Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine fetal death

Jodie M Dodd; Caroline A Crowther

doi:10.1002/14651858.CD004901.pub2

. 2010 Apr 14;2010(4):CD004901. doi: 10.1002/14651858.CD004901.pub2

Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine fetal death

Jodie M Dodd ¹, Caroline A Crowther ²

Editor: Cochrane Pregnancy and Childbirth Group³

PMCID: PMC6494643 PMID: 20393941

Abstract

Background

A woman may need to give birth prior to the spontaneous onset of labour in situations where the fetus has died in utero (also called a stillbirth), or for the termination of pregnancy where the fetus, if born alive would not survive or would have a permanent handicap. Misoprostol is a prostaglandin medication that can be used to induce labour in these situations.

Objectives

To compare the benefits and harms of misoprostol to induce labour to terminate pregnancy in the second and third trimester for women with a fetal anomaly or after intrauterine fetal death when compared with other methods of induction of labour.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2009).

Selection criteria

Randomised controlled trials comparing misoprostol with placebo or no treatment, or any other method of induction of labour, for women undergoing induction of labour to terminate pregnancy in the second and third trimester following an intrauterine fetal death or for fetal anomalies.

Data collection and analysis

Both authors independently assessed trial quality and extracted data.

Main results

We included 38 studies (3679 women).

Nine studies included pregnancies after intrauterine deaths, five studies included termination of pregnancies because of fetal anomalies when the fetus was still alive and the rest (24) presented the pooled data for intrauterine deaths, fetal anomalies and social reasons.

When compared with agents that have traditionally been used to induce labour in this setting (for example, gemeprost, prostaglandin E₂ and prostaglandin F_2alpha), vaginal misoprostol is as effective in ensuring vaginal birth within 24 hours, with a similar induction to birth interval. Vaginal misoprostol is associated with a reduction in the occurrence of maternal gastrointestinal side effects such as nausea, vomiting and diarrhoea when compared with other prostaglandin preparations. While the different treatments involving various prostaglandin preparations appear comparable for the reported outcomes, the information available regarding rare maternal complications, such as uterine rupture, is limited.

Authors' conclusions

The use of vaginal misoprostol in the termination of second and third trimester of pregnancy is as effective as other prostaglandin preparations (including cervagem, prostaglandin E₂ and prostaglandin F_2alpha), and more effective than oral administration of misoprostol. However, important information regarding maternal safety, and in particular the occurrence of rare outcomes such as uterine rupture, remains limited. Future research efforts should be directed towards determining the optimal dose and frequency of administration, with particular attention to standardised reporting of all relevant outcomes and assessment of rare adverse events. Further information is required about the use of sublingual misoprostol in this setting.

Plain language summary

Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or following intrauterine fetal death

A woman may need to give birth prior to the spontaneous onset of labour in middle to late pregnancy to terminate the pregnancy in situations where the fetus, if born alive, would not survive or would have permanent handicaps, or where the fetus has died in utero (also called a stillbirth). Misoprostol is a prostaglandin medication that can be used to induce labour in these situations. This review included 38 randomised controlled studies, involving 3679 women. Vaginal misoprostol was as effective as other agents in inducing labour and achieving vaginal birth within 24 hours, with a reduction in the occurrence of maternal side effects. Side effects include gastrointestinal disturbance (nausea, vomiting, diarrhoea). The information on rare adverse events (including uterine rupture) is limited.

Background

Description of the condition

A woman may need to give birth prior to the spontaneous onset of labour in situations where the fetus has died in utero (also called a stillbirth), or for the termination of pregnancy where the fetus, if born alive, would not survive or would have significant disability. This situation is psychologically stressful for the woman, her partner and family, and for the health professionals caring for her.

When a baby dies before birth, the options for care are either to wait for labour to start spontaneously or to induce labour. Most women (over 90%) begin to contract and labour within three weeks of their baby dying, but if labour does not begin, there is a risk of developing a disseminated intravascular coagulopathy (DIC) (Weiner 1999). This complication develops when various factors in the blood which usually stop a person from bleeding (clotting factors) are used faster than they can be replaced. This increases the risk of severe bleeding complications or haemorrhage.

A disadvantage of a long interval between fetal death and birth relates to the degree of information that can be obtained from a postmortem examination or autopsy of the baby. Where there has been a considerable delay between the death of the baby and birth, the tissue may begin to break down, limiting the amount of information that can be obtained about the cause of death (Weiner 1999). This may have implications for counselling about the risks for any future pregnancy.

Description of the intervention

Inducing labour may involve the use of the hormone oxytocin which causes the uterus to contract (Kelly 2001). When labour is induced early in pregnancy, this has been associated with long and painful labours, as the uterus is less sensitive to oxytocin before term (Weiner 1999). Prostaglandins have been used to induce labour and are particularly useful where a woman's cervix is unfavourable or not ready to commence labour (Mackenzie 1999). Prostaglandins have been administered orally (French 2001), vaginally (Kelly 2003), into the cervix (intracervical), outside the amniotic sac (extra‐amniotically) (Hutton 2001), or intravenously (Luckas 2000). There are also mechanical devices which have been developed to dilate or open the cervix (Boulvain 2001).

How the intervention might work

Misoprostol is a synthetic prostaglandin that is structurally related to prostaglandin E₁ (PGE₁). Misoprostol is licensed for use as an anti‐ulcer medication in the treatment of gastric ulcer disease and does not have a product license for use in pregnancy anywhere in the world. Despite this, the use of misoprostol in obstetric and gynaecological practice has increased, being used widely in the management of first and second trimester abortion (Dickinson 1998), and in the third trimester of pregnancy following intrauterine fetal death (Mariani‐Neto 1987). More recently, misoprostol has been used in the induction of labour at term in the presence of a viable fetus, with both vaginal (Hofmeyr 2003) and oral (Alfirevic 2006) routes of administration being used. Misoprostol has been investigated for use in the third stage of labour to prevent postpartum haemorrhage (Gulmezoglu 2007). Potential advantages to the use of misoprostol over other prostaglandin preparations include its stability at room temperature (other prostaglandins need to be stored in the refrigerator) and low cost. This has important implications for women in low‐resource countries.

The Cochrane reviews assessing misoprostol for the induction of labour at term in the presence of a live fetus (Alfirevic 2006; Hofmeyr 2003) concluded that there was considerable variation in both the dose and frequency of misoprostol administered to induce labour, and that at present the optimal dosing regimen is uncertain. There have been calls to further investigate the lowest effective dose of misoprostol, thereby minimising side effects and maximising safety for both the woman and her infant (Alfirevic 2006; Hofmeyr 2003).

Why it is important to do this review

The issues related to the use of low doses of misoprostol are a little different for women who are having labour induced to terminate their pregnancy because of fetal anomalies or after intrauterine fetal death. While side effects (including uterine hyperstimulation, nausea, vomiting, and diarrhoea) and safety (particularly rare complications such as uterine rupture) are important considerations for the woman, issues related to fetal wellbeing are not. Furthermore, it is necessary to consider the receptivity of the uterus to prostaglandin medication, especially at early gestational ages, where the use of low doses of misoprostol may be ineffective in inducing labour, or be associated with a long induction to delivery interval. Sensitivity of the uterus to medication may also be influenced by whether or not the fetus is alive at the time of induction.

The aim of this review is to assess the benefits and harms of misoprostol to induce labour after the death in utero of a fetus, or for fetal anomalies in the second or third trimester of pregnancy when compared with other methods of induction of labour.

Clinical trials of medical treatment, including misoprostol, for fetal deaths before 24 weeks are considered in a separate Cochrane review (Neilson 2006).

In addition, there is a published Cochrane protocol planning to review trials of medical treatments, including misoprostol, for mid‐trimester termination of pregnancy (Medema 2005).

Objectives

To compare, using the best available evidence, the benefits and harms of misoprostol to induce labour to terminate pregnancy in the second and third trimester for women with a fetal anomaly or after intrauterine fetal death when compared with other methods of induction of labour.

Methods

Criteria for considering studies for this review

Types of studies

All published, unpublished, and ongoing randomised controlled trials comparing misoprostol (either oral or vaginal administration) with placebo or no treatment, or any other method of induction of labour (including prostaglandins administered orally, vaginally, intracervically, extra‐amniotically; oxytocin; misoprostol (oral or vaginal); mifepristone; or mechanical methods of induction including extra‐amniotic Foley catheter or laminaria).

We excluded quasi‐randomised trials (e.g. those randomised by date of birth or hospital number). We have included studies reported only in abstract form in the 'Studies awaiting classification' category, and will include these in analyses when published as full reports.

Types of participants

Women undergoing induction of labour to terminate pregnancy in the second and third trimester following an intrauterine fetal death or for fetal anomalies. Where trials included a mix of indications for termination of pregnancy (including social reasons), they were eligible for inclusion if less than 30% of participants were undergoing termination of pregnancy for social indications, or where information was reported separately by indication.

Types of interventions

Misoprostol for the induction of labour to terminate pregnancy versus placebo or no treatment, or any other method of induction of labour to terminate pregnancy in the second and third trimester. We have included studies reporting comparisons between different routes of administration or different doses of misoprostol.

Types of outcome measures

Primary outcomes

Vaginal birth not achieved within 24 hours
Induction to delivery interval

Secondary outcomes

Analgesia requirements (as defined by trial authors)
Blood loss (as defined by trial authors)
Need for blood transfusion
Surgical evacuation of the uterus (as defined by trial authors)
Puerperal sepsis requiring antibiotic treatment
Maternal death or serious maternal morbidity (e.g. admission to intensive care unit; uterine rupture)
Side effects ‐ all
Side effects ‐ nausea
Side effects ‐ vomiting
Side effects ‐ diarrhoea
Side effects ‐ other
Psychological wellbeing of the woman (as defined by trial authors)
Maternal satisfaction with induction process

Only outcomes with available data appear in the analysis table. Outcome data that were not prestated by the review authors, but reported by the authors, are labelled as such in the analysis.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (November 2009).

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

quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE;
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 and MEDLINE, 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.

Data collection and analysis

Selection of studies

Both review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted a third person.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. We entered data into Review Manager software (RevMan 2008) and checked for accuracy.

When information regarding any of the above was 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 2008). We resolved any disagreement by discussion or by involving a third assessor.

(1) 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 have produced comparable groups.

We assessed the method as:

adequate (any truly random process, e.g. random number table; computer random number generator);
inadequate (any non random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear.

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

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

We assessed the methods as:

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

(3) Blinding (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 judged studies at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

adequate, inadequate or unclear for participants;
adequate, inadequate or unclear for personnel;
adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

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 state whether attrition and exclusions were reported, 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 was supplied by the trial authors, we re‐included missing data in the analyses. We assessed methods as:

adequate (defined as less than 20% incomplete data);
inadequate:
unclear.

(5) Selective 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:

adequate (where it was clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
inadequate (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; 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.

(6) Other sources of bias

We have described for each included study any important concerns we have about other possible sources of bias, including study design, early stopping of the trial due to data‐dependent processes or extreme baseline imbalance.

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

yes;
no;
unclear.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2008). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings. We explored the impact of the level of bias through undertaking Sensitivity analysis.

Measures of treatment effect

Dichotomous data

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

Continuous data

For continuous data, we used the mean difference if outcomes are measured in the same way between trials. We used the standardised mean difference to combine trials that measured the same outcome, but use different methods.

Unit of analysis issues

Cluster‐randomised trials

We did not identify any eligible cluster‐randomised trials.

Crossover trials

Crossover trials are not considered an appropriate study design to evaluate this intervention.

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 (considered to be more than 20%) 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. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. Where we identified substantial heterogeneity (above 50%), we have explored it by pre‐specified subgroup analysis.

Assessment of reporting biases

Where we suspect reporting bias (see ‘Selective reporting bias’ above), we have attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and the missing data were thought to introduce serious bias, we have explored the impact of including such studies in the overall assessment of results by a Sensitivity analysis.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2008). We used fixed‐effect inverse variance meta‐analysis for combining data where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where we suspected clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we used random‐effects meta‐analysis.

If we identified substantial heterogeneity in a fixed‐effect meta‐analysis, we have noted this and repeated the analysis using a random‐effects method.

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses:

oral versus vaginal route of administration of misoprostol;
dose of misoprostol used;
indication for induction of labour (that is intrauterine fetal death versus termination of live pregnancy); and
gestational age (second versus third trimester of pregnancy as defined by trial authors);
maternal parity; and
previous caesarean section.

We used the following primary outcomes in subgroup analysis:

vaginal birth not achieved within 24 hours;
induction to delivery interval.

For fixed‐effect meta‐analyses, we conducted planned subgroup analyses classifying whole trials by interaction tests as described by Deeks 2001. For random‐effects meta‐analyses, we assessed differences between subgroups by inspection of the subgroups’ confidence intervals; non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis

We did not conduct sensitivity analyses.

Results

Description of studies

Results of the search

Our search strategy identified 54 studies for consideration, of which we included 38 (involving 3679 women), excluded 11 studies and five studies are awaiting classification.

Included studies

Thirty‐eight studies (involving 3490 women) met our inclusion criteria. The interventions compared included:

vaginal misoprostol compared with oral misoprostol (Akoury 2004; Bebbington 2002; Behrashi 2008; Caliskan 2005; Chittacharoen 2003; Dickinson 2003; Elhassan 2008; Fadalla 2004; Gilbert 2001; Neto 1988; Nyende 2004);
vaginal misoprostol compared with vaginal gemeprost (alone or with oxytocin) (Dickinson 1998; Nor Azlin 2006; Nuutila 1997);
vaginal misoprostol compared with vaginal prostaglandin E2 (alone or with other agents) (Herabutya 1997; Jain 1999; Kara 1999; Makhlouf 2003; Owen 1999);
vaginal misoprostol compared with prostaglandin F2alpha (Akoury 2004; Ghorab 1998; Munthali 2001; Perry 1999; Su 2005; Zuo 1998);
vaginal misoprostol compared with oxytocin alone (Nakintu 2001);
vaginal misoprostol alone compared with vaginal misoprostol and oxytocin (Hidar 2001);
vaginal misoprostol compared with vaginal glyceryl trinitrate (Makhlouf 2003);
vaginal misoprostol alone compared with vaginal misoprostol and laminaria (Jain 1994);
vaginal misoprostol alone compared with vaginal misoprostol and nitric oxide donor (Hidar 2005);
oral misoprostol compared with prostaglandin F2alpha (Akoury 2004);
combination of oral and vaginal misoprostol compared with vaginal misoprostol alone (Dickinson 2003; Feldman 2003), oral misoprostol alone (Dickinson 2003), and dilation and evacuation (Grimes 2005);
sublingual misoprostol compared with vaginal misoprostol (Caliskan 2005; Elhassan 2008);
sublingual misoprostol compared with oral misoprostol (Caliskan 2005; Elhassan 2008); and two different doses of sublingual misoprostol (Caliskan 2009).

Dose and route of administration

There were several trials comparing a dosing interval of six hours with 12 hours (Herabutya 2005; Jain 1996; Nuutila 1997), and several trials comparing varying doses of vaginal misoprostol. These were arbitrarily divided into those comparing a low dose (less than 800 mcg in a 24‐hour period) with a moderate dose (between 800 mcg and 2400 mcg in a 24‐hour period) (Dickinson 2002; Niromanesh 2005), and those comparing a moderate dose (800 mcg to 2400 mcg in a 24‐hour period) with a high dose (in excess of 2400 mcg in a 24‐hour period) (Pongsatha 2004). The route of administration of misoprostol (vaginal, oral or combined oral and vaginal) varied considerably across trials, as did the dose used (a cumulative dose in 24 hours ranging from 400 mcg to 3200 mcg) and the dosing interval administered (from three‐hourly intervals to 12‐hourly intervals).

Participant population

Most trials recruited women undergoing termination of pregnancy in the presence of both a live fetus, and following intrauterine fetal death, with no separate reporting of outcomes by method of induction of labour and indication for induction.

Reported outcomes

There was variable reporting of the prespecified outcomes, with the majority of trials only reporting vaginal birth not achieved in 24 hours, induction to birth interval (often as a median and interquartile range precluding inclusion in the meta‐analysis), surgical evacuation of the uterus, and side effects from therapy. More severe but less common complications (including excessive blood loss, need for transfusion, and complications such as uterine rupture) were poorly reported. Maternal satisfaction with the process of induction of labour was reported in several trials, but reported as a median and interquartile range, precluding inclusion in the meta‐analysis.

For further details seeCharacteristics of included studies.

Excluded studies

We excluded 11 trials. Six trials involved only women undergoing termination of pregnancy for 'social' indications (Biswas 2007; El‐Refaey 1995; Guix 2005; Marquette 2005; Nigam 2006; Saha 2006); and three trials used quasi‐randomisation methods (Eng 1997; Herabutya 2001; Yapar 1996). In one trial, termination of pregnancy was effected in all women using the same misoprostol regimen, with randomisation occurring to administration on an inpatient versus outpatient basis (Gonzalez 2001). One trial involved women at seven to 12 weeks' gestation with early pregnancy failure (Ayudhaya 2006). For further details seeCharacteristics of excluded studies.

Studies awaiting classification

Five trials have been presented only in abstract form; we will assess these once further details are obtained (Abdel Fattah 1997; Agrawal 2006; Nuthalapaty 2004; Roy 2003; Surita 1997). For further details seeCharacteristics of studies awaiting classification.

Risk of bias in included studies

The overall quality of the included trials varied from good to fair. All trials were stated to be randomised, and while most utilised a random number table to generate the randomisation sequence, the method of randomisation was unclear in 13 of the trials (Behrashi 2008; Elhassan 2008; Fadalla 2004; Ghorab 1998; Herabutya 1997; Hidar 2005; Jain 1996; Kara 1999; Neto 1988; Niromanesh 2005; Nor Azlin 2006; Nyende 2004; Pongsatha 2004). Allocation concealment involved the use of sealed opaque envelopes in the majority of trials, but was considered to be unclear in 19 of the trials (Behrashi 2008; Caliskan 2005; Elhassan 2008; Fadalla 2004; Gilbert 2001; Ghorab 1998; Herabutya 1997; Hidar 2005; Jain 1994; Jain 1996; Jain 1999; Kara 1999; Makhlouf 2003; Nakintu 2001; Neto 1988; Niromanesh 2005; Nyende 2004; Pongsatha 2004; Zuo 1998). Blinding of women and outcome assessors was achieved in only one trial (Dickinson 1998), with women, caregivers and outcome assessors aware of the treatment allocated in all of the remaining trials. Four trials were stopped prior to reaching the projected sample size following an interim analysis of results (Dickinson 1998; Dickinson 2003; Gilbert 2001; Owen 1999), and one trial was stopped prior to reaching sample size due to difficulties with recruitment (Grimes 2005).

Refer to table Characteristics of included studies for further details.

Effects of interventions

Vaginal misoprostol versus oral misoprostol (Analysis 1)

We included 11 studies involving 855 women. Women administered vaginal misoprostol were more likely to achieve vaginal birth within 24 hours (risk ratio (RR) 0.18, 95% confidence interval (CI) 0.04 to 0.78; I² = 77%; random‐effects model (six studies, 507 women)) and had a shorter mean induction to birth interval (mean difference (MD) ‐5.54 hours, 95% CI ‐8.92 to ‐2.16; I² = 87%; random‐effects model (eight studies, 590 women)) when compared with women administered oral misoprostol. The test for heterogeneity was significant for these outcomes, possibly accounted for by the Chittacharoen 2003 trial, in which a much higher dose of oral misoprostol was used than in the other trials. There were no statistically significant differences for the other outcomes reported including need for analgesia, surgical evacuation of the uterus, and side effects including nausea, vomiting, diarrhoea and pyrexia.

Vaginal misoprostol six‐hourly dosing intervals versus 12‐hourly dosing intervals (Analysis 2)

We included three studies involving 416 women. There were no statistically significant differences identified between the dosing regimens for the outcomes vaginal birth not achieved in 24 hours or the mean induction to birth interval. However, the six‐hourly dosing interval was associated with an increase in women's experience of side effects, particularly vomiting (RR 2.26, 95% CI 1.09 to 4.71 (three studies, 416 women)).

Vaginal misoprostol versus Gemeprost (alone or with oxytocin) (Analysis 3)

We included four studies involving 315 women. There were no statistically significant differences identified between the two agents for the outcomes vaginal birth not achieved in 24 hours, mean induction to delivery interval, analgesic requirements, blood loss, or experience of side effects, although the outcome pyrexia was of borderline statistical significance (RR 0.38, 95% CI 0.13 to 1.06 (two studies, 154 women)). However, there was statistical heterogeneity identified, possibly accounted for by the low dose of misoprostol used in the trial by Nuutila (Nuutila 1997).

Vaginal misoprostol versus prostaglandin E₂ (alone or with other agents) (Analysis 4)

We included six studies involving 410 women. There were no statistically significant differences in a woman's chance of achieving vaginal birth within 24 hours (RR 0.62, 95% CI 0.36 to 1.04), or in their mean induction to birth interval (MD ‐1.71 hours, 95% CI ‐10.05 to 6.63; I² = 83%; random‐effects (four studies, 165 women)). Women administered misoprostol were less likely to experience any side effects (RR 1.59, 95% CI 1.05 to 2.40 (one study, 80 women)), to experience nausea (RR 0.59, 95% CI 0.35 to 0.99 (one study, 126 women)), or diarrhoea (RR 0.20, 95% CI 0.06 to 0.67 (three studies, 261 women)) when compared with women administered prostaglandin E₂.

Vaginal misoprostol versus prostaglandin F_2alpha (Analysis 5)

We included six studies involving 534 women. When compared with prostaglandin F_2alpha, vaginal misoprostol was not associated with a statistically significant difference in a woman's chance of achieving vaginal birth within 24 hours (RR 1.07, 95% CI 0.28 to 4.06; I² = 70%, random‐effects (three studies, 213 women) or in the mean induction to birth interval (MD ‐2.84, 95% CI ‐6.06 to 0.38; I² = 71%, random‐effects (four studies, 378 women)). Women administered vaginal misoprostol were less likely to require surgical evacuation of the uterus (RR 0.63, 95% CI 0.41 to 0.98 (five studies, 439 women)), and less likely to experience both nausea (RR 0.67, 95% CI 0.47 to 0.95 (three studies, 338 women)) and vomiting (RR 0.61, 95% CI 0.42 to 0.89 (four studies, 378 women)).

Vaginal misoprostol versus vaginal misoprostol and oxytocin (Analysis 6)

We identified a single trial of 76 women, with no statistically significant differences reported for the outcomes: mean induction to birth interval; surgical evacuation of the uterus; side effects; vomiting; diarrhoea; or pyrexia.

Vaginal misoprostol versus vaginal glyceryl tri‐nitrate (Analysis 7)

We identified a single trial of 100 women, in which no primary outcomes were reported. Women who were administered vaginal misoprostol were more likely to require analgesia (RR 2.22, 95% CI 1.12 to 4.40 (one study, 100 women)), and to experience any side effects (RR 75.00, 95% CI 4.73 to 1188.78), including vomiting (RR 35.00, 95% CI 2.16 to 566.54) and pyrexia (RR 31.00, 95% CI 1.91 to 504.35) when compared with women administered vaginal glyceryl tri‐nitrate.

Vaginal misoprostol versus vaginal misoprostol and laminaria (Analysis 8)

We identified a single trial of 68 women. There were no statistically significant differences identified between the two methods of induction for the following outcomes: vaginal birth not achieved in 24 hours; blood loss greater than 500 mL; need for transfusion; and side effects (vomiting, diarrhoea, and pyrexia).

Vaginal misoprostol versus vaginal misoprostol and vaginal nitric oxide donor (Analysis 9)

We identified a single trial involving 61 women, with no statistically significant differences reported for the following outcomes: vaginal birth not achieved in 24 hours; mean induction to birth interval; and any side effects.

Oral misoprostol versus prostaglandin F_2alpha (Analysis 10)

We identified a single trial involving 133 women. Women who were administered oral misoprostol had a longer mean induction to birth interval when compared with those women administered prostaglandin F_2alpha (MD 9.40, 95% CI 4.9 to 13.90 (one study, 133 women)). There were no statistically significant differences identified for the following outcomes: need for surgical evacuation of the uterus; nausea; vomiting; diarrhoea; and pyrexia.

Combined oral and loading dose vaginal misoprostol versus vaginal misoprostol alone (Analysis 11)

We included two studies involving 98 women. Women who received vaginal misoprostol alone had a longer mean induction to birth interval (MD 5.20, 95% CI 3.42 to 6.98 (one study, 43 women)) when compared with women who were administered oral misoprostol following a loading dose of vaginal misoprostol. There were no statistically significant differences identified for the following outcomes: vaginal birth not achieved in 24 hours; need for analgesia; surgical evacuation of the uterus; and side effects (nausea, vomiting, and diarrhoea).

Combined oral and loading dose vaginal misoprostol versus oral misoprostol alone (Analysis 12)

We identified one study involving 56 women. The addition of a loading dose of vaginal misoprostol reduced the chance of a woman not achieving vaginal birth within 24 hours when compared with oral misoprostol alone (RR 0.47, 95% CI 0.23 to 0.96 (one study, 56 women)). There were no other differences identified between the two methods of induction for the following outcomes: need for analgesia; surgical evacuation of the uterus; or side effects (nausea, vomiting, or diarrhoea).

Combined oral and loading dose vaginal misoprostol versus dilation and evacuation (Analysis 13)

We identified one study involving 18 women. There were no statistically significant differences identified between the two methods for the outcomes nausea, vomiting, or diarrhoea.

Sublingual misoprostol versus vaginal misoprostol (Analysis 14)

We identified two studies involving 202 women. Women who were administered sublingual misoprostol were more likely to achieve vaginal birth within 24 hours (RR 0.24, 95% CI 0.08 to 0.74 (two studies, 202 women)) and had a shorter mean induction to birth interval (MD ‐4.81 hours, 95% CI ‐8.26 to ‐1.37; I² = 66%, random‐effects (two studies, 202 women)) when compared with administration of vaginal misoprostol. There were no other differences identified between the two methods of induction for the following outcomes: need for analgesia; side effects (vomiting, diarrhoea, or pyrexia).

Sublingual misoprostol versus oral misoprostol (Analysis 15)

We identified two studies involving 204 women. Women who were administered sublingual misoprostol had a shorter mean induction to birth interval (MD ‐7.17 hours, 95% CI ‐13.73 to ‐0.60; I² = 88%, random‐effects (two studies, 202 women)) but were no more likely to achieve vaginal birth within 24 hours (RR 0.22, 95% CI 0.01 to 4.99; I² = 75%, random‐effects (two studies, 204 women)) when compared with administration of oral misoprostol. There were no other differences identified between the two methods of induction for the following outcomes: need for analgesia; and side effects (vomiting, diarrhoea, or pyrexia).

Sublingual misoprostol 100 mcg versus sublingual misoprostol 200 mcg (Analysis 16)

We identified one study involving 81 women. There were no statistically significant differences identified between the two doses of misoprostol for the following outcomes: vomiting, diarrhoea, or pyrexia.

Low dose vaginal misoprostol (< 800 mcg) versus moderate dose vaginal misoprostol (800 mcg to 2400 mcg) (Analysis 17)

We identified a single study involving 150 women. The use of lower cumulative doses of misoprostol was associated with an increased chance of a woman not achieving vaginal birth within 24 hours when compared with moderate doses of misoprostol (RR 1.85, 95% CI 1.13 to 3.03 (one study, 150 women)), and a reduction in the need for surgical evacuation of the uterus (RR 0.57, 95% CI 0.33 to 0.98 (one study, 150 women)). There were no significant differences identified for the following outcomes: need for analgesia; or side effects (nausea, vomiting, or diarrhoea).

Moderate dose vaginal misoprostol (800 mcg to 2400 mcg) versus high dose vaginal misoprostol (greater than 2400 mcg) (Analysis 18)

We identified a single study involving 178 women. The use of moderate cumulative doses of misoprostol over a 24‐hour period was associated with an increased mean induction to birth interval when compared with higher doses of misoprostol (MD 4.20 hours, 95% CI 1.36 to 7.04 (one study, 178 women)).

Subgroup analyses

It was not possible to explore the effect of induction of labour in the presence of a live fetus or following intrauterine fetal death. Where studies included both indications for termination of pregnancy, outcomes were not reported separately by indication for induction, or by the method of induction used. It was not possible to explore the effect of gestational age on the termination process, as studies did not separately report outcomes for women undergoing termination in the second or third trimester of pregnancy. Similarly, it was not possible to explore the effect of maternal parity, or the presence of a prior caesarean birth on the induction process, as women with a scarred uterus were often excluded from the trials.

Discussion

Misoprostol is being used widely in the obstetric community as an agent to induce labour for termination of pregnancy in the second and third trimesters of pregnancy for fetal anomaly or following intrauterine fetal demise. This systematic review includes the available randomised controlled trials comparing the use of misoprostol in second and third trimester of pregnancy with other methods of labour induction to terminate pregnancy. Overall, the quality of the trials available for inclusion was reasonable, although there was considerable variation in the outcomes reported, and in the regimen of misoprostol adopted.

When compared with agents that have traditionally been used to induce labour in this setting (for example, gemeprost, prostaglandin E₂ and prostaglandin F_2alpha), vaginal misoprostol is as effective in effecting vaginal birth within 24 hours, with a similar induction to birth interval. When compared with other prostaglandin preparations, the occurrence of maternal gastrointestinal side effects such as nausea, vomiting, and diarrhoea is reduced with the use of vaginal misoprostol. While the different treatments involving various prostaglandin preparations appear comparable for the reported outcomes, the information available regarding rare maternal complications, such as uterine rupture, is limited.

The use of oral misoprostol for induction of labour for termination in the second and third trimesters of pregnancy for fetal anomaly or following intra‐uterine fetal demise, is less effective than vaginal misoprostol, with women experiencing a longer induction to birth interval, and an increased chance of remaining undelivered 24 hours after the induction process commences. The more limited information available about the use of sublingual misoprostol in this setting would suggest that it is more effective than both oral or vaginal administration. Information about women's preferences for an oral induction method in this clinical setting is limited, with suggestions that satisfaction with the induction process is more related to the duration of the induction rather than the route of administration of medication (Akoury 2004; Dickinson 2003; Grimes 2005).

The Cochrane systematic reviews of the use of oral (Hofmeyr 2003) and vaginal (Alfirevic 2006) misoprostol for induction of labour at term in the presence of a live fetus identified significant variation in both the dose and frequency of drug administration, concluding that at present, the optimal regimen for misoprostol is uncertain. Similarly, there is wide variation in the dose, frequency of administration and route of administration of misoprostol to effect termination of pregnancy in the second or third trimester of pregnancy. There have been calls for further investigation of the lowest effective dose of misoprostol to induce labour at term in the presence of a live fetus, to ensure minimal side effects for the woman, and maintain safety for both the woman and fetus (Alfirevic 2006; Hofmeyr 2003). These efforts have been somewhat hampered by the preparation of misoprostol as a 100 mcg or 200 mcg tablet. Concerns about fetal safety and avoidance of toxicity are not relevant in the situation of induction of labour following fetal death or to effect termination of pregnancy in the second and third trimester. However, issues of side effects and safety for the woman remain. While this meta‐analysis indicates a low occurrence of medication side effects with the use of misoprostol, not all trials provided this information. There are insufficient data to assess the occurrence of rare but potentially life threatening complications for the woman, including uterine rupture, with not all trials reporting serious adverse outcomes, and at present a combined sample size underpowered to be able to detect all but large differences.

The use of low doses of misoprostol must take into account the receptivity of the uterus to prostaglandin agents, particularly at early gestational ages. The use of lower doses of misoprostol was associated with an increased chance of a woman not achieving vaginal birth within 24 hours, and a longer induction to birth interval, when compared with higher doses of misoprostol. In this situation, low dose medication may be ineffective in inducing labour or result in an unacceptably long induction to delivery interval. However, the increased dose of misoprostol to effect termination must be balanced against an increase in the occurrence of maternal gastrointestinal side effects. The effect of increasing the dose of misoprostol on the occurrence of rare but potentially life threatening maternal complications remains uncertain.

Future research efforts should be directed towards determining the optimal dose and frequency of administration, with particular attention to standardised reporting of all relevant outcomes and assessment of rare adverse events. Further information is required about the use of sublingual misoprostol in this clinical setting.

Authors' conclusions

Implications for practice.

Implications for research.

What's new

Date	Event	Description
3 April 2018	Amended	Added Published notes to clarify that this review has been relinquished by the review team. A new review team will prepare a new review on this topic, following a new protocol.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	6	507	Risk Ratio (IV, Random, 95% CI)	0.37 [0.15, 0.87]
1.1 Low Dose Misoprostol	1	100	Risk Ratio (IV, Random, 95% CI)	0.18 [0.04, 0.78]
1.2 Moderate Dose Misoprostol	3	213	Risk Ratio (IV, Random, 95% CI)	0.24 [0.14, 0.42]
1.3 High Dose Misoprostol	2	194	Risk Ratio (IV, Random, 95% CI)	0.96 [0.05, 16.96]
3 Mean induction to birth interval	8	640	Mean Difference (IV, Random, 95% CI)	‐5.54 [‐8.92, ‐2.16]
3.1 Low Dose Misoprostol	3	208	Mean Difference (IV, Random, 95% CI)	‐5.42 [‐7.83, ‐1.00]
3.2 Moderate Dose Misoprostol	3	216	Mean Difference (IV, Random, 95% CI)	‐6.53 [‐12.59, ‐0.47]
3.3 High Dose Misoprostol	2	216	Mean Difference (IV, Random, 95% CI)	‐3.60 [‐20.38, 13.19]
5 Analgesia required	3	239	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.84, 1.57]
6 Surgical evacuation of the uterus	6	491	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.54, 1.14]
7 Vomiting	4	333	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.48, 1.07]
8 Nausea	3	273	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.42, 1.13]
9 Diarrhoea	5	413	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.24, 3.26]
10 Pyrexia	4	356	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.42, 1.30]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	2	363	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.62, 1.22]
2 Mean induction to birth interval	1	53	Mean Difference (IV, Fixed, 95% CI)	‐4.70 [‐11.19, 1.79]
3 Need for analgesia	3	416	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.86, 1.42]
4 Blood loss > 500 mL	1	279	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.30, 5.81]
5 Mean blood loss	1	53	Mean Difference (IV, Fixed, 95% CI)	85.0 [26.53, 143.47]
6 Need for blood transfusion	2	363	Risk Ratio (M‐H, Fixed, 95% CI)	1.99 [0.18, 21.65]
7 Surgical evacuation of the uterus	3	416	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.68, 1.13]
8 Nausea	1	279	Risk Ratio (M‐H, Fixed, 95% CI)	1.74 [0.75, 4.01]
9 Vomiting	3	416	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.09, 4.71]
10 Diarrhoea	3	416	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.73, 1.86]
11 Pyrexia	2	363	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [1.36, 2.42]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	3	235	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.64, 2.62]
2 Mean induction to delivery interval	2	109	Mean Difference (IV, Random, 95% CI)	2.22 [‐14.44, 18.87]
3 Pain (VAS score greater than 5)	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.62, 1.38]
4 Analgesia required	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.42, 1.53]
5 Mean blood loss	1	55	Mean Difference (IV, Fixed, 95% CI)	‐61.0 [‐145.71, 23.71]
6 Surgical evacuation of the uterus	3	235	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.55, 1.03]
7 Nausea	2	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.70, 1.86]
8 Vomiting	2	181	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.16, 4.62]
9 Diarrhoea	3	235	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.07, 3.15]
10 Pyrexia	2	154	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.13, 1.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	4	251	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.36, 1.04]
1.1 Low Dose Misoprostol	2	109	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.44, 1.58]
1.2 Moderate Dose Misoprostol	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.5 [0.13, 2.00]
1.3 High Dose Misoprostol	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.10, 1.14]
2 Mean induction to birth interval	4	165	Mean Difference (IV, Random, 95% CI)	‐1.71 [‐10.05, 6.63]
2.1 Low Dose Misoprostol	3	149	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐9.53, 7.53]
2.2 Moderate Dose Misoprostol	1	16	Mean Difference (IV, Random, 95% CI)	‐27.3 [‐76.57, 21.97]
2.3 High Dose Misoprostol	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 Analgesia required	4	315	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.69, 1.11]
5 Blood loss > 500 mL	4	326	Risk Ratio (M‐H, Fixed, 95% CI)	2.73 [0.69, 10.78]
6 Need for blood transfusion	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Surgical evacuation of the uterus	5	380	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.20, 1.36]
8 Side effects ‐ any	1	80	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.05, 2.40]
9 Nausea	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.35, 0.99]
10 Vomiting	4	254	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.31, 2.45]
11 Diarrhoea	3	261	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.06, 0.67]
12 Pyrexia	5	380	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.24, 3.20]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	3	213	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.28, 4.06]
1.1 Low Dose Misoprostol	2	91	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.02, 26.21]
1.2 Moderate Dose Misoprostol	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 High Dose Misoprostol	1	122	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.50, 1.58]
2 Mean induction to birth interval	4	378	Mean Difference (IV, Random, 95% CI)	‐2.84 [‐6.06, 0.38]
2.1 Low Dose Misoprostol	2	91	Mean Difference (IV, Random, 95% CI)	‐0.76 [‐11.03, 9.51]
2.2 Moderate Dose Misoprostol	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 High Dose Misoprostol	2	287	Mean Difference (IV, Random, 95% CI)	‐3.62 [‐5.71, ‐1.53]
3 Blood loss > 500 mL	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.22, 2.20]
4 Need for blood transfusion	2	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Surgical evacuation of the uterus	5	439	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.41, 0.98]
6 Side effects ‐ any	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.41, 2.59]
7 Nausea	3	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.47, 0.95]
8 Vomiting	4	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.42, 0.89]
9 Diarrhoea	5	458	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.15, 1.82]
10 Pyrexia	5	458	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.14, 3.61]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean induction to birth interval	1	76	Mean Difference (IV, Fixed, 95% CI)	5.0 [‐0.72, 10.72]
2 Surgical evacuation of the uterus	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.98, 3.90]
4 Vomiting	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.35, 1.93]
5 Diarrhoea	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.08, 18.05]
6 Pyrexia	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	2.34 [0.77, 7.13]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2 Need for analgesia	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	2.22 [1.12, 4.40]
3 Blood loss > 500 mL	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	15.0 [0.88, 255.78]
4 Surgical evacuation of the uterus	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	9.0 [0.50, 162.89]
5 Side effects ‐ any	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	75.0 [4.73, 1188.67]
6 Vomiting	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	35.0 [2.16, 566.54]
7 Diarrhoea	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.92]
8 Pyrexia	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	31.0 [1.91, 504.35]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.47, 1.97]
2 Blood loss > 500 mL	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Need for blood transfusion	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Vomiting	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.13, 3.97]
5 Diarrhoea	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.37]
6 Pyrexia	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.03, 1.72]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.34, 2.33]
2 Mean induction to birth interval	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.5 [‐8.01, 7.01]
3 Side effects ‐ any	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.17, 1.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean induction to birth interval	1	133	Mean Difference (IV, Fixed, 95% CI)	9.40 [4.90, 13.90]
2 Surgical evacuation of the uterus	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.36, 1.69]
3 Nausea	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.56, 1.49]
4 Vomiting	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.56, 1.49]
5 Diarrhoea	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	2.60 [0.65, 10.41]
6 Pyrexia	1	133	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.57, 2.86]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [0.60, 5.50]
2 Mean induction to birth interval	1	43	Mean Difference (IV, Fixed, 95% CI)	5.20 [3.42, 6.98]
3 Need for analgesia	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.77, 1.39]
5 Surgical evacuation of the uterus	2	98	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.44, 1.57]
6 Nausea	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Vomiting	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Diarrhoea	1	55	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 birth not achieved in 24 hours	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.23, 0.96]
2 Need for analgesia	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.82, 1.55]
3 Surgical evacuation of the uterus	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.40, 1.85]
4 Nausea	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Vomiting	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Diarrhoea	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.83]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Nausea	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.56, 4.97]
2 Vomiting	1	18	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.48, 8.31]
3 Diarrhoea	1	18	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 birth not achieved in 24 hours	2	202	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.08, 0.74]
2 Induction to delivery interval	2	202	Mean Difference (IV, Random, 95% CI)	‐4.81 [‐8.26, ‐1.37]
3 Analgesic requirements	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.43, 2.31]
4 Vomiting	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.35, 1.33]
5 Diarrhoea	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	2.5 [0.51, 12.30]
6 Pyrexia	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.35, 2.89]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved within 24 hours	2	204	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.01, 4.99]
2 Induction to delivery interval	2	202	Mean Difference (IV, Random, 95% CI)	‐7.17 [‐13.73, ‐0.60]
3 Analgesic requirements	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.31, 1.35]
4 Vomiting	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.42, 1.71]
5 Diarrhoea	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.27, 2.56]
6 Pyrexia	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.24, 1.53]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Induction to delivery interval	1	162	Mean Difference (IV, Fixed, 95% CI)	‐0.47 [‐2.94, 2.00]
2 Vomiting	1	162	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.23, 1.28]
3 Diarrhoea	1	162	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.21, 1.83]
4 Pyrexia	1	162	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.32, 1.29]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal birth not achieved in 24 hours	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	1.85 [1.13, 3.03]
2 Pain (VAS score > 5)	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.47, 1.67]
3 Need for analgesia	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.73, 1.10]
4 Surgical evacuation of the uterus	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.33, 0.98]
5 Nausea	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.59, 1.59]
6 Vomiting	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.28, 1.17]
7 Diarrhoea	1	150	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [0.80, 6.39]
8 Vaginal birth not achieved in 24 hours	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	Trial conducted in Canada, January 1998‐February 2001.
Participants	240 women with singleton pregnancy undergoing termination of pregnancy for fetal anomaly at 15 to 24 weeks' gestation. Women were excluded if hypersensitivity to prostaglandins, prior classical caesarean section, hysterotomy, active bleeding, severe asthma, severe oligohydramnios, or prelabour ruptured membranes.
Interventions	Women randomised to 1) intra‐amniotic prostaglandin F2alpha and laminaria; 2) oral misoprostol (400 mcg at 4‐hourly intervals); or 3) vaginal misoprostol (400 mcg at 4‐hourly intervals).
Outcomes	Mean induction to delivery interval; surgical evacuation of the uterus; nausea; vomiting; diarrhoea; pyrexia.
Notes	Method of randomisation: computer generated.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated.
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Canada, September 1998‐November 2001.
Participants	114 women undergoing second trimester termination of pregnancy following both fetal demise or termination of a live fetus. Women were excluded if hypersensitive to prostaglandins or had limited English.
Interventions	Women randomised to vaginal misoprostol (400 mcg at 4‐hourly intervals) or oral misoprostol (200 mcg at hourly intervals for 3 hours then 400 mcg at 4‐hourly intervals).
Outcomes	Vaginal birth not achieved within 24 hours; induction to birth interval; mean blood loss; surgical evacuation of the uterus; serious maternal morbidity; pyrexia.
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Iran, 2006.
Participants	60 women with second trimester genetic termination of pregnancy or intrauterine fetal death. Exclusion if placenta praevia, contraindication to prostaglandin therapy, convulsions, glaucoma or inflammatory bowel disease.
Interventions	Vaginal misoprostol 400 mcg (to maximum 4 doses) vs oral misoprostol 400 mcg (to maximum 4 doses).
Outcomes	Induction to delivery interval; surgical evacuation of uterus.
Notes	Method of randomisation: stated to be "randomized trial".  Allocation concealment: not stated.  Blinding of participants, caregivers and outcome assessor: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated to be "randomized trial".
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Unclear risk	Not stated.
Other bias	Low risk

PERMALINK

Misoprostol for induction of labour to terminate pregnancy in the second or third trimester for women with a fetal anomaly or after intrauterine fetal death

Jodie M Dodd

Caroline A Crowther

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) Sequence generation (checking for possible selection bias)

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

(3) Blinding (checking for possible performance bias)

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

(5) Selective reporting bias

(6) Other sources of bias

(7) Overall risk of bias

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Crossover 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

Dose and route of administration

Participant population

Reported outcomes

Excluded studies

Studies awaiting classification

Risk of bias in included studies

Effects of interventions

Vaginal misoprostol versus oral misoprostol (Analysis 1)

Vaginal misoprostol six‐hourly dosing intervals versus 12‐hourly dosing intervals (Analysis 2)

Vaginal misoprostol versus Gemeprost (alone or with oxytocin) (Analysis 3)

Vaginal misoprostol versus prostaglandin E2 (alone or with other agents) (Analysis 4)

Vaginal misoprostol versus prostaglandin F2alpha (Analysis 5)

Vaginal misoprostol versus vaginal misoprostol and oxytocin (Analysis 6)

Vaginal misoprostol versus vaginal glyceryl tri‐nitrate (Analysis 7)

Vaginal misoprostol versus vaginal misoprostol and laminaria (Analysis 8)

Vaginal misoprostol versus vaginal misoprostol and vaginal nitric oxide donor (Analysis 9)

Oral misoprostol versus prostaglandin F2alpha (Analysis 10)

Combined oral and loading dose vaginal misoprostol versus vaginal misoprostol alone (Analysis 11)

Combined oral and loading dose vaginal misoprostol versus oral misoprostol alone (Analysis 12)

Combined oral and loading dose vaginal misoprostol versus dilation and evacuation (Analysis 13)

Sublingual misoprostol versus vaginal misoprostol (Analysis 14)

Sublingual misoprostol versus oral misoprostol (Analysis 15)

Sublingual misoprostol 100 mcg versus sublingual misoprostol 200 mcg (Analysis 16)

Low dose vaginal misoprostol (< 800 mcg) versus moderate dose vaginal misoprostol (800 mcg to 2400 mcg) (Analysis 17)

Vaginal misoprostol versus prostaglandin E₂ (alone or with other agents) (Analysis 4)

Vaginal misoprostol versus prostaglandin F_2alpha (Analysis 5)

Oral misoprostol versus prostaglandin F_2alpha (Analysis 10)

Methods	Trial conducted in Turkey, January‐December 2003.
Participants	153 women at 13 to 20 weeks' gestation presenting for termination with either fetal anomaly or intrauterine fetal death. Women with an allergy to misoprostol were excluded from the study.
Interventions	Women randomised to 1) oral misoprostol (100 mcg at 2 hourly intervals); 2) vaginal misoprostol (200 mcg at 4 hourly intervals); or 3) sublingual misoprostol (100 mcg at 2 hourly intervals).
Outcomes	Vaginal birth not achieved in 24 hours; induction to delivery interval; analgesic requirements; side effects.
Notes	Method of randomisation: computer generated sequence.  Allocation concealment: unclear (possibly sealed opaque envelopes).  Blinding: participants, caregivers and outcome assessor ‐ no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Unclear risk	Unclear ‐ possible use of sealed opaque envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Unclear risk	Unable to assess.

Methods	Trial conducted in Turkey, January 2004‐January 2007.
Participants	162 women presenting in the second trimester of pregnancy with either fetal anomaly or intrauterine fetal death requiring termination of pregnancy. Women with an allergy to prostaglandins or asthma were excluded from participation.
Interventions	Women were randomised to 1) sublingual misoprostol (100 mcg 2 hourly intervals); or 2) sublingual misoprostol (200 mcg 2 hourly intervals).
Outcomes	Induction to delivery interval; maternal side effects.
Notes	Method of randomisation: computer‐generated sequence.  Allocation concealment: sealed opaque envelopes.  Blinding of participants, caregivers and outcome assessors: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Thailand, July 1999‐June 2001.
Participants	80 women undergoing second or third trimester (16 to 41 weeks' gestation) termination of pregnancy following both fetal demise or termination of a live fetus. Women were excluded if prior classical caesarean section or hypersensitive to prostaglandins.
Interventions	Women randomised to vaginal misoprostol (200 mcg at 12‐hourly intervals) or oral misoprostol (400 mcg at 4‐hourly intervals).
Outcomes	Vaginal birth not achieved within 24 hours; induction to birth interval; narcotic analgesia requirements; nausea; vomiting; diarrhoea; pyrexia.
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Australia, July 1996‐February 1997.
Participants	150 women undergoing second trimester termination of pregnancy fetal anomalies or following intrauterine fetal death; trial stopped early after total 100 women randomised.
Interventions	Women randomised to 1) vaginal misoprostol (200 mcg at 6‐hourly intervals); 2) vaginal gemeprost (1 mg at 3‐hourly intervals).
Outcomes	Vaginal birth not achieved in 24 hours; median induction to birth interval; pain score > 5 (using VAS); analgesia requirements; surgical evacuation of the uterus; nausea; vomiting; diarrhoea; pyrexia.
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants (yes), caregivers (no) and outcome assessors (yes).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes.
Blinding (performance bias and detection bias)   All outcomes	Low risk	Blinding of participants and outcome assessor.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Unclear risk	Trial stopped early.

Methods	Trial conducted in Australia, March 1998‐February 1999.
Participants	150 women undergoing second or third trimester termination of pregnancy for fetal anomaly or after intrauterine fetal death.
Interventions	Women randomised to 1) vaginal misoprostol (200 mcg at 6‐hourly intervals); 2) vaginal misoprostol (400 mcg at 6‐hourly intervals); or 3) vaginal misoprostol loading dose (600 mcg) followed by vaginal misoprostol (200 mcg at 6‐hourly intervals).
Outcomes	Vaginal birth not achieved in 24 hours; median induction to birth interval; pain score > 5 (using VAS); analgesia requirements; surgical evacuation of the uterus; nausea; vomiting; diarrhoea.
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Australia, March 2001‐July 2002.
Participants	225 women undergoing second trimester termination of pregnancy for termination of a live fetus with anomalies; trial stopped early after total 84 women randomised.
Interventions	Women randomised to 1) vaginal misoprostol (400 mcg at 6‐hourly intervals); 2) oral misoprostol (200 mcg at 3‐hourly intervals); or 3) vaginal misoprostol loading dose (600 mcg) followed by oral misoprostol (200 mcg at 3‐hourly intervals).
Outcomes	Vaginal birth not achieved in 24 hours; induction to delivery interval (median); median pain score; need for analgesia; surgical evacuation; nausea; vomiting; diarrhoea; median maternal satisfaction.
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Sudan, February‐November 2006.
Participants	150 women with intrauterine fetal death in the second trimester of pregnancy. Women with prior uterine surgery, asthma, heart disease or more than 7 previous pregnancies were excluded from the study.
Interventions	Women were randomised to 1) oral misoprostol (100 mcg at 4‐hourly intervals); 2) vaginal misoprostol (100 mcg at 4‐hourly intervals); or 3) sublingual misoprostol (100 mcg at 4‐hourly intervals).
Outcomes	Vaginal birth not achieved in 24 hours; induction to delivery interval.
Notes	Method of randomisation: stated to be an "open randomised controlled clinical trial".  Allocation concealment: not stated.  Blinding of participants, caregivers, outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated to be an "open randomised controlled clinical trial".
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Sudan, February‐December 2002.
Participants	70 women undergoing second trimester termination of pregnancy following fetal demise. Women were excluded with prior uterine surgery, severe asthma, heart disease, parity greater than 7.
Interventions	Women randomised to vaginal misoprostol (100 mcg at 4‐hourly intervals) or oral misoprostol (100 mcg at 4‐hourly intervals).
Outcomes	Mean induction to birth interval; surgical evacuation of the uterus.
Notes	Method of randomisation: 'patients were randomised'.  Allocation concealment: not stated.  Blinding of participants, caregivers and outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated that "patients were randomised".
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in United States, January 2000‐June 2002.
Participants	40 women undergoing second trimester termination of pregnancy following fetal demise. Women were excluded with hypersensitivity to prostaglandins, scarred uterus.
Interventions	Women received vaginal misoprostol (800 mcg) and were then randomised to followed by either vaginal misoprostol (400 mcg at 8‐hourly intervals) or oral misoprostol (400 mcg at 8‐hourly intervals).
Outcomes	Mean induction to birth interval; analgesic requirements (% only), surgical evacuation of the uterus, side effects (% only).
Notes	Method of randomisation: random number table.  Allocation concealment: opaque sealed envelopes.  Blinding of participants, caregivers and outcome assessors: no.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number table.
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk

Methods	Trial conducted in Egypt; gestational age 16 to 24 weeks.
Participants	40 women undergoing termination of pregnancy following both fetal demise or termination of a live fetus.
Interventions	Women randomised to vaginal misoprostol (200 mcg at 8 hourly intervals) or intracervical prostaglandin F2 alpha.
Outcomes	Vaginal birth not achieved within 24 hours; induction to birth interval; surgical evacuation of the uterus; vomiting; diarrhoea; pyrexia.
Notes	Method of randomisation: "randomly allocated".  Allocation concealment: not stated.  Blinding of participants, caregivers and outcome assessors: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stated that patients were "randomly allocated".
Allocation concealment (selection bias)	Unclear risk	Not stated.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Not stated.
Incomplete outcome data (attrition bias)   All outcomes	Low risk
Selective reporting (reporting bias)	Low risk
Other bias	Low risk