Preterm prelabor rupture of membranes (PPROM) is associated with neonatal morbidity and mortality and maternal morbidity. Because of lack of evidence to justify the induction of labor (IoL) or expectant management (EM), a randomized controlled trial was performed as the PPROMEXIL (PPROM Expectant Management Versus Induction of Labor) trial, which tested the hypothesis that IoL would reduce the incidence of neonatal sepsis. In this trial, the incidence of neonatal sepsis in the EM group was 4.1%, and the risk of neonatal sepsis was not statistically decreased by IoL. After these results were obtained, a new trial called PPROMEXIL-2 was initiated, with a similar design as the PPROMEXIL study but with the aim to randomize an additional 200 women. The authors also intended to conduct a meta-analysis of all randomized studies comparing IoL with EM.
This nationwide randomized controlled trial was performed at 60 academic and nonacademic hospitals in the Netherlands. Women with a singleton or twin pregnancy were eligible for the PPROMEXIL trial when they were not in labor at least 24 hours after PPROM and were between 34 and 37 weeks’ gestation. For women in the IoL group, labor was induced within 24 hours after randomization. Women allocated to EM were monitored according to a standard local protocol, until labor started spontaneously, or if a participant reached 37 + 0 weeks’ gestation, labor was induced. Labor was induced before 37 + 0 weeks’ gestation when clinical signs of infection or another neonatal or maternal indication justified induction. Antibiotics were given according to local protocol. If PPROM occurred before 34 weeks’ gestation, corticosteroids were given for fetal pulmonary maturation. The primary outcome was neonatal sepsis. Secondary neonatal outcomes were respiratory distress syndrome (RDS), asphyxia, hypoglycemia, hyperbilirubinemia, total length of hospital stay and admission, length of stay in the neonatal intensive care unit (NICU), and perinatal death. Maternal outcome measures were antepartum hemorrhage, histologic or clinical signs of chorioamnionitis, total length of hospital stay, and admission to the intensive care unit. Data were analyzed on an intention-to-treat basis. Statistical analyses were performed using SPSS Statistics, version 17.0.
Of 241 women asked to participate, 195 consented, with 100 randomized to the IoL group and 95 to the EM group. The median gestational age at randomization was 251 days. Thirty-three women (17%) had PPROM before 34 weeks’ gestation. Women in the IoL group delivered on average 3.5 days earlier than women in the EM group. Women in the EM group stayed on average 4.4 days longer in the hospital. In the IoL group, 13 women (13%) had a cesarean delivery compared with 22 (22%) in the EM group (P = 0.081). Both groups received antibiotics similarly during admission and labor. Rates of epidural or spinal analgesia did not differ. Sepsis occurred in 3 neonates (3.0%) in the IoL group and 4 (4.1%) in the EM group. Hospital stays for neonates in the IoL and EM groups were 7.4 and 6.9 days, respectively. Seven (7.2%) and 8 (8.2%) neonates in the IoL and EM groups, respectively, were admitted to the NICU, with respective stays of 2.0 and 7.0 days. Respiratory distress syndrome developed in 6 newborns in the IoL group (6.0%) and 5 in the EM group (5.1%). Hypoglycemia was present in 8 neonates in each group; hyperbilirubinemia occurred in 20 (20%) in the IoL group and 21 (21%) in the EM group. Other neonatal outcomes also did not differ significantly in the 2 groups. Clinical chorioamnionitis was not seen in the IoL mothers but was present in 4 women in the EM group (4.3%). Histologic chorioamnionitis was present in 12 (18%) of the IoL women’s placentae and 18 (31%) of those in the EM group.
For the meta-analysis, 1428 neonates could be analyzed from 9 studies for neonatal sepsis, 1090 neonates (6 studies) for culture-proven sepsis, 1428 neonates (9 studies) for RDS, and 1417 women (9 studies) for cesarean delivery rate. The risk ratios of all outcomes were not statistically different.
The PPROMEXIL-2 trial found that IoL did not reduce the incidence of neonatal sepsis, nor did it influence the rates of cesarean delivery and RDS. Induction of labor did reduce the risk of clinical but not histologic chorioamnionitis. Further studies are required to determine the long-term impact of EM and IoL.
Departments of Obstetrics and Gynecology (D.P.v.d.H., J.L.v.d.H., C.W., J.G.N.) and Pediatrics (A.L.M.M.), Maastricht University Medical Center, GROW–School for Oncology and Developmental Biology, Maastricht; Departments of Obstetrics and Gynecology, Martini Hospital (D.P.v.d.H., A.J.v.L.), Groningen, and Department of Obstetrics and Gynecology (M.T.M.F.), University Medical Center Groningen, Groningen; Clinical Research Unit (B.C.O.) and Departments of Obstetrics and Gynecology, Academic Medical Center (B.W.J.M.), and Department of Obstetrics and Gynecology, VU Medical Center (C.J.M.d.G.), Amsterdam; Department of Pediatrics (R.M.J.M.), Atrium Medical Center, Heerlen; and Departments of Obstetrics and Gynecology (J.J.v.B.), VieCuri Medical Center, Venlo; Department of Obstetrics and Gynecology (K.W.M.B.), Leiden University Medical Center, Leiden; Department of Obstetrics and Gynecology (J.M.S.), ZGT, Almelo; Department of Obstetrics and Gynecology (M.P.), Máxima Medical Center, Veldhoven; Department of Obstetrics and Gynecology (A.K.), University Medical Center, Utrecht; Department of Obstetrics and Gynecology (M.D.W.), Sint Radboud University Medical Center, Nijmegen; Department of Obstetrics and Gynecology (J.J.D.), Erasmus Medical Center, and Department of Obstetrics and Gynecology (J.W.d.L.), Ikazia Hospital, Rotterdam; and Department of Obstetrics and Gynecology (B.M.C.A.), Albert Schweitzer Hospital, Dordrecht, the Netherlands.