Methods of induction of labour: a systematic review

Background Rates of labour induction are increasing. We conducted this systematic review to assess the evidence supporting use of each method of labour induction. Methods We listed methods of labour induction then reviewed the evidence supporting each. We searched MEDLINE and the Cochrane Library between 1980 and November 2010 using multiple terms and combinations, including labor, induced/or induction of labor, prostaglandin or prostaglandins, misoprostol, Cytotec, 16,16,-dimethylprostaglandin E2 or E2, dinoprostone; Prepidil, Cervidil, Dinoprost, Carboprost or hemabate; prostin, oxytocin, misoprostol, membrane sweeping or membrane stripping, amniotomy, balloon catheter or Foley catheter, hygroscopic dilators, laminaria, dilapan, saline injection, nipple stimulation, intercourse, acupuncture, castor oil, herbs. We performed a best evidence review of the literature supporting each method. We identified 2048 abstracts and reviewed 283 full text articles. We preferentially included high quality systematic reviews or large randomised trials. Where no such studies existed, we included the best evidence available from smaller randomised or quasi-randomised trials. Results We included 46 full text articles. We assigned a quality rating to each included article and a strength of evidence rating to each body of literature. Prostaglandin E2 (PGE2) and vaginal misoprostol were more effective than oxytocin in bringing about vaginal delivery within 24 hours but were associated with more uterine hyperstimulation. Mechanical methods reduced uterine hyperstimulation compared with PGE2 and misoprostol, but increased maternal and neonatal infectious morbidity compared with other methods. Membrane sweeping reduced post-term gestations. Most included studies were too small to evaluate risk for rare adverse outcomes. Conclusions Research is needed to determine benefits and harms of many induction methods.


Background
The incidence of labour induction has increased over the last decade [1]. Labour induction may be indicated by medical or obstetrical complications of pregnancy or may be requested or chosen for non-medical or social reasons. When a woman and her care provider decide that labor induction is desired, they must next choose a method of induction. Several factors may influence the choice of method for induction of labour including cervical and membrane status, parity, and patient and provider preference. In this paper we review the evidence for effectiveness of pharmacologic, mechanical, investigational, and complementary and alternative medicine means of third trimester labour induction. We also address possible harms of each method.
We conducted this review to summarize the best evidence available for pregnant women requiring induction of labor in the third trimester of pregnancy with a live fetus. We compared each method with placebo and with other methods of labor induction. The outcomes of this review were the clinically important benefits and harms of labor induction specified by the Cochrane Collaboration's Pregnancy and Childbirth Group in their generic protocol for induction of labour [2].

Methods
We conducted a comprehensive literature search of the English language literature using Medline and the Cochrane Database of Systematic Reviews. The search covered the period from January 1980 to November 2010. We used combinations of the following search terms "labor, induced/or induction of labor; prostaglandin or prostaglandins, misoprostol; Cytotec; 16,16,dimethylprostaglandin E2 or E2; dinoprostone; Prepidil; Cervidil: Dinoprost; Carboprost or hemabate; prostin, oxytocin, misoprostol, prostaglandins, membrane sweeping or membrane stripping, amniotomy, balloon catheter or Foley catheter, hygroscopic dilators, laminaria, dilapan, saline injection, nipple stimulation, intercourse, acupuncture, castor oil, herbs". Titles and abstracts were reviewed for possible exclusion by two reviewers (KK or EM and JC). If both reviewers excluded a citation, we eliminated that publication from further review. If at least one reviewer felt the citation might be included or if there was insufficient information to make a determination from the title and abstract, we obtained the full article for review. We identified additional articles for consideration of inclusion through cross checks of relevant bibliographies. Reference lists were created and full-text articles were retrieved for further consideration for inclusion.
In accordance with published guidelines for a "best evidence" review, [3][4][5] this study included high-quality systematic reviews and randomised controlled trials in a hierarchical fashion. If a high-quality systematic review was available, only randomised controlled trials (RCT) published after the search date for the systematic review were included, except in the instance in which we found a RCT that had not been identified by the systematic review's search or a RCT that had been identified by the systematic review's search but which was awaiting classification. In addition, we included studies with at least one other comparison group (control, placebo or another method) for women undergoing induction of labour at term with a live fetus. We excluded systematic reviews dealing exclusively with subgroups of participants, such as nulliparas or women with prelabour rupture of membranes or with only a particular dose or formulation of the method under study (i.e. low dose or sustained-release preparations). We excluded dose-ranging studies, comparisons of two different formulations of the same method and studies in which subjects in one or more treatment arm received several different methods of labour induction. We did not exclude studies in which subjects received oxytocin augmentation after cervical ripening.
If five or more randomised controlled trials involving a method of induction were published subsequent to the search date of the most recent included systematic review or were "awaiting classification" in the systematic review, we conducted meta-analyses of the primary outcomes reported in these studies. Two authors, VR and UP extracted data independently. Differences were resolved by a third reviewer (EM) after careful review of each manuscript. The new data were added to the data on the comparison available in the Cochrane review. We computed risk ratios and 95% confidence intervals for the main outcome measures reported in these subsequent studies using Comprehensive Meta-Analysis, Version 2, Englewood, NJ. We used the fixed effects method for these analyses in order to match the measures of effect reported by the included Cochrane reviews.
We arranged the methods of labour induction according to types including pharmacologic methods, nonpharmacologic methods, complementary and alternative medicine methods, and investigational methods. However, for comparisons of methods with each other, we followed the pre-specified hierarchy used for the series of induction of labour Cochrane Reviews and arranged labour induction methods in that specific order [2]. In each subsection of this paper, we compare each method with those methods prior to it on this list. (see Table 1) All full text articles were independently reviewed by two authors (EM and KK) for possible inclusion. In order to be included in this review, trials had to report on one or more of the outcomes of interest specified by the Cochrane Collaboration induction of labour generic protocol [2]. The Cochrane generic protocol identified the most clinically important benefits and harms of labor induction as the outcomes of interest. These included the following five primary outcomes which were felt to be of most clinical importance: vaginal delivery not achieved within 24 hours (or period specified by authors), uterine hyperstimulation with fetal heart rate (FHR) changes, caesarean section, serious neonatal morbidity or perinatal death (e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood), serious maternal morbidity or death (e.g. uterine rupture, admission to intensive care unit, septicaemia) [2]. Secondary outcomes included unfavourable or unchanged cervix after 12 or 24 hours, need for oxytocin augmentation, uterine hyperstimulation without FHR changes, uterine rupture, epidural analgesia, instrumental vaginal delivery, meconium stained amniotic fluid, Apgar score less than seven at five minutes, neonatal intensive care admission, neonatal encephalopathy, perinatal death, disability in childhood, maternal side effects including nausea, vomiting and diarrhea. Other secondary outcomes included postpartum hemorrhage, serious maternal complications, maternal infections including chorioamnionitis and endometritis, and neonatal infections including meningitis, pneumonia, and sepsis. Maternal satisfaction data were included when available. For each of the methods of induction, we reported the significant measures of effect (odds ratios or risk ratios) on our outcomes of interest from the included systematic reviews and RCTs.
Due to the large number of methods, comparisons and outcomes, we did not include discussion of subgroup analyses. However, because of the importance of cervical status as a determinant of failure of induction of labor to achieve vaginal birth, we reported on the effect of induction methods on caesarean deliveries for the subgroup with unfavorable cervices, where available in the Cochrane reviews.
Two authors (EM and JC) assigned quality scores to each included full-text article based on the Scottish Intercollegiate Guidelines Network (SIGN) quality assessment instruments. These quality assessment instruments are designed to assess the internal validity of each study, and the degree to which the studies' performance minimized bias [6]. The Scottish Intercollegiate Guidelines Network publishes methodology checklists for critical appraisal of both randomised controlled trials and for systematic reviews [6].
We systematically reviewed benefits and harms of each induction method and calculated number needed to treat (NNT) and number needed to harm (NNH) for each significant comparison among methods. For comparisons including only one trial, we used the "treat as one trial" method of calculating the NNT [7]. When more than one trial was included in the comparison, we calculated NNT from pooled odds ratios and risk ratios reported in the included meta-analyses using the Visual Rx, version 2; this method is less prone to bias than the "treat as one trial" method of NNT calculation [8,9]. For the purpose of NNT calculations from pooled estimates, we used risk ratios or odds ratios where reported for adverse outcomes and odds ratios to calculated NNT from positive outcomes [9]. When odds ratios were not available in the source studies, we calculated them from available data using Comprehensive Meta-Analysis, Version 2, Englewood, NJ. NNT estimates were rounded up to the next whole number whereas NNH estimates were rounded down to the nearest whole number [7,10].
For each method of induction, two authors (EM and KK) assigned a level of evidence based on the "GRADE" (Grading of Recommendations Assessment, Development and Evaluation) system [11]. In this system, the overall strength of evidence is assigned not only based on study design and conduct, but also on factors such as the consistency and precision of the results and the likelihood of publication bias. Overall strength of evidence is classified in the GRADE system as high, intermediate, low or very low. The levels of evidence were assigned in the following manner. If the preponderance of evidence supporting a particular method of labor induction for the outcomes of interest is strong enough that further research would be unlikely to change the reviewers' confidence in the estimate of effect, the evidence quality was assessed as high [11]. If further research would be likely to have an important impact on confidence in the estimate, the evidence quality was assessed as moderate [11]. If further research would be very likely to have an important impact in the estimate of effect, the quality of evidence was assessed as low, and if the estimate of effect is very uncertain, the evidence was assessed as very low [11].
These same authors (EM and KK) also assigned a balance of benefits and harms and a grade of recommendation according to GRADE system guidelines [11,12]. For each clinical intervention under study, the balance of benefits and harms is assessed, and a grade of recommendation is classified as strong or weak. This systematic review does not have a "stand alone" study protocol. In reporting outcomes from included study, we followed PRISMA guidelines [13]. This is a systematic review of previously-published data and as such does not require ethics approval.

Results
We reviewed 2048 abstracts, of which 283 full text articles were examined for further consideration for inclusion and from which 46 studies were included. Thus, we included a total of 46 studies in this systematic review . Included studies are listed in Table 2. The flow of abstracts and articles through the review process is outlined in Figure 1. A summary of the overall quality of evidence and strength of recommendation for each intervention is presented in Table 3.

Intravaginal prostaglandins (PGE2 and PGF2a)
Our search identified one Cochrane systematic review of vaginal prostaglandin E2 (PGE2) or F2α (PGF2α) [14]. Within this review, 37 studies compared PGE2 with placebo. Of these, two trials with 384 women addressed the primary outcome of achieving vaginal delivery within 24 hours. These studies demonstrated that PGE2 reduced failure to achieve vaginal delivery within 24 hours compared with placebo (36/199  0.14 to 0.25; NNT = 2). However, there was significant between-study heterogeneity in these two included studies, (P < 0.0001), possibly resulting from differences in baseline characteristics of included women and differences in dosing regimens studies [14].
Thirty-four trials with 6399 women compared rates of caesarean section and demonstrated similar rates between PGE2 and placebo groups. Fourteen trials including 1259 women reported that uterine hyperstimulation with FHR changes was increased with vaginal PGE2 compared with placebo (28/ These trials did not demonstrate a difference in cesarean section rates or any other outcomes of interest between PGF2α and placebo [14].

Unfavorable cervix subgroup
The authors conducted subgroup analyses of trial participants who had cervices unfavorable for induction. There was no difference in the risk of caesarean delivery between vaginal PGE2 and placebo in the subgroup of women with unfavorable cervices (22 trials, 2173 women, 225/1093 versus 254/1080, RR 0.87, 95% CI 0.75 to 1.02) [14].
Summary: Compared with placebo, vaginal PGE2 increases vaginal delivery rates within 24 hours. However, overall risk of cesarean section was not changed. PGE2 increases uterine hyperstimulation with FHR changes.

Cervical PGE2
Our search identified one Cochrane systematic review of the use of intracervical prostaglandins for cervical ripening and induction of labour compared with placebo/no treatment [15]. This Cochrane review included 28 trials with 3764 women that compared intracervical PGE2 with placebo/no treatment. Four of the studies (n = 198) found that use of cervical PGE2 was superior to placebo in decreasing the number of women who did not achieve vaginal delivery within 24 hours (44/100 versus 71/98; RR 0.61, 95% CI 0.47 to 0.79; NNT = 4). In 27 trials including 3734 women, there was a non-significant trend toward decreased risk of caesarean section for women receiving cervical PGE2 (344/1941 versus 360/1793; RR 0.88; 95% CI 0.77 to 1.01). There were no significant increases in risk of hyperstimulation with FHR changes. However, 11 trials with 2531 women demonstrated significant increases in hyperstimulation without FHR changes (67/1344 versus 37/1187; RR 1.59, 95% CI 1.09 to 2.33; NNH = 55). Serious maternal and neonatal morbidity and mortality were infrequently reported and available data revealed similar findings in the PGE2 and placebo groups [15].

Subgroup with unfavorable cervix
Compared with placebo, there was a non-significant trend toward fewer caesarean sections among women receiving cervical PGE2 (27 studies, 3716 women, 343/ 1931 versus 359/1785, RR 0.88; 95% CI, 0.77 to 1.01). In 26 trials with 3586 women whose cervix were unfavorable for induction, there was no difference in caesarean deliveries between women receiving intracervical and intravaginal PGE2 [15]. Summary: Intracervical PGE2 appears more effective than placebo in achieving vaginal delivery within 24 hours.

Oxytocin
Our search identified one Cochrane systematic review which included 61 trials with 12,819 women and evaluated oxytocin for induction of labour [16]. Comparisons were made between intravenous (IV) oxytocin versus placebo/expectant management (   ; however there was significant heterogeneity among the included trials for this comparison, (I 2 = 65%, P = 0.001) and the authors' analysis of the studies included in this comparison using the random effects method was not statistically significant. Likewise, NICU admissions were reduced by oxytocin compared to placebo or expectant management, (7 studies, 4387 women, 264/ 2196 versus 333/2191; RR 0.79, 95% CI 0.68 to 0.92, NNT = 32). However, there was significant between study heterogeneity for this comparison (I 2 = 70%, P = 0.0003) and this result was no longer statistically significant when the random effects method was used for analysis. The majority of the studies included in these comparisons required ruptured membranes for entry, likely influencing this result. Data were insufficient to establish conclusions regarding neonatal and maternal mortality or serious morbidity [16]. Three trials including 260 women reported that oxytocin was associated with more failures to achieve vaginal delivery within 24 hours than vaginal PGE2 (73/132 versus 40/128; RR1.77, 95% CI 1.31 to 2.38; NNH = 5). When comparing oxytocin with vaginal PGE2, there was no significant difference in the rates of caesarean section (26 trials, 4514 women, 274/2259 versus 246/2255; RR 1.11, 95% CI 0.94 to 1.30). The incidence of uterine hyperstimulation with fetal heart rate (FHR) changes was very low and not different between groups. Fewer women receiving oxytocin developed chorioamnionitis than those receiving vaginal PGE2 (4 trials, 2742 women, 54/1381 versus 81/1361; RR 0.66, 95% CI 0.47 to 0.92, NNT = 50). Data were insufficient to draw conclusions regarding neonatal and maternal mortality or morbidity; based on limited data, there were no differences between groups [16].
There were only three trials with 291 women that compared oxytocin with PGF2α. None reported on the number of women failing to deliver vaginally within 24 hours. There were no significant differences in uterine hyperstimulation with FHR changes (one trial 23 women) or rates of caesarean delivery (3 trials 280 women). There were no cases of serious neonatal morbidity or perinatal deaths in the two studies that reported this outcome [16].

Randomised controlled trials published after the search date of systematic reviews
Our search identified one study including 240 women that compared oxytocin with vaginal prostaglandin E2 for premature rupture of membranes at term [17]. In this study, oxytocin was associated with a significantly shorter time from induction to delivery (3.4 +/-1.5 versus 9.6 +/-4.7 hours; p = 0.02). There was no difference in the risk of caesarean section [17].
Summary: Oxytocin is more effective than expectant management or placebo but less effective than vaginal and cervical PGE2 in bringing about vaginal delivery within 24 hours. Oxytocin resulted in more caesarean deliveries than cervical PGE2.

Amniotomy
We identified one Cochrane systematic review of amniotomy for induction of labour [18]. This review included two studies with 310 total participants. One included study compared women receiving amniotomy with those receiving either oxytocin alone or no intervention. This study was underpowered to detect differences in any outcome of interest and the review concluded that no meaningful results could be drawn from these comparisons. The second included study compared amniotomy alone to a single dose of vaginal prostaglandins for women with a favourable cervix and found a significant increase in the need for oxytocin augmentation in the amniotomy alone group compared with the women receiving PGE2 (260 women, 57/130 versus 20/130; RR 2.85, 95% CI 1.82 to4.46; NNH = 3). There was no difference in caesarean deliveries [18].

Subgroup with unfavorable cervix
There were no studies that included participants with unfavorable cervices [18].
Summary: Compared with vaginal PGE2, amniotomy increases the need for oxytocin augmentation.

Oxytocin with amniotomy
Our search identified one Cochrane systematic review including 17 trials with 2566 women comparing IV oxytocin plus amniotomy with other methods for induction of labour [19]. This review compared amniotomy plus oxytocin (in varying doses), with placebo, vaginal prostaglandin E2 or F2α, or amniotomy alone. Oxytocin plus amniotomy resulted in fewer cases of meconium stained amniotic fluid than placebo or no treatment (one trial, 184 participants, 3/92 versus 13/92; RR 0.23, 95% CI 0.07 to 0.78; NNT = 9). There were no other significant differences in our outcomes of interest for this comparison [19].
One study with 30 participants compared oxytocin plus amniotomy with cervical prostaglandins. This study was too small to detect any differences in outcomes of interest. Likewise, only two studies with 309 total participants compared oxytocin plus amniotomy with oxytocin alone. These studies were also underpowered to detect differences in any outcome of interest [19].

Unfavorable cervix subgroup
The review included two trials with 106 women who had cervices unfavorable for induction of labor. There was no difference in caesarean birth among women allocated to amniotomy and oxytocin versus vaginal prostaglandins. There were no other trials including women with cervices unfavorable for induction [19].
Summary: Oxytocin plus amniotomy is more effective than amniotomy alone in achieving vaginal delivery within 24 hours. Oxytocin plus amniotomy may be associated with more postpartum hemorrhage and less maternal satisfaction than vaginal prostaglandins.

Vaginal Misoprostol
The Cochrane review of vaginal misoprostol for labour induction included 121 trials [20]. There were no significant difference in vaginal deliveries not achieved with 24 hours among five trials with 769 women that compared vaginal misoprostol with placebo/no treatment. Likewise, in five trials with 777 women, there were no significant differences in hyperstimulation with FHR changes. Compared with placebo/no treatment, vaginal misoprostol was associated with more hyperstimulation without FHR changes ( [20].

Unfavorable cervix subgroup
Compared with placebo, there was no difference in caesarean deliveries for women receiving vaginal misoprostol (7 trials, 862 women). There was no difference in the likelihood of caesarean deliveries among women receiving misoprostol or women receiving vaginal PGE2 (28 trials, 5832 women), cervical PGE2 (21 trials, 2499 women) or oxytocin (14 trials, 1598 women) [20].
Summary: Vaginal misoprostol is more likely to result in vaginal delivery within 24 hours than vaginal or cervical PGE2 or oxytocin but is associated with increased uterine hyperstimulation. Compared with IV oxytocin, vaginal misoprostol may reduce the likelihood of caesarean delivery.

Oral Misoprostol
The Cochrane review of oral misoprostol compared to other methods of labour induction included 56 RCTs with a total of 11,590 participants [21]. There were seven trials with 669 women that compared oral misoprostol to placebo. Women assigned to receive oral misoprostol were more likely to give birth vaginally within 24  . There were no statistically significant differences between the groups in any of the other outcomes, including hyperstimulation with and without FHR changes and the frequency of meconium-stained amniotic fluid. There was significant heterogeneity (P = 0.002) among studies comparing oral misoprostol and vaginal PGE2 for the outcome of uterine hyperstimulation without FHR changes, likely related to the differing doses of oral misoprostol used in the included studies [21].
Eight trials including 1026 women compared oral misoprostol with IV oxytocin. Meconium staining of the amniotic fluid was seen more frequently in the misoprostol group (6 trials, 916 women, 47/477 versus 24/ 439; RR 1.72, 95% CI 1.08 to 2.74; NNH = 26), but oral misoprostol was not associated with any other differences in adverse fetal, neonatal or maternal outcomes [21].
Twenty-six trials with 5096 participants compared oral with vaginal misoprostol. The oral route of administration was associated with more frequent use of oxytocin ( [21].

Unfavorable cervix subgroup
There were no studies comparing oral misoprostol with placebo, vaginal PGE2, intracervical PGE2, or oxytocin that reported on caesarean deliveries among women with unfavorable cervices. Among women with unfavorable cervices who were randomized to receive oral misoprostol or vaginal misoprostol there were no differences in caesarean deliveries among primiparous (2 studies, 85 participants) or multiparous (1 study, 24 participants) subjects [21].
Randomised controlled trials published after the search date of systematic reviews Subsequent to the search date of the Cochrane review, we identified one study with 87 participants that compared oral misoprostol with placebo [22]. This study found oral misoprostol superior to placebo in achieving delivery within 24 hours (19/43 versus 6/44, P = 0.024, NNT = 4). An additional study that compared oral misoprostol with PGE2 found that more women receiving misoprostol delivered vaginally within 12 hours, although vaginal deliveries within 24 hours did not differ [23]. More women receiving oral misoprostol were satisfied with their induction method [23].
Summary: Oral misoprostol reduced caesarean sections compared with vaginal PGE2 and placebo. Compared with vaginal misoprostol, oral misoprostol is associated with fewer contractile abnormalities, but more need for oxytocin augmentation.

Buccal or sublingual misoprostol
Our search uncovered three systematic reviews comparing sublingual or buccal misoprostol with other methods of labour induction [24][25][26]. The Cochrane review by Muzonzini [24] and colleagues and the review by Bartusevicius and colleagues [25] both included the same three studies with a total of 507 women and reached similar conclusions. Two of the studies with a total of 350 women compared buccal or sublingual misoprostol (50 μg) to oral misoprostol (50 or 100 μg) and one study with 157 participants compared buccal and vaginal misoprostol. Neither review found significant differences in any outcome of interest [24,25].

Unfavorable cervix subgroup
The Cochrane reviewers did not conduct any subgroup analyses according to cervical status [24].

Other systematic reviews
In 2008 Souza and colleagues published a systematic review of studies comparing sublingual or buccal misoprostol with vaginal misoprostol for induction of labour. This review included five studies with 740 subjects [26]. The authors found no significant differences in the rates of vaginal delivery not achieved within 24 hours, hyperstimulation, or cesarean deliveries. There were more cases of uterine tachysystole, defined as more than five contractions in 10 minutes for at least 20 minutes, among women assigned to sublingual misoprostol (5 trials, 740 women, 42/368 versus 26/372; OR 1.70, 95% CI 1.02 to 2.83; NNH = 24, 95% CI 10 to 771), although there was significant heterogeneity among studies included in this comparison (P = 0.04) [26].

Randomised controlled trials published after the search date of systematic reviews
Our search identified two additional studies carried out subsequent to the search dates of these systematic reviews. One of these studies compared sublingual misoprostol 50 μg with amniotomy and oxytocin for induction of labour among 50 women at term with favourable cervices [27]. This study was terminated early when an interim analysis revealed that significantly fewer women allocated to sublingual misoprostol delivered within 24 hours (15/22 versus21/21; RR 0.68, 95% CI 0.51 to 0.91; NNH = 3). There were no differences in other maternal or fetal outcomes, although maternal satisfaction was significantly higher with sublingual misoprostol. The second study included 150 women and compared 50 μg misoprosol by oral, vaginal, or sublingual routes [28]. This study found that the induction to delivery interval was significantly decreased among women receiving sublingual misoprostol compared with the vaginal and oral routes ( ). Fewer babies born to mothers receiving sublingual misoprostol had Apgar scores less than seven at one minute (0/50 versus 6/100, P = 0.003, NNT = 17) [28].
Summary: Compared with vaginal misoprostol, administration of misoprostol by the buccal or sublingual route increases uterine tachysystole.

Mechanical methods
Our search identified three systematic reviews evaluating mechanical methods for induction of labour. The Cochrane review studied mechanical methods including laminaria tents, synthetic equivalents such as Dilapan, Foley catheters, and other types of balloon catheter for induction of labour. It included 45 RCTs that compared mechanical methods with PGE2, misoprostol, oxytocin, and placebo. Most trials had small sample sizes [29].
The authors did not find any advantage of mechanical methods compared with placebo or no treatment in the pre-specified outcomes of vaginal delivery not achieved within 24 hours or caesarean deliveries (1 trial, 48 women). There was no difference in caesarean deliveries between women receiving mechanical methods and women receiving placebo or no treatment (6 studies, 416 participants). There was no difference in any other outcome of interest, including chorioamnionitis (1 trial, 240 participants) and endometritis (2 trials, 288 participants) [29].
More women assigned to mechanical methods did not achieve vaginal delivery within 24 hours than those assigned to cervical PGE2 ( [29]. Analysis of four studies with 198 women comparing mechanical methods with oxytocin found that mechanical methods resulted in fewer caesarean deliveries (18/103 versus 30/95; RR 0.55, 95% CI 0.33 to 0.91; NNT = 8). There was no difference in hyperstimulation without FHR changes, postpartum hemorrhage, or serious maternal morbidity or death in 1 trial with 60 women. No other outcomes could be evaluated for this comparison [29].
Four studies including 618 women compared mechanical methods to vaginal misoprostol. There were no statistical differences in the likelihood of achieving vaginal delivery within 24 hours (2 studies, 234 women) or in caesarean deliveries (4 studies, 618 women). There was reduced risk for uterine hyperstimulation with FHR changes seen in three trials including 434 women comparing mechanical methods to vaginal misoprostol (8/ 226 versus 19/208; RR 0.41, CI 0.20 to 0.87; NNT = 19). There were no differences noted in infectious morbidity or neonatal outcomes [29].

Unfavorable cervix subgroup
There was no difference in caesarean deliveries among 396 women enrolled in five randomized controlled trials comparing mechanical methods with placebo or no treatment, in 10 trials with 738 women comparing mechanical methods with vaginal PGE2 or in 12 trials with 1614 women comparing mechanical methods with intracervical PGE2. There was no difference in cesarean sections in three trials with 482 participants comparing mechanical methods with vaginal misoprostol. In the subgroup of women with unfavorable cervices, mechanical methods were less likely to result in caesarean delivery than oxytocin (3 trials, 178 women, 15/93 versus 27/ 85, RR 0.50, 95% CI, 0.29 to 0.87, NNT = 7) [29].

Other systematic reviews
Our search identified a second systematic review that compared mechanical methods of labour induction with PGE2, misoprostol, hyaluronidase or placebo [30]. This systematic review, which included 30 randomised, controlled trials with a total of 4468 participants, focused on the outcomes of maternal and neonatal infectious morbidity. The authors defined maternal infectious morbidity as maternal temperature greater than 38°C, endometritis or chorioamnionitis. They defined neonatal infectious morbidity as fever, suspected or proven sepsis, or need for antibiotics. Controls were the pooled group of women who had received other pharmacologic methods of labour induction. Compared with controls, women undergoing labour induction with mechanical methods were more likely to experience infectious morbidity ( [30]. A third systematic review compared mechanical methods (Foley catheter balloon) with locally applied prostaglandins (vaginal PGE2, cervical PGE2 and vaginal misoprostol) [31]. This systematic review included 27 randomized controlled trials that included 3532 participants. When compared with all locally applied prostaglandins (LAPG) combined, there were no differences between mechanical methods and prostaglandins in caesarean deliveries (27 trial, 3532 participants), participants with cervices that were unfavorable or unchanged after 12 to 24 hours (6 trials, 613 participants), ripening to delivery interval (13 trials, 1270 participants), vaginal deliveries within 12 to 24 hours (13 trials, 1779 women), maternal fevers (19 trials, 2421 women), 5-minute Apgar scores less than 7 (14 trials, 1661 women), meconium staining (13 trials 1841 women), or admission of the neonate to a NICU (12 trials, 1796 women). Women who received LAPG were less likely to require oxytocin augmentation than those receiving mechanical methods (16 trials, 1644 participants, RR 0.73, 95% CI 0.62 to 0.86, P = 0.0002), but were more likely to experience excessive uterine activity, defined as tachysystole, hypertonus, or hyperstimulation syndrome (21 trials, 2661 participants, 244/1306 versus 147/1355, RR, 2.35; 95% CI, 1.41 to 3.90; P = .001, NNH for locally applied prostaglandins when compared with mechanical methods = 7). There was significant heterogeneity noted for the outcomes of excessive uterine activity, vaginal delivery within 12-24 hours, and for need for oxytocin augmentation [31].

Randomised controlled trials published after the search date of systematic reviews
We included one additional trial that was published subsequent to the search date of the third systematic review [32]. This trial randomly assigned 240 women to receive vaginal misoprostol 25 μg or a Foley catheter for labor induction. This study found that the Foley catheter was associated with a longer induction to vaginal delivery interval than the vaginal misoprostol (20.2 hours versus 17.3 hours, P = 0.016). There were no significant differences in other outcomes of interest [32].
Summary: Mechanical methods are less likely to result in uterine hyperstimulation than PGE2 or vaginal misoprostol, but may be associated with increased maternal and neonatal infectious morbidity.

Membrane Sweeping
Our search identified one Cochrane systematic review of 22 trials which included 2797 subjects that compared membrane sweeping with oxytocin, PGE2, or no treatment [33]. There was no difference in rates of caesarean deliveries, serious neonatal morbidity, perinatal death, serious maternal or neonatal infections when comparing membrane sweeping with no treatment. A policy of routine membrane sweeping from 37 weeks onward reduced the likelihood of gestation continuing to both 41 ( Data comparing membrane sweeping with PGE2 and with oxytocin were insufficient to draw conclusions of relative efficacy [33].

Unfavorable cervix subgroup
There was no difference in caesarean sections among women allocated to membrane sweeping versus no treatment (3 trials, 200 women) nor in two trials with 252 women comparing membrane sweeping with vaginal prostaglandins nor in one trial with 69 women comparing membrane sweeping with oxytocin [33].
Randomised controlled trials published after the search date of systematic reviews or awaiting classification Among the studies awaiting classification in the Cochrane review were five high quality RCTs [34][35][36][37][38]. In addition, we identified one additional high quality RCT that was published after the Cochrane review's search date [39]. Of these, five studies with 1700 participants compared membrane sweeping with no treatment or vaginal exam alone [35][36][37][38][39]. In a meta-analysis that added our independently-extracted data from the two studies [36,37] that evaluating the effect of membrane sweeping on post-term gestations to the data reported in the Cochrane review, membrane sweeping significantly decreased the number of pregnancies progressing to 42 weeks' gestation (8 studies, 1874 participants, 102/ 902 versus 194/862, RR 0.53, 95% CI 0.43 to 0.65, NNT = 10). There was no significant heterogeneity for this comparison. Thus the addition of these two new trials did not alter the conclusion reached by the Cochrane review.
DeMiranda found that membrane sweeping significantly reduced the time from randomization to delivery by one day (3.50 versus 4.47 days, mean difference 0.97 days; 95% CI 0.60 to 1.35) [36]. In a more recent study involving 351 women, Yildirim and colleagues found that membrane sweeping significantly increased the likelihood of spontaneous labor by 41 weeks' gestation (162/179 versus 118/ 167, P = 0.0001) [38]. By contrast, Hamdan found that membrane sweeping did not increase the proportion of women planning trial of labor after prior cesarean section (TOLAC) who entered spontaneous labor [39]. The Hill study was designed to test whether membrane sweeping increases prelabour rupture of membranes, but found no overall difference in this outcome [37]. One study with 60 participants compared membrane sweeping with a single dose of intracervical PGE2 [34]. Use of cervical PGE2 resulted in a significantly shorter intervention to delivery interval than did membrane sweeping (26.23 hours versus 19.15 hours, P < 0.01) [34].
Summary: Membrane sweeping reduces the risk of post-term gestation.

Castor Oil
Our search identified one systematic review of the efficacy of castor oil for induction of labour [40]. The authors of this Cochrane review identified only one study with 100 subjects comparing castor oil with no treatment. The trial was judged to be of poor methodologic quality due to methods of allocation. There were no observed differences in rates of caesarean delivery, meconium stained fluid, or Apgar less than 7 at five minutes. More women receiving castor oil reported experiencing nausea (52/52 versus 0/48; RR 97.08, 95% CI 6.16 to 150.34; NNH = 1) [40].

Unfavorable cervix subgroup
In one trial with 100 women, there was no difference in caesarean deliveries between women who received castor oil or no treatment [40].
Summary: Compared with no treatment, castor oil is associated with increased maternal side effects.

Acupuncture
Our search identified a Cochrane systematic review that included 3 trials with 212 women that focused on acupuncture for induction of labour [41]. Compared with standard care (oxytocin, prostaglandins, or "routine care"), more women undergoing acupuncture did not require the use of other induction methods (2 trials, 147 women, 49/73 versus 34/74; RR 1.45, 95% CI 1.08 to1.95; NNT = 5). No differences were found in time to delivery, rates of caesarean delivery, instrumental vaginal delivery, or epidural anesthesia. Fetal or neonatal outcomes were not estimable [41].

Unfavorable cervix subgroup
There was no data in the included trials concerning the effect of acupuncture for labor induction in women with unfavorable cervices [41].

Randomised controlled trials published after the search date of systematic reviews
We identified three further trials with 684 participants, three published after the search date of the systematic review [42][43][44] and one that was not identified by the Cochrane search [45]. These studies did not reveal any differences between acupuncture and placebo or no treatment in any outcome of interest.
Summary: The use of acupuncture for induction of labour is investigational; no advantages for this method have been demonstrated.

Breast Stimulation
Our search identified one systematic review that combined six studies with 719 subjects that evaluated breast stimulation for labour induction [46]. There were no differences in cesarean deliveries, meconium staining, or uterine hyperstimulation when comparing breast stimulation with no treatment. Breast stimulation decreased the number of women who were not in labour within 72 hours (4 studies, 437 women, 136/217 versus 206/ 220; RR 0.67, 95% CI 0.60 to 0.74; NNT = 4). Breast stimulation was associated with less postpartum hemorrhage (2 studies, 300 women, 1/150 versus 9/150; RR 0.16, 95% CI 0.03 to 0.87; NNT = 20). There were more perinatal deaths among pregnancies assigned to breast stimulation than to no treatment, although this difference was not statistically significant (3 studies, 337 participants, 3/167 versus 0/170; RR 8.17, 95% CI 0.45 to 147.8). This result should be interpreted with caution, as all of the deaths occurred in a single trial conducted among high risk women in a developing country [46].
Two studies with a total of 99 subjects compared breast stimulation with oxytocin. There were no differences in caesarean deliveries. In one trial with 37 women, more women assigned to breast stimulation were not in labour within 72 hours compared with those who were allocated to the oxytocin group, although this difference was of borderline statistical significance (10/17 versus 5/20; RR 2.35, 95% CI 1.00 to 5.54). There were no differences in uterine hyperstimulation or meconium staining. There were three perinatal deaths in the breast stimulation group versus one in the oxytocin group, a non-significant difference. All deaths were from the same trial conducted among high risk women in a developing-world setting [46].

Unfavorable cervix subgroup
There was no information on cesarean deliveries in the one included trial that included women with unfavorable cervices [46].
Summary: Breast stimulation may reduce the number of women not in labour within 72 hours compared to no treatment but is less effective than oxytocin for this outcome. More research is needed to evaluate the safety of breast stimulation.

Intercourse
The Cochrane review of intercourse for induction of labour included one study with 28 subjects [47]. Participants were assigned to have intercourse nightly for three nights versus no intercourse. There were no differences in delivery within three days or five minute Apgar less than seven [47].

Unfavorable cervix subgroup
There was no information on cervical status or cesarean deliveries in the one included study [47].
Summary: There is not enough evidence to evaluate the efficacy and safety of intercourse for induction of labour.

Homeopathic methods
Our search identified one systematic review of two studies with 133 participants that compared homeopathic herbs for labour induction with placebo [48]. Only one of the studies included in the Cochrane review reported on the pre-specified clinical outcomes of interest. That study included 40 subjects and reported no difference in rates of vaginal delivery not achieved with 24 hours, caesarean deliveries, operative vaginal delivery, need for oxytocin augmentation of labour, or length of labour [48].

Unfavorable cervix subgroup
There was no information in the included study on cervical status [48].
Summary: There is not enough evidence to evaluate the risks and benefits of homeopathy for induction of labour.

Hypnotic Relaxation
We identified one quasi-randomised study of hypnotic relaxation for induction of labour in post-term pregnancies [49]. Forty women were assigned to hypnotic relaxation and an equal number to no intervention based on alternate days of the week. Controls were also chosen based on the baseline characteristics of parity, gestational age, and cervical status. There were no differences in delivery within 24 hours or time to delivery. The authors did not report any other outcomes [49].

Unfavorable cervix subgroup
There was no information on the effect of hypnotic relaxation among women with unfavorable cervices [49].
Summary: Compared to no intervention, hypnotic relaxation did not affect likelihood of delivery within 24 hours. Data were insufficient to evaluate any other outcome.

Extra-amniotic prostaglandins
Extra-amniotic placement of prostaglandins has been studied as a combination of a mechanical method (Foley catheter) with a pharmacologic method (prostaglandins) [50]. The authors found that women allocated to extraamniotic F2α prostaglandins were more likely to be not vaginally delivered within 24 hours than women receiving vaginal misoprostol (1 trial, 152 women, 34/76 versus 14/76, RR 2.43; 95% CI 1.42 to 4.15; NNH = 3). Women were more likely to be satisfied with extraamniotic prostaglandins compared with vaginal PGE2 (1 trial, 62 women, mean difference 4.40, 95% CI 3.50 to 5.30). Evaluation of other maternal and fetal outcomes was limited due to the small numbers of included women and many different types of comparison [50].

Unfavorable cervix subgroup
There was no difference in caesarean deliveries among women receiving extra-amniotic PGE2 versus extra-amniotic placebo (2 trials, 60 participants) nor between women receiving extra-amniotic PGF2α and extraamniotic placebo (1 trial, 25 participants). There was no difference in caesarean sections between women receiving extra-amniotic PGE2 and vaginal PGE2 (3 trials with 142 women), or between women receiving extra-amniotic PGE2 and intracervical PGE2 (1 trial 194 women). One trial with 30 participants with unfavorable cervices found no difference in caesarean deliveries between women receiving extra-amniotic PGE2 and oxytocin. In one trial with 77 women there was no difference in caesarean sections between women receiving an intracervical Foley catheter and extra-amniotic PGE2. There was no data for comparison of vaginal or oral misoprostol with extra-amniotic PGE2 among women with unfavorable cervices [50].
Summary: Data are insufficient to recommend extraamniotic prostaglandins.

Intravenous prostaglandins
In the 1970s and 1980s, IV prostaglandins were investigated as a potential option for induction of labour [51]. Our search identified one systematic review comparing IV prostaglandins (PGE 2 or IV PGF2α) with oxytocin. This Cochrane review included thirteen trials, with a total of 1165 women, which were carried out between 1970 and 1987. Compared with IV oxytocin, the use of IV prostaglandin was associated with higher rates of uterine hyperstimulation both with FHR changes (5 trials, 390 women, 9/199 [51].

Unfavorable cervix subgroup
In 1 trial with 100 primiparous participants, there was no difference in caesarean section among women receiving IV prostaglandins and women receiving IV oxytocin [51].
Summary: Intravenous prostaglandins have no advantages and increase maternal side effects compared to other methods of induction. This method of induction of labour has not entered into general use and is of historical interest only.

Oral prostaglandins (excluding misoprostol)
Our search identified one Cochrane systematic review comparing oral PGE2 with other methods of induction of labour [52]. This review included 19 studies with 2588 women. Included studies compared oral PGE2 with placebo, cervical or vaginal PGE2, or oral or IV oxytocin, with or without amniotomy. There was no difference in the number of participants who achieved vaginal delivery within 24 hours between women receiving oral PGE2 and controls who received IV oxytocin. Oral PGE2 was associated with fewer caesarean deliveries than placebo (3 studies, 195 [52].
Summary: Oral prostaglandins are associated with increased maternal vomiting and diarrhea compared with IV oxytocin.

Mifepristone
Our search uncovered one systematic review of mifepristone for induction of labour combining 10 trials including 1108 women [53]. The authors found that mifepristone was superior to placebo in achieving a favourable cervical score or initiating labour within 29; NNH = 11), but did not adversely affect neonatal outcomes [53].
The reviewers included one study comparing mifepristone to oxytocin for induction of labor among women with PROM at term. That study found that compared with oxytocin, mifepristone decreased the proportion of women who were delivered vaginally within 24 [53].
Summary: The use of mifepristone for labour induction is currently investigational.

Oestrogens
Our search uncovered one systematic review of oestrogens with or without amniotomy for induction of labour that included seven RCTs and a total of 465 women [54]. Five studies including 306 subjects compared oestrogen with placebo. There were no differences in rates of caesarean deliveries, operative vaginal deliveries or uterine hyperstimulation with or without FHR changes between groups. There were no differences between oestrogens and vaginal prostaglandins in caesarean deliveries, uterine hyperstimulation with or without FHR changes, or epidural analgesia (1 trial, 60 women). There were no differences between oestrogens and cervical prostaglandins in cesarean deliveries or instrumental vaginal deliveries (2 trials, 151 women). There was no difference between oestrogens and cervical prostaglandins in serious maternal complications or NICU admissions in 1 trial with 85 women. There were no differences between oestrogens and oxytocin in caesarean deliveries or operative vaginal deliveries in one trial including 66 women [54].

Unfavorable cervix subgroup
In three trials including 162 women, there was no difference in caesarean sections between women receiving oestrogens and placebo. There was no difference in caesarean deliveries between women receiving oestrogens and vaginal prostaglandins (1 trial, 60 women), cervical prostaglandins (one trial, 66 women), extra-amniotic prostaglandins (one trial, 30 women), or oxytocin (one trial, 66 women) [54].
Summary: The use of oestrogens for induction of labour is currently investigational.

Corticosteroids
In a Cochrane review, Kavanagh and colleagues identified eight studies examining the use of corticosteroids for labour induction [55]. Seven of these did not meet the authors' inclusion criteria. The one included trial had 66 women and evaluated post-term pregnancies which were randomly assigned to receive two dexamethasone injections (12 and 24 hours prior to oxytocin infusion) or no treatment prior to oxytocin. There were no differences in caesarean deliveries, uterine hyperstimulation with or without FHR changes, Apgar less than 7 at five minutes or maternal fevers [55].

Unfavorable cervix subgroup
There was no information about the efficacy of corticosteroids for induction of labor among women with unfavorable cervices [55].
Summary: The use of corticosteroids for induction of labour is currently investigational.

Relaxin
Our search identified one Cochrane review that combined four studies including 267 women who used relaxin for induction of labour [56]. Compared with placebo or no treatment, relaxin reduced the number of participants with unfavourable cervices after 24 hours (3 studies, 173 women, 21/96 versus 37/75; RR 0.45, 95% CI 0.28 to 0.72; NNT = 4), but the need for oxytocin augmentation was not reduced (3 trials, 196 women, 65/ 121 versus 53/75; RR 0.83, 95% CI 0.65 to1.06). There were no differences in the rates of cesarean delivery, operative vaginal deliveries, or uterine hyperstimulation without FHR changes. There were insufficient data to evaluate perinatal death or morbidity [56].

Unfavorable cervix subgroup
In three trials with 207 women, there was no difference in caesarean deliveries in women allocated to receive relaxin compared with placebo [56].
Summary: The use of relaxin for induction of labour is currently investigational.

Unfavorable cervix subgroup
This included systematic review did not report any subgroup analyses according to cervical status [57].
Summary: The use of hyaluronidase for induction of labour is currently investigational.

Isosorbide Mononitrate
Our search identified two randomised controlled trials with a total of 502 participants comparing isosorbide mononitrate, a nitric oxide donor, with placebo [58] or PGE2 [59]. The Habib trial compared isosorbide mononitite tablets with a pyridoxine placebo; after receiving the trial medication, subjects received PGE2 or oxytocin according to hospital protocol. Compared with placebo, isosorbide mononitrate reduced the number of women who required treatment with PGE2 (32 of 51 versus 46 of 51, P = 0.002). However, isosorbide mononitrate increased the need for oxytocin augmentation (48 of 51 versus 27 of 51, P = 0.0001). More women who received placebo experienced uterine tachysystole. Compared with placebo, isosorbide mononitrate significantly shortened the admission to delivery interval (102 women, 13.45 +/-6.63 versus 20.12 +/-8.19; P = 0.0001). There was no difference in vaginal deliveries or cesarean sections between the groups [58]. The PRIM study compared isosorbide mononitrate to PGE2 [59]. Compared with PGE2, isosorbide mononitrite significantly lengthened the time from treatment to delivery (398 participants, 39,7 ± 12.0 hours versus 26.9 +.12.5 hours, mean difference -12.8 hours, 95% CI -15.2 hours--10.4 hours, P < 0.0001). There was no difference in spontaneous vaginal deliveries, operative vaginal deliveries, or cesarean sections [59].

Unfavorable cervix subgroup
Both the Osman and Habib trials required the qualifying women to have cervices unfavorable for induction [58,59].
Summary: The use of isosorbide mononitrite for induction of labour is currently investigational.

Discussion
Our best-evidence review of the literature suggests that many commonly-recommended methods for induction of labour have important trade-offs between benefits and harms. Compared with placebo, use of vaginal and cervical prostaglandin E2 was consistently associated with reduced likelihood of failure to deliver vaginally within 24 hours but increased risk for hyperstimulation with and without FHR changes. Vaginal misoprostol reduced failure to achieve vaginal delivery within 24 hours compared with vaginal and cervical PGE2, but increased uterine contractile abnormalities. Likewise, vaginal misoprostol reduced caesarean deliveries compared with IV oxytocin, but increased uterine hyperstimulation. Mechanical methods for induction of labour were associated with reduced rates of uterine hyperstimulation compared with vaginal PGE2 and vaginal misoprostol, but were also associated with increased risk for maternal and neonatal infectious complications in the one included systematic review that compared mechanical methods with all other methods pooled. Intravenous oxytocin with and without amniotomy did not appear to have significant benefits compared with vaginal PGE2.
Of the non-pharmacologic methods, membrane sweeping appeared to have the strongest evidence-base. It was successful in reducing post-term gestations without increasing clinically-important harms. There is not enough evidence of benefit/safety to recommend the other non-pharmacologic methods of breast stimulation and sexual intercourse.
Our review included evaluation of several investigational methods of induction of labour, of which hyaluronidase appears the most promising. In one small trial, hyaluronidase reduced the need for oxytocin augmentation and for caesarean delivery. These findings need to be confirmed in large, appropriately-powered randomised controlled trials.
Our review may have been limited by restricting our search to the English-language literature and by publication bias. Because we used the Cochrane hierarchy, we compared each method of labour induction only with methods above them on the Cochrane hierarchy list. This may have limited the total number of comparisons made. Likewise, the included studies contained heterogeneous populations of women with both intact and ruptured membranes and cervices favourable and unfavourable for induction. The large number of methods of induction considered in our review precluded subgroup analyses according to membrane status. Likewise, we were not able to consider variation in pharmacologic preparation and dosing of the different compounds under study. In our review of methods of induction of labor in the setting of unfavorable cervix, we did not identify a clear best choice for induction of labor in this setting.
Despite the large amount of evidence that we were able to bring to bear on several common methods of labour induction, we also found considerable imprecision surrounding benefits and harms of many of the included methods. Numbers of included women in most induction randomized trials were too small to exclude differences in rare adverse outcomes such as uterine rupture, amniotic fluid embolism, or perinatal asphyxia.
Further research is necessary to identify potential risks and benefits of both commonly-used and investigational methods of induction of labour.

Conclusion
Clinicians should use the best available evidence to choose methods of labour induction. Researchers and funding agencies should prioritize studies that can help to definitively guide care in these situations. Women should be given information about what is known and not known regarding methods of induction in order to be able to participate fully in making decisions about induction of labour.