Simplifying oral misoprostol protocols for the induction of labour

Induction of labour is carried out worldwide for a broad range of maternal and fetal indications, so as to improve pregnancy outcomes. Oral misoprostol has been widely discussed as a method of labour induction. It is recommended for this indication by the World Health Organization (WHO), the International Federation of Gynecology and Obstetrics (FIGO), and the Society of Obstetricians and Gynaecologists of Canada (SOGC). A systematic review comparing misoprostol with Foley catheter and dinoprostone induction agents suggests that ‘Oral misoprostol for the induction of labour is safer than vaginal misoprostol and has the lowest rate of caesarean section’. A recently completed UK National Institute of Health Research (NIHR) funded network and cost-effectiveness analysis included 31 induction regimes evaluated in 611 trials with over 100 000 trial participants. Titrated low-dose oral misoprostol was identified as likely to be the most costeffective method, and also had a favourable safety profile. Sublingual or buccal misoprostol had significantly higher rates of hyperstimulation. This recent evidence is in contrast with the current National Institute for Health and Care Excellence (NICE) guidelines that do not recommend the use of misoprostol, citing that misoprostol is not labelled for labour induction, and that accurate concentrations and reliable drug delivery cannot be guaranteed given that low-dose formulations are not available. ‘Oral misoprostol’, however, is not a single entity and systematic reviewers have struggled to cope with the wide variation in protocols (Table 1). Published randomised trials have a wide variety of misoprostol doses (20–200 lg) and frequency of administration (1–6 hourly). Some protocols use a single dose for the whole induction period, whereas others escalate the dose until the desired effect is achieved. Some use misoprostol purely for cervical ripening and replace it with an oxytocin infusion once membrane rupture is feasible, whereas others use oral misoprostol continuously until delivery. But the variation doesn’t stop there. Until recently there was no commercially produced low-dose misoprostol tablet, and so clinicians developed their own ways of preparing and administering the intended dose. Some practitioners divided the small and notoriously crumbly 200or 100-lg tablets into fragments. Others made up 1-lg/ml solutions by dissolving tablets in tap water. It is only recently that commercially available 25-lg tablets have become available (Cipla, India; Azanta A/S, Denmark), but these are not yet widely available. Is there evidence to suggest that any of these protocols are superior? Subgroup analyses of some important clinical outcomes show a clear dose effect. For example, when comparing oral misoprostol with dinoprostone, the rate of hyperstimulation increases as the initial dose rises from 25 to 200 lg. It would therefore appear that there are safety benefits of using doses of 20–25 lg, even if they may result in a slower induction process. This is supported by a systematic review of just the studies that used 20–25 lg of oral misoprostol, which found lower caesarean section and lower hyperstimulation rates compared with standard induction methods. And whereas in previous studies researchers have been forced to either use cut 200-lg tablets or solution, high-quality 25-lg tablets are now available. Findings from a non-inferiority randomised controlled trial (RCT) of oral misoprostol 50mcg versus Foley catheter for induction of labour showed equivalent safety and effectiveness, whereas misoprostol tablets (25 lg) has recently been found to be more an effective than Foley catheter when given orally in a large Medical Research Council (MRC) labour induction study. The use of regimens in which misoprostol is given every 2 hours is supported by pharmacokinetic studies that show that oral misoprostol reaches its peak serum level within 30 minutes, but that its half-life is only 90 minutes as misoprostol acid is rapidly metabolised by the liver and