primary outcome:
Vaginal prostaglandin (PGE2 and PGF2a) for induction of labour at term
Five primary outcomes were chosen as being most representative of the clinically important measures of effectiveness and complications:(1) vaginal delivery not achieved within 24 hours (or period specified by trial authors);
(2) uterine hyperstimulation with fetal heart rate (FHR) changes;
(3) caesarean section;
(4) serious neonatal morbidity or perinatal death (e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood);
(5) serious maternal morbidity or death (e.g. uterine rupture, admission to intensive care unit, septicaemia).Perinatal and maternal morbidity and mortality are infrequent and so composite outcomes have been used. This is not an ideal solution because some components of morbidity are clearly less severe than others and adverse events tend to cluster in individuals, so care is needed to count individuals rather than events. It is also possible for an intervention to cause more deaths but less severe morbidity, however, in the context of labour induction at term, this is unlikely. All of these events will be rare, and a modest change in their incidence will be easier to detect if composite outcomes are presented. The incidence of individual components where available will be explored as secondary outcomes (see below).Fifteen trials included some measurement of time from induction to delivery as an outcome but in only two trials (384 women) (Egarter 1989; Ulmsten 1985) is 'Vaginal delivery not achieved within 24 hours' reported in a suitable format to contribute data to this review. Of the trials reporting time from induction to delivery in a format that is not useable in the meta‐analysis, the largest trial (Hannah 1996) (2522 women) compared PGE2 gel with expectant management for women with ruptured membranes (ROM). The authors reported a reduction in the median time from ROM to delivery in the group given PGE2 compared to those in an expectant management. Of the two studies contributing data to this outcome, the larger study by Egarter 1989 (345 women), included both primiparae and multiparae, all with a favourable cervix (Bishop score (BS) > 4), intact membranes and the study used a higher dose of PGE2 (3 mg tablet). They found more women delivered within 24 hours with vaginal PGE2 compared with expectant management (up to 42 weeks' gestation) (12% of the PGE2 group versus 100% expectant management group were undelivered after 24 hours (risk ratio (RR) 0.12, 95% confidence interval (CI) 0.08 to 0.18). The smaller trial by Ulmsten (39 women) included only primiparae with an unfavourable cervix and used a single dose of 2 mg PGE2 suppository compared with a placebo. In this trial (Ulmsten 1985), 79% of the PGE2 group and 90% of the placebo group were undelivered after 24 hours (RR 0.88, 95% CI 0.67 to 1.15). Although both trials' findings are compatible with an increase in vaginal delivery within 24 hours, differences between the interventions used, comparisons groups and characteristics of the participants contribute to the marked heterogeneity observed when the results are combined (I² = 98%). Given the heterogeneity, it is reasonable not to combine these results in meta‐analysis, but if combined, a random‐effects model should be used; the CIs are wider and the difference does not reach statistical significance, (18.1% versus 98.9%, average RR 0.32, 95% CI 0.02 to 4.83, (heterogeneity: Tau² = 3.77; Chi² = 125.43, df = 1 (P < 0.00001); I² = 98%), two trials, 384 women, (test for subgroup differences: Chi² = 43.14, df = 1 (P < 0.00001), I² = 97.7%) (Analysis 1.1). Overall therefore, although not certain, it is likely that vaginal prostaglandin E2 compared with placebo or no treatment reduces the likelihood of vaginal delivery not being achieved within 24 hours.'Uterine hyperstimulation with fetal heart rate (FHR) changes' was reported in 15 studies (Analysis 1.2). An increase in uterine hyperstimulation with FHR changes is seen in association with vaginal PGE2 (4.8% versus 1.0%, RR 3.16, 95% CI 1.67 to 5.98, 15 trials, 1359 women) in comparison with placebo. This RR is reduced compared to previous versions of this review (which was 4.4% versus 0.5%, RR 4.14, 95% CI 1.93 to 8.90), because of a small decrease in event rate in the PGE2 group and an increase event rate in the control group. Uterine hyperstimulation with FHR changes did not occur in either arms of four trials (Chua 1995; Dommisse 1980; O'Brien 1995; Sawai 1991) and is influenced by one trial (Rayburn 1992) where the estimate is a 30‐fold increase in hyperstimulation rates associated with FHR changes (based on 13 events in the PGE2 group and zero in the control group, 12.9% versus 0.0%, RR 30.44, 95% CI 1.83 to 505.65). The new trial (Bezircioglu 2012) had a higher event rate in both arms of the trial. The estimated rates of hyperstimulation with FHR changes seen in either the once only or repeated dose subgroups compared with placebo or no treatment are compatible with no difference between the groups (Analysis 1.2).The caesarean section rate is lower in the PGE2 groups compared with placebo/expectant management, the estimates are compatible with no difference or a reduction of 10% or more in caesarean section (13.5% versus 14.8%, RR 0.91, 95% CI 0.81 to 1.02, 36 trials, 6599 women) (Analysis 1.3). This finding is mirrored when the data were considered by parity, membrane status or cervical favourability. There was no statistical heterogeneity, and the results were similar when only higher quality studies were considered.Serious neonatal (Analysis 1.4) or maternal morbidity or death (Analysis 1.5) are rare events and there are insufficient data to make conclusions about the impact of PGE2 on this outcome.There is no evidence of a difference in vaginal delivery rates not achieved in 24 hours (37.0% versus 36.9%, RR 1.03, 95% CI 0.84 to 1.26, three trials, 566 women) (Analysis 14.1). There is no evidence of a difference between gel or tablet regarding uterine hyperstimulation with FHR changes (0.5% versus 1.0%, RR 2.00, 95% CI 0.18 to 21.71, one trial, 200 women) (Analysis 14.2), or caesarean section rates (17.9% versus 19.8%, RR 0.91, 95% CI 0.72 to 1.17, six trials 1046 women) (Analysis 14.3). There are insufficient data to make any conclusions regarding serious maternal morbidity or death.There were no data available regarding vaginal delivery not achieved in 24 hours. A reduction in hyperstimulation with FHR changes was seen in association with PGE2 gel use in comparison with PGE2 pessaries (1.3% versus 11.2%, RR 0.16, 95% CI 0.03 to 0.87, two trials, 159 women) (Perryman 1992; Smith 1990) (Analysis 20.1). The dose used in both arms of one trial (Perryman 1992) was 5 mg of PGE2, which is much higher than commonly used as a single dose. The other trial (Smith 1990) compared 2.5 mg PGE2 gel with a vaginal 'chip' containing 3 mg to 3.5 mg of PGE2. For these reasons, these results should be interpreted with caution. There was no evidence that caesarean section rates differed between the two delivery systems (20.3% versus 31.3%, RR 0.65, 95% CI 0.38 to 1.11, two trials, 159 women) (Analysis 21.2).No evidence of a difference was seen between caesarean section rates between tablet and pessary (9.3% versus 8.1%, RR 1.13, 95% CI 0.64 to 1.99, three trials, 491 women) (Analysis 22.1). No data were available regarding vaginal delivery not achieved in 24 hours.There is no evidence of a difference between vaginal delivery not achieved in 24 hours (43.1% versus 37.3%, RR 1.15, 95% CI 0.92 to 1.45, three trials, 450 women) (Analysis 26.1). The outcome uterine hyperstimulation rates with FHR changes was reported by five trials and no difference was detected (4.9% versus 2.2%, RR 2.15, 95% CI 0.89 to 5.21, five trials, 643 women) (Analysis 26.2), however, in two of these trials there were no events reported in either arm (El Shawarby 2006; Triglia 2010). In the three remaining trials there was an increase in events in the controlled release arms of the trials but this increase was greatest in the Smith 1994 trial. Caesarean section rates are not different between the two groups (20.4% versus 20.1%, RR 1.02, 95% CI 0.82 to 1.26, 11 trials, 1262 women) (Analysis 26.3). Serious neonatal morbidity or mortality was reported in two trials that included 320 women, poor neonatal outcomes were infrequent so these studies are too small to detect any difference that might exist, and there was a single event in the other PGE2 arm, which may be due to chance (Analysis 26.4). This is also true of maternal morbidity and mortality.A reduction in hyperstimulation with FHR changes is seen in association with low‐dose regimens (Smith 1990), but this is a small trial and the reduction does not reach statistical significance (2.9% versus 20.0%, RR 0.15, 95% CI 0.02 to 1.13, one trial, 69 women) (Analysis 30.1). The trial (Smith 1990) used a 3 mg to 3.5 mg pessary in the high‐dose arm. Caesarean section rates do not appear to be different between the two groups (12.1% versus 12.1%, RR 1.02, 95% CI 0.78 to 1.33, seven trials, 1546 women) (Analysis 30.2). There were no neonatal deaths or cases of serious neonatal morbidity in the one trial reporting this outcome (MacKenzie 1997a). No data were available regarding vaginal delivery not achieved in 24 hours.