BACKGROUND:Various methods are used for cervical ripening during the induction of labour. It is still debatable which of these methods of treatment is optimal. OBJECTIVE:To compare treatment techniques for cervical ripening in the induction of labour. SEARCH STRATEGY:Medline, Embase, and the Cochrane Collaboration databases were searched using the keywords 'cervical ripening', 'labour induced', 'misoprostol', 'dinoprostone', and 'Foley catheter'. SELECTION CRITERIA:Randomised controlled trials (RCTs) of cervical ripening during the induction of labour, evaluating rates of failure to achieve vaginal delivery within 24 hours, incidence of uterine hyperstimulation with fetal heart rate (FHR) changes, and rates of caesarean section. Studies including women with prelabour rupture of membranes were excluded. DATA COLLECTION AND ANALYSIS:Outcome data were collected and analysed through pairwise meta-analysis and network meta-analysis within a Bayesian framework. MAIN RESULTS:A total of 96 RCTs (17,387 women) were included in the meta-analysis. Vaginal misoprostol was the most effective cervical ripening method to achieve vaginal delivery within 24 hours, but had the highest incidence of uterine hyperstimulation with FHR changes. The use of a Foley catheter to induce labour was associated with the lowest rate of uterine hyperstimulation accompanied by FHR changes. The caesarean section rate was lowest using oral misoprostol for the induction of labour. AUTHOR'S CONCLUSIONS:No method of labour induction demonstrated overall superiority when considering all three clinical outcomes. Decisions regarding the choice of induction method will depend upon the relative preference for effecting vaginal delivery within 24 hours, minimising the incidence of uterine hyperstimulation with adverse FHR changes and avoiding caesarean section. TWEETABLE ABSTRACT:Oral misoprostol for the induction of labour is safer than vaginal misoprostol and has the lowest rate of caesarean section.

OBJECTIVE:To evaluate whether cervical ripening with oral misoprostol increases cesarean delivery risk and prolongs time to vaginal delivery compared with vaginal misoprostol in a predominantly overweight population. METHODS:This single center, retrospective cohort study was performed at a tertiary care academic medical center and compared labor induction outcomes with vaginal misoprostol to outcomes with oral misoprostol after a complete institutional shift to oral misoprostol. Labor induction using 25 micrograms vaginal misoprostol in 2013-2014 was compared with 50 micrograms oral misoprostol in 2014-2015. The primary outcome was cesarean delivery. Secondary outcomes included time to vaginal delivery, uterine tachysystole, maternal hemorrhage, and composite adverse neonatal outcomes. Demographics and outcomes were analyzed using standard statistical tests. Multivariable regression models accounting for potential confounders were created for the primary and secondary outcomes with adjusted odds ratios (aOR) as the measures of effect. RESULTS:There were 138 women in the oral and 138 women in the vaginal misoprostol groups. In the overall cohort, the median (interquartile range) body mass index was 31.7 (28.2-36.8) and most women (72%) were of either black or Hispanic race or ethnicity. The frequency of cesarean delivery was higher in the oral than the vaginal misoprostol group (32% vs 21%; P=.04). The adjusted odds of cesarean was higher with oral misoprostol (aOR 2.01; 95% CI 1.07-3.76). Among nulliparous women, the frequency of cesarean delivery was 41% in the oral and 28% in the vaginal misoprostol groups (aOR 2.79; 95% CI 1.26-6.19). Women had a longer time to vaginal delivery in the oral compared with vaginal misoprostol group (41 vs 31 hours respectively, P=.01). Tachysystole occurred more frequently with vaginal misoprostol (20% vs 11%; P=.04). CONCLUSION:Compared with vaginal misoprostol, oral misoprostol may be associated with increased risk of cesarean delivery and longer time to vaginal delivery.

BACKGROUND:Misoprostol is widely used for cervical ripening and labour induction as it is heat-stable and inexpensive. Oral misoprostol 25 μg given 2-hourly is recommended over vaginal misoprostol 25 μg given 6-hourly, but the need for 2-hourly fetal monitoring makes oral misoprostol impractical for routine use in high-volume obstetric units in resource-constrained settings. OBJECTIVES:To compare the efficacy and safety of oral misoprostol initiated at 25 or 50 μg versus 25 μg vaginal misoprostol given at 4- to 6-hourly intervals for labor induction in women at or beyond term (≥ 37 weeks) with a single viable fetus and an unscarred uterus. SEARCH STRATEGY:We identified eligible randomized, parallel-group, labor-induction trials from recent systematic reviews. We additionally searched PubMed, Cochrane CENTRAL, Epistemonikos, and clinical trials registries from February 1, 2020 to December 31, 2022 without language restrictions. Database-specific keywords for cervical priming, labor induction, and misoprostol were used. SELECTION CRITERIA:We excluded labor-induction trials exclusively in women with ruptured membranes, in the third trimester, and those that initiated misoprostol at doses not specified in the review's objectives. The primary outcomes were vaginal birth within 24 h, cesarean section, perinatal mortality, neonatal morbidity, and maternal morbidity. The secondary outcomes were uterine hyperstimulation with fetal heart rate changes, and oxytocin augmentation. DATA COLLECTION AND ANALYSIS:Two or more authors selected studies independently, assessed risk of bias, and extracted data. We derived pooled weighted risk ratios with 95% confidence intervals (CIs) for each outcome, subgrouping trials by the dose and frequency of misoprostol regimens. We used the I statistic to quantify heterogeneity and the random-effects model for meta-analysis when appropriate. We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to assess certainty (confidence) in the effect estimates. MAIN RESULTS:Thirteen trials, from Canada, India, Iran, and the US, randomizing 2941 women at ≥37 weeks of gestation with an unfavorable cervix (Bishop score <6), met the eligibility criteria. Five misoprostol regimens were compared: 25 μg oral versus 25 μg vaginal, 4-hourly (three trials); 50 μg oral versus 25 μg vaginal, 4-hourly (five trials); 50 μg followed by 100 μg oral versus 25 μg vaginal, 4-hourly (two trials); 50 μg oral, 4-hourly versus 25 μg vaginal, 6-hourly (one trial); and 50 μg oral versus 25 μg vaginal, 6-hourly (two trials). The overall certainty in the evidence ranged from moderate to very low, due to high risk of bias in 11/13 trials (affecting all outcomes), unexplained heterogeneity (1/7 outcomes), indirectness (1/7 outcomes), and imprecision (4/7 outcomes). Vaginal misoprostol probably increased vaginal deliveries within 24 h compared with oral misoprostol (risk ratio [RR] 0.82, 95% CI 0.70-0.96; 11 trials, 2721 mothers; moderate-certainty evidence); this was more likely with 4-hourly than with 6-hourly vaginal regimens. The risk of cesarean sections did not appreciably differ (RR 1.00, 95% CI 0.80-1.26; 13 trials, 2941 mothers; very low-certainty evidence), although oral misoprostol 25 μg 4-hourly probably increased this risk compared with 25 μg vaginal misoprostol 4-hourly (RR 1.69, 95% CI 1.21-2.36; three trials, 515 mothers). The risk of perinatal mortality (RR 0.67, 95% CI 0.11-3.90; one trial, 196 participants; very low-certainty evidence), neonatal morbidity (RR 0.84, 95% CI 0.67-1.06; 13 trials, 2941 mothers; low-certainty evidence), and maternal morbidity (RR 0.83, 95% CI 0.48-1.44; 6 trials; 1945 mothers; moderate-certainty evidence) did not differ appreciably. The risk of uterine hyperstimulation with fetal heart rate changes may be lower with oral misoprostol (RR 0.70, 95% CI 0.52-0.95; 10 trials, 2565 mothers; low-certainty evidence). Oxytocin augmentation was probably more frequent with oral compared with vaginal misoprostol (RR 1.29, 95% CI 1.10-1.51; 13 trials, 2941 mothers; moderate-certainty evidence). CONCLUSIONS:Low-dose, 4- to 6-hourly vaginal misoprostol regimens probably result in more vaginal births within 24 h and less frequent oxytocin use compared with low-dose, 4- to 6-hourly, oral misoprostol regimens. Vaginal misoprostol may increase the risk of uterine hyperstimulation with fetal heart changes compared with oral misoprostol, without increasing the risk of perinatal mortality, neonatal morbidity, or maternal morbidity. Indirect evidence indicates that 25 μg vaginal misoprostol 4-hourly may be more effective and as safe as the recommended 6-hourly vaginal regimen. This evidence could inform clinical decisions in high-volume obstetric units in resource-constrained settings.

Misoprostol, a prostaglandin E(1) analogue, is widely used in the US and other countries for cervical ripening and labour induction. Its use for these indications is not approved by the US Food and Drug Administration (FDA). The manufacturer of misoprostol issued a letter to American healthcare providers in August 2000, cautioning against the use of misoprostol in pregnant women and citing a lack of safety data for its use in obstetrical practice. The only FDA-approved indication in the product labelling is the treatment and prevention of intestinal ulcer disease resulting from nonsteroidal anti-inflammatory drug use. Multiple trials have proven that when applied vaginally, misoprostol is an effective agent for cervical ripening and labour induction in term pregnancy. The use of oxytocin augmentation is reduced when intravaginal misoprostol is used compared with other agents. Misoprostol use in obstetrics carries the added benefits of temperature stability at room temperature, which is unlike other prostaglandin preparations which require refrigeration or freezing, and reduced cost. However, debate continues regarding the optimal dose, dosage regimen, and route of administration. Uterine contraction abnormalities are often found in association with higher misoprostol doses (50 microg or more) given vaginally or orally. Some trials also indicate increased frequencies of meconium passage, neonatal acidaemia and caesarean delivery for fetal distress in women receiving higher doses of vaginally applied misoprostol. However, most trials fail to demonstrate a significant change in the caesarean delivery rate with the use of misoprostol, although a recent meta-analysis indicated that the use of intravaginal misoprostol is associated with a lowering of the caesarean rate when compared with pooled controls. Low-dose misoprostol (25 microg) is an effective agent for cervical ripening and labour induction when used in a judicious and cautious fashion. There are insufficient data to support the widespread use of oral misoprostol for cervical ripening and labor induction. Some trials suggest that this approach may be effective; however, the ideal dose and administration regimen have yet to be defined.

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 μg followed by 50 μg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography-tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one-compartment nonlinear clearance model. The absorption rate constant (k ) was dependent on both route and dose of administration: buccal 25 μg 0.724 (95% confidence interval, 0.54-0.92) h ; 50 μg 0.531 (0.37-0.63) h ; vaginal 25 μg 0.507 (0. 2-1. 4) h ; and 50 μg 0.246 (0.103-0.453) h . Relative bioavailability for vaginal compared to buccal route was 2.4 (1.63-4.77). There was no effect of body mass index or age on apparent clearance 705 (431-1099) L/h or apparent volume of distribution 632 (343-1008) L. The area under the concentration-time curve to 4 h following the first 25 μg dose of misoprostol was 16.5 (15.4-17.5) pg h/ml for buccal and 34.3 (32.5-36.1) pg h/ml for vaginal administration. The rate of buccal absorption was two times faster than that of vaginal, whereas bioavailability of vaginal administration was 2.4 times higher than that of buccal. Decreased time to delivery observed with vaginal dosing may be due to higher exposure to misoprostol acid compared to buccal.