Title: Which method is best for the induction of labour: A systematic review network meta-analysis and cost-effectiveness analysis
Funder: Department of Health (England)

Abstract: The research question: The number of women whose labours are induced is increasing with average rates in England in excess of 20% (140000 women per annum)(1). A broad range of methods for induction are available including pharmacological mechanical and alternative interventions with considerable variation in effectiveness safety and cost. National Institute of Clinical Excellence (NICE) recognises the importance of the topic; the guideline on induction of labour was last updated in 2008(3) and recommended that vaginal PGE2 is the preferred method but stopped short of recommending the most cost-effective regimen or type of PGE2 (tablets gel or slow-release pessary). Since guidelines were published the evidence from randomised controlled trials (RCTs) on PGE2 and other induction methods has increased significantly and we have identified 169 reports of RCTs published since 2008. Further NICE recommendations were based on pair-wise comparisons; a coherent analysis of all RCTS comparing all the competing treatments with associated health economic modelling has not been performed. As the number of women facing induction increases and as new evidence emerges it is now important to address questions about which methods of inducing labour are most effective cost-effective safe and acceptable to women. To decide what works best we propose to carry out a systematic review and network meta-analysis (NMA) to synthesise evidence from all RCTs of labour induction interventions to provide a quantitative summary of the evidence on the relative effects and safety of different methods. We will use the NMA data to build a comprehensive economic decision model to determine which methods are the most cost-effective. Scope and methods: The proposed systematic review and NMA will include the most up to date evidence; we have carried out a scoping exercise to estimate the number of trials that would contribute data. Overall 564 relevant RCTs are already included in Cochrane reviews and a further 277 reports have yet to be incorporated. Using these estimates we developed a network diagram setting out all comparisons examined in trials which revealed that at least 400 trials would contribute to the indirect comparisons of prostaglandins at least 91 to Foley catheter and 30 to alternative/complementary methods. Participants and interventions: We will include trials recruiting women due for 3rd trimester labour induction comparing any method of cervical ripening or labour induction either with no treatment placebo or with any other method/s. We will record information relating to setting patient characteristics (e.g. reason for induction previous caesarean) and dose for use in subgroup analysis. Outcomes: The NMA will focus on 7 key outcomes selected by a formal iterative process carried out by the multidisciplinary group who prepared the first NICE guideline on induction of labour in 2001. These are: vaginal delivery not achieved within 24 hours; uterine hyperstimulation with fetal heart rate (FHR) changes; caesarean section; serious neonatal morbidity or perinatal death; serious maternal morbidity or death; maternal satisfaction with the method used; and cost resource use and utility outcomes. Search methods: To identify trials for inclusion in the NMA an information expert will search the CPCG’s Specialist Register (which incorporates searches of CENTRAL MEDLINE EMBASE NHS EED relevant journals and conference proceedings) along with NHS NICE Technology Appraisals and Clinical Guidelines and the NIHR HTA series for previous cost-effectiveness analyses and economic data. Review and NMA methods: We will use Cochrane methods to select eligible trials and to extract outcome data. We will assess trial quality using a domain-based evaluation of risk of bias. This assessment will be used as part of sensitivity analysis. We will work in close collaboration with the Cochrane Multiple Interventions Methods Group (of which DMC is co-convenor). We will conduct standard meta-analyses for each pair-wise comparison of treatments and each outcome and present results of both fixed- and random-effects analyses. We will explore possible reasons for any heterogeneity such as risk of bias and other potential effect modifiers. Between-study heterogeneity will be quantified using the between-study variance (t2) and the I2 statistic. For each separate outcome we will construct a network meta-analysis (NMA) which will be compared with the pair-wise results.(40) NMA is a method of synthesising information from trials by simultaneously combining all the direct (head to head) and indirect evidence. NMA enables estimation of relative intervention effect estimates for every pair-wise contrast in a connected evidence network even if they have not been compared directly in an RCT. It also enables the ranking of treatments according to the probability that each is the best or worst for a given outcome. All analyses will be performed within a Bayesian framework using WinBUGS software (version 1.4.3). (There is more information on statistical methods in the project plan.) Cost-effectiveness analysis: We will build a health economic decision model to address the question: which is the most cost-effective method (including timing dose and mode of administration) for the induction of labour and explore whether this differs in subgroups. The model structure will be informed by a systematic review of previous economic models that address this or related questions. Data inputs for efficacy by subgroup will be informed by the NMA and cost/resource/utility inputs will be informed by data sources identified in previous models and the systematic review. The output: We will summarise findings of the systematic review NMA and cost-effectiveness analysis which will be published as an HTA monograph. We will publish the results in the Cochrane Library and other high impact peer-review journals: different publications will focus on the overall analysis as well as sections of the network (e.g. which type and dose of PGE2 works best for which groups of women). The outputs will be of value to clinicians women guideline authors and policy makers within the NHS. The researchers: The multidisciplinary team is well placed to carry out the project with expertise in evidence synthesis NMA biostatistics cost-effectiveness analysis and obstetric practice.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH