NIHR Signal New evidence compares effectiveness of prostaglandin drugs for inducing labour

Published on 7 February 2015

This review partly funded by the NIHR provides the largest pooling of international data on the effectiveness of prostaglandin drugs used to induce labour. It found that the most effective prostaglandin for inducing vaginal birth within 24 hours was a vaginal misoprostol tablet (≥50 micrograms). Low dose misoprostol solution (<50 micrograms) given by mouth had the lowest risk of needing a caesarean section. No evidence was available on costs. These findings may have important implications for clinical practice and guidelines, particularly as misoprostol is not currently recommended and it does not have a licence in the UK for induction of labour.

New evidence compares effectiveness of prostaglandin drugs for inducing labour

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Why was this study needed?

Induction of labour is used in one in every five deliveries in the UK. Using drugs to induce labour can sometimes lead to the use of delivery instruments like forceps, or emergency caesarean sections. Induction of labour therefore has a large impact on women and their babies, the best method should be selected and its use needs to be clearly justified.

Prostaglandins have been widely used for induction of labour and a number of prostaglandins have been tested in clinical trials. The NIHR partially funded this systematic review to assess all available evidence on the safety and effectiveness of the different types of prostaglandins in clinical use.

What did this study do?

This systematic review included 280 randomised clinical trials (RCTs) including 48,068 women. All RCTs compared prostaglandins with either: a placebo, no treatment, a different drug, or the same drug given by different route or dose. The results were analysed using network meta-analysis, where different treatments are compared directly within trials and indirectly across trials to give an overall measure of the effect of a treatment. Twelve different types of prostaglandins were included and each preparation was examined separately as different routes of administration and doses may be associated with different effects.

The review was comprehensive in scope and well executed. However, about half of the trials were judged to be at high risk of bias. To try and account for this, the authors re-ran the analyses where possible with only the high quality trials included, and reported that the results were not materially different.

What did it find?

  • Vaginal misoprostol tablet (≥50 micrograms) was the best treatment for achieving vaginal birth within 24 hours. The odds of failing to achieve vaginal birth within 24 hours were reduced by 94% compared with placebo (odds ratio [OR] 0.06, 95% credible interval [CI] 0.02 to 0.12). This result was calculated from a subset of 94 trials.
  • However, vaginal prostaglandin E2 tablet, the currently recommended treatment, showed similar effectiveness. It reduced the odds of failing to achieve vaginal birth within 24 hours by 92%.
  • Low dose oral misoprostol solution (<50 micrograms) led to fewer caesarean sections. The odds were reduced by 35% compared with placebo (OR 0.65, 95% CI 0.49 to 0.83). This was calculated from a subset of 269 trials.
  • Vaginal prostaglandin E2 tablet reduced the odds of caesarean section by just 7%.

What does current guidance say on this issue?

The NICE 2008 guideline for induction of labour recommends vaginal prostaglandin E2 (PGE2, dinoprostone) as the preferred drug method for induction of labour unless there are specific clinical reasons for not using it, in particular the risk of uterine overstimulation. PGE2 can be given using a pessary inserted into the vagina, a gel or tablet; no other routes are recommended. Misoprostol is not licensed in the UK for induction of labour and is only recommended by NICE for women where the foetus has died while in the uterus, or in the context of a clinical trial.

WHO guidance for induction of labour does not recommend misoprostol for women with previous caesarean section.

What are the implications?

Misoprostol does not have a UK licence for induction of labour and its use is considered as off-label. Its wider adoption in clinical practice is unlikely without a regulatory change and updated recommendations in national guidelines. However, further safety information is still needed, particularly in relation to maternal outcomes. The NICE guidance on induction in labour was last reviewed in 2014 and considered not in need of updating. The next review will be in June 2016.

Assessment of safety in this meta-analysis was limited to caesarean section. The lack of data or poor reporting meant it was not possible to reliably investigate other safety outcomes. The authors highlight the need for further study of these outcomes, particularly looking at the risk of rupture of the uterus with vaginal misoprostol.

The findings of this meta-analysis have potentially important implications for national and international guidelines on induction of labour. However there remains significant gaps in the evidence base, and as such it will remain to be seen whether these findings will result in updated recommendations.

Citation

Alfirevic Z, Keeney E, Dowswell T et al. Labour induction with prostaglandins: a systematic review and network meta-analysis. BMJ. 2015;350:h217. This project was funded by the National Institute for Health Research HTA Programme (project number 12/126/17).

Bibliography

Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induction of labour. Cochrane Database of Systematic Reviews 2014; (6): CD001338.

NICE. Induction of labour. CG70. London: National Institute for Health and Care Excellence; 2008.

NICE. Induction of labour in late intrauterine fetal death: vaginal misoprostol (after oral mifepristone). NICE advice [ESUOM11]. London: National Institute for Health and Care Excellence; 2013.

WHO. WHO recommendations for induction of labour. Geneva: World Health Organization; 2011

Why was this study needed?

Induction of labour is used in one in every five deliveries in the UK. Using drugs to induce labour can sometimes lead to the use of delivery instruments like forceps, or emergency caesarean sections. Induction of labour therefore has a large impact on women and their babies, the best method should be selected and its use needs to be clearly justified.

Prostaglandins have been widely used for induction of labour and a number of prostaglandins have been tested in clinical trials. The NIHR partially funded this systematic review to assess all available evidence on the safety and effectiveness of the different types of prostaglandins in clinical use.

What did this study do?

This systematic review included 280 randomised clinical trials (RCTs) including 48,068 women. All RCTs compared prostaglandins with either: a placebo, no treatment, a different drug, or the same drug given by different route or dose. The results were analysed using network meta-analysis, where different treatments are compared directly within trials and indirectly across trials to give an overall measure of the effect of a treatment. Twelve different types of prostaglandins were included and each preparation was examined separately as different routes of administration and doses may be associated with different effects.

The review was comprehensive in scope and well executed. However, about half of the trials were judged to be at high risk of bias. To try and account for this, the authors re-ran the analyses where possible with only the high quality trials included, and reported that the results were not materially different.

What did it find?

  • Vaginal misoprostol tablet (≥50 micrograms) was the best treatment for achieving vaginal birth within 24 hours. The odds of failing to achieve vaginal birth within 24 hours were reduced by 94% compared with placebo (odds ratio [OR] 0.06, 95% credible interval [CI] 0.02 to 0.12). This result was calculated from a subset of 94 trials.
  • However, vaginal prostaglandin E2 tablet, the currently recommended treatment, showed similar effectiveness. It reduced the odds of failing to achieve vaginal birth within 24 hours by 92%.
  • Low dose oral misoprostol solution (<50 micrograms) led to fewer caesarean sections. The odds were reduced by 35% compared with placebo (OR 0.65, 95% CI 0.49 to 0.83). This was calculated from a subset of 269 trials.
  • Vaginal prostaglandin E2 tablet reduced the odds of caesarean section by just 7%.

What does current guidance say on this issue?

The NICE 2008 guideline for induction of labour recommends vaginal prostaglandin E2 (PGE2, dinoprostone) as the preferred drug method for induction of labour unless there are specific clinical reasons for not using it, in particular the risk of uterine overstimulation. PGE2 can be given using a pessary inserted into the vagina, a gel or tablet; no other routes are recommended. Misoprostol is not licensed in the UK for induction of labour and is only recommended by NICE for women where the foetus has died while in the uterus, or in the context of a clinical trial.

WHO guidance for induction of labour does not recommend misoprostol for women with previous caesarean section.

What are the implications?

Misoprostol does not have a UK licence for induction of labour and its use is considered as off-label. Its wider adoption in clinical practice is unlikely without a regulatory change and updated recommendations in national guidelines. However, further safety information is still needed, particularly in relation to maternal outcomes. The NICE guidance on induction in labour was last reviewed in 2014 and considered not in need of updating. The next review will be in June 2016.

Assessment of safety in this meta-analysis was limited to caesarean section. The lack of data or poor reporting meant it was not possible to reliably investigate other safety outcomes. The authors highlight the need for further study of these outcomes, particularly looking at the risk of rupture of the uterus with vaginal misoprostol.

The findings of this meta-analysis have potentially important implications for national and international guidelines on induction of labour. However there remains significant gaps in the evidence base, and as such it will remain to be seen whether these findings will result in updated recommendations.

Citation

Alfirevic Z, Keeney E, Dowswell T et al. Labour induction with prostaglandins: a systematic review and network meta-analysis. BMJ. 2015;350:h217. This project was funded by the National Institute for Health Research HTA Programme (project number 12/126/17).

Bibliography

Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induction of labour. Cochrane Database of Systematic Reviews 2014; (6): CD001338.

NICE. Induction of labour. CG70. London: National Institute for Health and Care Excellence; 2008.

NICE. Induction of labour in late intrauterine fetal death: vaginal misoprostol (after oral mifepristone). NICE advice [ESUOM11]. London: National Institute for Health and Care Excellence; 2013.

WHO. WHO recommendations for induction of labour. Geneva: World Health Organization; 2011

Labour induction with prostaglandins: a systematic review and network meta-analysis

Published on 7 February 2015

Alfirevic, Z.,Keeney, E.,Dowswell, T.,Welton, N. J.,Dias, S.,Jones, L. V.,Navaratnam, K.,Caldwell, D. M.

Bmj Volume 350 , 2015

OBJECTIVES: To assess the effectiveness and safety of prostaglandins used for labour induction. DESIGN: Systematic review with Bayesian network meta-analysis DATA SOURCES: The Cochrane Pregnancy and Childbirth Group's Database of Trials (which incorporates the results of a broad generic search for all pregnancy and postpartum trials). Sources included are CENTRAL, Medline, Embase, NHS Economic Evaluation Database, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised clinical trials of prostaglandin or prostaglandin analogues used for third trimester cervical ripening or labour induction versus placebo or no treatment, alternative prostaglandin dose or administration, or a different type of prostaglandin. We included studies recruiting women with a viable fetus, but had no other restrictions relating to indication for labour induction or language of publication. Outcomes assessed were serious neonatal morbidity (trialist defined) or perinatal death; serious maternal morbidity (trialist defined) or death; vaginal delivery not achieved within 24 hours, caesarean section, and uterine hyperstimulation with fetal heart rate changes. RESULTS: 280 randomised clinical trials were included (48 068 women) in the review. Maternal and neonatal mortality and serious morbidity were rarely reported and are summarized narratively. Unresolved inconsistency was observed for the hyperstimulation outcome. Relative to placebo, the odds of failing to achieve a vaginal delivery were lowest for vaginal misoprostol (>/=50 microg) (odds ratio 0.06 (95% credible interval 0.02 to 0.12)), with a 39% absolute probability of event (95% credible interval 1% to 94%). Compared with placebo, odds of caesarean section were lowest for titrated oral misoprostol solution (<50 microg) (odds ratio 0.65 (0.49 to 0.83)), with an absolute probability of event of 15% (3% to 40%). CONCLUSIONS: Low dose(<50 microg) titrated oral misoprostol solution had the lowest probability of caesarean section, whereas vaginal misprostol (>/=50 microg) had the highest probability of achieving a vaginal delivery within 24 hours. These findings have important implications for a series of current national and international guidelines for induction of labour and future research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2013:CRD42013005116.

NICE states that "Misoprostol tablets are licensed in the UK to treat ulcers of the stomach and gut and to prevent ulcers associated with taking certain anti-inflammatory pain medication in adults. Misoprostol does not have a UK licence to induce labour. Misoprostol comes in the form of a tablet and can be given through the mouth, under the tongue or it can be inserted into the vagina. There are fewer side effects when misoprostol is inserted into the vagina compared with taking it through the mouth. However, when it is inserted into the vagina, the oral tablets may need to be split using a pill cutter to get a lower dose, which can make it difficult to get an exact dose."

Commentary

This is a very interesting systematic review and could potentially have a major influence on obstetric and midwifery practice in the UK as it suggests that induction of labour with oral misoprostol solution may reduce the risk of caesarean section compared with other methods. However, it should be noted that around 50% of the included studies were judged to have a high risk of bias. It is also noteworthy that the authors were unable to analyse the data on hyper-stimulation. Further research is needed before UK practitioners should change their practice in this area.

Dr Rhona Hughes, Clinical Director of Obstetrics, Royal Infirmary, Edinburgh