Misoprostol for cervical ripening and induction of labour
Low-dose oral misoprostol (20–25 µg 2-hourly) is safer and more effective than vaginal misoprostol and therefore may be seen as the first-line option for cervical ripening and induction of labour. Vaginal misoprostol in doses above 25 µg 4-hourly is more effective than other conventional methods of labour induction, but is associated with a greater risk uterine hyperstimulation.
RHL Commentary by Abdel-Aleem H
Induction of labour is extensively used all over the world in cases in which continuation of pregnancy is hazardous to the mother and/or her fetus. In 2004 and 2005, one in every five deliveries in the United Kingdom was induced (1). Unpublished data from the WHO Global Survey on Maternal and Perinatal Health, which included 373 health-care facilities in 24 countries and nearly 300 000 deliveries, showed that 9.6% of the deliveries involved labour induction. Overall, the survey found that facilities in African countries tended to have lower rates of induction of labour (lowest: 1.4% in Niger) compared with Asian and Latin American countries (highest: 35.5% in Sri Lanka) (2). In Assiut University Hospital, Assiut, Egypt, which is a referral facility with 15000 deliveries per year, the frequency of labour induction in 2008 was 9.3% of all deliveries.
Inducing labour when the cervix is ripe is not difficult, but complications increase significantly when the cervix is not ripe. There is a plethora of techniques available for induction of labour. However, prostaglandins remain the single most effective means of achieving cervical ripening and inducing labour when combined with a judiciously timed amniotomy, providing good clinical effectiveness and patient satisfaction. Prostaglandin E2 is registered for labour induction in many countries. However, it is expensive in developing countries and, because it is sensitive to temperature changes, it needs to be kept under refrigeration. In settings with high average parity, an induction regimen using only oxytocin without prostaglandin E2 is potentially dangerous. In Assiut University Hospital, for example, oxytocin was still the most widely used method of induction (62.9 %) in 1999; prostaglandin E2 was used in only 6.5% of cases. In such settings there is an urgent need for an affordable drug to optimize induction outcomes.
Misoprostol (a prostaglandin E1 analogue) has several potential advantages: it is stable at room temperature, it is relatively inexpensive and it can be given via several routes (oral, vaginal, sublingual, buccal). These properties make misoprostol an ideal agent for induction of labour, particularly in settings where the use of prostaglandin E2 is not possible owing to lack of availability, facilities for storage, or financial constraints.
Since the use of a powerful uterotonic such as misoprostol can lead to adverse maternal and perinatal effects, it is important to review the effectiveness and the side-effects of misoprostol use in cervical priming and induction of labour. This commentary evaluates three Cochrane reviews that sought to determine the effectiveness and safety of misoprostol administered orally (3), buccally (sublingually) (4), or vaginally (5) for third-trimester cervical ripening and induction of labour.
2. METHODS OF THE REVIEW
All three reviews include adequately controlled randomized controlled trials that could be identified. The respective authors of the reviews analysed the data in the included trials appropriately. The search for trials was comprehensive, assessment of quality of the included trials was adequate, and the data are presented clearly (in tables as well as in text). Two of the of the three reviews – vaginal misoprostol for cervical ripening and induction of labour (3) and oral misoprostol for induction of labour (5) – were updated in 2009 and 2008, respectively.
3. RESULTS OF THE REVIEW
The total number of trials included in the reviews on vaginal misoprostol, buccal misoprostol and oral misoprostol was 121, three and 56, respectively. Results obtained in the reviews are presented below for each of the comparisons made in the trials.
Misoprostol versus placebo
Ten trials (involving 1141 women) had compared vaginal misoprostol with placebo and seven had compared oral misoprostol (669 women) with placebo. Compared to placebo, vaginal misoprostol was associated with reduced failure to achieve vaginal delivery within 24 hours [average relative risk (RR) 0.51, 95% confidence interval (CI) 0.37–0.71]. Vaginal misoprostol showed a trend towards less failure to deliver within 24 hours (five trials, 735 women, average RR 0.56, 95% CI 0.31–1.03) and had a clear effect on cervical ripening (two trials, average RR of unchanged cervix at 12–24 hours 0.09, 95% CI 0.03– 0.24). Uterine hyperstimulation without fetal heart rate changes was increased (six trials, 794 women, RR 3.52, 95% CI 1.78–6.99).
Women receiving oral misoprostol were more likely to deliver vaginally within 24 hours (RR 0.16; 95% CI 0.05–0.49), needed less oxytocin (RR 0.35; 95% CI 0.28–0.44) and had a lower caesarean section rate (RR 0.61; 95% CI 0.41–0.93).
Misoprostol versus oxytocin
For this comparison, there were 25 trials with 3074 participants. Vaginal misoprostol appeared to be more effective than oxytocin for the induction of labour (10 trials, average RR for failure to achieve vaginal delivery within 24 hours 0.65, 95% CI 0.47–0.90). Two trials that had used less than 50 µg misoprostol showed no reduction in failure to achieve vaginal delivery within 24 hours. Twenty-five studies showed a reduction in caesarean section risk with the use of misoprostol (average RR 0.76, 95% CI 0.60–0.96). However, uterine hyperstimulation without fetal heart rate changes was more common in women who had received misoprostol (15 trials, RR 2.24, 95% CI 1.82–2.77). Compared with women in the oxytocin group, fewer women in the misoprostol group received epidural analgesia (three trials, RR 0.82, 95% CI 0.67–1.00). The incidence of vaginal instrumental delivery was lower in the misoprostol group (13 trials, RR 0.74, 95% CI 0.56–0.99). There were no differences between vaginal misoprostol and oxytocin in terms of perinatal or maternal adverse outcomes.
Eight trials (1026 participants) compared oral misoprostol (dose between 20 µg and 100 µg) with intravenous oxytocin. The only difference was an increase in meconium-stained liquor with oral misoprostol (RR 1.72, 95% CI 1.08–2.74).
Misoprostol versus other prostaglandins
A total of 38 trials with 7022 participants had compared vaginal misoprostol with vaginal prostaglandins (mainly dinoprostone). Overall, failure to achieve vaginal delivery within 24 hours was reduced (22 trials, average RR 0.77, 95% CI 0.66–0.89) with vaginal misoprostol in all but two trials using less than 50 µg misoprostol in the first six hours. Uterine hyperstimulation with fetal heart rate changes and meconium-stained amniotic fluid were more common with misoprostol. Caesarean section rates varied between trials.
Ten trials had compared oral misoprostol with vaginal dinoprostone (3368 participants). Women who had received oral misoprostol were less likely to deliver by caesarean section (RR 0.87, 95% CI 0.77–0.98). Compared with those receiving vaginal dinoprostone, fewer women in oral misoprostol group delivered within 24 hours; there were no other significant differences.
There were 27 trials with 3311 participants that had compared vaginal misoprostol with intracervical prostaglandins. Failure to achieve vaginal delivery within 24 hours was consistently reduced with misoprostol (13 trials, RR 0.63, 95% CI 0.56–0.71). Uterine hyperstimulation with fetal heart rate changes was more common with misoprostol than with intracervical prostaglandin (20 trials, RR 2.32, 95% CI 1.64–3.28). Misoprostol increased the risk of having meconium-stained amniotic fluid (14 trials, RR 1.29, 95% CI 1.04–1.59). There were no statistically significant differences in perinatal or maternal health outcomes.
Comparison of oral misoprostol with intracervical prostaglandin was studied in four trials involving 681 women. The women in the trials were only those who had intact membranes and they received doses of 50 µg (two trials, 291 women) and 200 µg (two trials, 390 women). Uterine hyperstimulation, with and without fetal heart rate changes, was more frequent in those treated with misoprostol (RR 3.57, 95% CI 1.11–11.54 and RR 17.00,; 95% CI 1.00–290.42, respectively). On the other hand, more women in the oral misoprostol group achieved vaginal delivery within 24 hours (51% versus 41%). However, the difference was only marginally statistically significant (RR 0.81, 95% CI 0.65–1.00).
Oral versus vaginal misoprostol
Twenty-six trials with 5096 participants had compared oral and vaginal misoprostol and found no difference in the primary outcomes. However, there were fewer babies born with a low Apgar score at five minutes in the oral misoprostol group (RR 0.65, 95% CI 0.44–0.97). There was evidence of less uterine hyperstimulation with oral misoprostol, but heterogeneity makes these outcomes difficult to interpret.
Buccal versus vaginal misoprostol (initial doses 200 µg versus 50 µg)
Only one study with 152 women was available for this comparison. Compared with the vaginal route, the buccal route was associated with slightly fewer caesarean sections (18/73 versus 28/79, RR 0.70, 95% CI 0.42 –1.15), but this difference was not statistically significant. There were no significant differences between the two routes with regard to any other outcome.
Sublingual versus oral misoprostol
In the two studies available for this comparison, when the same dosage was used for both oral and sublingual routes, the latter was associated with fewer instances of failure to achieve vaginal delivery within 24 hours (12/50 versus 19/50, RR 0.63, 95% CI 0.34–1.16), less oxytocin augmentation (17/50 versus 23/50, RR 0.74, 95% CI 0.45–1.21) and less caesarean section (8/50 versus15/50; RR 0.53, 95% CI 0.25 –1.14). However, none of these differences was statistical significant. When a smaller dose was used sublingually rather than orally, there were no differences between the two routes with respect to any of the outcomes.
4.1 Applicability of the results
The effectiveness of oral and vaginal misoprostol is similar for induction of labour, although oral misoprostol is associated with a lower risk of low Apgar score at 5 minutes. Oral misoprostol is more effective than placebo for ripening the cervix and shortening the administration-to-delivery interval, and vaginal misoprostol is more effective than oxytocin for the induction of labour. While oral misoprostol is similar in efficacy to oxytocin for the induction of labour, oral misoprostol is associated with an increase in meconium-stained liquor in women with ruptured membranes. Vaginal misoprostol is more efficacious than other prostaglandins for the induction of labour, and oral misoprostol use results in fewer caesarean sections than vaginal dinoprostone. Overall, there were no significant differences between sublingual versus oral misoprostol.
Subgroup analyses in the systematic review suggest that the optimal dosage of oral misoprostol is 20–25 µg given two-hourly. Vaginal misoprostol in doses above 25 µg four-hourly was more effective than conventional methods of labour induction, but caused more uterine hyperstimulation. Lower doses were similar to conventional methods in terms of effectiveness and risks. At the same dosage level, sublingual misoprostol appears to be at least as effective as oral misoprostol. Finally, since the trials included in the reviews were conducted in both developed and developing countries, the findings of these reviews would be applicable to all settings.
4.2 Implementation of the intervention
Since misoprostol is a relatively inexpensive drug, its use as an agent for cervical ripening and induction of labour would be a low-cost intervention in hospital settings. In order to implement this intervention at the hospital level, the drug would first need to be registered for obstetric use. In 2007, the WHO Expert Committee on the Selection and Use of Essential Medicines included misoprostol 25-µg tablets to its list and this inclusion will hopefully enable the national essential lists to include low-dose misoprostol for labour induction (6). Where misoprostol remains unlicensed for induction of labour, many practitioners will prefer to use a licensed product like dinoprostone. In 2011, WHO issued guidelines on induction of labour (7), which included the use of oral and vaginal misoprostol for induction of labour. These guidelines are based partly on the findings of the three Cochrane reviews evaluated in this commentary. Adaptation and implementation of these guidelines in different settings is endorsed.
A problem with implementing this intervention may be that the recommended dose of 25 µg is not available widely, especially for oral use. In Egypt, 25-µg vaginal misoprostol tablets are available but to the knowledge of this author these tablets are not available in most other developing countries. To prepare an oral dose of 20−25 µg, clinicians may dissolve a 200 µg tablet in 200 ml of water. However, the efficacy of dissolved tablets should be tested before widespread use. In addition, the presence of food in the stomach could reduce the maximum plasma concentrations of misoprostol acid, which is the active metabolite of misoprostol (8).
The studies included in the review were not large enough to exclude the possibility of rare but serious adverse events following induction of labour with misoprostol, particularly uterine rupture, which has been reported anecdotally.
4.3 Implication for research
The acceptability to women of the different routes of administration of misoprostol should be evaluated. Further questions for research with regard to labour induction include: What constitutes an optimum induction? What is the balance between effectiveness and safety (including the acceptable delay between induction and delivery)? Can misoprostol be used to induce labour outside the hospitals setting? Finally, there is a need to follow up mothers and neonates over the long term to detect rare but serious side-effects of misoprostol.
Sources of support. None.
- NICE clinical guideline 70. Induction of labour. London: National Institute for Health and Clinical Excellence; July 2008.
- WHO Global Survey on Maternal and Perinatal Health. Induction of labour data. Geneva, World health Organization, 2010 (available at: http://www.who.int/reproductivehealth/topics/best_practices/global_survey)
- Alfirevic Z, Weeks A. Oral misoprostol for induction of labour. Cochrane Database of Systematic Reviews 2006;Issue 2. Art. No.: CD001338; DOI: 10.1002/14651858.CD001338.pub2.
- Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening and induction of labour. Cochrane Database of Systematic Reviews 2004;Issue 4. Art. No.: CD004221; DOI: 10.1002/14651858.CD004221.pub2.
- Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database of Systematic Reviews 2010;Issue 10. Art. No.: CD000941; DOI: 10.1002/14651858.CD000941.pub2.
- WHO model list of essential medicines:15th list, March 2007. Geneva: World Health Organization; 2007 (available at: http://www.who.int/medicines/publications/essentialmedicines/en/).
- WHO recommendations for induction of labour. Geneva: World Health Organization, 2011 (available at: http://whqlibdoc.who.int/publications/2011/9789241501156_eng.pdf)
- Karim A, Rozek LF, Smith ME, Kowalaski KG. Effects of food and antacid on oral absorption of misoprostol, a synthetic prostaglandin E1 - analogue. Journal of Clinical Pharmacology 1989;29:439-443.
This document should be cited as: Abdel-Aleem H. Misoprostol for cervical ripening and induction of labour: RHL commentary (last revised: 1 May 2011). The WHO Reproductive Health Library; Geneva: World Health Organization.