Objective
The evidence for the management of near term prelabor rupture of membranes is poor. From January 2007 until September 2009, we performed the PPROM Expectant Management versus Induction of Labor (PPROMEXIL) trial. In this trial, we showed that in women with preterm prelabor rupture of membranes (PPROM), the incidence of neonatal sepsis was low, and the induction of labor (IoL) did not reduce this risk. Because the PPROMEXIL trial was underpowered and because of a lower-than-expected incidence of neonatal sepsis, we performed a second trial (PPROMEXIL-2), aiming to randomize 200 patients to improve the evidence in near-term PPROM.
Study Design
In a nationwide multicenter study, nonlaboring women with PPROM between 34 and 37 weeks’ gestational age were eligible for inclusion. Patients were randomized to IoL or expectant management (EM). The primary outcome measure was neonatal sepsis.
Results
From December 2009 until January 2011, we randomized 100 women to IoL and 95 to EM. Neonatal sepsis was seen in 3 neonates (3.0%) in the IoL-group versus 4 neonates (4.1%) in the EM group (relative risk, 0.74; 95% confidence interval, 0.17–3.2). One of the sepsis cases in the IoL group resulted in neonatal death because of asphyxia. There were no significant differences in secondary outcomes.
Conclusion
The risk of neonatal sepsis after PPROM near term is low. Induction of labor does not reduce this risk.
Preterm prelabor rupture of membranes (PPROM) is associated with neonatal morbidity and mortality as well as maternal morbidity. In international guidelines, no clear recommendation is given on the management of PPROM between 34 and 37 weeks.
For Editors’ Commentary, see Contents
A recent Cochrane review on the management of PPROM prior to 37 weeks demonstrated insufficient evidence for the management of PPROM in clinical practice.
Given this lack of evidence to justify the induction of labor or expectant management, a randomized controlled trial was performed as the PPROMEXIL (PPROM Expectant Management versus Induction of Labor) trial. In this trial, we tested the hypothesis that induction of labor (IoL) would reduce the incidence of neonatal sepsis.
In the PPROMEXIL trial, the incidence of neonatal sepsis in the expectant group was 4.1%, which is lower than the expected 7.5%, and the risk of neonatal sepsis was not decreased by induction of labor (2.6% vs 4.1%; relative risk [RR], 0.64; 95% confidence interval [CI], 0.25–1.6). In contrast, in the IoL group, the risk of neonatal hypoglycemia and hyperbilirubinemia was increased (RR, 2.2; 95% CI, 1.4–3.4, and RR, 1.5; 95% CI, 1.1–1.9, respectively). Because of this lack of power, there remained equipoise on the subject after the completion of our PPROMEXIL trial.
In view of this equipoise and in view of uncertainty of the continuation of the other large ongoing trial on the subject at that time, Preterm Prelabour Rupture of Membranes Close to Term Trial (PPROMT), which was dependent on funding, we decided to set up a new trial called PPROMEXIL-2, with a similar design as our PPROMEXIL study, aiming to randomize an additional 200 women. We planned to combine the results of the PPROMEXIL trials with the results of the possible prematurely terminated PPROMT trial into an individual patient data metaanalysis, which would then reach the planned power calculation of the PPROMT trial. The decision to start PPROMEXIL-2 was made after the completion and analysis of the results of PPROMEXIL, and it should therefore be considered as an independent trial.
Materials and Methods
We performed a nationwide randomized controlled trial in The Netherlands between December 2009 until January 2011. The methods of this trial have been described earlier extensively by van der Ham et al. The PPROMEXIL-2 trial was a randomized controlled trial that ran in 60 academic and nonacademic hospitals in The Netherlands. For the PPROMEXIL-2 trial, no changes were made in this trial protocol or in the outcome measures. This trial was registered in the ISRCTN register: ISRCTN05689407 ( http://www.controlled-trials.com/ISRCTN05689407/ppromexil ).
The PPROMEXIL-2 study was approved by the Medical Ethics Committee of the Maastricht University Medical Center as an amendment of the PPROMEXIL trial (MEC 05-240).
Women with a singleton or twin pregnancy were eligible for the PPROMEXIL trial when they were not in labor 24 hours after PPROM between 34 and 37 weeks of gestational age. PPROM had to be diagnosed after 26+0 weeks. Women with a monochorionic multiple pregnancy, nonreassuring cardiotocogram, meconium stained amniotic fluid, major fetal anomalies, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, or severe preeclampsia and signs of intrauterine infections were not eligible.
Randomization was performed in a password-protected, web-based database in a 1:1 for immediate delivery (IoL) versus expectant management (EM). If women were allocated to IoL, labor was induced within 24 hours after randomization. IoL was performed according to the Dutch national guidelines. If a cesarean section was indicated (for example, in the case of a child in breech position), this was done as soon as feasible after randomization. Women allocated to EM were monitored according to a standard local protocol, until delivery started spontaneously. If a participant reached 37+0 weeks’ gestational age (GA), labor was induced. Labor was induced prior to 37+0 weeks of gestation when there were clinical signs of infection or on another neonatal or maternal indication that justified induction of labor. Data were collected by research staff in a web-based, password-protected database.
The Dutch guidelines on PPROM give no clear recommendation on the use of antibiotics prior to labor. Therefore, antibiotics were administered according to local protocol. In pregnancies with PPROM prior to 34 weeks’ gestation, corticosteroids were given for fetal pulmonary maturation. Administration of tocolytics was dependent on the local protocol.
Outcome measures
The primary outcome was neonatal sepsis, defined as a positive blood culture taken at birth (not Staphylococcus epidermidis ) or within 72 hours 2 or more symptoms of infection (apnea, temperature instability, lethargy, feeding, intolerance, respiratory distress, hemodynamic instability) plus 1 of the following 3 items: (1) positive blood culture (culture-proven sepsis); (b) C-reactive protein greater than 20 (suspicion sepsis); or (3) positive surface cultures of a known virulent pathogen (suspicion of sepsis).
When the local investigator classified a case as sepsis or when criteria for sepsis were registered in the database, the case was judged by an independent panel of pediatricians (A.L.M.M., R.M.J.M.) who were not aware of the allocation of randomization. After the relevant data were presented to the panel, they adjudicated between neonatal sepsis (proven or suspected sepsis) or no sepsis.
Secondary neonatal outcome measures were respiratory distress syndrome, asphyxia, hypoglycemia, hyperbilirubinemia, total length of hospital stay and admission, and length of stay on the neonatal intensive care unit (NICU) and perinatal death.
Maternal outcome measures were antepartum hemorrhage, signs of (histological or clinical) chorioamnionitis, total length of hospital stay, and admission to the intensive care unit. Finally, we recorded mode of delivery and need for anesthesia. No changes to trial outcomes were made after the trial commenced.
Statistical analysis and metaanalysis
Within a well-organized nationwide Dutch research consortium, it seemed feasible to recruit 200 patients within approximately 1 year. These 200 patients combined with the 536 patients of the PPROMEXIL trial and the estimated number of included patients at the end of 2010 for the PPROMT trial would provide the power calculation as calculated by the investigators of the PPROMT trial (1812 women). Therefore, no separate power calculation was done for this trial.
Data were analyzed on an intention-to-treat basis. The RRs, absolute risk reduction, mean difference (MD), and 95% CIs were calculated for the relevant outcome measures. P < .05 was considered to indicate statistical significance. Statistical analyses were performed using SPSS Statistics (version 17.0; SPSS Inc, Chicago, IL).
We further updated a recent Cochrane review on the subject for sepsis (overall), culture proven neonatal sepsis, respiratory distress syndrome (RDS), and the cesarean section rate as we did after the PPROMEXIL trial with the data from the PPROMEXIL trial and the current PPROMEXIL-2 trial, using Review Manager Software version 5.1.
Results
From December 2009 until January 2011, a total of 241 women were asked to participate in the trial, of which 198 women (82%) gave informed consent. Of these women, 3 had to be excluded because they had been randomized at a gestational age longer than 36+6 weeks. The remaining 195 women were eligible for analysis. A total of 100 women were randomized to induction of labor (IoL group) and 95 to expectant management (EM group). Figure 1 outlines the study profile.
Baseline characteristics are shown in Table 1 . The median gestational age at randomization was 251 days. Thirty-three women (17%) had PPROM prior to 34 weeks’ GA. Table 2 shows data on pregnancy outcome and mode of delivery. Women in the IoL group delivered on average 3.5 days earlier (95% CI, 1.8–5.2 days) than women in the EM group. Women in the EM group stayed on average 4.4 days longer in the hospital (95% CI, 2.2–6.7 days).
| Characteristics a | Induction of labor | Expectant management |
|---|---|---|
| (n = 100) | (n = 95) | |
| Maternal age (range) [± sd ], y | 30.5 (19.4–43.6) [± 5.3] | 29.4 (19.2–41.8) [± 5.0] |
| Nulliparous, n (range) (%) | 48 (0–6) (48) | 49 (0–4) (52) |
| Twin pregnancy, n (%) | 0 (0) | 3 (3.2) |
| Ethnic origin | ||
| White, n (%) | 78 (78) | 67 (71) |
| Other ethnic origin, n (%) | 15 (15) | 18 (19) |
| Unknown, n (%) | 7 (7.0) | 10 (11) |
| Education | ||
| Primary school (4-12 y), n (%) b | 0 (0) | 2 (4.0) |
| Secondary school (12 to 16-18 y), n (%) b | 9 (17) | 3 (6.0) |
| Lower professional school, n (%) b | 5 (9.3) | 6 (12) |
| Medium professional school, n (%) b | 20 (37) | 23 (46) |
| Higher professional school, n (%) b | 19 (35) | 11 (22) |
| University, n (%) | 1 (1.9) | 5 (10) |
| Maternal smoking, n (%) | 25 (27) | 25 (27) |
| Body mass index | ||
| At booking (range) [± sd ], kg/m 2 c | 26.2 (16.5–53.3) [± 6.6] | 25.0 (15.8–46.3) [± 6.4] |
| At study entry (range) [± sd ], kg/m 2 c | 30.1 (17.8–56.2) [± 8.1] | 29.6 (20.8–46.3) [± 5.6] |
| Antenatal administration of corticosteroids, n (%) | 20 (22) | 13 (16) |
| Diagnostic test for rupture of membranes d | ||
| Positive history, n (%) | 67 (70) | 71 (76) |
| Positive ferning, n (%) | 48 (79) | 34 (67) |
| Positive pH test, n (%) | 2 (7.7) | 2 (7.7) |
| Positive PAMG-1 test, n (%) | 11 (32) | 19 (50) |
| Decrease amniotic fluid on ultrasound, n (%) | 53 (76) | 52 (70) |
| Ruptured membranes e | ||
| <34 wks, n (%) | 20 (20) | 13 (14) |
| 34+0 to 34+6 wks, n (%) | 11 (11) | 16 (17) |
| 35+0 to 35+6 wks, n (%) | 29 (29) | 28 (30) |
| 36+0 to 36+6 wks, n (%) | 40 (40) | 37 (39) |
| Gestational age at PPROM, median [IQR], d | 249 [240–254] | 249 [241–253] |
| Gestational age at randomization, median [IQR], d | 251 [242–255] | 251 [243–255] |
| Fetal position at data entry | ||
| Cephalic, n (%) | 96 (96) | 87 (92%) |
| Breech, n (%) | 4 (4.0) | 8 (8.4%) |
| Maternal temperature at inclusion, mean [± sd ], ̊C | 36.8 [± 0.44] | 36.8 [± 0.44] |
a Percentages given are related to available data per characteristic and may differ from total number of patients;
b Percentages are given as part of known educational level;
c Outcome characteristic with more than 5% missing data; ethnic origin: data available from 178 cases (91%); education: data available from 104 cases (53%); maternal smoking: data available from 184 cases (94%); body mass index at booking: data available from 161 cases (84%); body mass index at start study available from 84 cases (44%); antenatal administration of corticosteroids: data available from 173 cases (89%); maternal temperature at inclusion: data available from 172 cases (90%);
d Sum of tests exceeds 100% because more than 1 test could be applied on the same patient; percentages are given as part of applied tests. Data on positive history were available from 190 of 195 cases (97%). Ferning was done in 112 cases, pH test was done in 52 cases, PAMG-1 test was done in 72 cases, and ultrasound was done in 146 cases;
e In one woman, the term at rupture of membranes was unknown.
| Outcome a | Induction of labor | Expectant management | Relative risk/mean difference (95% CI; P value) | Absolute risk reduction (95% CI) |
|---|---|---|---|---|
| (n = 100 or 100) b | (n = 95 or 98) c | |||
| Onset of labor d | ||||
| Spontaneously, n (%) | 15 (15) | 54 (57) | 0.26 (0.16–0.43; < .001) | 42.3% (30.0–54.5%) |
| Planned cesarean section, n (%) | 3 (3.0) | 8 (8.5) | 0.36 (0.10–1.3; .100) | 5.5% (−1.1% to 12.1%) |
| Induction, n (%) | 81 (82) | 32 (34) | 2.40 (1.79–3.23; < .001) | −47.9% (−60.0% to −35.6%) |
| Gestational age at birth, mean [± sd ] (median) [IQR], d | 250.5 [± 6.5] (252) [244–256] | 254.0 [± 5.3] (256) [251–258] | −3.5 (−5.2 to −1.8; < .001) | NA |
| Gestational age at birth from | ||||
| 34+0 to 34+6 wks, n (%) | 25 (25) | 7 (7.1) | 3.50 (1.59–7.72; < .001) | −17.9% (−37.7% to −8.0%) |
| 35+0 to 35+6 wks, n (%) | 21 (21) | 21 (21) | 0.98 (0.57–1.68; .941) | 0.43% (−11.0% to 11.8%) |
| 36+0 to 36+6 wks, n (%) | 49 (50) | 47 (48) | 1.02 (0.77–1.36; .884) | −1.04% (−15.0% to 12.9%) |
| 37+0 to 37+6 wks, n (%) | 5 (5.0) | 23 (23) | 0.21 (0.08–0.54; < .001) | 18.5% (9.1–27.9%) |
| Longer than 38 wks, n (%) | 0 (0) | 0 (0) | — | — |
| Interval between randomization and birth, mean [± sd ] (median) [IQR], h | 39 [± 66] (24) [12–47] | 110 [± 131] (74) [33–165] | −71 (−99 to −42; < .001) | NA |
| Interval between rupture of membranes and birth, mean [± sd ] (median) [IQR], h | 133 [± 186] (63) [42–113] | 193 [± 230] (123) [64–208] | −61 (−120 to −1.1; < .001) | NA |
| Mode of delivery | ||||
| Spontaneously vaginally, n (%) | 78 (78) | 68 (69) | 1.12 (0.95–1.33; .169) | −8.6% (−20.8% to 3.6%) |
| Vaginally assisted, n (%) | 9 (9.0) | 8 (8.1) e | 1.10 (0.44–2.74; .834) | −0.84% (−8.6% to 7.0%) |
| Cesarean section, n (%) | 13 (13) | 22 (22) f | 0.58 (0.31–1.08; .081) | 9.4% (−1.1% to 20.0%) |
| Any instrumental delivery, n (%) | 22 (22) | 30 (31) | 0.72 (0.44–1.16; .169) | 8.6% (−3.6 to 20.8%) |
| Antibiotics | ||||
| During admission, n (%) | 36 (36%) | 46 (48%) | 0.74 (0.53–1.04; .079) | 12.4% (−1.3% to 26.2%) |
| During labor, n (%) | 28 (29%) | 33 (36%) | 0.80 (0.53–1.22; .305) | 7.0% (−6.3% to 20.3%) |
| During admission or labor, n (%) | 40 (42%) | 51 (55%) | 0.83 (0.62–1.11; .206) | 9.5% (−5.1% to 24.1%) |
| Epidural and/or spinal analgesia, n (%) | 25/99 (25%) | 27/91 (30%) | 0.85 (0.54–1.35; .495) | 4.4% (−8.2 to 17.1%) |
| Hemorrhage, mean (range) [± sd ], mL | 351 (50–2000) [± 296] | 505 (50–3800) [± 587] | −155 (−286 to −22; .022) | NA |
| Total maternal admission, mean [± sd ] (median) [IQR], d | 8.8 [± 5.3] (7) [5–11] | 13.2 [± 9.5] (10) [7–16] | −4.4 (−6.7 to −2.2; < .001) | NA |
a Percentages, relative risks, 95% CI, and P value given are related to available data per characteristic and may differ from total number of patients;
b The number of women in the IoL group was 100, and the number of newborns in the IoL group was 100;
c The number of women in the EM group was 95, and the number of newborns in the EM group was 98;
d From 2 women the onset of labor was unknown;
e Including 1 forcipal extraction;
f Including 2 cesarean sections after vacuum extraction failed.
The mode of delivery was not statistically significant different. There were fewer cesarean sections in the IoL group (13 [13%] vs 22 [22%]; RR, 0.58; 95% CI, 0.31–1.08; P = .081). This difference was partly because of the higher number of planned cesarean sections in the EM group (3 vs 8), which was known at baseline and could not be due to randomization.
Antibiotics during admission and during labor were administered equally. There were no differences in the rates of epidural and/or spinal analgesia.
Neonatal sepsis
Neonatal sepsis was seen in 3 neonates (3.0%) in the IoL group versus four (4.1%) in the EM group (RR, 0.74; 95% CI, 0.17–3.2) ( Table 3 ). One neonate in the IoL group who had a proven sepsis died 48 hours postpartum because of the complications of a severe asphyxia and anemia. During labor, fetal blood sampling was performed because of a suboptimal cardiotocography. This procedure resulted in heavy blood loss, after which an emergency cesarean section was performed. An asphyctic male neonate (arterial pH 6.98 mmol/L and Apgar score 0/0) was born and was transferred to an NICU center in which multiorgan failure occurred with a Sarnat stage 3 asphyxia and positive blood cultures for group B Streptococcus . The child died 48 hours postpartum. This case was reported to the Medical Ethical Committee of the Maastricht University Medical Center, and it was extensively discussed by our panel of neonatologists (A.L.M.M, R.M.J.M.) as well as by an independent gynecologist. Neonatal death was considered to be related to the severe asphyxia and anemia and not to neonatal sepsis. Induction of labor was not considered to be the cause of this severe adverse event.
| Outcome a | Induction of labor (n = 100) | Expectant management (n = 98) | Relative risk/mean difference (95% CI; P value) | Absolute risk reduction (95% CI) |
|---|---|---|---|---|
| Primary outcome | ||||
| Proven neonatal sepsis, n (%) | 1 (1.0) | 2 (2.0) | 0.49 (0.05–5.3; .549) | 1.04% (−2.37% to 4.5%) |
| Suspected neonatal sepsis, n (%) | 2 (2.0) | 2 (2.0) | 0.98 (0.14–6.82; .983) | 0.04% (−3.9% to 4.0%) |
| Sepsis overall, n (%) | 3 (3.0) | 4 (4.1) | 0.74 (0.17–3.20; .680) | 1.08% (−4.1% to 6.2%) |
| Secondary outcome | ||||
| Apgar score, 5 min <7, n (%) | 2 (2.0) | 1 (1.0) | 1.92 (0.18–20.8; .585) | −0.96% (−4.4% to 2.5%) |
| Neonatal temperature >38,0°C, n (%) b | 3 (5.8) | 2 (3.9) | 1.47 (0.26–8.44; .663) | −1.85% (−10.1% to 6.4%) |
| pH umbilical artery <7.1 mmol/L, n (%) b | 3 (4.1) | 2 (2.7) | 1.52 (0.26–8.84; .638) | −1.41% (−7.3% to 4.5%) |
| Birthweight, mean [±SD], g | 2652 [± 393] | 2718 [± 419] | −66 (−181 to 48; .256) | NA |
| RDS (no grade classified), n (%) | 6 (6.0) | 5 (5.1) | 1.18 (0.37–3.73; .783) | −0.0.90% (−7.3% to 5.5%) |
| RDS grade I or II, n (%) | 3 (3.1) | 0 (0) | ( P = .082) | −3.06% (−6.5% to 0.35%) |
| RDS grade III or IV, n (%) | 0 (0) | 0 (0) | NA | NA |
| Wet lung, n (%) | 0 (0) | 3 (3.1) | ( P = .078) | 3.06% (−0.35% to 6.5%) |
| Asphyxia, n (%) | 1 (1.0) | 0 (0) | ( P = .319) | −1.01% (−3.0% to 0.96%) |
| Pneumothorax/pneumomediastinum, n (%) | 0 (0) | 0 (0) | NA | NA |
| Meconium aspiration syndrome, n (%) | 1 (1.0) | 0 (0) | ( P = .321) | −1.00% (−3.0% to 0.95%) |
| Neonatal meningitis, n (%) | 0 (0) | 0 (0) | NA | NA |
| Late onset sepsis, n (%) | 1 (1.0) | 0 (0) | ( P = .319) | −1.01% (−3.0% to 0.96%) |
| Hypoglycemia, n (%) | 8 (8.1) | 8 (8.2) | 0.99 (0.39–2.53; .983) | 0.08% (−7.5% to 7.7%) |
| Hyperbilirubinemia, n (%) | 20 (20) | 21 (21) | 0.95 (0.55–1.64; .861) | 1.02% (−10.4% to 12.4%) |
| Necrotizing enterocolitis, n (%) | 1 (1.0) | 0 (0) | ( P = .319) | −1.01% (−3.0% to 0.96%) |
| HIE grade 1 or 2, n (%) | 0 (0) | 0 (0) | NA | NA |
| HIE grade 3 or 4, n (%) | 1 (1.0) | 0 (0) | ( P = .319) | −1.01% (−3.0% to 0.96%) |
| IVH grade 1 or 2, n (%) b | 1 (1.0) | 0 (0) | ( P = .321) | −1.01% (−3.0% to 0.96%) |
| IVH grade 3 or 4, n (%) b | 0 (0) | 0 (0) | NA | NA |
| PVL grade 1 or 2, n (%) | 0 (0) | 1 (1.0) | ( P = .313) | 1.03% (−0.98% to 3.0%) |
| PVL grade 3 or 4, n (%) | 0 (0) | 0 (0) | NA | NA |
| Convulsions, n (%) | 0 (0) | 0 (0) | NA | NA |
| Other neurological disorders, n (%) | 1 (1.0) | 0 (0) | ( P = .319) | −1.01% (−3.0% to 0.96%) |
| Other disorders, n (%) | 6 (6.1) | 14 (15) | 0.41 (−17 to −0.24; .044) | 8.8% (0.24–17.4%) |
| Intrapartum death, n (%) | 0 (0) | 0 (0) | NA | NA |
| Neonatal death, n (%) | 1 (1.0) c | 0 (0) | ( P = .321) | −1.00% (−3.0% to 0.95%) |
| Hospital admission, n (%) | 95 (96) | 95 (98) | 0.98 (0.93 to 1.03; .421) | 1.98% (−2.8% to 6.8%) |
| Length of hospital stay, mean [± sd ] | 7.4 [± 6.1] | 6.9 [± 6.0] | 0.52 (−1.2 to 2.3; .559) | NA |
| (median) [IQR], d | (4) [3–12] | (5) [2–9] | ||
| NICU admission, n (%) | 7 (7.0) | 8 (8.2) | 0.86 (0.32 to 2.3; .757) | 1.16% (−6.2% to 8.5%) |
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