NIHR Signal New methods to induce labour may increase chance of vaginal delivery, but safety questions remain

Published on 26 July 2016

This review compared different methods for induction of labour. Misoprostol and oxytocin with amniotomy (membrane rupture), were most likely to lead to vaginal delivery within 24 hours. They were also expected to be most cost effective. There is limited information on the safety of misoprostol which may increase the risk of over-stimulating the uterus.

Current NICE guidance recommends induction by prostaglandin given vaginally. This guidance is under review and an update is expected to be available later this year.

This study highlights the need to continually review the effectiveness and costs of interventions, along with patient experience.

New methods to induce labour may increase chance of vaginal delivery, but safety questions remain

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Why was this study needed?

Most pregnancies result in a spontaneous birth by 42 weeks, but one in five births in the UK are induced. There are a variety of methods for inducing birth, including medication (such as vaginal tablets or intravenous infusions) and mechanical procedures (such as cervical sweeping and rupture of membranes [amniotomy]).

Following induction more than two thirds of women still need additional help to give birth, such as suction cup assistance or caesarean section.

This review set out to compare the effectiveness of the different methods of labour induction, and to look at their cost effectiveness.

What did this study do?

This large systematic review compared the results from 611 randomised controlled trials investigating 31 different methods of inducing birth. The authors performed a network meta-analysis, looking at direct evidence from “head-to-head” trials, and also making indirect comparisons of different interventions across trials. The cost-effectiveness analysis was carried out from a UK NHS perspective, using cost data from the NHS, British National Formulary and manufacturers.

The main outcomes of interest were vaginal delivery within 24 hours and other safety outcomes such as rates of caesarean section, over-stimulation of the uterus, neonatal intensive care admission, and the newborn’s Apgar score (indicating overall health in the first few minutes). There was limited information on serious maternal or newborn illness and mortality. The authors observed that the sample size of some trials was too small to reliably detect differences in the outcomes (underpowered) and there was uncertainty around risk estimates.

What did it find?

  • The interventions most likely to lead to vaginal delivery within 24 hours were intravenous oxytocin with amniotomy (odds ratio [OR] 0.05, 95% credible interval [CrI] 0.01 to 0.14) and higher dose (≥50 micrograms) vaginal misoprostol (OR 0.09, 95% CrI 0.06 to 0.24). Prostaglandin vaginal gels, pessaries and tablets also significantly decreased risk but to a slightly lesser extent (OR range between 0.11 and 0.16).
  • Low dose oral misoprostol delivered in a gradually increasing dose as needed (titrated) was associated with lowest risk of caesarean section (OR 0.62, 95% CrI 0.47 to 0.80). Vaginal misoprostol, prostaglandin vaginal gel or cervical injection, and urinary catheter were also associated with significantly decreased risk. Other interventions had no statistically significant link with caesarean section.
  • Misoprostol was most likely to increase risk of over-stimulating the uterus whether delivered vaginally, by oral tablet, or when held either under the tongue (sublingual) or against the cheek (buccal). The highest risk was when delivered by the sublingual or buccal routes (OR 4.25, 95% CrI 1.71 to 9.02). However, there was high uncertainty in these estimates. Vaginal or cervical prostaglandin had unclear links with uterine over-stimulation.
  • None of the interventions showed statistically significant links with neonatal intensive care admission, with the exception of prostaglandin delivered outside of the amniotic membranes which decreased risk (OR 0.40, 95% CrI 0.16 to 0.82).
  • Buccal or sublingual misoprostol and intravenous oxytocin with amniotomy had the highest probability of being cost effective at a willingness-to-pay threshold of £20,000, followed by titrated (low-dose) oral misoprostol solution and intravenous oxytocin with amniotomy.

What does current guidance say on this issue?

To maximise the chances of spontaneous birth, 2014 NICE guidance recommends women are offered a vaginal assessment with an optional cervical sweep. The first choice induction method is prostaglandin, delivered vaginally as a gel, tablet or controlled-release pessary. Dinoprostone is the only drug licensed for this use in practice. Misoprostol is currently not licensed but can be used “off-label” in cases of intrauterine foetal death. Oxytocin with amniotomy has been used in the past but now is not often used as an initial induction method unless prostaglandin can’t be used.

Other interventions included in this review are specifically not recommended by NICE because of evidence of a lack of effectiveness or potential harm.

What are the implications?

This review found that oxytocin with amniotomy and misoprostol, interventions not currently recommended by NICE, were more likely to result in vaginal birth within 24 hours and may be cost effective. However, these results should be viewed with caution because of the uncertainty around some results and the limited safety data available. For example, misoprostol was linked with increased risk of over-stimulating the uterus and amniotomy may increase the risk of infection if labour is prolonged. Additionally, many of the differences observed were potentially not large enough to be clinically meaningful. The mother’s experience when using the different methods also needs to be considered.

It seems likely that these data will be considered as part of the review of NICE guidelines later this year.

Citation and Funding

Alfirevic V, Keeney E, Dowswell T et al. Methods to induce labour: a systematic review, network meta-analysis and cost-effectiveness analysis. BJOG. 2016. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 12/126/17).

Bibliography

NICE. Inducing 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). ESUOM. London: National Institute for Health and Care Excellence; 2013.

Why was this study needed?

Most pregnancies result in a spontaneous birth by 42 weeks, but one in five births in the UK are induced. There are a variety of methods for inducing birth, including medication (such as vaginal tablets or intravenous infusions) and mechanical procedures (such as cervical sweeping and rupture of membranes [amniotomy]).

Following induction more than two thirds of women still need additional help to give birth, such as suction cup assistance or caesarean section.

This review set out to compare the effectiveness of the different methods of labour induction, and to look at their cost effectiveness.

What did this study do?

This large systematic review compared the results from 611 randomised controlled trials investigating 31 different methods of inducing birth. The authors performed a network meta-analysis, looking at direct evidence from “head-to-head” trials, and also making indirect comparisons of different interventions across trials. The cost-effectiveness analysis was carried out from a UK NHS perspective, using cost data from the NHS, British National Formulary and manufacturers.

The main outcomes of interest were vaginal delivery within 24 hours and other safety outcomes such as rates of caesarean section, over-stimulation of the uterus, neonatal intensive care admission, and the newborn’s Apgar score (indicating overall health in the first few minutes). There was limited information on serious maternal or newborn illness and mortality. The authors observed that the sample size of some trials was too small to reliably detect differences in the outcomes (underpowered) and there was uncertainty around risk estimates.

What did it find?

  • The interventions most likely to lead to vaginal delivery within 24 hours were intravenous oxytocin with amniotomy (odds ratio [OR] 0.05, 95% credible interval [CrI] 0.01 to 0.14) and higher dose (≥50 micrograms) vaginal misoprostol (OR 0.09, 95% CrI 0.06 to 0.24). Prostaglandin vaginal gels, pessaries and tablets also significantly decreased risk but to a slightly lesser extent (OR range between 0.11 and 0.16).
  • Low dose oral misoprostol delivered in a gradually increasing dose as needed (titrated) was associated with lowest risk of caesarean section (OR 0.62, 95% CrI 0.47 to 0.80). Vaginal misoprostol, prostaglandin vaginal gel or cervical injection, and urinary catheter were also associated with significantly decreased risk. Other interventions had no statistically significant link with caesarean section.
  • Misoprostol was most likely to increase risk of over-stimulating the uterus whether delivered vaginally, by oral tablet, or when held either under the tongue (sublingual) or against the cheek (buccal). The highest risk was when delivered by the sublingual or buccal routes (OR 4.25, 95% CrI 1.71 to 9.02). However, there was high uncertainty in these estimates. Vaginal or cervical prostaglandin had unclear links with uterine over-stimulation.
  • None of the interventions showed statistically significant links with neonatal intensive care admission, with the exception of prostaglandin delivered outside of the amniotic membranes which decreased risk (OR 0.40, 95% CrI 0.16 to 0.82).
  • Buccal or sublingual misoprostol and intravenous oxytocin with amniotomy had the highest probability of being cost effective at a willingness-to-pay threshold of £20,000, followed by titrated (low-dose) oral misoprostol solution and intravenous oxytocin with amniotomy.

What does current guidance say on this issue?

To maximise the chances of spontaneous birth, 2014 NICE guidance recommends women are offered a vaginal assessment with an optional cervical sweep. The first choice induction method is prostaglandin, delivered vaginally as a gel, tablet or controlled-release pessary. Dinoprostone is the only drug licensed for this use in practice. Misoprostol is currently not licensed but can be used “off-label” in cases of intrauterine foetal death. Oxytocin with amniotomy has been used in the past but now is not often used as an initial induction method unless prostaglandin can’t be used.

Other interventions included in this review are specifically not recommended by NICE because of evidence of a lack of effectiveness or potential harm.

What are the implications?

This review found that oxytocin with amniotomy and misoprostol, interventions not currently recommended by NICE, were more likely to result in vaginal birth within 24 hours and may be cost effective. However, these results should be viewed with caution because of the uncertainty around some results and the limited safety data available. For example, misoprostol was linked with increased risk of over-stimulating the uterus and amniotomy may increase the risk of infection if labour is prolonged. Additionally, many of the differences observed were potentially not large enough to be clinically meaningful. The mother’s experience when using the different methods also needs to be considered.

It seems likely that these data will be considered as part of the review of NICE guidelines later this year.

Citation and Funding

Alfirevic V, Keeney E, Dowswell T et al. Methods to induce labour: a systematic review, network meta-analysis and cost-effectiveness analysis. BJOG. 2016. [Epub ahead of print].

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 12/126/17).

Bibliography

NICE. Inducing 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). ESUOM. London: National Institute for Health and Care Excellence; 2013.

Methods to induce labour: a systematic review, network meta-analysis and cost-effectiveness analysis

Published on 22 March 2016

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

Bjog , 2016

OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of labour induction methods. METHODS: We conducted a systematic review of randomised trials comparing interventions for third-trimester labour induction (search date: March 2014). Network meta-analysis was possible for six of nine prespecified key outcomes: vaginal delivery within 24 hours (VD24), caesarean section, uterine hyperstimulation, neonatal intensive care unit (NICU) admissions, instrumental delivery and infant Apgar scores. We developed a decision-tree model from a UK NHS perspective and calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit, and cost-effectiveness acceptability curves. MAIN RESULTS: In all, 611 studies comparing 31 active interventions were included. Intravenous oxytocin with amniotomy and vaginal misoprostol (>/=50 mug) were most likely to achieve VD24. Titrated low-dose oral misoprostol achieved the lowest odds of caesarean section, but there was considerable uncertainty in ranking estimates. Vaginal (>/=50 mug) and buccal/sublingual misoprostol were most likely to increase uterine hyperstimulation with high uncertainty in ranking estimates. Compared with placebo, extra-amniotic prostaglandin E2 reduced NICU admissions. There were insufficient data to conduct analyses for maternal and neonatal mortality and serious morbidity or maternal satisfaction. Conclusions were robust after exclusion of studies at high risk of bias. Due to poor reporting of VD24, the cost-effectiveness analysis compared a subset of 20 interventions. There was considerable uncertainty in estimates, but buccal/sublingual and titrated (low-dose) misoprostol showed the highest probability of being most cost-effective. CONCLUSIONS: Future trials should be designed and powered to detect a method that is more cost-effective than low-dose titrated oral misoprostol. TWEETABLE ABSTRACT: New study ranks methods to induce labour in pregnant women on effectiveness and cost.

Expert commentary

This is an important study as it’s encouraging us as a profession to take a fresh look at what we do as obstetricians and gynaecologists on a daily basis. The information regarding low dose misoprostol should prompt further studies using the suggested outcome measures from the authors. The results from the trials using low dose oral misoprostol are compelling. Finally, the possibility of using misoprostol in a way that is less invasive would be welcomed by women everywhere.

Dr Sonji Clarke, Consultant Obstetrician, Guys and St Thomas' NHS Foundation Trust