Oral misoprostol for induction of labour

Zarko Alfirevic; Nasreen Aflaifel; Andrew Weeks

doi:10.1002/14651858.CD001338.pub3

. 2014 Jun 13;2014(6):CD001338. doi: 10.1002/14651858.CD001338.pub3

Oral misoprostol for induction of labour

Zarko Alfirevic ¹, Nasreen Aflaifel ¹, Andrew Weeks ^1,^✉

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6513439 PMID: 24924489

Abstract

Background

Misoprostol is an orally active prostaglandin. In most countries misoprostol is not licensed for labour induction, but its use is common because it is cheap and heat stable.

Objectives

To assess the use of oral misoprostol for labour induction in women with a viable fetus.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (17 January 2014).

Selection criteria

Randomised trials comparing oral misoprostol versus placebo or other methods, given to women with a viable fetus for labour induction.

Data collection and analysis

Two review authors independently assessed trial data, using centrally‐designed data sheets.

Main results

Overall, there were 75 trials (13,793 women); these were of mixed quality.

In nine trials comparing oral misoprostol with placebo (1109 women), women using oral misoprostol were more likely to give birth vaginally within 24 hours (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.05 to 0.49; one trial; 96 women) and less likely to undergo caesarean birth (RR 0.72, 95% CI 0.54 to 0.95; 8 trials; 1029 women). Differences in ‘uterine hyperstimulation with fetal heart rate changes’ were compatible with no effect (RR 2.71, 95% CI 0.84 to 8.68; 7 trials; 669 women).

Ten trials compared oral misoprostol with vaginal prostaglandin (dinoprostone) (3,240 women). There was little difference in the frequency of: vaginal birth within 24 hours (RR 1.10, 95% CI 0.99 to 1.22; 5 trials; 2,128 women), uterine hyperstimulation with fetal heart rate changes (RR 0.95, 95% CI 0.59 to 1.53; 7 trials; 2,352 women), and caesarean birth (RR 0.92, 95% CI 0.81 to 1.04; 10 trials; 3240 women).

Five trials compared administration of oral misoprostol with intracervical prostaglandin E2 (681 women). Oral misoprostol was associated with fewer instances of failure to achieve vaginal birth within 24 hours (RR 0.78, 95% CI 0.63 to 0.97; 3 trials; 452 women) but more frequent uterine hyperstimulation with fetal heart rate changes (RR 3.57, 95% CI 1.11 to 11.54; 3 trials; 490 women). The available data for this comparison were however limited and the differences in caesarean birth were small (RR 0.85, 95% CI 0.63 to 1.16; 5 trials; 742 women).

Nine trials compared oral misoprostol with intravenous oxytocin (1282 women). There were no obvious differences in the frequency of: vaginal birth within 24 hours (RR 0.79, 95% CI 0.59 to 1.05; 6 trials; 789 women), or uterine hyperstimulation with fetal heart rate changes (RR 1.30, 95% CI 0.43 to 3.91; 7 trials; 947 women). There were, however, fewer caesarean births with oral misoprostol (RR 0.77, 95% CI 0.60 to 0.98; 9 trials; 1282 women).

Thirty‐seven trials compared oral misoprostol with vaginal misoprostol (6417 women). There was little difference in the frequency of: vaginal birth within 24 hours (RR 1.08, 95% CI 0.86 to 1.36; 14 trials; 2,448 women), uterine hyperstimulation with fetal heart rate changes (RR 0.71, 95% CI 0.47 to 1.08; 29 trials; 5,503 women), and caesarean birth (RR 0.93, 95% CI 0.81 to 1.07; 35 trials; 6,326 women).

The incidence of serious neonatal or maternal morbidity or death was rare and no meaningful results were available for any of the comparisons.

Authors' conclusions

Where misoprostol remains unlicensed for the induction of labour, many practitioners will prefer to use a licensed product like dinoprostone. If using oral misoprostol, the evidence suggests that the dose should be 20 to 25 mcg in solution. Given that safety is the primary concern, the evidence supports the use of oral regimens over vaginal regimens. This is especially important in situations where the risk of ascending infection is high and the lack of staff means that women cannot be intensely monitored.

Plain language summary

Oral misoprostol for induction of labour

Oral misoprostol is effective at inducing (starting) labour. It is more effective than placebo, as effective as vaginal misoprostol and vaginal dinoprostone, and results in fewer caesarean sections than oxytocin. However, there are still not enough data from randomised controlled trials to determine the best dose to ensure safety.

Induction of labour in late pregnancy is used to prevent complications when the pregnant woman or her unborn child are at risk. Reasons for induction include being overdue, pre‐labour rupture of membranes and high blood pressure. Prostaglandins are hormones that are naturally present in the uterus (womb); they soften the cervix and stimulate contractions in labour. The artificial prostaglandin E2 dinoprostone can be administered vaginally to induce labour but it is unstable at room temperature and is expensive. Oral misoprostol is a cheap and heat stable prostaglandin E1 synthetic analogue originally developed for the treatment of stomach ulcers.

The search for trials took place in January 2014. This review of 75 randomised controlled trials (13,793 women) found that oral misoprostol appears to be at least as effective as current methods of induction.

Nine trials (1,282 women) showed that oral misoprostol was equivalent to intravenous infusion of oxytocin. There were no obvious differences in the number of women who had a vaginal birth within 24 hours, or the number of women who experienced uterine hyperstimulation with changes to the baby's heart rate, although there were fewer caesarean sections in the group of women who were given oral misoprostol.

For the 37 thirty seven trials (6,417 women) that compared oral and vaginal misoprostol, there was little difference in the number of women who had a vaginal birth within 24 hours, uterine hyperstimulation with changes to the baby's heart rate, or caesarean section.

In 10 trials (3,240 women) comparing oral misoprostol with a vaginal prostaglandin (dinoprost), there was little difference in the frequency of vaginal birth within 24 hours, uterine hyperstimulation with changes to the baby's heart rate, or caesarean section.

The nine trials that compared oral misoprostol with placebo (1,109 women) and found that oral misoprostol is more effective than placebo for inducing labour. Women in the oral misoprostol group were more likely to have vaginal birth within 24 hours, and less likely to have a caesarean section. There was little difference between groups in terms of the number of women who experienced uterine hyperstimulation with changes to the baby's heart rate.

Five trials compared oral misoprostol with intracervical (inserted into the entrance of the womb) prostaglandin E2 (681 women). Oral misoprostol was associated with fewer instances of failure to achieve vaginal birth within 24 hours but more frequent uterine hyperstimulation with changes to the baby's heart rate. The available data for this comparison was limited and the differences in caesarean birth were small.

Overall, the incidence of serious illness or death of the mother or her baby was rare and no meaningful results were available for any of the comparisons in this review.

Using oral misoprostol to induce labour is effective at achieving vaginal birth. It is more effective than placebo, as effective as vaginal misoprostol and vaginal dinoprostone, and results in fewer caesarean sections than using oxytocin alone.

In some countries where misoprostol is not licenced for the purpose of inducing labour, many clinicians may prefer to use some other licensed product such as dinoprostone. Where oral misoprostol is used, evidence suggests that an appropriate dose may be 20 to 25 mcg in solution. Given that safety is the primary concern, the evidence supports the use of oral regimens over vaginal regimens. This is particularly important in settings where the mother is at a higher risk of infection and where there may be insufficient staff to closely monitor the mother and her baby.

Background

This review is one of a series of reviews of methods of labour induction using a standardised protocol. For more detailed information on the rationale for this methodological approach, please refer to the currently published 'generic' protocol (Hofmeyr 2009). The generic protocol describes how a number of standardised reviews will be combined to compare various methods of preparing the cervix of the uterus and inducing labour.

Induction of labour is a common clinical situation. The reasons for an induction are either clinical (post‐term pregnancy, prelabour rupture of membranes, hypertensive disorders) or social (parents' and clinicians' convenience).

Prostaglandins have been widely used for labour induction, particularly if the cervix is not 'favourable' (Keirse 1993). Prostaglandin E2 (PGE2 or dinoprostone) appears to be the prostaglandin of choice when used vaginally in the form of gel, tablets or pessaries. Unfortunately, vaginal PGE2 preparations are expensive and unstable at room temperature.

Oral administration of prostaglandins is less effective (Keirse 1989) and has been virtually abandoned, mainly due to gastrointestinal side effects. However, interest in oral prostaglandins has increased with the introduction of a new synthetic prostaglandin E1 analogue ‐ misoprostol. This drug is used mainly for the prevention and treatment of nonsteroidal anti‐inflammatory drug‐induced ulcers of the digestive tract. It is relatively cheap and stable at room temperature. Used for this indication, oral misoprostol is usually given in two to four doses of 200 micrograms (mcg) per day and the time to maximum concentration is 10 to 20 minutes (versus 60 to 80 minutes in the case of vaginal administration, Abdel‐Aleem 2003). Side effects are dose dependent and are mainly confined to the digestive tract, such as diarrhoea and nausea (Garris 1989).

Uterine contractions induced by misoprostol are often strong enough to expel products of conception in early pregnancy. Widespread use of misoprostol in Brazil for termination of pregnancy (Costa 1993) resulted in the identification of teratogenic effects including abnormalities of extremities (clubfoot, agenesis of the feet and hands, syndactyly, constriction rings) and Mobius sequence (loss of function of the motor cranial nerves, especially VI, VII and XII) (Fonseca 1991; Gonzales 1999; Pastuszak 1998). These defects affect less than 1% of exposed fetuses (Philip 2002). Maternal death from uterine rupture at 16 weeks' gestation after self‐medication with misoprostol has been reported (Costa 1993).

Randomised trials, which have evaluated the effectiveness of a vaginally administered misoprostol for labour induction with a viable fetus, have been reviewed for The Cochrane Library (Hofmeyr 2010). Oral use is particularly attractive because of easy and non‐invasive administration. However, there are inherent risks of such an approach. An overdose, causing uterine hyperstimulation may precipitate labour, and may be life‐threatening for both mother and fetus. It is therefore, important that oral misoprostol is evaluated in a systematic fashion to assess if it can be recommended for routine clinical practice.

Despite having been widely studied for several reproductive health indications, misoprostol's licence has never been extended. This is thought to be due to the manufacturer's concerns about potential adverse publicity generated by the powerful US anti‐abortion lobby. Off‐label drug use is common in obstetrics, and includes many drugs, which would be considered mandatory in everyday practice (e.g. corticosteroids to prevent neonatal respiratory distress syndrome after premature labour and oxytocin 10 international units intramuscularly to prevent postpartum haemorrhage). Despite this, many practitioners are concerned about the potential legal consequences of using an off‐label drug should a serious adverse event occur, especially if an effective licensed alternative is available (Weeks 2005). Now that the patent for misoprostol has expired, generic misoprostol products licensed for reproductive health indications have become available in various parts of the world such as Brazil, France and Egypt. The arrival of licensed products will ease the medico‐legal concerns of those wishing to use misoprostol for induction of labour.

Description of the condition

Induction of labour is used to bring an end to pregnancy when the benefits of giving birth at that time outweigh the risks of the induction process.

Description of the intervention

Oral misoprostol is given as a regular medication to pregnant women either as a tablet or in solution. The dosage and form of the medication varies, but it is generally used only until the woman's cervix is fully ripened. If further uterine stimulation is required after this, an intravenous infusion of oxytocin is generally used until birth, although some studies have continued the use of low‐dose misoprostol.

How the intervention might work

Similar to other prostaglandins, oral misoprostol acts on the uterus to soften (or 'ripen') the cervix and to stimulate contractions.

Why it is important to do this review

Oral misoprostol is a low‐cost and effective method for induction which is in common use in many parts of the world. Until recently, the drug was not licensed for use in pregnancy and so the drug manufacturers had neither formally evaluated it nor packaged the drug for induction of labour. There has been confusion therefore over which misoprostol regimen to use, and the use of excessive doses in late pregnancy has been thought to have been responsible for serious complications including uterine rupture. A formal evaluation of the many published studies is therefore very important to guide national and international recommendations for its appropriate use.

Objectives

To determine, from randomised controlled trials, the effectiveness and safety of oral misoprostol for third trimester induction of labour.

Methods

Criteria for considering studies for this review

Types of studies

Clinical trials comparing oral misoprostol for labour induction with placebo/no treatment or other methods for labour induction. Quasi‐randomised trials were not included. This review includes only induction methods listed above oral misoprostol on a predefined list of methods of labour induction (seeData collection and analysis). We have included only trials that have some form of random allocation to the study groups and report at least one of the prestated outcomes. We have also included studies that compare various oral misoprostol regimens.

In this review we make no distinction between cervical ripening and induction of labour if the aim was to achieve vaginal birth as safely as possible. However, we excluded the studies if the primary aim of intervention was to 'facilitate' spontaneous onset of labour over a long period of time (for example, oral misoprostol every other day between 40 and 42 weeks' gestation).

Types of participants

Pregnant women due for third trimester induction of labour who carry a viable fetus.

Types of interventions

Oral misoprostol compared with placebo/no treatment or six other methods for labour induction placed above oral misoprostol on a predefined list (seeData collection and analysis):

placebo/no treatment;
vaginal prostaglandin E2;
intracervical prostaglandin E2;
oxytocin alone;
amniotomy alone;
amniotomy + oxytocin;
vaginal misoprostol.

We will not discuss any of the comparisons listed above without relevant trials in this review. For the details of this selection strategy, please refer to Data collection and analysis.

In previously published versions of this review, we proposed to compare low‐, medium‐ and high‐dose regimens. We defined low‐dose regimens as less than 50 micrograms (mcg), medium‐dose as 50 to 100 mcg inclusive and high‐dose as more than 100 mcg. These arbitrary groups proved impractical because most trials used either 25 mcg, 50 mcg or 100 mcg doses. In order to study dose‐related effects, we decided to group regimens into: (i) 0 to 25 mcg, (ii) 26 to 50 mcg, (iii) 51 to 199 mcg and (iv) 200 mcg or more. We acknowledge that this change has been driven to some extent by the trials' data and is therefore a potential source of bias. Also, the same dose can be given at varying intervals (usually between two and six hours) and these differences could influence the primary outcomes. 'Low‐dose' regimens with two‐hourly administration may result in a higher cumulative dose over 24 hours than 'high‐dose' regimens. However, the plasma half‐life of oral misoprostol is short (20 to 40 minutes) and, therefore, it would appear that dose is more important than frequency. Consequently, at least at this point in time, we have not planned analyses based on frequency of administration.

Types of outcome measures

Two authors of labour induction reviews (Justus Hofmeyr and Zarko Alfirevic) prespecified the clinically relevant outcomes for trials of methods of cervical ripening/labour induction. After discussion a consensus has been reached by all registered Cochrane Pregnancy and Childbirth Group review authors with an interest in labour induction.

Primary outcomes

We chose five primary outcomes as being most representative of the clinically important measures of ineffectiveness and complications:  (1) vaginal delivery not achieved within 24 hours (includes all caesarean sections);  (2) uterine hyperstimulation with fetal heart rate (FHR) changes;  (3) caesarean section;  (4) serious neonatal morbidity or perinatal death (e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood);  (5) serious maternal morbidity or death (e.g. uterine rupture, admission to intensive care unit, septicaemia).

Perinatal and maternal morbidity and mortality are composite outcomes. This is not an ideal solution because some components are clearly less severe than others. It is possible for one intervention to cause more deaths but fewer babies with severe morbidity. However, in the context of labour induction at term this is unlikely. All these events will be rare, and a modest change in their incidence will be easier to detect if composite outcomes are presented. We will explore the incidence of individual components as secondary outcomes.

Secondary outcomes

Secondary outcomes relate to measures of clinical ineffectiveness, complications and satisfaction.

Measures of ineffectiveness:  (6) cervix unfavourable/unchanged after 12 to 24 hours;  (7) oxytocin augmentation.

Complications:  (8) uterine hyperstimulation without FHR changes;  (9) uterine rupture;  (10) epidural analgesia;  (11) instrumental vaginal delivery;  (12) meconium‐stained liquor;  (13) Apgar score less than seven at five minutes;  (14) neonatal intensive care unit admission;  (15) neonatal encephalopathy;  (16) perinatal death;  (17) disability in childhood;  (18) maternal side effects (all);  (19) maternal nausea;  (20) maternal vomiting;  (21) maternal diarrhoea;  (22) other maternal side effects;  (23) postpartum haemorrhage (as defined by the trial authors);  (24) serious maternal complications (e.g. intensive care unit admission, septicaemia but excluding uterine rupture);  (25) maternal death.

Measures of satisfaction:  (26) woman not satisfied;  (27) caregiver not satisfied.

'Uterine rupture' includes all clinically significant ruptures of unscarred or scarred uteri. We have excluded asymptomatic scar dehiscence noted incidentally at the time of surgery.

While we have sought all of the above outcomes, only those with data appear in the analysis tables.

The terminology of uterine hyperstimulation is problematic (Curtis 1987). In the reviews we use the term 'uterine hyperstimulation without FHR changes' to include uterine tachysystole (more than five contractions per 10 minutes for at least 20 minutes) and uterine hypersystole/hypertonus (a contraction lasting two minutes or more) and 'uterine hyperstimulation with FHR changes' to denote uterine hyperstimulation syndrome (tachysystole or hypersystole with fetal heart rate changes such as persistent decelerations, tachycardia or decreased short‐term variability).

Outcomes are included in the analysis if data were available according to original allocation and reasonable measures were taken to minimise observer bias.

Only outcomes with available data appear in the analysis tables. We have, nevertheless, extracted and reported data on outcomes that were not prestated above. However, we have clearly labelled them as such ('not prespecified'). In order to minimise the risk of bias, we have based the conclusions solely on the prestated outcomes.

The methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (17 January 2014).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE
weekly searches of Embase;
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.

We did not apply any language restrictions, and included data from abstracts so long as there was sufficient information on the study method, population and outcomes.

Data collection and analysis

To avoid duplication of data in a series of reviews on interventions for labour induction as described in the generic protocol for methods for cervical ripening and labour induction in late pregnancy (Hofmeyr 2009), the labour induction methods were listed in a specific order, from one to 27. Each review included comparisons between one of the methods (from two to 27) with only those methods above it on the list. Thus, this review of oral misoprostol (8) could include comparisons with any of the following: (1) placebo/no treatment; (2) vaginal prostaglandins; (3) intracervical prostaglandins; (4) intravenous oxytocin; (5) amniotomy; (6) intravenous oxytocin with amniotomy; (7) vaginal misoprostol. The current list is as follows:

(1) placebo/no treatment;  (2) vaginal prostaglandins (Kelly 2009);  (3) intracervical prostaglandins (Boulvain 2008);  (4) intravenous oxytocin (Alfirevic 2009);  (5) amniotomy (Bricker 2000);  (6) intravenous oxytocin with amniotomy (Bimbashi 2012; Howarth 2001);  (7) vaginal misoprostol (Hofmeyr 2010);  (8) oral misoprostol (this review);  (9) mechanical methods including extra‐amniotic Foley catheter (Jozwiak 2012);  (10) membrane sweeping (Boulvain 2005);  (11) extra‐amniotic prostaglandins (Hutton 2001);  (12) intravenous prostaglandins (Luckas 2000);  (13) oral prostaglandins (French 2001);  (14) mifepristone (Hapangama 2009);  (15) oestrogens with or without amniotomy (Thomas 2001);  (16) corticosteroids (Kavanagh 2006a);  (17) relaxin (Kelly 2013);  (18) hyaluronidase (Kavanagh 2006b);  (19) castor oil, bath, and/or enema (Kelly 2013a);  (20) acupuncture (Smith 2013);  (21) breast stimulation (Kavanagh 2005);  (22) sexual intercourse (Kavanagh 2001);  (23) homoeopathic methods (Smith 2003);  (24) nitric oxide donors (Kelly 2011);  (25) buccal or sublingual misoprostol (Muzonzini 2004);  (26) hypnosis (Nishi 2013);  (27) other methods for induction of labour.

The reviews were analysed by the following clinical categories of participants:

previous caesarean section or not;
nulliparity or multiparity;
membranes intact or ruptured;
cervix favourable, unfavourable or undefined.

For most reviews, the initial data extraction process was conducted centrally. This was co‐ordinated from the Clinical Effectiveness Support Unit (CESU) at the Royal College of Obstetricians and Gynaecologists, UK, in co‐operation with the Pregnancy and Childbirth Group of The Cochrane Collaboration. This process allowed the data extraction process to be standardised across all the reviews. From 2001, the data extraction was no longer conducted centrally.

The trials were initially reviewed on eligibility criteria, using a standardised form and the basic selection criteria specified above. Following this, a standardised data extraction form was developed and then piloted for consistency and completeness. This pilot process involved the researchers at the CESU and previous review authors in the area of induction of labour. For a description of the methods used to carry out the initial reviews, seeHofmeyr 2009.

For this update we used the following methods when assessing the reports identified by the updated search.

Selection of studies

Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion with the third author.

Data extraction and management

We designed a form to extract data. For eligible studies, at least two review authors extracted the data using the agreed form. We resolved discrepancies through discussion with the third author. We entered data into Review Manager software (RevMan 2012) and checked it for accuracy.

When information regarding any of the above is unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving the third author.

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods used to blind outcome assessment as:

low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re‐included missing data in the analyses which we undertook.

We assessed methods as:

low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We described for each included study any important concerns we have about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

low risk of other bias;
high risk of other bias;
unclear whether there is risk of other bias.

(7) Overall risk of bias

We made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.

Continuous data

We did not analyse any continuous data in this update. In future updates, if we include continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster‐randomised trials

We did not include any cluster‐randomised trials in this update. If included in future updates, we will include cluster‐randomised trials in the analyses along with individually‐randomised trials. We will adjust their sample sizes using the methods described in the Handbook [Section 16.3.4 or 16.3.6] using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity or subgroup analysis to investigate the effects of the randomisation unit.

Cross‐over trials

Cross‐over trials are not eligible for inclusion in this review.

Dealing with missing data

For included studies, we noted levels of attrition. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either the Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

Funnel plots were not used to assess reporting bias.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2012). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful we did not provide a summary statistic.

If random‐effects analyses were used, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².

Where the data allowed, the results were analysed by the following clinical categories of participants:

previous caesarean section or not;
nulliparity or multiparity;
membranes intact or ruptured;
cervix favourable, unfavourable or undefined.

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, we investigated it using subgroup and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, we used random‐effects analysis to produce it (see details in Data synthesis).

In the main analysis ("all women") for each comparison (i.e. not on the clinical categories) we carried out the following subgroup analyses:

dose‐related effects of oral misoprostol, regimens: 0 to 25 mcg versus 26 to 50 mcg versus 51 to 199 mcg versus 200 mcg or more.

The subgroup analysis was conducted for all outcomes within the main analysis.

We assessed subgroup differences by interaction tests available within RevMan (RevMan 2012). We reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

In the event of significant heterogeneity, we carried out sensitivity analyses to explore the effect of trial quality (judged according to the method and reporting of allocation concealment), with poor‐quality studies (allocation concealment inadequate or not reported) being excluded from the analyses in order to assess whether this explained the heterogeneity. No other sensitivity analysis was conducted.

Results

Description of studies

Results of the search

We have included 76 studies in the current review, containing a total of 14,412 women. Only 160 women in three studies had undergone previous caesarean section (Carlan 2001 (V50); How 2001 (V25); Patil 2005).

Included studies

Placebo/no treatment as comparator

Nine studies were categorised under this comparison. Only two studies compared oral misoprostol with no treatment (expectant management) (Javaid 2008; Rath 2007). In both studies only women with ruptured membranes were included and those randomised to the expectant group had no treatment for 20 to 24 hours. Seven studies compared oral misoprostol with placebo. Two of these studies used initial 50 mcg doses (Cheung 2006; Levy 2007); three studies used initial 100 mcg doses (Hoffman 2001; Lo 2003; Lyons 2001); and two used 200 mcg doses (Beigi 2003; Ngai 1996). In Cheung 2006, women were randomised three ways: to placebo, 50 mcg or 100 mcg misoprostol. As 50 mcg is the most commonly recommended dose for oral misoprostol, we chose to include only the outcomes for the placebo versus 50 mcg dose. We have also included the outcomes for the 50 mcg versus 100 mcg doses in that section of the review. In Hoffman 2001 women in both arms received dinoprostone after 12 hours if not in active labour. The participants all had ruptured membranes at term except in Beigi 2003, where women with intact membranes were also included.

Dinoprostone as comparator

In 10 studies, the comparison was with the prostaglandin dinoprostone administered vaginally (Dallenbach 2003 (T); Dodd 2006; Gherman 2001a; Henrich 2008 (T); Hofmeyr 2001(T); le Roux 2002 (V50); Majoko 2002 (V50); Moodley 2003; Shetty 2004; Tessier 1997). The studies included only women with intact membranes, except for Hofmeyr 2001(T), which also included women with ruptured membranes and Henrich 2008 (T) and Tessier 1997 did not specify the membrane status for the included women. The initial dosage of misoprostol was 50 mcg or less in all studies except for Shetty 2004, where 100 mcg was used. In Majoko 2002 (V50), the initial dose was 10 mcg and each successive four‐hourly dose was doubled to a maximum of 400 mcg. In the studies by Dallenbach 2003 (T) and Hofmeyr 2001(T), women received 20 mcg oral misoprostol (dissolved in water) two‐hourly for two doses and then 40 mcg two‐hourly. Doses could also be given in labour if contractions slowed. In the studies by Moodley 2003 and Dodd 2006, women received 20 mcg of oral solution two‐hourly. A third arm of the Moodley 2003 study, where women received an initial 25 mcg of vaginal misoprostol followed by 20 mcg oral misoprostol, is not included in this review.

Oral misoprostol was compared with intracervical dinoprostone in the studies by Bartha 2000 and Patil 2005 (both 200 mcg dose), as well as Langenegger 2005, Sheela 2007 (V25) and Nagpal 2009 (50 mcg dose). All studies included only women with intact membranes except for Nagpal 2009 which included only women with ruptured membranes.

In the Tessier 1997 study, 23 of the 267 women had undergone a caesarean section in a previous pregnancy.

Oxytocin as comparator

Nine studies compared oral misoprostol with oxytocin. In six, the women had ruptured membranes at term (Al‐Hussaini 2003; Butt 1999; Crane 2003; Dodd 2006a (T); Mozurkewich 2003; Ngai 2000), whilst in two other trials women with intact membranes were also included (Nigam 2004; Wing 2004), and one study included a mix of women with ruptured and intact membranes (Aalami‐Harandi 2013 (T)). In most trials the dose was 100 mcg. However, in Dodd 2006a (T) (abstract form only), an hourly dose of titrated oral solution starting with 5 mcg was used; in Butt 1999 and Nigam 2004, 50 mcg was used; and in Crane 2003, 75 mcg was used. Aalami‐Harandi 2013 (T) used a 200 mcg tablet of misoprostol dissolved in 200 mL water, and administered 25 mL (25 mcg) every two hours.

Vaginal misoprostol as comparator

The most common comparison in this review is with vaginal misoprostol (37 studies). The figure in brackets after the study reference indicates the initial dosage of vaginal misoprostol used in the comparison. In 16 studies the participants had intact membranes (Adair 1998 (V50); Bennett 1998 (V50); Carlan 2001 (V50); Fisher 2001 (V50); Khazardoost 2011 (V25); Kwon 2001 (V50); le Roux 2002 (V50); Majoko 2002 (V50); Mehrotra 2010 (V50); Nopdonrattkaoon 2003 (V50); Paungmora 2004 (V50); Pongsatha 2005 (V50); Sheela 2007 (V25); Shetty 2001 (V50); Shetty 2003 (V25); Wing 1999 (V25)) and in three studies they had ruptured membranes (Jindal 2011 (V50); Puga 2001 (V50); Rizvi 2007 (V25)). Eleven studies included women with both intact and ruptured membranes (Cheng 2008 (T) (V25); Colon 2005 (V25); Deshmukh 2013 (V50); Dyar 2000 (V50); Hall 2002 (V25); Pais'wong 2008 (V25); Rahman 2013 (V25); Souza 2013(V25)(T); Toppozada 1997 (V100); Uludag 2005 (V50); Wing 2000 (V25)), whilst in six studies the membrane status was not clarified (Adam 2005 (V50); Elhassan 2007 (V50); Schneider 2004 (V25); Sheikher 2009 (V25); Sitthiwattanawong 1999; Sultana 2006 (V100)). Most trials used a 50 mcg dose of oral misoprostol (16 studies), but three used 20 to 25 mcg (Cheng 2008 (T) (V25); How 2001 (V25); Souza 2013(V25)(T)), 11 used 100 mcg (Hall 2002 (V25); Khazardoost 2011 (V25); Paungmora 2004 (V50); Pongsatha 2005 (V50); Puga 2001 (V50); Rizvi 2007 (V25); Shetty 2003 (V25); Sultana 2006 (V100); Toppozada 1997 (V100; Uludag 2005 (V50); Wing 2000 (V25)) and two used 200 mcg (Adair 1998 (V50); Carlan 2001 (V50)). In Majoko 2002 (V50), the initial dose was 10 mcg and each successive four‐hourly dose was doubled, to a maximum of 400 mcg. In Colon 2005 (V25), the initial dose was 50 mcg, but increased to 100 mcg for subsequent doses. The dosage of vaginal misoprostol varied from 25 mcg to 100 mcg. The initial dose of vaginal misoprostol is stated in mcg after the year of article publication.

Two studies (Carlan 2001 (V50); How 2001 (V25)) included women who had previous caesarean sections (131 and 27 respectively).

Sublingual misoprostol as comparator

There was just one study (Elhassan 2007 (V50)) which compared 50 mcg of oral, vaginal and sublingual misoprostol (50 women in each group).

Vaginal dinoprostone insert as comparator

One study (Rouzi 2014) compared titrated oral misoprostol solution at 20 mcg with a 10 mcg dinoprostone vaginal, inserted for a maximum of 24 hours.

Other comparisons

There were several other randomised trials comparing different oral misoprostol protocols. In one study Kipikasa 2005 compared 25 mcg and 50 mcg doses every three days for nine days. This study was conducted on an outpatient basis. Two studies compared 50 mcg and 100 mcg doses (Cheung 2006; Shetty 2002) and two studies by the same team examined frequency of dosaging. They initially compared 50 mcg given four‐hourly or six‐hourly (Pongsatha 2001) and then conducted a similar study comparing 100 mcg three‐hourly and six‐hourly (Pongsatha 2002). In this review, we have grouped together the dosage frequency studies with dosage subgroups.

One study compared a regimen of oral misoprostol 25 mcg given three‐hourly until in labour (with oxytocin only if contractions settled) with a regimen of two oral misoprostol tablets followed by routine oxytocin (De 2006). Another examined two management policies for women with ruptured membranes at term (Shetty 2002a). One group received oral misoprostol 50 mcg four‐hourly at recruitment and the other had conservative management for 24 hours followed by PGE2 1 to 2 mg six‐hourly. The study by Thaisomboon 2012 (T) included only women with intact membranes. In this study, one group received hourly misoprostol solution 20 mcg (200 mcg tablet dissolved in 200 mL of tap water). If no uterine contractions were achieved after the first four doses the dose was doubled to 40 mcg up to a maximum of eight doses. The other group received misoprostol solution orally 50 mcg every four hours (20 mL of 200 mcg misoprostol in 80 mL water). The study was double blinded by the use of 20 mL of placebo solution between doses.

Excluded studies

Four exclusions are potentially controversial. We have excluded the study by Windrim 1997 because 138 women in the comparator group were induced with four different methods (intracervical dinoprostone, vaginal dinoprostone, oxytocin, vaginal misoprostol). We felt that these methods are too different to be compared to oral misoprostol as one intervention. Ascher‐Walsh 2000 used oral misoprostol to achieve spontaneous onset of labour, i.e. oral misoprostol or placebo were given in three‐day intervals between 40 and 42 weeks of pregnancy. This review with its clinical outcomes concentrates on methods to achieve vaginal birth as quickly as possible, so we decided to exclude this trial.The study by Zvandasara 2008 was excluded as it included women with intrauterine fetal death (four women). Finally,the study by Rasheed 2007 (V50) included data on 25 women who were not randomised.These women were undergoing induction of labour with oral misoprostol (their normal unit induction method) just before the trial started. We therefore included their data with the oral misoprostol arm within the data set from the 285 women who were in the randomised group. The additional data has resulted in an uneven balance between the groups (165 versus 145), and the data derived from those randomised alone are not retrievable from the manuscript.

A number of studies were excluded as they used a combination of techniques. We excluded the studies by Kadanali 1996 and Bricker 2008 because they used vaginal misoprostol followed by oral administration. These studies are therefore included in the Cochrane review of vaginal misoprostol by Hofmeyr 2003. The study by Neto 1988 concentrated on the uterine effects of oral and vaginal misoprostol. Five women received oral misoprostol in the dose of 200 mcg four‐hourly, five women received 400 mcg four‐hourly and five women received a single 200 mcg tablet vaginally. The reported outcomes included initiation, dynamics and duration of uterine contractions. Clinical outcomes were not reported and we have therefore excluded the study. We excluded Bozhinova 2007 as the comparison of oral misoprostol was with combined vaginal and sublingual misoprostol. Delaney 2001 was excluded as women had an artificial rupture of membranes performed at study entry and the oxytocin or oral misoprostol was only used for those who were not in labour one hour later.

We excluded Ho 2010 as it is a study of labour augmentation in women with 'failure to progress in labour' rather than labour induction.

As reported above, the study by Moodley 2003 had three arms. We have included outcomes from the groups treated with oral misoprostol and vaginal dinoprostone in this review, but not from the third group, where women received a mixture of oral and vaginal misoprostol.

Several studies are still ongoing (DebBarma 2013; Gherman 2002; Pranuthi 2011), awaiting translation or have not been not been reported fully yet (Atkinson 2000; Bonebrake 2001; Butler 2004; Getgan 2003; Goedken 2000; Madhavi 2011; Niroomanesh 2011; Pearson 2002; Saldivar 2001; Tuipae 1999; Vijitrawiwat 2003; Yazdani 2012; Young 2001).

Risk of bias in included studies

See Figure 1; Figure 2 for a summary of 'Risk of bias' assessments.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Where the treatment was not blinded there is a real possibility of bias, both in clinical decision making and assessment of outcomes. A clinician with a prior belief that oral misoprostol is effective and safe might be less likely to perform a caesarean section in case of fetal distress or slow labour. On the other hand, a clinician who is anxious about possible risks of the new treatment may be more likely to intervene.

Incomplete outcome data

There was wide variation in the outcomes reported in the studies, and some were not consistent with the outcomes in this review. So whilst 'vaginal birth within 24 hours' is an important summary primary outcome in this review, it is rarely used by trialists, many of whom prefer a continuous variable of time to birth (which is not one of the Cochrane outcomes). Similarly not all published papers use the strict Cochrane definition of hyperstimulation with or without fetal heart rate abnormalities despite these being important outcomes. In assessing these outcomes, the authors have had to use judgement in matching the reported outcomes (for example "hyperstimulation") with the predefined Cochrane outcomes. Increasingly, however, trialists are turning to the Cochrane reviews for their selection of outcomes, and so recent high‐quality studies are well matched to the Cochrane outcomes set.

Selective reporting

There is a wide variation in reported outcomes, but no evidence of selective reporting was found.

Other potential sources of bias

None.

Effects of interventions

(1) Comparison with placebo (analyses 1 to 4)

Nine trials with 1109 participating women in total compared oral misoprostol with placebo or no treatment.

Primary outcomes: women using oral misoprostol were more likely to give birth vaginally within 24 hours (although this was only assessed in one trial of 96 women (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.05 to 0.49) in which women in both arms were given dinoprostone after 12 hours), Analysis 1.1. Oral misoprostol was associated with lower caesarean section (CS) rates (RR 0.72, 95% CI 0.54 to 0.95), Analysis 1.3.

1.1 — Comparison 1 Oral misoprostol versus placebo/ no treatment (1): all women, Outcome 1 Vaginal delivery not achieved in 24 hours.

1.3 — Comparison 1 Oral misoprostol versus placebo/ no treatment (1): all women, Outcome 3 Caesarean section.

Secondary outcomes: oral misoprostol was also associated with less oxytocin augmentation (RR 0.42, 95% CI 0.37 to 0.49), Analysis 1.7, fewer admissions to the neonatal intensive care unit (RR 0.42, 95% CI 0.32 to 0.56), Analysis 1.14, and lower rates of epidural use (RR 0.81, 95% CI 0.69‐0.96) Analysis 1.6 There were no other clinically important differences in prespecified outcomes, including measures of uterine hyperstimulation. Most of the women studied had ruptured membranes, and analysis confined to this subgroup demonstrated similar findings to the overall analysis.

1.7 — Comparison 1 Oral misoprostol versus placebo/ no treatment (1): all women, Outcome 7 Oxytocin augmentation.

1.14 — Comparison 1 Oral misoprostol versus placebo/ no treatment (1): all women, Outcome 14 Neonatal intensive care unit admission.

Subgroups: in the subgroup of all women with ruptured membranes, there was a significant increase in the number of women with a vaginal birth within 24 hours (one study of 96 women, RR 0.16, 95% CI 0.05 to 0.49), Analysis 3.1. In the subgroups of all women with intact membranes and primigravid women with ruptured membranes, there were no significant changes in the primary outcomes.

3.1 — Comparison 3 Oral misoprostol versus placebo/ no treatment (1): all women with ruptured membranes, Outcome 1 Vaginal delivery not achieved in 24 hours.

(2) Comparison with vaginal dinoprostone (analyses 5 to 11)

A total of 3,240 women were randomised to oral misoprostol or vaginal dinoprostone in 10 trials. The most common dose of misoprostol used in these studies was 20 mcg oral solution given two‐hourly.

Primary outcomes: there was no effect on CS rate in those treated with oral misoprostol (RR 0.92, 95% CI 0.81 to 1.04), Analysis 5.3 or in the number of women not achieving vaginal birth within 24 hours (RR 1.09, 95% CI 0.99 to 1.20), Analysis 5.1,

Secondary outcomes: women treated with misoprostol more frequently had an unchanged cervix after 12 to 24 hours (RR 1.41, 95% CI 1.01 to 1.96), Analysis 5.6. There were no other statistically significant differences between the groups in any of the outcomes, including hyperstimulation rates and frequency of meconium‐stained liquor.

5.6 — Comparison 5 Oral misoprostol versus vaginal PG (2): all women, Outcome 6 Cervix unfavourable/unchanged after 12‐24 hours.

Subgroups: six trials (n = 2,129) provided the data for a subgroup of women with intact membranes. The data show that women induced with misoprostol have fewer CSs (RR 0.85, 95% CI 0.73 to 0.99), Analysis 6.3. However, they had slower labours with increased rates of unchanged cervix after 12 to 24 hours (RR 1.51, 95% CI 1.03 to 2.20), Analysis 6.6 and a lower rate of vaginal birth within 24 hours (RR 1.12, 95%CI 1.01‐1.25) Analysis 6.1. There were no other significant differences.

6.3 — Comparison 6 Oral misoprostol versus vaginal PG (2): all women with intact membranes, Outcome 3 Caesarean section.

6.6 — Comparison 6 Oral misoprostol versus vaginal PG (2): all women with intact membranes, Outcome 6 Cervix unfavourable/unchanged after 12‐24 hours.

Only two trials provided the data for women with ruptured membranes and there were only data for two outcomes. The number of women who did not achieve vaginal birth within 24 hours was reduced in the misoprostol group (RR 0.60, 95% CI 0.37 to 0.97), Analysis 7.1, i.e. induction with oral misoprostol achieved vaginal birth within the first 24 hours more frequently compared with vaginal dinoprostone. There were no other significant differences in primary outcomes between the subgroups.

7.1 — Comparison 7 Oral misoprostol versus vaginal PG (2): all women with ruptured membranes, Outcome 1 Vaginal delivery not achieved within 24 hours.

Only one study recruited women with previous CSs (n = 267) of which 23 had previous CS. No uterine ruptures were reported.

(3) Comparison with intracervical prostaglandin E2 (analyses 12, 13 and 14)

This comparison was found in five trials, involving 681 women randomised to oral misoprostol or intracervical dinoprostone. Four trials included only women with intact membranes and one included only women with ruptured membranes. Three used misoprostol doses of 50 mcg (352 women) and two used 200 mcg (two trials, 390 women).

Primary outcomes: the rate of uterine hyperstimulation with fetal heart rate (FHR) changes was significantly higher in those treated with misoprostol (RR 3.57, 95% CI 1.11 to 11.54), Analysis 12.2. However, significantly more women in the oral misoprostol group achieved vaginal birth within 24 hours (39% versus 49%, RR 0.78, 95% CI 0.63 to 0.97), Analysis 12.1.

12.2 — Comparison 12 Oral misoprostol versus intracervical PG (3): all women, Outcome 2 Uterine hyperstimulation with FHR changes.

12.1 — Comparison 12 Oral misoprostol versus intracervical PG (3): all women, Outcome 1 Vaginal delivery not achieved within 24 hours.

Secondary outcomes: the rate of uterine hyperstimulation without FHR changes was significantly higher in those treated with misoprostol (RR 6.25, 95% CI 1.14 to 34.31), Analysis 12.8. Only one study considered maternal dissatisfaction, and this was lower in those treated with oral misoprostol (RR 0.51, 95% CI 0.27 to 0.96), Analysis 12.19. There were no other differences between the groups.

12.8 — Comparison 12 Oral misoprostol versus intracervical PG (3): all women, Outcome 8 Uterine hyperstimulation without FHR changes.

12.19 — Comparison 12 Oral misoprostol versus intracervical PG (3): all women, Outcome 19 Women not satisfied.

Subgroups: the subgroups for those with intact membranes found the oral misoprostol group to have a significantly higher rate of uterine hyperstimulation with FHR changes (RR 4.60, 95% CI 1.19 to 17.80), Analysis 13.2. There was an increase in the number of women with a vaginal birth within 24 hours but this was not statistically significant (RR 0.81, 95% CI 0.65 to 1.00), Analysis 13.1. In the subgroup with ruptured membranes, there was only one study and this showed no significant difference in any of the primary outcomes.

13.2 — Comparison 13 Oral misoprostol versus intracervical PG (3): all women with intact membranes, Outcome 2 Uterine hyperstimulation with FHR changes.

13.1 — Comparison 13 Oral misoprostol versus intracervical PG (3): all women with intact membranes, Outcome 1 Vaginal delivery not achieved within 24 hours.

There was substantial heterogeneity for the 'need for oxytocin' outcome (I² = 80%), Analysis 12.7. Sensitivity and subgroup analysis indicated that this was not related to the poor quality study or dose.

12.7 — Comparison 12 Oral misoprostol versus intracervical PG (3): all women, Outcome 7 Oxytocin augmentation.

(4) Comparison with intravenous oxytocin (analyses 15, 16, 17, 18 and 19)

Nine trials including 1282 women have compared oral misoprostol with intravenous oxytocin. Five studies used 100 mcg (818 women), two studies used 50 mcg (178 women), one used 20 mcg solution (30 women) and one study used 25 mcg solution (256 women).

Primary outcomes: the CS rate was significantly lower in women who received oral misoprostol (RR 0.77, 95% CI 0.60 to 0.98), Analysis 15.3, but there were no significant differences seen in any of the other primary outcomes. However, the meta‐analysis of uterine hyperstimulation syndrome indicated substantial heterogeneity, Analysis 15.2. This may be explained by the trial by Crane 2003. which used a dose of 75 mcg four‐hourly. That study found significantly less hyperstimulation with misoprostol, whilst the remainder found no difference.

15.3 — Comparison 15 Oral misoprostol versus oxytocin (4): all women, Outcome 3 Caesarean section.

15.2 — Comparison 15 Oral misoprostol versus oxytocin (4): all women, Outcome 2 Uterine hyperstimulation with FHR changes.

Secondary outcomes: meconium staining of the liquor was seen more frequently in the misoprostol group (RR 1.65, 95% CI 1.04 to 2.60), Analysis 15.11, but this was not reflected in significant differences in any adverse fetal or neonatal outcomes.There were no other statistically significant differences between the oral misoprostol and intravenous oxytocin groups (except for oxytocin use, which was naturally higher in the oxytocin group).

Subgroups: in six of the trials (758 women) there were outcome data for women with ruptured membranes. In this subgroup, the percentage of women with meconium‐stained liquor (and the RR) was similar to that in the overall results (Analysis 15.11), but the reduced numbers meant that the difference was not statistically significant (RR 1.71, 95% CI 0.91 to 3.23), Analysis 16.6.

16.6 — Comparison 16 Oral misoprostol versus oxytocin (4): all women with ruptured membranes, Outcome 6 Meconium‐stained liquor.

There were no data reported for the subgroup of women with intact membranes.

(5) Comparison with sublingual misoprostol (analysis 20)

There was just one study of poor methodological quality in this comparison which compared 50 mcg of oral, vaginal and sublingual misoprostol (50 in each group, Elhassan 2007 (V50)). There was no significant difference in CS rate, but the oral misoprostol group had significantly higher rates of meconium‐stained liquor than the sublingual misoprostol group (RR 10.50, 95% CI 4.07 to 27.09), Analysis 20.2, and significantly lower rates of instrumental vaginal birth (RR 0.47, 95% CI 0.22 to 0.99), Analysis 20.3.

20.2 — Comparison 20 Oral versus sublingual misoprostol (5): all women, Outcome 2 Meconium‐stained liquor.

20.3 — Comparison 20 Oral versus sublingual misoprostol (5): all women, Outcome 3 Instrumental delivery.

(6) Comparison with vaginal misoprostol (analyses 21 to 29)

This was the most commonly studied comparison, with 37 trials and 6417 randomised women.

Primary outcomes: the overall outcome for the rate of uterine hyperstimulation with FHR changes was highly heterogenous. The interaction test indicated that there was a significant difference between dosage subgroups (Test for subgroup differences: Chi² = 18.50, df = 3 (P = 0.0003), I² = 83.8%) with less hyperstimulation in the 25 mcg oral misoprostol dose (RR 0.30, 95% CI 0.07 to 1.19), rising to an increase in hyperstimulation with the 200 mcg oral misoprostol dose (RR 1.61, 95% CI 1.07 to 2.43), Analysis 21.2. Sensitivity analysis revealed that the overall result was not affected by the removal of low‐quality studies.

21.2 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 2 Uterine hyperstimulation with FHR changes.

The overall outcome for vaginal birth within 24 hours was also highly heterogenous, Analysis 21.1, but the interaction test did not indicate a subgroup difference in relation to oral misoprostol dosage. Sensitivity analysis with removal of the low‐quality studies did not explain the heterogeneity.

21.1 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 1 Vaginal delivery not achieved within 24 hours.

The overall outcomes for the CS rate was also heterogenous (Heterogeneity: Tau² = 0.06; Chi² = 60.78, df = 34 (P = 0.003); I² = 44%), Analysis 21.3. The heterogeneity was not affected by the removal of low‐quality studies and the interaction test showed that there was no significant interaction between dosage subgroups.

21.3 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 3 Caesarean section.

There were no other significant findings in the two remaining primary outcomes.

Secondary outcomes: when all the data are considered together, the only statistically significant differences without heterogeneity were a reduction in the Apgars of less than seven at five minutes in the oral misoprostol group (RR 0.60, 95% CI 0.44 to 0.82), Analysis 21.13, and a decrease in postpartum haemorrhage (RR 0.57, 95% CI 0.34 to 0.95), Analysis 21.21. However, the oral misoprostol group had an increase in meconium‐stained liquor (RR 1.22, 95% CI 1.03 to 1.44), Analysis 21.12.

21.13 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 13 Apgar score < 7 at 5 minutes.

21.21 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 21 Postpartum haemorrhage.

21.12 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 12 Meconium‐stained liquor.

The overall outcome for the rate of uterine hyperstimulation without FHR changes was also highly heterogenous, Analysis 21.8. The heterogeneity was not affected by the removal of low‐quality studies and the interaction test showed that there was no significant interaction between dosage subgroups.

21.8 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 8 Uterine hyperstimulation without FHR changes.

The overall outcome for the use of oxytocin was also highly heterogenous, and the interaction test showed that there was a significant dosage subgroup interaction (Test for subgroup differences: Chi² = 9.10, df = 3 (P = 0.03), I² = 67.0%), Analysis 21.7. However, this was not in a dose‐dependent manner. The heterogeneity was not affected by the removal of low‐quality studies.

21.7 — Comparison 21 Oral versus vaginal misoprostol (6): all women, Outcome 7 Oxytocin augmentation.

No uterine ruptures were reported in the women who had previous CSs.

Subgroups:

Intact membranes (analyses 22, 24, 27)

Seventeen of the 34 trials gave data for women with intact membranes. As with the overall data, there was no difference in any of the primary outcomes. The outcomes for vaginal birth not achieved in 24 hours and uterine hyperstimulation with FHR changes showed significant heterogeneity. Only one study examined the effect on vaginal birth within 24 hours in women with intact membranes (Wing 1999 (V25)) according to parity. That study showed a significant worsening in primigravid women given oral misoprostol (RR 1.25, 95% CI 1.01 to 1.55), Analysis 24.1, but not in multiparous women (RR 1.41, 95% CI 0.94 to 2.11), Analysis 27.1.

24.1 — Comparison 24 Oral versus vaginal misoprostol (6): all primiparae, Outcome 1 Vaginal delivery not achieved within 24 hours.

27.1 — Comparison 27 Oral versus vaginal misoprostol (6): all multiparae, Outcome 1 Vaginal delivery not achieved within 24 hours.

Fifteen trials that reported uterine hyperstimulation with FHR changes showed no significant change in hyperstimulation in the oral misoprostol group (average RR 0.83, 95% CI 0.46 to 1.52; Heterogeneity: Tau² = 0.33; Chi² = 22.75, df = 11 (P = 0.02); I² = 52%), Analysis 22.2. However, there was significant heterogeneity in the results, with a significant association with dosage. The two 200 mcg studies had a significantly higher rate of uterine hyperstimulation with FHR changes and removing them from the analysis removed the overall heterogeneity and left the results as (RR 0.41, 95% CI 0.19 to 0.91).

22.2 — Comparison 22 Oral versus vaginal misoprostol (6): all women with intact membranes, Outcome 2 Uterine hyperstimulation with FHR changes.

Ruptured membranes (analysis 25)

Only two trials reported women with ruptured membranes as a subgroup (Jindal 2011 (V50); Puga 2001 (V50)). The only two reported primary outcomes (CS and uterine hyperstimulation with FHR changes) showed no significant difference between oral and vaginal routes, Analysis 25.1; Analysis 25.2.

25.1 — Comparison 25 Oral versus vaginal misoprostol (6): all women with ruptured membranes, Outcome 1 Uterine hyperstimulation with FHR changes.

25.2 — Comparison 25 Oral versus vaginal misoprostol (6): all women with ruptured membranes, Outcome 2 Caesarean section.

Primiparae (analyses 24)

Only three trials reported outcomes for this subgroup. An increase in the number of women who did not birth vaginally within 24 hours was seen in the trial by Wing 1999 (V25), in which a 50 mcg dose was used in primips with intact membranes and an unfavourable cervix (RR 1.25, 95% CI 1.01 to 1.55), Analysis 24.1.

Multiparae (analyses 27)

Only two trials analysed this subgroup of women separately (Hall 2002 (V25); Toppozada 1997 (V100)) and they found no difference in the four reported outcomes, Analysis 27.1; Analysis 27.2; Analysis 27.3; Analysis 27.4.

27.2 — Comparison 27 Oral versus vaginal misoprostol (6): all multiparae, Outcome 2 Caesarean section.

27.3 — Comparison 27 Oral versus vaginal misoprostol (6): all multiparae, Outcome 3 Serious neonatal morbidity or perinatal death.

27.4 — Comparison 27 Oral versus vaginal misoprostol (6): all multiparae, Outcome 4 Serious maternal morbidity or death.

(7) Hourly 20 mcg titrated oral misoprostol versus four‐hourly oral misoprostol 50 mcg (analysis 30)

One study of 64 women compared the effect of using hourly 20 mcg solution and four‐hourly 50 mcg solution (Thaisomboon 2012 (T)). There were no differences in any of the 12 outcomes, Analysis 30.1; Analysis 30.2; Analysis 30.3; Analysis 30.4; Analysis 30.5; Analysis 30.6; Analysis 30.7; Analysis 30.8; Analysis 30.9; Analysis 30.10; Analysis 30.11; Analysis 30.12.

30.1 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 1 Vaginal delivery not achieved within 24 hours.

30.2 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 2 Caesarean section.

30.3 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 3 Serious neonatal morbidity or perinatal death.

30.4 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 4 Oxytocin augmentation.

30.5 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 5 Uterine hyperstimulation without FHR changes.

30.6 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 6 Uterine rupture.

30.7 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 7 Apgar score < 7 at 5 minutes.

30.8 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 8 Neonatal intensive care unit admission.

30.9 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 9 Nausea.

30.10 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 10 Vomiting.

30.11 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 11 Diarrhoea.

30.12 — Comparison 30 Hourly 20mcg titrated oral misoprostol versus 4‐hrly oral misoprostol 50mcg (7): all women, Outcome 12 Postpartum haemorrhage.

(8) Oral misoprostol 25 mcg three‐daily versus 50 mcg three‐daily (analysis 31)

In one study (Kipikasa 2005), single oral doses of misoprostol were given every three days to women as outpatients. In this study there was no significant difference in any of the reported outcomes, Analysis 31.1; Analysis 31.2; Analysis 31.3; Analysis 31.4; Analysis 31.5; Analysis 31.6; Analysis 31.7; Analysis 31.8; Analysis 31.9; Analysis 31.10; Analysis 31.11; Analysis 31.12; Analysis 31.13; Analysis 31.14; Analysis 31.15.

31.1 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 1 Uterine hyperstimulation with FHR changes.

31.2 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 2 Caesaraean section.

31.3 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 3 Serious maternal morbidity or death.

31.4 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 4 Oxytocin augmentation.

31.5 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 5 Uterine hyperstimulation without FHR changes.

31.6 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 6 Uterine rupture.

31.7 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 7 Meconium‐stained liquor.

31.8 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 8 Neonatal intensive care unit admission.

31.9 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 9 Perinatal death.

31.10 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 10 Nausea.

31.11 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 11 Maternal side effects(all).

31.12 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 12 Nausea.

31.13 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 13 Vomiting.

31.14 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 14 Diarrhoea.

31.15 — Comparison 31 Oral misoprostol 25 mcg 3‐daily versus 50 mcg 3‐daily (8): all women, Outcome 15 Shivering.

(9) Oral misoprostol 50 mcg versus 100 mcg (analyses 32, 33, 34)

Two studies containing 317 women addressed the relationship between the 50 and 100 mcg doses (Cheung 2006; Shetty 2002). There were no significant differences between the 50 mcg and 100 mcg oral doses in any of the 11 outcomes assessed.

(10) Oral misoprostol 50 mcg, three‐ to four‐hourly versus six‐hourly (analyses 35, 36)

Two trials compared the outcomes when women were given oral tablets either three‐ to four‐hourly or six‐hourly. One study with 89 women (Pongsatha 2001) compared 50 mcg oral regimen four‐ or six‐hourly whilst the other, with 133 women (Pongsatha 2002), compared 100 mcg given orally three‐ or six‐hourly. There were no differences in any of the outcomes studied when the data were combined, although there was significant heterogeneity in results for the outcomes of uterine hyperstimulation with FHR changes and oxytocin augmentation. In the study using 100 mcg, there was significantly less need for oxytocin augmentation when the misoprostol was given three‐ to four‐hourly compared to when it was used six hourly (RR 0.72, 95% CI 0.54 to 0.96), Analysis 35.3.2.

35.3 — Comparison 35 Oral misoprostol 3/4‐hourly versus 6‐hourly (10): all women, Outcome 3 Oxytocin augmentation.

(11) Oral misoprostol three‐hourly versus oral misoprostol x two then routine oxytocin (analyses 37 and 38)

One study compared the use of oral misoprostol 25 mcg used three‐hourly until in labour with a policy of two oral misoprostol doses (25 mcg) followed by routine oxytocin (De 2006). There were no statistically significant differences in any of the 10 outcomes.

(12) Oral misoprostol versus delayed vaginal prostaglandins (analysis 39)

Another small study of 61 women compared two policies for dealing with ruptured membranes at term (Shetty 2002a). One group had immediate oral misoprostol (50 mcg) whilst the other waited for 24 hours and then had vaginal prostaglandins (1 mg or 2 mg depending on Bishop Score). The only statistically significant outcome was in the 'vaginal birth not achieved in 24 hours' outcome, which was reduced in the immediate oral misoprostol group (RR 0.52, 95% CI 0.32 to 0.83), Analysis 39.1.

39.1 — Comparison 39 Oral misoprostol versus delayed vaginal postaglandins (12): all women, Outcome 1 Vaginal delivery not achieved in 24 hours.

(13) Oral misoprostol versus dinoprostone vaginal insert (analysis 40)

One study compared the use of hourly titrated oral misoprostol with 10 mcg dinoprostone vaginal insert placed for a maximum of 24 hours (Rouzi 2014). There were no statistically significant differences in any of the 10 outcomes.

Discussion

Efficacy compared to other induction agents

Oral misoprostol is more effective than placebo and equivalent to intravenous oxytocin, vaginal misoprostol and vaginal dinoprostone for the induction of labour in women. Oral misoprostol results in fewer caesarean sections than oxytocin alone. In the comparisons with oxytocin infusions, there seems to be a higher rate of meconium staining at all dosages, but this was not associated with any adverse effect on the fetus. It is possible that the meconium staining could be a direct effect of the misoprostol on the fetal gut. Gastrointestinal stimulation leading to diarrhoea is a well‐described side effect of oral misoprostol in adults, and small amounts of misoprostol in the fetus could lead to the expulsion of meconium and hence meconium‐stained liquor. This effect is also seen with vaginal misoprostol, but it appears to be smaller. This may be due to the lower peak serum concentrations that occur following vaginal administration.

There have been concerns in the past about uterine hyperstimulation with oral misoprostol. In studies where most women were given low dose oral misoprostol (20‐25 mcg two‐hourly), the hyperstimulation rates were the same as for vaginal dinoprostone (i.e. around 5% overall and 2.9% with fetal heart rate (FHR) abnormalities).

There were fewer studies comparing oral misoprostol and intracervical dinoprostone, but these found that the oral misoprostol (at doses of 50 and 200 mcg) resulted in stronger contractions than the dinoprostone. This led to higher rates of hyperstimulation and a more rapid labour, but with no effect on fetal outcomes.

Whilst no increase in adverse fetal outcomes was seen in these studies, this meta‐analysis contains too few studies to exclude a difference in adverse outcomes which are rare (see additional Table 1 for numbers needed). However, the comparable safety data on vaginal dinoprostone are also limited. There are nearly 14,000 women in the trials in this review, which compares favourably with the Cochrane review of the current standard treatment vaginal dinoprostone (PGE2) with 10,000 women (Kelly 2009).

1. Sample size calculation.

Outcomes	Baseline rate	? Important change	Rel. Risk	Total sample size
Failure to achieve vaginal birth within 24 hours	30%	21%	0.7	778
Caesarean section (CS)	10%	7%	0.7	1294
Hyperstimulation	1%	0.7%	0.7	30,716
Perinatal mortality and morbidity	0.5%	0.35%	0.7	61,686
Uterine rupture in women with previous CS	0.5%	0.35%	0.7	61,686
Maternal death or serious morbidity	0.2%	0.14%	0.7	154,598

Date	Event	Description
26 April 2018	Feedback has been incorporated	The authors have responded to Feedback 1 and Feedback 2.
21 March 2018	Amended	The review has been amended following Feedback 1 and Feedback 2. In the previous version of this review, we erroneously included a study (Matonhodze 2003) that was actually a subset of another multicentre included study (Hofmeyr 2001(T)). This has now been rectified and we have adjusted the results of the comparison with vaginal dinoprostone. Consequently, the results and discussion have been amended accordingly. This review will no longer be updated in its current form and Published notes has been updated with more information about this.

Date	Event	Description
13 April 2015	Feedback has been incorporated	Feedback 2 submitted by Eva Rydahl and Jette Aaroe Clausen.
9 April 2015	Feedback has been incorporated	Feedback 1 submitted by Jim Thornton.
17 January 2014	New citation required but conclusions have not changed	Nineteen new studies included: (Aalami‐Harandi 2013 (T); Deshmukh 2013 (V50); Elhassan 2007 (V50); Henrich 2008 (T); Javaid 2008; Jindal 2011 (V50); Khazardoost 2011 (V25); Kipikasa 2005; Mehrotra 2010 (V50); Nagpal 2009; Rahman 2013 (V25); Rath 2007; Rizvi 2007 (V25); Rouzi 2014; Sheikher 2009 (V25); Sitthiwattanawong 1999; Souza 2013(V25)(T); Sultana 2006 (V100); Thaisomboon 2012 (T)).
17 January 2014	New search has been performed	Search updated and updated meta‐analysis and text.
21 September 2009	Amended	Search updated. Twenty‐two reports added to Studies awaiting classification.
5 June 2008	New search has been performed	Search updated. Fifteen new studies have been added.
5 June 2008	Amended	Converted to new review format.
31 October 2005	New search has been performed	Search updated; 28 new trials have been added to the review and the text has been updated.
31 October 2005	New citation required and conclusions have changed	Previously, with only 13 trials in total, most of the comparisons showed no major differences. Now, with over 8600 women randomised in 41 trials, differences between the induction methods are emerging. Oral misoprostol is now found to be more effective than placebo, as effective as oxytocin (in women with ruptured membranes) and possibly more effective than vaginal dinoprostone. With higher doses of misoprostol, uterine hyperstimulation is a problem. A 50 mcg oral dose is as effective as vaginal misoprostol and there is a lower rate of side effects. It may therefore be preferable.    As with all methods of induction there remain unanswered questions about safety. For rarer outcomes such as uterine rupture or stillbirth the meta‐analysis is still too small to demonstrate significant differences. Whilst these doubts remain, the use of products licensed for induction (e.g. dinoprostone and oxytocin) is recommended.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.05, 0.49]
1.1 100 mcg	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.05, 0.49]
2 Uterine hyperstimulation with FHR changes	7	669	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [0.84, 8.68]
2.1 50 mcg	2	195	Risk Ratio (M‐H, Fixed, 95% CI)	5.15 [0.25, 105.31]
2.2 100 mcg	3	238	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [0.54, 8.87]
2.3 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	3.15 [0.13, 75.08]
3 Caesarean section	8	1029	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.54, 0.95]
3.1 Dose not specified	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.38, 1.32]
3.2 50 mcg	3	495	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.54, 1.35]
3.3 100 mcg	2	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.40, 1.40]
3.4 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.28, 0.97]
4 Serious neonatal morbidity or perinatal death	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.1 200 mcg	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.1 200 mcg	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Epidural analgesia	2	232	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.69, 0.96]
6.1 50 mcg	1	130	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.77, 1.03]
6.2 100 mcg	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.44, 1.01]
7 Oxytocin augmentation	7	933	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.37, 0.49]
7.1 Dose not specified	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.43, 0.97]
7.2 50 mcg	3	495	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.38, 0.55]
7.3 100 mcg	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.29, 0.60]
7.4 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.16, 0.40]
8 Uterine hyperstimulation without FHR changes	5	784	Risk Ratio (M‐H, Random, 95% CI)	4.78 [0.73, 31.23]
8.1 50 mcg	2	430	Risk Ratio (M‐H, Random, 95% CI)	2.06 [0.39, 10.87]
8.2 100 mcg	2	198	Risk Ratio (M‐H, Random, 95% CI)	13.0 [1.77, 95.73]
8.3 200 mcg	1	156	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Postpartum haemorrhage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Instrumental vaginal delivery	5	379	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.37, 1.17]
11.1 50 mcg	3	197	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.30, 3.32]
11.2 100 mcg	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.4 [0.13, 1.19]
11.3 200 mcg	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.31, 1.74]
12 Meconium‐stained liquor	4	561	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.66, 1.89]
12.1 50 mcg	2	365	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.65, 2.60]
12.2 100 mcg	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.31, 3.11]
12.3 200 mcg	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.27, 2.62]
13 Apgar score < 7 at 5 minutes	3	332	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.24, 2.26]
13.1 100 mcg	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.22]
13.2 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.26, 3.95]
14 Neonatal intensive care unit admission	5	734	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.32, 0.56]
14.1 50 mcg	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.27, 0.50]
14.2 100 mcg	2	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.36, 1.68]
14.3 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.15, 2.52]
15 Perinatal death	2	180	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.99]
15.1 Dose not specified	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.99]
15.2 200 mcg	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Nausea	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.24, 102.49]
16.1 200 mcg	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.24, 102.49]
17 Vomiting	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [0.42, 6.93]
17.1 200 mcg	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [0.42, 6.93]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation with FHR changes	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.37, 132.17]
2 Caesarean section	2	172	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.39, 1.64]
3 Serious maternal morbidity or death	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	5	2128	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.22]
1.1 25 mcg	4	1928	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.99, 1.25]
1.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.83, 1.29]
2 Uterine hyperstimulation with FHR changes	7	2352	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.59, 1.53]
2.1 25 mcg	4	1827	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.51, 1.41]
2.2 50 mcg	2	325	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.26, 9.01]
2.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.24, 102.85]
3 Caesarean section	10	3240	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.81, 1.04]
3.1 25 mcg	6	2355	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.75, 1.01]
3.2 50 mcg	3	685	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.83, 1.35]
3.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.58, 1.48]
4 Serious neonatal morbidity or perinatal death	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.1 25 mcg	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	2	1436	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.1 25 mcg	2	1436	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Cervix unfavourable/unchanged after 12‐24 hours	2	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.01, 1.96]
6.1 25 mcg	2	930	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [1.01, 1.96]
6.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Oxytocin augmentation	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 25 mcg	3	1239	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.73, 1.30]
7.2 50 mcg	3	685	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.97, 1.69]
7.3 100 mcg	1	200	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.98, 1.66]
8 Uterine hyperstimulation without FHR changes	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
8.1 25 mcg	5	2123	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.32, 2.03]
8.2 50 mcg	2	325	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.29, 1.76]
8.3 100 mcg	1	200	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.37, 133.78]
9 Ruptured uterus	7	2757	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.1 25 mcg	5	2130	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 50 mcg	2	627	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Epidural analgesia	2	799	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.98, 1.19]
10.1 25 mcg	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.98, 1.22]
10.2 50 mcg	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.76, 1.18]
11 Instrumental vaginal delivery	6	2524	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.88, 1.24]
11.1 25 mcg	4	1857	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.83, 1.30]
11.2 50 mcg	2	467	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.73, 1.45]
11.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.71, 1.75]
12 Meconium‐stained liquor	8	2548	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.86, 1.32]
12.1 25 mcg	4	1463	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.89, 1.54]
12.2 50 mcg	4	885	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.67, 1.44]
12.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.41, 1.60]
13 Apgar score < 7 at 5 minutes	6	2181	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.32, 1.10]
13.1 25 mcg	4	1856	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.35, 1.25]
13.2 50 mcg	2	325	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.16]
14 Neonatal intensive care unit admission	9	3181	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.59, 1.05]
14.1 25 mcg	6	2354	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.57, 1.10]
14.2 50 mcg	2	627	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.19, 1.53]
14.3 100 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.47, 2.12]
15 Neonatal encephalopathy	2	1101	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.1 25 mcg	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 50 mcg	1	360	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Perinatal death	4	1899	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.06, 15.97]
16.1 25 mcg	3	1632	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.06, 15.97]
16.2 50 mcg	1	267	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (all)	3	1632	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.77, 1.36]
17.1 25 mcg	3	1632	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.77, 1.36]
17.2 50 mcg	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
18 Nausea	3	1023	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.44, 1.11]
18.1 25 mcg	2	965	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.41, 1.07]
18.2 50 mcg	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	2.14 [0.21, 22.35]
19 Vomiting	3	1632	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.79, 1.54]
19.1 25 mcg	2	1432	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.71, 1.56]
19.2 50 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.68, 2.35]
20 Diarrhoea	2	965	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.87]
20.1 25 mcg	2	965	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.87]
20.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
21 Shivering	2	891	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.81, 1.37]
21.1 25 mcg	2	891	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.81, 1.37]
21.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
22 Postpartum haemorrhage	3	1633	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.11]
22.1 25 mcg	3	1633	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.11]
22.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 Serious maternal complications	1	692	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.1 25 mcg	1	692	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
23.2 50 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 Hyperpyrexia	2	965	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
24.1 25 mcg	2	965	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	4	1666	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [1.01, 1.25]
2 Uterine hyperstimulation with FHR changes	4	1218	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.51, 3.09]
3 Caesarean section	6	2129	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.73, 0.99]
4 Serious neonatal morbidity or perinatal death	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.1 25 mcg	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.1 25 mcg	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Cervix unfavourable/unchanged after 12‐24 hours	1	741	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [1.03, 2.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	2	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.37, 0.97]
2 Caesarean section	1	125	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.81, 5.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	2	437	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.86, 1.79]
2 Uterine hyperstimulation with FHR changes	2	320	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.22, 12.46]
3 Caesarean section	2	580	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.56, 1.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	2	453	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.61, 1.27]
2 Uterine hyperstimulation with FHR changes	1	171	Risk Ratio (M‐H, Fixed, 95% CI)	2.7 [0.29, 25.44]
3 Caesarean section	1	334	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.62, 1.24]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	3	452	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.63, 0.97]
1.1 50 mcg	2	252	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.63, 1.10]
1.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.52, 1.00]
2 Uterine hyperstimulation with FHR changes	3	490	Risk Ratio (M‐H, Fixed, 95% CI)	3.57 [1.11, 11.54]
2.1 50 mcg	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.55]
2.2 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	4.6 [1.19, 17.80]
3 Caesarean section	5	742	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.63, 1.16]
3.1 50 mcg	3	352	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.59, 1.45]
3.2 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.52, 1.22]
4 Serious neonatal morbidity or perinatal death	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Cervix unfavourable/unchanged after 12‐24 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.43, 1.03]
6.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.43, 1.03]
7 Oxytocin augmentation	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 50 mcg	3	352	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.20, 1.88]
7.2 200 mcg	1	200	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.61, 0.96]
8 Uterine hyperstimulation without FHR changes	2	251	Risk Ratio (M‐H, Fixed, 95% CI)	6.25 [1.14, 34.31]
8.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.06, 14.78]
8.2 200 mcg	1	190	Risk Ratio (M‐H, Fixed, 95% CI)	17.0 [1.00, 290.42]
9 Uterine rupture	4	642	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.1 50 mcg	2	252	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Perinatal death	2	391	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Instrumental vaginal delivery	3	451	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.62, 1.44]
11.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 5.06]
11.2 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.63, 1.49]
12 Meconium‐stained liquor	3	452	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [0.96, 2.36]
12.1 50 mcg	2	252	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [0.84, 3.03]
12.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.77, 2.67]
13 Apgar score < 7 at 5 minutes	2	391	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.07]
13.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.07]
13.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Neonatal intensive care unit admission	4	552	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.48, 2.06]
14.1 50 mcg	3	352	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 5.06]
14.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.51, 2.36]
15 Neonatal encephalopathy	2	391	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Maternal death	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (all)	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.05, 5.43]
17.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.05, 5.43]
18 Postpartum haemorrhage	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 5.06]
19 Women not satisfied	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.27, 0.96]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	2	391	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.65, 1.00]
1.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.67, 1.19]
1.2 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.52, 1.00]
2 Uterine hyperstimulation with FHR changes	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	4.6 [1.19, 17.80]
2.1 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	4.6 [1.19, 17.80]
3 Caesarean section	3	581	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.62, 1.20]
3.1 50 mcg	1	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.59, 1.66]
3.2 200 mcg	2	390	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.52, 1.22]
4 Serious neonatal morbidity or perinatal death	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.1 200 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.16, 1.44]
1.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.16, 1.44]
2 Caesarean section	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.21, 4.42]
2.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.21, 4.42]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	3	265	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.56, 1.64]
2 Uterine hyperstimulation with FHR changes	6	749	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.33, 3.05]
3 Caesarean section	6	758	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.66, 1.28]
4 Serious neonatal morbidity or perinatal death	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Meconium‐stained liquor	4	648	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.91, 3.23]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation with FHR changes	1	303	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [0.82, 3.01]
2 Caesarean section	2	362	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.67, 1.52]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Caesarean section	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.74, 3.26]
1.1 50 mcg	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.74, 3.26]
2 Meconium‐stained liquor	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	10.5 [4.07, 27.09]
2.1 50 mcg	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	10.5 [4.07, 27.09]
3 Instrumental delivery	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.22, 0.99]
3.1 50mcg	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.22, 0.99]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	14	2448	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.86, 1.36]
1.1 25 mcg	3	627	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.27, 1.90]
1.2 50 mcg	7	1249	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.93, 1.61]
1.3 100 mcg	3	394	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.63, 1.55]
1.4 200 mcg	1	178	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.64, 1.67]
2 Uterine hyperstimulation with FHR changes	29	5503	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.47, 1.08]
2.1 25 mcg	3	627	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.07, 1.19]
2.2 50 mcg	16	2507	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.23, 0.70]
2.3 100 mcg	8	1187	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.66, 1.87]
2.4 200 mcg	2	1182	Risk Ratio (M‐H, Random, 95% CI)	1.61 [1.07, 2.43]
3 Caesarean section	35	6326	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.81, 1.07]
3.1 25 mcg	2	407	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.11, 2.68]
3.2 50 mcg	20	3348	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.79, 1.14]
3.3 100 mcg	12	1389	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.66, 1.09]
3.4 200 mcg	2	1182	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.48]
4 Serious neonatal morbidity or perinatal death	10	1772	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.33]
4.1 25 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 50 mcg	6	1203	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.60, 1.33]
4.3 100 mcg	2	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 200 mcg	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	9	1389	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 20.90]
5.1 25 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 50 mcg	6	971	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 20.90]
5.3 100 mcg	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 200 mcg	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Serious maternal complications	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.1 25mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Oxytocin augmentation	31	5756	Risk Ratio (M‐H, Random, 95% CI)	1.20 [1.08, 1.34]
7.1 25 mcg	3	627	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.27, 2.23]
7.2 50 mcg	18	2930	Risk Ratio (M‐H, Random, 95% CI)	1.44 [1.15, 1.79]
7.3 100 mcg	8	1017	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.90, 1.22]
7.4 200 mcg	2	1182	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.93, 1.09]
8 Uterine hyperstimulation without FHR changes	18	2621	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.46, 1.03]
8.1 25 mcg	3	627	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.19, 1.16]
8.2 50 mcg	9	1318	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.44, 1.27]
8.3 100 mcg	6	676	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.33, 1.71]
9 Uterine rupture	8	2276	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.1 25 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 50 mcg	6	1072	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 200 mcg	1	1004	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Epidural analgesia	5	1859	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.96, 1.11]
10.1 25 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.12, 72.77]
10.2 50 mcg	3	655	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.95, 1.19]
10.3 200 mcg	1	1004	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.91, 1.11]
11 Instrumental vaginal delivery	18	3485	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.86, 1.22]
11.1 25 mcg	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 6.96]
11.2 50 mcg	11	1767	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.82, 1.30]
11.3 100 mcg	5	514	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.92, 2.27]
11.4 200 mcg	1	1004	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.61, 1.18]
12 Meconium‐stained liquor	24	3634	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [1.03, 1.44]
12.1 25 mcg	2	420	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.74, 1.88]
12.2 50 mcg	13	2194	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [1.02, 1.59]
12.3 100 mcg	9	1020	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.82, 1.54]
13 Apgar score < 7 at 5 minutes	19	4009	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.44, 0.82]
13.1 25 mcg	3	627	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.15, 1.02]
13.2 50 mcg	10	1701	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.33, 0.87]
13.3 100 mcg	4	499	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.17, 1.22]
13.4 200 mcg	2	1182	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.51, 1.37]
14 Neonatal intensive care unit admission	22	4170	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.86, 1.20]
14.1 25 mcg	2	427	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.27, 1.64]
14.2 50 mcg	10	1648	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.80, 1.32]
14.3 100 mcg	9	913	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.65, 1.25]
14.4 200 mcg	2	1182	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.85, 1.75]
15 Neonatal encephalopathy	5	1014	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.10]
15.1 25 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 50 mcg	4	907	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.10]
15.3 100 mcg	1	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Perinatal death	9	1434	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.1 25 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.2 50 mcg	4	797	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.3 100 mcg	5	459	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16.4 200 mcg	1	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (all)	3	447	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.53, 1.50]
17.1 25 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 50 mcg	1	173	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.49, 1.55]
17.3 100 mcg	2	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.29, 3.21]
18 Nausea	9	1563	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.94, 1.60]
18.1 25 mcg	3	627	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.03, 2.47]
18.2 50 mcg	4	777	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.70, 1.38]
18.3 100 mcg	2	159	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.49, 18.78]
19 Vomiting	10	1635	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.90, 1.79]
19.1 25 mcg	3	627	Risk Ratio (M‐H, Fixed, 95% CI)	1.62 [0.90, 2.93]
19.2 50 mcg	5	797	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.62, 1.53]
19.3 100 mcg	2	211	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.63, 14.59]
20 Diarrhoea	14	2300	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.78, 1.95]
20.1 25 mcg	3	627	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.63, 3.63]
20.2 50 mcg	7	1226	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.58, 1.92]
20.3 100 mcg	4	447	Risk Ratio (M‐H, Fixed, 95% CI)	1.57 [0.42, 5.85]
21 Postpartum haemorrhage	10	1478	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.34, 0.95]
21.1 25 mcg	2	420	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.17, 2.40]
21.2 50 mcg	4	698	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.35, 1.25]
21.3 100 mcg	4	360	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.12, 1.13]
22 Woman not satisfied	1	204	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.08, 18.82]
22.1 25 mcg	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 50 mcg	1	204	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.08, 18.82]
23 Vaginal delivery not achieved within 24 hours (subgroup by quality)	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
23.1 High quality	13	2248	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.81, 1.37]
23.2 Unknown/poor quality	1	59	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.50, 1.58]
24 Shivering	3	539	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.43, 1.80]
24.1 25 mcg	1	207	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.07, 16.56]
24.2 50 mcg	2	332	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.41, 1.82]
25 Uterine hyperstimulation with FHR changes (subgroup by quality)	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
25.1 High quality	18	3911	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.39, 1.13]
25.2 Unknown/poor quality	10	1392	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.28, 1.49]
26 Caesarean section (subgroup by quality)	34	5948	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.79, 1.06]
26.1 High quality	19	4010	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.71, 1.03]
26.2 Unknown/poor quality	15	1938	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.78, 1.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	7	1104	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.98, 1.76]
2 Uterine hyperstimulation with FHR changes	14	3068	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.46, 1.52]
3 Caesarean section	17	3494	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.89, 1.14]
4 Serious neonatal morbidity or perinatal death	4	755	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious maternal morbidity or death	4	732	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	1	106	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [1.01, 1.55]
2 Serious neonatal morbidity or perinatal death	1	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Serious maternal morbidity or death	1	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation with FHR changes	2	373	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.71, 2.29]
2 Caesarean section	2	373	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.81, 2.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.94, 2.11]
2 Caesarean section	2	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.11, 1.65]
3 Serious neonatal morbidity or perinatal death	2	138	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Serious maternal morbidity or death	2	138	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

PERMALINK

Oral misoprostol for induction of labour

Zarko Alfirevic

Nasreen Aflaifel

Andrew Weeks

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Placebo/no treatment as comparator

Dinoprostone as comparator

Oxytocin as comparator

Vaginal misoprostol as comparator

Sublingual misoprostol as comparator

Vaginal dinoprostone insert as comparator

Other comparisons

Excluded studies

Risk of bias in included studies

1.

2.

Allocation

Sequence generation

Allocation concealment

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

(1) Comparison with placebo (analyses 1 to 4)

1.1. Analysis.

1.3. Analysis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.92, 2.00]
2 Caesarean section	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.77, 2.22]
3 Serious neonatal morbidity or perinatal death	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Oxytocin augmentation	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.59, 1.68]
5 Uterine hyperstimulation without FHR changes	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.92, 17.40]
6 Uterine rupture	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Apgar score < 7 at 5 minutes	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Neonatal intensive care unit admission	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Nausea	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Vomiting	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Diarrhoea	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.00]
12 Postpartum haemorrhage	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved within 24 hours	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.95, 1.40]
2 Uterine hyperstimulation with FHR changes	2	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.09]
3 Caesarean section	2	317	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.73, 1.70]
4 Uterine hyperstimulation without FHR changes	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.01, 4.01]
5 Oxytocin augmentation	2	317	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.90, 1.46]
6 Epidural analgesia	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.66, 1.30]
7 Instrumental vaginal delivery	2	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.59, 1.38]
8 Meconium‐stained liquor	2	317	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.71, 1.90]
9 Apgar score < 7 at 5 minutes	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.06, 15.69]
10 Neonatal intensive care unit admission	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.39, 1.63]
11 Nausea	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.71, 1.55]
12 Diarrhoea	1	251	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation with FHR changes	2	222	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.07, 4.30]
1.1 50mcg	1	89	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.02, 1.42]
1.2 100mcg	1	133	Risk Ratio (M‐H, Random, 95% CI)	1.43 [0.25, 8.31]
2 Caesarean section	2	222	Risk Ratio (M‐H, Fixed, 95% CI)	1.41 [0.71, 2.80]
2.1 50 mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	1.60 [0.49, 5.30]
2.2 100mcg	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.56, 3.06]
3 Oxytocin augmentation	2	222	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.63, 1.07]
3.1 50mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.63, 2.08]
3.2 100mcg	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.54, 0.96]
4 Uterine hyperstimulation without FHR changes	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.25, 8.31]
4.1 100mcg	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.25, 8.31]
5 Instrumental vaginal delivery	2	222	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.23, 1.61]
5.1 50mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.16, 2.53]
5.2 100mcg	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.14, 2.30]
6 Meconium‐stained liquor	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	3.20 [0.13, 76.60]
6.1 50mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	3.20 [0.13, 76.60]
7 Nausea	2	222	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.04, 1.31]
7.1 50mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.51]
7.2 100mcg	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.02, 1.59]
8 Diarrhoea	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.51]
8.1 50mcg	1	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.01, 8.51]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.56, 1.42]
2 Uterine hyperstimulation with FHR changes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Caesarean section	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.44, 1.73]
4 Uterine hyperstimulation without FHR changes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.77]
5 Instrumental vaginal delivery	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.31, 5.81]
6 Apgar score < 7 at 5 minutes	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Neonatal intensive care unit admission	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.77]
8 Postpartum haemorrhage	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Diarrhoea	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Vomiting	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.31, 5.81]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.59, 1.47]
2 Caesarean section	1	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.48, 1.89]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24 hours	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.32, 0.83]
1.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.32, 0.83]
2 Uterine hyperstimulation with FHR changes	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Caesarean section	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.33, 3.21]
3.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.33, 3.21]
4 Oxytocin augmentation	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.44, 1.49]
4.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.44, 1.49]
5 Uterine hyperstimulation without FHR changes	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.16, 6.87]
5.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.16, 6.87]
6 Instrumental vaginal delivery	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.61, 2.60]
6.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.61, 2.60]
7 Apgar score < 7 at 5 minutes	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Neonatal intensive care unit admission	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
8.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
9 Nausea	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.22, 2.20]
9.1 50 mcg	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.22, 2.20]
10 Oxytocin augmentation	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation with FHR changes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.4 [0.46, 4.23]
2 Caesarean section	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.24, 1.05]
3 Serious neonatal morbidity/perinatal death	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.88, 55.60]
4 Oxytocin augmentation	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.58, 1.06]
5 Uterine hyperstimulation without FHR changes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.50, 3.28]
6 Meconium‐stained liquor	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.39, 2.53]
7 Apgar score < 7 at 5 minutes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Perinatal death	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.71]
9 Nausea	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.32, 28.23]
10 Vomiting	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 21.62]

Methods	Computer‐generated randomisation.
Participants	260 with singleton cephalic pregnancy and a live fetus at term with BS < 6.
Interventions	Group 1: oral misoprostol 200 mcg dissolved in 200 mL of water. 25 mL was administered every 2 hrs until contractions started for a maximum 12 doses. Group 2: oxytocin at infusion rate of 2 mU/min increased by 2 mU/min every 15 minutes to a maximum dose 38 mU/min.
Outcomes	Labour and delivery outcomes.  Limited neonatal outcomes. Limited side effect outcomes.
Notes	4 postrandomisation exclusions.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	The study did not address this outcome.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Non‐blinded trial.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Non‐blinded trial.

Methods	Sequentially numbered opaque envelopes.
Participants	178 women with intact membranes and unfavourable cervix (BS < 7). Each woman had either medical or obstetric complication requiring delivery.
Interventions	Oral misoprostol 200 mcg and 1/2 tablet placebo vaginally or oral placebo tablet and a 1/2 tablet of 100 mcg misoprostol (50 mcg) vaginally. Doses were repeated every 6 hours (maximum 3) or until labour was established.
Outcomes	Labour and delivery outcomes.  Neonatal outcomes.
Notes	No postrandomisation exclusions.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Block randomisation‐no more details.
Allocation concealment (selection bias)	Low risk	Placebo controlled trial.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Other bias	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Randomised double blinded study.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Randomised double blinded study.

Methods	"Randomized", but method not specified.
Participants	80 women with singleton pregnancies and BS < 5.
Interventions	Oral or vaginal misoprostol 50 mcg 6‐hourly (max 4 doses).
Outcomes	Brief maternal and fetal outcomes.
Notes	Short report only ‐ few details.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomized", but method not specified.
Allocation concealment (selection bias)	Unclear risk	Method was not described.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Other bias	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’.