test, χ2, and Fisher exact test where appropriate.
Between August 1998 and August 2000 a total of 430 women with preterm PROM were identified among the 6,003 deliveries (7.2%) that occurred at the University of Alabama at Birmingham. Mean (± standard deviation) maternal age for the study cohort was 24.7 ± 5.8 years. Forty-three percent of the women in the study cohort were nulliparous. Racial composition of the study was 60% African American, 35% Caucasian, 2% Hispanic, and 3% other. Mean gestational age of preterm PROM for the study cohort was 32.4 ± 3.8 weeks, with a mean delivery gestational age of 32.9 ± 3.4 weeks and average length of latency 3.3 ± 6.8 days. The gestational age distribution of the preterm PROM cases is shown in Figure 1. As expected based on our management protocol, latency (defined as the number of days from the onset of preterm PROM to delivery) was significantly longer at 34 weeks of gestation or less when compared with the 36 week preterm PROM delivery group (Table 1). Neonatal mortality was uncommon in the study cohort but was more frequent among those women with preterm PROM occurring at 28 weeks of gestation or less. Composite major neonatal morbidity was significantly higher among pregnancies delivered at 33 weeks of gestation or less after preterm PROM as compared with those who delivered at 36 weeks of gestation (Fig. 2). Composite neonatal minor morbidity was significantly higher among pregnancies delivered at 34 weeks of gestation or less after preterm PROM as compared with those who delivered at 36 weeks of gestation (Fig. 2). Individual major and minor morbidity rates for each gestational age group are reported in Tables 2 and 3, respectively. Respiratory distress syndrome was the most common major morbidity noted across each gestational age group. The incidence of respiratory distress syndrome was significantly higher among those infants delivered at 32 weeks of gestation or less after preterm PROM as compared with the 36-week delivery group. Of the individual minor morbidities noted, hyperbilirubinemia, with or without phototherapy, was by far the most common minor morbidity encountered, with a significantly increased incidence of this complication noted among the infants delivered at 34 weeks of gestation or less.
Both maternal and infant length of hospital stay were significantly longer for cases of preterm PROM delivered at 34 weeks of gestation or less as compared with those who delivered at 36 weeks of gestation (Tables 1 and 3, respectively). Composite maternal infection morbidity rates were significantly increased for preterm PROM related–deliveries at 32 weeks of gestation or less when compared with the 36-week delivery group. No maternal deaths were noted in this study (Table 1). The rates of chorioamnionitis and endomyometritis for each gestational age group are reported in Table 1.
The decision to abandon expectant management of women with preterm PROM in favor of delivery requires a close assessment of the potential risks related the to development of intrauterine infection in those pregnancies expectantly managed compared with the gestational age–related risks for neonatal morbidity and mortality related to intentional delivery. To date, only 3 small, randomized clinical trials have compared the maternal and neonatal outcomes related to immediate delivery compared with expectant management in women with preterm PROM between 30 and 36 weeks of gestation.23–25 Mercer et al23 randomly assigned 93 women with preterm PROM between 32 and 36 weeks of gestation that had confirmed fetal lung maturity (determined by vaginal pool foam stability index) either to immediate delivery or to expectant management. These investigators demonstrated a significant reduction in the incidence of chorioamnionitis (11%) in the women with immediate delivery as compared with those in the expectant management group (28%) (P < .05).23 Although there was a trend toward decreased incidence of sepsis workups and confirmed sepsis, there were no significant differences in any of the evaluated major neonatal outcomes between the 2 study groups.23 Cox et al24 randomly assigned 129 women with preterm PROM between 30 and 34 weeks of gestation to either immediate delivery or expectant management. No fetal lung maturity testing, tocolytics, or corticosteroids were used in the study participants. Similar to the Mercer study, the incidence of chorioamnionitis was significantly less in the women in the immediate delivery group (2%) as compared with the expectant management group (15%) (P < .05).24 No significant differences, however, were noted between the 2 groups with regard to any of the evaluated neonatal outcomes.24 Naef et al25 evaluated aggressive compared with conservative management of women with preterm PROM at 34 to 37 weeks of gestation. In this prospective investigation, 120 women with preterm PROM were randomly assigned to receive oxytocin induction or observation. Chorioamnionitis occurred more often (16% compared with 2%, P = .007), and maternal hospital stay was significantly longer (5.2 ± 6.8 days compared with 2.6 ± 1.6 days, P = .006) in the women conservatively managed as compared with the induction group.25 No significant differences were noted in the incidence of major neonatal morbidities between the 2 groups.25 Although these studies suggest that neonatal outcomes are similar between women who were managed expectantly compared with immediate induction, these investigations lacked sufficient statistical power to fully evaluate neonatal outcomes. In addition, these studies have not evaluated differences in minor morbidity rates or length of hospital stay between infants born after immediate delivery and those who were managed expectantly.
Despite the pivotal importance of accurate data regarding major and minor neonatal morbidities in pregnancies complicated by preterm PROM, few studies have attempted fully to characterize these morbidities in an attempt to identify an optimal gestational age for delivery of pregnancies complicated by preterm PROM. In the current study we have provided a comprehensive assessment of maternal and neonatal major and minor morbidities in women with preterm PROM who weremanaged under a standardized management protocol. We have demonstrated no improvement in the composite major and minor neonatal morbidity rates for those pregnancies delivered beyond 34 weeks of gestation. Both maternal and neonatal length of hospital stay were also similar for infants delivered beyond 34 weeks of gestation in our investigation. Our findings are similar to those reported by Jothivijayarani et al.26 These investigators characterized maternal and neonatal outcomes of 79 women with preterm PROM between 32 and 36 weeks of gestation, noting a marked decrease in the incidence of respiratory distress syndrome beyond 34 weeks of gestation.26 In addition, infant length of hospital stay and the incidence of hyperbilirubinemia decreased significantly after 34 weeks of gestation. Neerhoff et al,27 in a study of 236 women with preterm PROM between 32 and 36 weeks of gestation, noted similar decreases in infant length of hospital stay and the incidence of hyperbilirubinemia in infants born at 34 weeks of gestation or more when compared with infants born at less than 34 weeks of gestation. Our data question the benefit of continued expectant management beyond 34 weeks of gestation with modern obstetric and neonatal management.
Data from our investigation, and those from others, clearly call for further research to elucidate the optimal delivery gestational age for women who develop preterm PROM between 30 and 36 weeks of gestation. A large randomized trial of induction compared with expectant management of women with preterm PROM diagnosed beyond 30 to 33 weeks of gestation is needed to adequately address important issues related to major and minor, as well as long-term, maternal and infant outcomes.
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