Different methods for the induction of labour in outpatient settings

Therese Dowswell; Anthony J Kelly; Stefania Livio; Jane E Norman; Zarko Alfirevic

doi:10.1002/14651858.CD007701.pub2

. Author manuscript; available in PMC: 2014 Nov 24.

Published in final edited form as: Cochrane Database Syst Rev. 2010 Aug 4;(8):CD007701. doi: 10.1002/14651858.CD007701.pub2

Different methods for the induction of labour in outpatient settings

Therese Dowswell ², Anthony J Kelly ³, Stefania Livio ¹, Jane E Norman ⁴, Zarko Alfirevic ¹

PMCID: PMC4241469 EMSID: EMS58186 PMID: 20687092

Abstract

Background

Induction of labour is carried out for a variety of indications and using a range of pharmacological, mechanical and other methods. For women at low risk, some methods of induction of labour may be suitable for use in outpatient settings.

Objectives

To examine pharmacological and mechanical interventions to induce labour in outpatient settings in terms of feasibility, effectiveness, maternal satisfaction, healthcare costs and, where information is available, safety. The review complements existing reviews on labour induction examining effectiveness and safety.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (December 2009) and reference lists of retrieved studies.

Selection criteria

We included randomised controlled trials examining outpatient cervical ripening or induction of labour with pharmacological agents or mechanical methods.

Data collection and analysis

Two authors independently extracted data and assessed eligible papers for risk of bias. We checked all data after entry into review manager software.

Main results

We included 28 studies with 2616 women examining different methods of induction of labour where women received treatment at home or were sent home after initial treatment and monitoring in hospital.

Studies examined vaginal and intracervical PGE₂, vaginal and oral misoprostol, isosorbide mononitrate, mifepristone, oestrogens, and acupuncture. Overall, the results demonstrate that outpatient induction of labour is feasible and that important adverse events are rare. There was no strong evidence that agents used to induce labour in outpatient settings had an impact (positive or negative) on maternal or neonatal health. There was some evidence that, compared to placebo or no treatment, induction agents reduced the need for further interventions to induce labour, and shortened the interval from intervention to birth. We were unable to pool results on outcomes relating to progress in labour as studies tended to measure a very broad range of outcomes.

There was no evidence that induction agents increased interventions in labour such as operative deliveries. Only two studies provided information on women’s views about the induction process, and overall there was very little information on the costs to health service providers of different methods of labour induction in outpatient settings.

Authors’ conclusions

Induction of labour in outpatient settings appears feasible. We do not have sufficient evidence to know which induction methods are preferred by women, or the interventions that are most effective and safe to use in outpatient settings.

Medical Subject Headings (MeSH): * Ambulatory Care; Acupuncture Therapy [methods]; Feasibility Studies; Labor, Induced [* methods]; Oxytocics; Randomized Controlled Trials as Topic

MeSH check words: Female, Humans, Pregnancy

BACKGROUND

Introduction

The number of women whose labours are induced has risen dramatically over the past two decades. Rates in the USA and the UK now exceed 20% of all births (Glantz 2003; Kirby 2004; NHS 2007). There is an enormous variation in reported induction rates and the reasons for this variability are not clear. In some units in the USA, up to half of all births follow induction of labour (Rayburn 2002). There is no convincing evidence that the increase in inductions has been associated with improvements in maternal, fetal or neonatal outcomes, and women who are induced tend to be less satisfied with their experience of childbirth (Shetty 2005). In this context, and with increasing pressure on healthcare resources, it is particularly important to address questions about how to provide safe induction of labour, in settings and ways that are acceptable to women, and in the most cost-effective way possible.

A number of pharmacological and mechanical methods of cervical ripening and induction of labour are available, and these have been the focus of a series of previous Cochrane reviews which share generic protocols (Hofmeyr 2000; Kelly 2001). In these reviews, the safety and effectiveness of different methods and agents have been examined, but less attention has been paid to the setting in which cervical ripening and induction of labour take place. In this review we will bring together some of the studies included in previous reviews, focusing specifically on those studies where labour induction has been carried out in outpatient settings. For most methods of induction, the number of trials carried out in outpatient settings is likely to be small, and here, the purpose of the review is mainly descriptive, examining issues such as feasibility, health service utilisation and women’s views about their care. For some interventions, there may be sufficient data to address questions of effectiveness and safety. In this way the review will complement existing ones rather than simply duplicating findings. A related review includes trials in which the same methods of ripening or induction have been compared in outpatient and hospital settings (Kelly 2009b).

Cervical ripening and induction of labour in outpatient settings

Induction of labour is carried out for a variety of indications and using a range of pharmacological, mechanical and other methods. The main indication for induction of labour is prolonged pregnancy, and there is evidence from a related Cochrane review (Gülmezoglu 2006) that for pregnancies that have continued beyond 41 weeks, induction of labour may reduce perinatal mortality. Other inductions are carried out on an individual basis. Most inductions of labour are carried out in inpatient settings. Outpatient procedures may not be safe for women with important risk factors, and some methods may only be feasible and safe in hospital, or in settings with specialised staff and facilities available. For example, outpatient induction is unlikely to be suitable for women with serious medical conditions or complications in the current pregnancy (Sawai 1995). Some women may be unsuitable for home care simply because they live at an unacceptable travelling distance from emergency care facilities.

Ideally, the agents or methods used for cervical ripening at home would achieve changes in the cervix similar to the normal physiological changes which promote the ‘spontaneous’ onset of labour, but without causing uterine contractions (Sawai 1995). Most methods for cervical ripening or induction of labour do have some undesirable side effects, including, on occasions, excessive uterine activity. The consequences of excessive uterine activity as a result of iatrogenic uterine hyperstimulation can be life-threatening for the mother and fetus.

Sometimes drugs to induce labour can only be administered by intravenous infusion or by repeated injections, or using specialist procedures that cannot easily be carried out in an outpatient setting. Drugs that can be taken orally, or procedures that are simple to perform, and require only limited monitoring, may lend themselves more readily for use in an outpatient setting. At least theoretically, outpatient induction may offer a number of advantages to women, clinical staff and providers of health services. Outpatient induction may be more convenient to, and preferred by, women; it may reduce hospital bed occupancy and, therefore, be associated with lower healthcare costs.

A number of papers have set out indications for outpatient cervical ripening or induction such as post-dates pregnancy in women who are otherwise well, and where there have been no signs of fetal distress. Several outpatient induction protocols have been described in observational studies suggesting that such inductions are feasible, safe and acceptable to women (Elliott 1992; McGill 2007; Neale 2002).

Why it is important to do this review

For some methods, and for selected groups of women, induction of labour is already being carried out in outpatient settings. A number of randomised controlled trials examining cervical ripening and induction of labour in outpatient settings have now been completed. This review brings together evidence from these trials to provide an overview of the feasibility of outpatient induction. If sufficient data were available we had also planned to provide information on the relative costs of different methods and their acceptability to women. Where possible, we have pooled data from trials examining the same methods to address questions of safety. In the context of this review, the issue of safety is of great importance. At the same time, it is unlikely that the safety will be adequately addressed in studies of randomised cohorts. Severe maternal and neonatal mortality and morbidity are likely to be very rare events in the low-risk population included in studies of outpatient induction. Information on adverse events and the relative safety of outpatient methods is most likely to emerge where there have been several large studies and where the same methods have been directly compared in different settings. Information on rare adverse events takes time to accumulate, but by systematically recording information on adverse events in all the studies included in the review, we may shed some light on this question.

In this review we have not included studies where the same method of cervical ripening or induction of labour was compared in outpatient versus inpatient settings: this has been addressed in a related Cochrane review (Kelly 2009b).

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

All published and unpublished randomised trials which compared different methods of cervical ripening or induction of labour carried out in outpatient settings. All trials included random allocation to intervention and control groups. We did not include quasi-randomised trials. We included studies reported in abstracts and brief reports provided sufficient information was available to allow us to assess eligibility and risk of bias; where such information was not provided we attempted to contact trial authors. We planned to include cluster-randomised trials if they were otherwise eligible. We have not included crossover studies as we did not consider that they were appropriate in this topic area.

Types of participants

Pregnant women with a viable fetus suitable for cervical ripening or induction of labour at or near term (greater than 35 weeks) in an outpatient setting.

Types of interventions

We have included studies examining outpatient cervical ripening or induction of labour with pharmacological agents or mechanical methods. We have included studies where different methods of induction of labour in outpatient settings are compared; where a method is compared with a placebo; where a method is compared with expectant management; or where different doses of the same drug are compared. ‘Outpatient’ has been defined by the trialists, and includes any cervical ripening or induction of labour intervention (with the exception of membrane sweeping) that can be carried out at home or within community healthcare settings. It also includes a package of care initially provided in hospital (fetal monitoring, drug administration) after which the woman is allowed home until later review or until admission in labour. We have not included interventions where women remain in hospital throughout (even if they are in ‘day-care’ settings, or in other parts of the hospital, but are not formally admitted as inpatients), as a purpose of the review is to examine outcomes where women do not have immediate access to emergency care facilities.

Types of outcome measures

Clinically relevant outcomes for trials of methods of cervical ripening and labour induction have been pre-specified by two authors of labour induction reviews (Justus Hofmeyr and Zarko Alfirevic) (Hofmeyr 2000). We have used most of these outcomes (relevant to both inpatient and outpatient settings) in this review.

In addition, we have attempted to use relevant outcome measures to quantify any cost effectiveness benefits of outpatient ripening.

Primary outcomes

Failure to achieve vaginal delivery within 24 hours.
Additional induction agents required.
Length of hospital stay.
Use of emergency services.
Mother not satisfied.
Caregiver not satisfied.
Serious neonatal morbidity or perinatal death (composite outcome will include, for example, seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood).
Serious maternal morbidity or death (composite outcome will include, for example, uterine rupture, admission to intensive care unit, septicaemia).

Secondary outcomes

Outcomes related to measures of effectiveness, complications and satisfaction.

Measures of effectiveness

Vaginal delivery not achieved within 48 and 72 hours.
Randomisation to delivery interval.
Oxytocin augmentation.
Pain relief requirements (epidural, opioids).

Complications

Uterine hyperstimulation (with fetal heart rate (FHR) changes).
Uterine hyperstimulation (without FHR changes).
Instrumental vaginal delivery.
Caesarean section.
Apgar score less than seven at five minutes.
Neonatal intensive care unit admission.
Perinatal death.
Postpartum haemorrhage (as defined by the trial authors).
Serious maternal complications (considered as separate outcomes, e.g. intensive care unit admission, septicaemia, uterine rupture).
Serious neonatal complications (considered as separate outcomes).

In the absence of formal economic evaluation, we had planned to estimate potential cost savings and the impact of interventions used within an outpatient setting. These estimates could involve using some measures of effectiveness and complications in combination with estimates of healthcare provision. There were insufficient data reported in the trials to allow us to carry out this analysis.

We have also included some additional outcomes that may serve as ‘proxy’ measures of progress towards labour or delivery.

Indicators of ‘progress’ in labour such as: preterm rupture of membranes, diagnosis of active/spontaneous labour, self-referral back to hospital, Bishop scores at fixed time points post-randomisation.
‘Failed induction’ (as defined by trialists, but excluding the use of oxytocin for augmentation in women already in established labour).
Time to delivery including the interval from randomisation to delivery; interval to admission along with length of labour.

Detailed definitions for outcomes

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 less severe morbidity. However, in the context of labour induction at term, this is unlikely. All these events are rare, and a modest change in their incidence will be easier to detect if composite outcomes are presented. The incidence of individual components are explored as secondary outcomes (see above).
‘Uterine rupture’ includes all clinically significant ruptures of unscarred or scarred uteri. Trivial scar dehiscence noted incidentally at the time of surgery is excluded.
The terminology of uterine hyperstimulation is problematic (Curtis 1987). In the reviews, the term ‘uterine hyperstimulation’ is defined as uterine tachysystole (more than five contractions per 10 minutes for at least 20 minutes) and uterine hypersystole/hypertonus (a contraction lasting at least two minutes).
‘Uterine hyperstimulation with FHR changes’ is usually defined as uterine hyperstimulation syndrome (tachysystole or hypersystole with FHR changes such as persistent decelerations, tachycardia or decreased short-term variability). However, due to varied reporting, there is the possibility of subjective bias in the interpretation of these outcomes. Also, it is not always clear from the trials if these outcomes are reported in a mutually exclusive manner. More importantly, continuous monitoring is unlikely in an outpatient setting. Therefore, there is a high risk of biased reporting of uterine hyperstimulation (with or without FHR changes). It is possible that bias will favour the outpatient setting (i.e. by failure to recognise mild forms of hyperstimulation without continuous monitoring). On the other hand, clinicians who favour inpatient induction may, in the absence of continuous monitoring, label any maternal description of painful, frequent uterine contractions as hyperstimulation. Therefore, in the absence of blinding, hyperstimulation and other ‘soft’ outcomes should be interpreted with extreme caution.

While we sought data on all of the outcomes listed above, we have documented only those with data in the analysis tables. We have included outcomes in the analysis if reasonable measures were taken to minimise observer bias, and data were available according to original treatment allocation.

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 (December 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.

Searching other resources

We searched the reference lists of retrieved studies.

We did not apply any language restrictions.

Data collection and analysis

We carried out data collection and analysis (including the selection of studies, data extraction and management, assessment of risk of bias, and data entry and analysis) using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009).

Selection of studies

Two review authors (A Kelly, T Dowswell) independently assessed the eligibility for inclusion of all the studies we identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted a third review author.

Data extraction and management

We adapted the data extraction form used in the series of Cochrane reviews on the induction of labour. All review authors were involved in data extraction, with two authors independently extracting data from each study report. We resolved discrepancies through discussion or, if required, we consulted a third author. We entered data into Review Manager software (RevMan 2008) and checked them 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 2009). We resolved any disagreement by discussion or by involving a third author.

(1) Sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence.

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); or
unclear.

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

We have described for each included study the method used to conceal the allocation sequence and have assessed 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); or
unclear.

(3) Blinding (checking for possible performance bias)

Interventions to ripen the cervix or to induce labour in outpatient settings include both pharmacological and mechanical methods. Although some studies may be placebo controlled, we envisaged that in many studies blinding women and care providers would not be feasible. However, we have described for each included study any methods used to blind study participants and personnel from knowledge of which intervention a participant received. We have noted where there was partial blinding (e.g. outcome assessment may be blind for some types of outcomes).

We have 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 have 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 have stated 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 supplied by the trial authors, we have re-included missing data in the analyses. We assessed methods as:

adequate (where there was no or low levels of attrition (less than 20%) and where attrition was balanced across groups);
inadequate (where there were high levels of attrition or where attrition was not balanced across groups);
unclear.

(5) Selective reporting bias

We have noted if we had concerns about selective reporting bias, for example, where not all the study’s pre-specified outcomes were reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; or where a study failed to include results of a key outcome.

(6) Other sources of bias

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

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

yes;
no;
unclear.

(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 2009). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

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

Continuous data

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

Unit of analysis issues

Cluster-randomised trials

No cluster randomised trials were identified by the search strategy. However, if such trials are identified in the future, provided that they are otherwise eligible, we will include them in updates of the review and will analyse them along with individually randomised trials. Their sample sizes will be adjusted using the methods described in Gates 2005 and Higgins 2009 using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, this will be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC.

Crossover trials

We have not included crossover trials in the review; it was unlikely that such trials would be identified in this topic area.

Dealing with missing data

For included studies, we have noted levels of attrition. We planned to explore 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 have 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 were known to be missing.

Assessment of heterogeneity

We have assessed heterogeneity by visual inspection of the forest plots for each analyses and have quantified the level of heterogeneity by examining the I², T² and Chi² statistics for each analysis. Where we identified substantial heterogeneity (T² greater than zero and either I² greater than 30% or a significant Chi² test for heterogeneity (P value less than 0.1)) we explored it by pre-specified subgroup analysis. In the presence of moderate or high levels of heterogeneity, we have used random-effects meta-analysis and have included along with the risk ratio and the 95% confidence interval, the values of I², T² and the P value of the Chi² test for heterogeneity with the 95% prediction interval. In analyses where an intervention appears to favour a particular intervention, but where there is high heterogeneity and the prediction interval includes the null value of one, we would advise caution in the interpretation of results. In such cases we cannot rule out the possibility that the treatment effect in a single study may be different (in size and direction) from that suggested by the meta-analysis.

Assessment of reporting biases

We did not formally assess reporting bias as part of the risk of bias assessment. For most of the studies we carried out data extraction from published study reports; without access to study protocols it can be difficult to assess whether there has been any selective reporting. Where we suspected reporting bias (see ‘Selective reporting bias’ above), we planned to contact study authors asking them to provide any suspected missing outcome data.

We were not able to explore possible publication bias using funnel plots as none of the comparisons included sufficient studies.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2008). We anticipated that there would be a variety of methods for cervical ripening and induction of labour used in different trials. We planned therefore only to pool data to calculate an overall treatment effect where the same method of induction was used in different trials. We have used fixed-effect meta-analysis for combining data where trials examined 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 differed between trials, we used random-effects meta-analysis. Where we identified substantial statistical heterogeneity we have used a random-effects method and have indicated the levels of heterogeneity as part of the presentation of results.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analyses using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Data permitting, we planned subgroup analysis by:

nulliparous versus multiparous women;
induction indication (e.g. postdate (41 weeks’ gestation or greater)).

We planned to use only primary outcomes in subgroup analysis. In view of the small number of studies included in each comparison we were not able to carry out the planned analyses. In all but three of the included studies (Incerpi 2001; Lelaidier 1994; Rayburn 1999) the main indication for induction of labour was ‘postdates’ pregnancy. The majority of studies recruited both primi- and multiparous women, and separate figures were not provided for subgroups. Further, very few of the included studies provided information on the review’s primary outcomes. In updates of the review, as more studies are added, and more data become available, we may be able to include planned subgroup analysis.

Sensitivity analysis

If, in the future, we identify any cluster randomised trials and use published ICC values, we will carry out sensitivity analysis examining the effect of changing the ICC.

We planned to investigate the impact of including poorer quality studies (for example, where allocation concealment was unclear) by carrying out sensitivity analysis. We intended to temporarily remove those studies assessed as being of poorer quality from the analysis to examine any changes in the size of the treatment effect, or the direction of findings. We did not carry out this additional analysis as only a small number of studies contributed outcome data for each different comparison, and very few studies reported on the review’s primary outcomes. In updates of the review as more studies become available, we plan to carry out sensitivity analysis by study quality.

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Results of the search

We identified 72 reports, representing 55 separate studies (some trials were reported in more than one published paper). We have included 28 studies in the review, excluded 25, and two studies are awaiting further assessment (Ascher-Walsh 2000; Thakur 2005; see Characteristics of studies awaiting classification tables).

Included studies

Twenty-eight studies including 2616 women.

The studies included a variety of different comparisons.

Vaginal prostaglandin (PGE₂) versus expectant management or placebo (five studies) (Hage 1993; Newman 1997; O’Brien 1995; Sawai 1991; Sawai 1994).
Intracervical prostaglandin (PgE₂) versus expectant management or placebo (seven studies) (Buttino 1990; Gittens 1996; Larmon 2002; Lien 1998; Magann 1998; McKenna 1999; Rayburn 1999).
Vaginal misoprostol versus placebo (four studies) (Incerpi 2001; McKenna 2004; Oboro 2005; Stitely 2000). In addition, one study compared two different doses of misoprostol (Kipikasa 2005).
Intracervical prostaglandin (PGE₂) versus vaginal misoprostol (one study) (Meyer 2005).
Oral misoprostol versus placebo (one study) (Lyons 2001).
Mifepristone versus placebo (five studies) (Elliott 1998; Frydman 1992; Giacalone 1998; Lelaidier 1994; Stenlund 1999).
Oestrogen versus placebo (one study) (Larmon 2002).
Vaginal isosorbide mononitrate (IMN) versus placebo (three studies) (Bollapragada 2006; Bullarbo 2007; Habib 2008).
Acupuncture versus routine care (one study) (Harper 2006).

(The study by Larmon 2002 was a three-arm trial comparing intracervical PGE₂, oestrogen and placebo and is included in more than one comparison.)

In all trials it was intended that women would spend part of the study period at home. In the majority of studies women received the initial treatment in a hospital setting (and frequently underwent a period of surveillance) before discharge home. Women were advised to seek help or return to hospital if any problems arose, if labour commenced, or after a predefined period. In some studies, women self-administered the study intervention at home, and again were advised to return either if they had concerns, if labour started, or for review after a specified period (e.g. in the study by Bollapragada 2006 women scheduled for labour induction were given vaginal IMN with instructions on self-administration 48, 32 and 16 hours before the scheduled induction time).

The studies almost invariably recruited healthy women at term. A small number of studies focused on women with particular histories. In the trials by Gittens 1996, Lelaidier 1994 and Rayburn 1999 women that had had a previous caesarean delivery were recruited; Incerpi 2001 focused on women with insulin-dependent diabetes and Newman 1997 included women with diabetes along with those requiring induction of labour for postmaturity. Two studies (Lelaidier 1994; Rayburn 1999) recruited women who had had a previous caesarean section (CS) and who were aiming to achieve a vaginal delivery. In the remaining studies the main indication for induction of labour was prolonged pregnancy, although recruitment was not always restricted to this group. Four studies included only primiparous women (Bollapragada 2006; Elliott 1998; Hage 1993; Harper 2006) and two multiparous women only (Lelaidier 1994; Rayburn 1999).

The main recruitment criterion in all of these studies was that labour had not already started (i.e. women were not having regular painful contractions). Most of the studies also specified a Bishop score indicating an unfavourable cervix as an inclusion criterion although the definition of an unfavourable cervix (low Bishop score) varied. No studies specifically recruited women where the cervix was favourable. Where it was mentioned, studies invariably recruited women with intact membranes; no studies specifically focused on women with ruptured membranes. Most of these studies specifically mentioned that multiple pregnancies were excluded, and at recruitment it was usually specified as an inclusion criterion that the fetus was in good condition with no signs of distress (e.g. normal fetal heart rate monitoring and normal amniotic fluid volume).

Further information on interventions, participants and inclusion and exclusion criteria are set out in the Characteristics of included studies tables.

Excluded studies

We excluded 25 trials. The main reason for excluding studies was their study design.

Four studies used a crossover design; we had decided to exclude crossover trials as we did not think this design was appropriate in this topic area; in all of these studies the focus was on breast stimulation. Women in the control groups initially received no intervention, while those in intervention groups were asked to stimulate their nipples for a specified time period; after this time period, women then crossed over into the control or intervention arm (Adewole 1993; Di Lieto 1989; Elliott 1984; Salmon 1986). In four studies (Damania 1988; Griffin 2003; Manidakis 1999) there was too little information on study methods to allow us to ascertain whether group allocation was truly random, or to allow us to carry out an assessment of risk of bias (the studies by Griffin 2003 and Manidakis 1999 were reported in brief abstracts; we attempted to contact the authors for more information without success). Two studies used quasi-randomisation and were at high risk of bias (Garry 2000; Kadar 1990). Evans 1983 described findings from two separate studies, one of which seemed to be carried out in a hospital setting and included a control group receiving no treatment; a second “outpatient” study did not include a control group; different doses of porcine ovarian relaxin were compared. In the study by Ohel 1996, whilst there seemed to be random allocation to treatment groups, results were not reported by randomisation group, and we were not able to include data in the review. In one study reported in a brief abstract, no original data were reported in the results section (Krammer 1995).

A number of studies focused on interventions that we had either specifically excluded (e.g. Doany 1997; Kaul 2004; Magann 1999; and Salamalekis 2000 looked at membrane sweeping), or interventions that are not used nowadays in clinical practice (extra amniotic saline infusion was examined by Moghtadaei 2007; it was not clear that women in both arms of this trial were discharged home; Spallicci 2007 examined the use of hyaluronidase injection).

In five studies it was not clear that the study was carried out in an outpatient setting or that the women were expected to spend some of the study period at home (Damania 1992; Herabutya 1992; Rayburn 1988; Voss 1996; Ziaei 2003).

Rijnders 2007 looked at the same intervention comparing home versus hospital settings and has been included in a related review (Kelly 2009b).

Finally, Dorfman 1987 looked at homeopathic preparations (caulophyllum-arnica-actea and racemosa-pulsatilla-gelsemium) used with the intention of generally preparing women for childbirth rather than for labour induction.

More information on excluded studies is set out in the Characteristics of excluded studies tables.

Risk of bias in included studies

Allocation

We assessed most of the studies included in the review as using adequate methods to generate the randomisation sequence and to conceal group allocation.

Sequence generation was either computer generated or derived from random number tables in 22 of the 28 included studies. In six trials the methods used to generate the randomisation order were not clear (Elliott 1998; Gittens 1996; Hage 1993; Lyons 2001; Newman 1997; Sawai 1991).

Sixteen studies used either external or pharmacy randomisation services, or identical coded drug packs from pharmacy to conceal group allocation (Bollapragada 2006; Buttino 1990; Frydman 1992; Giacalone 1998; Habib 2008; Incerpi 2001; Kipikasa 2005; Lelaidier 1994; Lien 1998; McKenna 1999; McKenna 2004; O’Brien 1995; Oboro 2005; Rayburn 1999; Sawai 1994; Stitely 2000). Four trials used sealed, opaque, sequentially numbered envelopes to conceal allocation (Bullarbo 2007; Harper 2006; Larmon 2002; Magann 1998); envelopes were also used in the Meyer 2005 and Stenlund 1999 trials, although in the former it was not stated that they were sealed, and in the latter that they were opaque. In six trials methods to conceal group allocation were not clear (Elliott 1998; Gittens 1996; Hage 1993; Lyons 2001; Newman 1997; Sawai 1991).

Blinding

Most (21) of the included studies were placebo controlled, and women and clinical staff were described as blind to group allocation. However, it was not always clear when the randomisation code was broken, so it was difficult to assess whether outcome assessment was carried out by blinded investigators. In two of the placebo controlled trials blinding may not have been convincing; in the Kipikasa 2005 trial women in the two groups were both given tablet fragments (either an eighth or a quarter of whole tablets) so the tablets may have not appeared identical (at least to staff). In the Larmon 2002 study women may have been blind to intra-vaginal preparations, but staff are unlikely to have been.

In six trials women in the two arms of the studies were given different interventions and therefore blinding was not feasible, or not attempted (Gittens 1996; Harper 2006; Meyer 2005; Newman 1997; Rayburn 1999; Stenlund 1999). The lack of blinding in these studies may have affected some of the outcomes examined in the review.

Incomplete outcome data

Loss of women to follow up and missing data were not serious problems in most of the included studies. Rates of attrition were less than 10% in 19 of the trials. In six studies the levels of attrition were not clear (Gittens 1996; Hage 1993; Harper 2006; Incerpi 2001; Lyons 2001; Newman 1997). In the study by Sawai 1991, attrition was approximately 12% and some of the exclusions were for non-compliance. Attrition was also high in the study by Bollapragada 2006; in this trial randomisation occurred up to nine days before the initiation of treatment, hence 80 of the 350 women did not start treatment as they had already gone into labour. To reduce risk of bias, the authors reported an intention-to-treat analysis (including all women randomised) for the trial’s primary outcomes but not for secondary outcomes. In the study by Kipikasa 2005 there were inconsistencies in figures between the text and the tables.

Other potential sources of bias

In many of these studies women were likely to receive other interventions at some stage in their treatment as well as the study allocated intervention (e.g. amniotomy, membrane sweeping, additional medication) and these in turn may have affected other outcomes (e.g. length of labour and rate of CS). Without adequate blinding, it is possible that women in intervention and control groups may have had different co-interventions, or co-interventions at different stages. For example, in the study by Harper 2006 women in the intervention group attended for treatment on three occasions, and at these visits (not available to women in the control group) women may have been exposed to a range of co-interventions, or additional tests or observations, that may have had an impact on outcomes.

Other sources of bias included baseline imbalance in parity between groups (Oboro 2005) and imbalance in numbers of randomised women between the treatment and control groups (Elliott 1998).

Effects of interventions

Induction of labour in outpatient settings: 28 studies with 2616 women

(1) Vaginal prostaglandin (PGE₂) versus expectant management or placebo: five studies, 335 women

Primary outcomes

We included five studies in this comparison (Hage 1993; Newman 1997; O’Brien 1995; Sawai 1991; Sawai 1994). None of the studies collected information on most of the review’s primary outcomes. We do not have information on the numbers of women achieving vaginal delivery within 24 hours, on length of hospital stay, on the use of emergency services or on maternal satisfaction. Maternal and perinatal deaths were not reported.

O’Brien 1995 and Sawai 1991 reported the numbers of women requiring further (non-study) induction agents with fewer women in the PGE2 group needing further medication to induce labour. While 14.8% of the PGE2 group needed further induction agents this applied to 28.9% of the control group. However, as only two relatively small studies contributed data for this outcome, results were of borderline statistical significance (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.27 to 0.99).

Secondary outcomes

There was only limited information on the impact of interventions on the health of mothers and babies. O’Brien 1995 and Sawai 1994 reported rates of chorioamnionitis and results favoured women in the PGE₂ group (RR 0.37, 95% CI 0.15 to 0.90). There was no statistically significant differences between groups for uterine hyperstimulation (with or without fetal heart rate (FHR) changes) (Analysis 1.5). There was no information on the use of antibiotics or on rates of endometritis.

There was no statistically significant evidence of differences between groups for Apgar scores at five minutes (Analysis 1.18) or for admission to a neonatal intensive care unit (NICU) (RR 0.32, 95% CI 0.10 to 1.03). There was no information on neonatal infection or on the use of antibiotics.

Four of the studies reported rates of CS and there was no evidence of a difference between groups (Analysis 1.7). O’Brien 1995 examined the use of epidural; again, there was no strong evidence of any difference between groups (Analysis 1.10).

Additional outcomes

While none of these five studies reported the numbers of women achieving vaginal delivery within a certain specified period, other ‘proxy’ measures of progress towards labour or delivery were included. Each study reported different outcomes.

Hage 1993 reported on the rate of change in Bishop scores and, compared with women receiving PGE₂, those in the control group were more likely to have score changes of less than three at follow up (RR 0.13, 95% CI 0.03 to 0.47) although it was not clear when follow up occurred.

Newman 1997 reported figures for the number of women going into “spontaneous labour” within 48 hours of treatment commencing; it was more likely for labour to start in the PGE₂ group compared with women receiving routine care (RR 6.43, 95% CI 2.12 to 19.48).

O’Brien 1995 reported that the median interval from study enrolment to delivery was four days in the PGE₂ group (range 0 to 28 days) versus 10 days (range 0 to 26 days) in controls (P = 0.002). The shorter interval between randomisation and delivery was reflected in a lower gestational age at delivery in the intervention group (Analysis 1.26). It was also reported that, during the five-day treatment period, compared with controls, significantly more women in the intervention group were admitted to hospital “for labour” (RR 2.70, 95% CI 1.47 to 4.97), although it was not clear whether this included women in active labour only, or women admitted after PROM or for other reasons. The numbers of women diagnosed with post-term pregnancy was small in both groups (two women in the intervention group and three in the control group).

Sawai 1991 describes Bishop scores in control and intervention groups at hospital admission, but there were differences between groups at baseline and the authors report no significant differences between groups at follow up (data not shown). Sawai 1994 reported the mean gestational age at hospital admission (although the indications for admission included pregnancy complications as well as signs of the onset of labour). The difference between groups was not significant (Analysis 1.27).

(2) Intracervical prostaglandin (PGE₂) versus expectant management or placebo: seven studies, 678 women

Primary outcomes

We included seven studies in this comparison (Buttino 1990; Gittens 1996; Larmon 2002; Lien 1998; Magann 1998; McKenna 1999; Rayburn 1999).

Three studies looked at whether, compared with no treatment or placebo, women receiving intracervical PGE₂ were less likely to need further (non-study) interventions to induce labour. There was no strong evidence of a difference between groups (RR 0.98, 95% CI 0.74 to 1.32). Lien 1998 also examined whether women given intracervical PGE₂ were less likely to receive further doses of prostaglandin to induce labour. Again, there was no evidence to suggest a difference between groups (RR 1.61, 95% CI 0.22 to 1.67).

Buttino 1990 reported on the number of women failing to achieve vaginal delivery within 48 to 72 hours and, although results favoured the PGE₂ group, they did not reach statistical significance (RR 0.83, 95% CI 0.68 to 1.02).

Rayburn 1999 reported rates of uterine rupture, and there were no events in either the PGE₂ group or amongst controls (Analysis 2.6). There was no information on serious neonatal morbidity of death, or on the review’s other primary outcomes.

Secondary outcomes

The impact of interventions on maternal health were explored in five of these studies (Buttino 1990; Larmon 2002; Lien 1998; McKenna 1999; Rayburn 1999). There was no strong evidence that there were differences between women receiving PGE₂ compared to controls for uterine hyperstimulation (with or without FHR changes), postpartum haemorrhage, chorioamnionitis or endometritis (Analysis 2.7; Analysis 2.9; Analysis 2.16; Analysis 2.17). Two studies looked at side effects from treatment, and there was no evidence of a difference between women in the two arms of these trials (Analysis 2.26).

There were no statistically significant differences between groups for neonatal Apgar scores at five minutes, or for the number of babies admitted to NICU (Analysis 2.20; Analysis 2.21).

All seven studies examined the numbers of women undergoing CS; numbers were similar for women receiving PGE₂ compared with controls (RR 0.90, 95% CI 0.72 to 1.12). There was no strong evidence of differences between groups for other interventions in labour including the number of women having assisted vaginal delivery or oxytocin augmentation. (Analysis 2.11; Analysis 2.12). The included studies did not provide information on other review outcomes including the use of antibiotics, neonatal infection, or use of epidural.

Additional outcomes

All seven studies collected information on progress towards labour and delivery; again reported outcomes were different in each study. Buttino 1990 and Lien 1998 reported no significant differences between women in the PGE₂ group and controls in the interval between the first dose of drug or placebo and delivery (Analysis 2.24).

Larmon 2002 found no differences between groups for the median number of days from recruitment to hospital admission (16.8 days for the PGE₂ group versus 15.4 days for controls). For other outcomes reported in this study (Bishop score on admission, and estimated gestational age on admission) there were no significant differences between groups. However, some women were admitted for induction rather than in labour and it was not clear if these mean figures included all women.

Lien 1998 and Magann 1998 reported the estimated gestational age at delivery and found no difference between groups for this outcome (Analysis 2.27) (there was high heterogeneity for this outcome and results should be interpreted with caution). These same two studies provided information on the number of women requiring induction for ‘postdates’ pregnancy (women reaching 42 weeks’ gestation). In view of high heterogeneity and different clinical management in the two studies, we did not pool results for this outcome but have set out the data in Analysis 2.28. While in the Magann 1998 study more women in the control group required induction (22 of 35 women) compared to the PGE₂ group (seven of 35 women) the results were difficult to interpret as some women had been admitted to hospital for induction at an earlier stage because of changes in Bishop score, or for other reasons.

McKenna 1999 reported the median time from recruitment to admission to hospital, and the interval was shorter in the PGE₂ group compared with controls (2.5 days versus 7 days, P = 0.02) however, reasons for admission included change in Bishop score, as well as for onset of labour. This study also reported the number of women delivering within two days of treatment commencing; more women gave birth within two days if they had had the active treatment (RR 3.10, 95% CI 1.29 to 7.47).

Finally, Rayburn 1999 reported the numbers of women delivering at various gestational ages (all deliveries). There were no statistically significant differences between groups at any of the time points measured (data not shown).

(3) Vaginal misoprostol versus placebo: four studies, 274 women

Primary outcomes

Four studies compared vaginal misoprostol with placebo (Incerpi 2001; McKenna 2004; Oboro 2005; Stitely 2000). In all four studies the initial dose of misoprostol was 25 mcg; in the study by Incerpi 2001 women received a second dose after three to four days if labour had not commenced, and in the study by Stitely 2000 a second dose was administered after one day.

For this comparison, only Oboro 2005 reported on the rate of perinatal death with no significant differences between groups; there were no deaths in the active treatment group (n = 38) compared with one stillbirth (reason not reported) in the control group (n = 39) (RR 0.34, 95% CI 0.01 to 8.14).

None of the studies provided information on the number of women achieving vaginal delivery within 24 hours.

There was no other information on serious maternal or neonatal morbidity.

Secondary outcomes

There was little information from these studies on the impact of interventions on mothers’ and babies’ health. There was no strong evidence of differences between intervention and control groups for uterine hyperstimulation (with or without FHR changes), Apgar scores at five minutes, neonatal infection, or admission to NICU (Analysis 3.5; Analysis 3.6; Analysis 3.18; Analysis 3.19; Analysis 3.21).

There were no statistically significant differences between groups for interventions in labour including the number of women undergoing CS, assisted vaginal delivery, or epidural (Analysis 3.7; Analysis 3.8; Analysis 3.10).

No information was provided in these studies on other review outcomes including maternal or neonatal infection, use of antibiotics or other maternal or neonatal complications.

Additional outcomes

Incerpi 2001 reported the mean dose of oxytocin used for each group; there was no significant evidence of any difference between the two groups (Analysis 3.24).

McKenna 2004 provides data on the interval from treatment to vaginal delivery; the difference between groups was not significant (Analysis 3.32). This author also reported the mean interval from recruitment to delivery, which was less for the misoprostol group compared with women receiving placebo (Analysis 3.33); information was provided separately for nulliparous and multiparous women (Analysis 3.34). It was not clear whether the figures included those women who had had CS, or other interventions in labour.

Stitely 2000 gave information about the number doses of medication given to the women (Analysis 3.25) and the number of women requiring subsequent doses on study days two and three; fewer women received further doses in the intravaginal misoprostol group (P < 0.01 for both time points, Analysis 3.26; Analysis 3.27).

Oboro 2005 reports that the interval from the commencement of treatment to hospital admission was significantly shorter for the misoprostol group both for nulliparous and parous women (Analysis 3.28; Analysis 3.29; Analysis 3.30). There was also evidence from this trial that the gestational age at labour was reduced in the misoprostol group compared with controls, with labour approximately a week earlier in the misoprostol group (mean difference (MD) −0.80, 95% CI −1.05 to −0.55). There was also evidence that the time to preterm rupture of membranes was shorter in the misoprostol group (Analysis 3.31), although it was not clear whether this was the interval from commencement of treatment or from hospital admission.

(4) Vaginal misoprostol 25 mcg versus 50 mcg: one study with 52 women

Primary and secondary outcomes

Kipikasa 2005 looked at two different doses of vaginal misoprostol. There was no information on any of the review’s primary outcomes or most secondary outcomes. There were no differences between groups in the number of women requiring further induction agents, undergoing CS or in the number of babies admitted to NICU (Analysis 4.1; Analysis 4.3; Analysis 4.4). There were no cases of uterine hyperstimulation in either group. One baby in the higher dose group had a low Apgar score (less than six) at five minutes.

Additional outcomes

The interval to delivery was reported to be shorter in the group receiving the higher dose of misoprostol; with women receiving 50 mcg delivering, on average, one and a half days earlier than those receiving 25 mcg (MD 1.5, 95% CI 1.19 to 1.81).

(5) Intracervical PGE₂ versus vaginal misoprostol: one study, 84 women

Primary outcomes

One study is included in this comparison between intracervical PGE2 and vaginal misoprostol (Meyer 2005). None of the review’s primary outcomes were considered in this study.

Secondary outcomes

There was no strong evidence of differences between intervention and control groups for uterine hyperstimulation, rate of CS, Apgar scores at five minutes and admission to NICU (Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4).

Additional outcomes

It was reported that the proportion of women not requiring oxytocin was 22% in the misoprostol group versus 2% in for those in the PGE₂ group (P = 0.006). The dose of oxytocin used was also reported to be significantly decreased in those women receiving misoprostol (P = 0.008 for cumulative dose of oxytocin) (data not shown).

The interval from the administration of the cervical ripening agent to admission was shorter for women who received misoprostol (Analysis 5.6), and misoprostol was also reported to increase by 32% the number of women starting labour or with SROM during the ripening period (Analysis 5.7).

Misoprostol was reported to increase the number of deliveries within 24 and 48 hours, but the differences between groups were not statistically significant (Analysis 5.8; Analysis 5.9).

(6) Oral misoprostol versus placebo: one study, 40 women

Primary outcomes and secondary outcomes

Lyons 2001 was the only study included in this comparison and it provided information on only three of the review’s pre-specified outcomes. There was no evidence of differences between women in the misoprostol and placebo groups in the need for further induction agents, uterine hyperstimulation or chorioamnionitis (Analysis 6.3; Analysis 6.4; Analysis 6.2).

Additional outcomes

Management of post-term pregnancies with oral misoprostol was associated with a reported significant decrease in the need for postdates inductions: 27% versus 59% with placebo (P < 0.05). Women in the misoprostol group had a significantly shorter interval from the first dose to active labor (Analysis 6.5), and this is reflected in the longer duration of treatment in the placebo group (Analysis 6.6).

(7) Mifepristone versus placebo: five studies, 393 women

Primary outcomes

We included five studies in this comparison (Elliott 1998; Frydman 1992; Giacalone 1998; Lelaidier 1994; Stenlund 1999). Women in the mifepristone group were less likely to require further medication to induce labour compared with controls ((random-effects) RR 0.59, 95% CI 0.37 to 0.95). However, there was considerable heterogeneity for this outcome (heterogeneity: I² = 74%, T² = 0.16, Chi² test for heterogeneity P = 0.009). The wide 95% prediction interval (0.08 to 4.39) indicates that this result should be interpreted cautiously as some further study might yield a ‘negative’ result.

Stenlund 1999 examined serious neonatal morbidity (the number of babies requiring antI-convulsive therapy); there was no statistically significant difference between groups (Analysis 7.2). Lelaidier 1994 reported on perinatal mortality and there were no deaths in either group (Analysis 7.17).

Secondary outcomes

There was only limited evidence on the impact of mifepristone on maternal and neonatal health. There were no significant differences between intervention and control groups for uterine rupture, chorioamnionitis, infant Apgar scores at five minutes or admission to NICU (Analysis 7.12; Analysis 7.14; Analysis 7.18; Analysis 7.19).

There was no strong evidence that the intervention had an impact on interventions in labour including CS, assisted vaginal delivery, oxytocin augmentation or use of epidural (Analysis 7.7; Analysis 7.8; Analysis 7.9; Analysis 7.10).

Two of the five studies looked at failure to achieve changes in the cervix after 24 to 48 hours and here results favoured the mifepristone group (RR 0.36, 95% CI 0.20 to 0.63) (Analysis 7.23). Information was not reported on the other secondary review outcomes.

Additional outcomes

None of the studies reported on the number of women achieving vaginal delivery within 24 hours but Elliott 1998 described the number of women in spontaneous labour within 72 hours. There was no evidence of a difference between groups receiving mifepristone versus placebo (Analysis 7.24). The time to onset of labour was similar in all three study groups, with amedian of 81 hours 15 minutes for placebo, 80 hours 20 minutes for 50 mg mifepristone, and 75 hours 50 minutes for 200 mg mifepristone.

Giacalone 1998 reported on “spontaneous labour” within 48 hours and results favoured the mifepristone group (RR 2.05, 95% CI 1.27 to 3.30). There was a shorter interval between the beginning of treatment and onset of labour, and between treatment and vaginal delivery for the mifepristone group (the median interval to labour onset was 31.7 hours for mifepristone group versus 53.9 hours for placebo, and 31.3 hours versus 58.5 hours between treatment and delivery; with a reported P value = 0.02 for both outcomes).

Stenlund 1999 reported that during the first 48 hours after treatment started, 83.3% of women with mifepristone and 41.7% with placebo went into labour or had a ripe cervix (Analysis 7.22). The median time to onset of labour from commencing treatment was 24 hours 10 minutes for women who had mifepristone and 52 hours for women with placebo.

Mifepristone significantly reduced the total dose of oxytocin for women having both vaginal and caesarean deliveries in the study by Frydman 1992 (Analysis 7.26; Analysis 7.27) and also by Lelaidier 1994 (Analysis 7.28). Lelaidier 1994 reported the interval between the start of treatment and the onset of labour; the interval was significantly shorter in the mifepristone group (Analysis 7.29).

(8) Oestrogen versus placebo: one study, analysis for 77 women

Primary and secondary outcomes

We included one study in this comparison and there was no information reported on any of the review’s primary outcomes (Larmon 2002).

There were no statistically significant differences between intervention and control groups for outcomes relating to maternal and infant wellbeing, or interventions in labour including the numbers of women having CS, assisted delivery, oxytocin augmentation or infection, or in infant admission to NICU (Analysis 8.7; Analysis 8.8; Analysis 8.9; Analysis 8.14; Analysis 8.15; Analysis 8.19).

(9) Vaginal isosorbide mononitrate (IMN) versus placebo: three studies, 652 women

Primary outcomes

Bollapragada 2006 examined the number of women failing to achieve vaginal delivery within 24 hours of the intervention, and found no statistically significant difference between groups (RR 0.97, 95% CI 0.83 to 1.15). Three studies presented information on the need for further induction agents and the results favoured the IMN group (RR 0.83, 95% CI 0.74 to 0.92).

Bollapragada 2006 provided information on perinatal death, but with one reported perinatal death in this study the confidence interval is wide and estimates unreliable (Analysis 9.18).

Two of these studies reported on maternal satisfaction with the induction process. Bullarbo 2007 found no difference in levels of satisfaction between women in the two arms of the trial. In the study by Bollapragada 2006 et al, women were asked to rate their satisfaction with the induction process at home. On five of the six measures of satisfaction, women in the placebo group were slightly more satisfied with their care compared with those in the IMN group, although the differences between groups were not large, and the mean scores in both groups suggested general satisfaction (Analysis 9.5).

Secondary outcomes

There was no evidence that the intervention had any significant impact on maternal health including uterine hyperstimulation and postpartum haemorrhage (Analysis 9.6; Analysis 9.15). IMN seemed to be associated with increased side effects, including nausea and particularly headaches (Analysis 9.11; Analysis 9.12). In one study 22/112 women in the IMN group reported severe headaches compared with only 1/108 in the placebo group (Analysis 9.16).

The intervention did not seem to be associated with any differences between groups for neonatal infection, Apgar scores at five minutes or admission to NICU (Analysis 9.19; Analysis 9.20; Analysis 9.22).

Women in the two arms of these trials had similar rates of interventions in labour and there were no statistically significant differences for CS, assisted vaginal delivery, oxytocin augmentation or use of epidural (Analysis 9.7; Analysis 9.8; Analysis 9.9; Analysis 9.10). Bollapragada 2006 reported on the number of women who had no change to the cervix 24 to 48 hours following treatment, and women in the placebo group were more likely to have no change in Bishop score (RR 0.83, 95% CI 0.70 to 0.97). Bollapragada 2006 collected information on the cost of providing care; the mean overall cost of the care package was very similar for women in the two groups (MD 11.98, 95% CI −105.34 to 129.30).

Non pre-specified outcomes

Bollapragada 2006 reported the mean interval from hospital admission to delivery for all women, and for those women having vaginal deliveries, along with the mean change in Bishop scores at 48 hours after baseline; there were no significant differences between groups for any of these outcomes (data not shown).

Bullarbo 2007 reported that women in the IMN group were more likely to start labour within 24 hours compared with controls (RR 2.75, 95% CI 1.29 to 5.88) while Habib 2008 reported no significant difference between groups for women admitted either in labour or with a ripe cervix (Bishop score six or more) (RR 3.80, 95% CI 1.54 to 9.40). Habib 2008 reported a result favouring IMN for the interval between admission and delivery, although it was not clear that those women undergoing CS or receiving other interventions were excluded from this analysis (MD −6.67 hours, 95% CI −9.56 to −3.78).

(10) Acupuncture versus routine care: one study 56 women

Primary and secondary outcomes

Harper 2006 presented limited information relevant to this review. There was no strong evidence that the intervention had any impact on the number of women having CS or on the use of medication to induce labour (Analysis 10.1; Analysis 10.2). There were no significant differences between groups for women starting labour spontaneously, cervical dilatation at hospital admission, or the mean time from study enrolment to delivery (data not shown).

DISCUSSION

Summary of main results

The studies included in the review examined 10 different types of interventions in outpatient settings. Overall, the results demonstrate that outpatient induction of labour is feasible and that important adverse events are rare (Table 1; Table 2; Table 3). However, the safety data should be treated with considerable caution. First, very few of the studies provided information on maternal and neonatal death or serious morbidity. It may not be safe to assume that because adverse outcomes were not reported, they did not occur. Further, even where outcomes such as perinatal mortality, maternal complications or serious neonatal morbidity were reported, the finding that there was no apparent difference between groups was not surprising as none of these studies had the statistical power to detect differences for such rare outcomes in relatively low-risk populations.

Table 1. Uterine hyperstimulation with outpatient inductions.

	UTERINE HYPERSTIMULATION
PGE2 (vaginal)
Hage 1993	1/18 PGE group (FHR status unknown), 0/18 in placebo group
Newman 1997	2/28 PGE group (FHR status unknown), 0/30 in controls (no treatment)
O’Brien 1995	1/50 PGE group (normal FHR), 0/50 in placebo group
TOTAL	4/96 PGE, 0/98 in controls
PGE2 (intracervical)
Buttino 1990	1/23 PGE group (with FHR decelerations), 0/20 in placebo group
Lien 1998	2/43 PGE group, 1/47 placebo group with FHR deceleration in both
McKenna 1999	1/30 PGE group (fetal bradycardia), 0/31 placebo group
Rayburn 1999	1/143 PGE group, 0/151 control (no treatment) with hyperstimulation 11/143 FHR decelerations in PGE group, 12/151 in control
TOTAL	5/239 PGE, 1/249 control with hyperstimulation
Intravaginal misoprostol
Stitely 2000	2/27 misoprostol group with FHR deceleration, 2/33 placebo group 1/27 misoprostol with tachysystole without FHR changes, 0/33 placebo group
Incerpi 2001	3/57 misoprostol with hyperstimulation (FHR unknown), 2/63 placebo group 2/57 misoprostol with hypertonus, 5/57 misoprostol with tachysystole, none control
McKenna 2004	1/33 misoprostol (FHR deceleration), 0/35 placebo group
Oral misoprostol
Lyons 2001	1/18 misoprostol, 2/22 placebo group (FHR unknown) with hyperstimulation
Mifepristone
Giacalone 1998	4/41 mifepristone group, 0/42 placebo group with hypertonia (FHR unknown)
Lelaidier 1994	0/16 in both groups
TOTAL	4/57 mifepristone, 0/58 placebo with hypertonia
IMN
Habib 2008	0/51 IMN group, 2/51 placebo group with hyperstimulation (abnormal FHR) 1/51 IMN, 8/51 placebo group with tachysystolia (FHR normal)

	NEONATAL COMPLICATIONS
PGE2 vaginal
Sawai 1991	0/24 in PGE2 group; 2/26 in placebo group to NICU
Sawai 1994	2/38 in PGE2; 4/42 in placebo group to NICU
O’Brien 1995	1/50 in PGE2; 5/50 in placebo group to NICU
TOTAL	3/112 PGE, 11/118 control to NICU
PGE2 intracervical
Larmon 2002	6/41 PGE group, 8/43 placebo group with complication such as tachypnea, meconium aspiration, meconium or admission to NICU
Magann 1998	3/35 PGE2 vs 0/35 control NICU admission
McKenna 1999	1/30 PGE, 2/31 placebo group with complication
TOTAL	10/106 PGE, 10/109 controls with neonatal complications/admitted to NICU
Vaginal misoprostol
Stitely 2000	1/27 misoprostol, 3/33 placebo group to NICU
Incerpi 2001	18/57 misoprostol, 20/63 placebo group to NICU
McKenna 2004	0/33 misoprostol, 1/35 placebo group to NICU
Oboro 2005	1/38 misoprostol, 1/39 control (no treatment) to NICU
TOTAL	20/155 misoprostol, 25/170 control to NICU
Misoprostol 25mcg versus 50mcg
Kipikasa 2005	1/23 25 mcg, 2/26 50 mcg misoprostol to NICU
Intracervical PGE2 versus intravaginal misoprostol
Meyer 2005	5/42 PGE, 4/42 misoprostol to NICU
Mifepristone
Elliott 1998	0/50 mifepristone, 1/30 placebo group to NICU
Giacalone 1998	5/41 mifepristone, 4/42 control to NICU
TOTAL	5/91 mifepristone, 5/72 control to NICU
IMN
Bollapragada 2006	18/177 IMN, 16/173 placebo group to NICU
Bullarbo 2007	13/100 IMN, 9/100 placebo group to NICU
Habib 2008	0/51 IMN, 1/51 placebo group to NICU
TOTAL	31/328 IMN, 26/324 placebo group to NICU

	MATERNAL COMPLICATIONS
Intracervical PGE2
Larmon 2002	4/41 PGE, 10/43 placebo group with complication such as endometritis, chorioamnionitis and pre-eclampsia
Lien 1998	6/43 PGE, 3/47 placebo group with complication such as endometritis and chorioamnionitis
McKenna 1999	1/30 PGE with PPH, 0/31 placebo group 2/30 PGE, 2/31 placebo group with infection
Rayburn 1999	8/143 PGE, 7/151 control (no treatment) with endometritis
TOTAL	21/257 PGE2, 22/272 control with maternal complications
IMN
Bollapragada 2006	blood loss > 500 ml: 59/177 IMN, 47/173 placebo group
Bullarbo 2007	blood loss > 1000 ml: 14/100 IMN, 12/100 placebo group
Habib 2008	PPH: 2/51 IMN, 3/51 placebo group
TOTAL	75/328 IMN, 62/324 placebo group with maternal complications

Methods	RCT.
Participants	Setting: large teaching hospital in Glasgow, Scotland, UK. 350 women randomised. Inclusion criteria: primiparous women at term (gestational age > 37 weeks) with singleton pregnancy and Bishop score < 7. Women were scheduled for induction (97% for prolonged pregnancy: 40 weeks + 10 days gestation). Women recruited were willing to self-administer vaginal tablets Exclusion criteria: women with ruptured membranes, less than 16 years age, who needed delivery within the next 48 hrs, or with fetal compromise requiring daily fetal monitoring
Interventions	Intervention group: self-administered vaginal IMN 40 mg every 16 hrs to max of 3 doses (48 hrs, 32 hrs and 16 hrs prescheduled admission for induction) Comparison group: self-administered placebo, same regimen as intervention group
Outcomes	Time from hospital admission to delivery, women’s views on induction process, pain, mode of delivery, cost to NHS, neonatal outcomes
Notes	One of the review authors, Jane Norman (JN) was an investigator on this trial. JN was not involved in assessing the eligibility of the study for inclusion, data extraction or assessment of risk of bias
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer generated sequence.
Allocation concealment?	Yes	Central randomisation with automated telephone service. Women were given information and consented after the decision to induce labour had been made. Randomisation in the antenatal clinic up to 9 days before treatment commenced
Blinding? Women	Yes	Treatment packs for intervention and control groups were described as identical, prepared by pharmacy
Blinding? Clinical staff	Yes
Blinding? Outcome assessor	Yes
Incomplete outcome data addressed? All outcomes	Yes	350 randomised. 80 women did not initiate treatment as they went in to labour before the scheduled time for taking medication, a further 11 women withdrew (including 2 with breech presentation). All women randomised were included in an ITT analysis for primary outcomes (but not in secondary analysis)
Free of other bias?	Yes	No baseline imbalance apparent.

Methods	RCT, 2-arm trial.
Participants	Setting: 43 women attending antenatal clinics in California, USA Inclusion criteria: women with “post-dates” pregnancies (gestational age > 41 weeks and 6 days based on reliable menstrual history and early ultrasound confirmation) with reactive NST Exclusion criteria: contraindications to prostaglandins.
Interventions	Intervention group: intracervical PGE2 0.5 mg. Comparison group: visually identical placebo gel. Women in both groups were observed for 1 hr with external fetal monitoring and then discharged home
Outcomes	Bishop score on admission, mode of delivery, interval to delivery, length of labour, infant birthweight and Apgar score
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	External sequence generation by hospital pharmacy.
Allocation concealment?	Yes	Coded syringes of identical appearance were dispensed from pharmacy
Blinding? Women	Yes	Placebo controlled trial.
Blinding? Clinical staff	Yes
Blinding? Outcome assessor	Unclear	Not clear when code was revealed.
Incomplete outcome data addressed? All outcomes	Yes	All women randomised appeared to be included in the analyses
Free of other bias?	Yes	No other bias apparent.

Methods	RCT. 4-arm trial.
Participants	Setting: Edinburgh, UK. 80 women recruited with induction of labour scheduled 72 hrs after recruitment Inclusion criteria: primiparous women aged 18-40, normal viable fetus, 37-41 weeks (confirmed by 1st trimester ultrasound scan), cephalic presentation, Bishop score < 5 Exclusion criteria: women who showed signs of labour onset, placental insufficiency or contraindication to mifepristone,
Interventions	Intervention: group 1: (25 women) oral mifepristone 50 mg. Group 2: (25 women) oral mifepristone 200 mg. (In this review we have combined both groups in the analysis although it was not clear how randomisation was achieved in the higher dose study.) Comparison groups: placebo (2 groups of women 25 compared with the lower dose and 5 with the higher dose. We have combined placebo groups in the analysis in this review as data were reported together in the results in the study reports; group size was very unbalanced for the second part of the study.)
Outcomes	Additional induction agents required, labour within 72 hrs, CS, oxytocin augmentation. NICU admission
Notes	It was not clear why the placebo group for the higher dose comparison was so small (5 women) or how randomisation was performed to achieve the unbalanced intervention and control groups
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	“Pre-determined randomisation code.”
Allocation concealment?	Unclear	“Treatment in predetermined numeric order”. It was not clear why the group allocation in the placebo arms of the trial were very unbalanced
Blinding? Women	Yes	“Neither the patient nor the physician had knowledge of whether a simple oral dose of mifepristone or placebo was given.”
Blinding? Clinical staff	Yes
Blinding? Outcome assessor	Yes
Incomplete outcome data addressed? All outcomes	Unclear	All women randomised seemed to be accounted for in the analysis, although there was serious imbalance in group size
Free of other bias?	Unclear	In the second part of the study (higher dose) the treatment to placebo ratio was 1:5. It was not clear how randomisation was performed, or why the control group was so small

Methods	RCT 2-arm parallel group design.
Participants	120 women attending an antenatal clinic in a hospital in France, 1990-91 Inclusion criteria: termpregnancy scheduled for induction (range of indications), Bishop score < 4 Exclusion criteria: malpresentation, ruptured membranes, multiple pregnancy, > 1 previous CS or known medical condition
Interventions	Intervention group: active tablets mifepristone 200 mg. All women received a box with 2 tablets, the first to be taken on the morning of day 1 and the second on the morning of day 2 Comparison group: placebo tablets. Same regimen as intervention group IOL scheduled for 4 days after intervention, women reported to the hospital each day over the 4 day study period and were asked to report drug reactions, pain, bleeding or contractions
Outcomes	Labour within 4-day study period, other induction agents required, duration of labour, mode of birth, Apgar score < 7 at 5 min
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Tablets were supplied by pharmacy according to a “balanced randomisation list”. Block size 4
Allocation concealment?	Yes	Small block size might mean that allocation order could potentially be anticipated in advance but the drug packs were described as being of similar appearance
Blinding? Women	Yes	Described as a double-blind study.
Blinding? Clinical staff	Yes	Placebo described as being of similar appearance.
Blinding? Outcome assessor	Yes
Incomplete outcome data addressed? All outcomes	Unclear	120 women were randomised but 8 were excluded from the results because of a deterioration in their condition within 12 hours of the first pill (3 in the mifepristone group and 5 in the placebo group)
Free of other bias?	Unclear	Additional induction agents were used for some women so labour and other outcomes may be affected by co-interventions

Methods	RCT (little information on study methods).
Participants	32 women. Inclusion criteria: women with previous CS, gestational age 39 weeks with Bishop score < 6
Interventions	Intervention group: Intracervical PGE2 repeated weekly. Comparison group: expectant management.
Outcomes	CS.
Notes	Brief abstract, little information provided.
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	No information.
Allocation concealment?	Unclear	“prospectively randomised.”
Blinding? Women	No	Not feasible.
Blinding? Clinical staff	No

Methods	RCT, placebo controlled trial.
Participants	Setting: not clear. 36 women. Inclusion criteria: healthy, nulliparous women, 41 weeks’ gestation and Bishop score < 9
Interventions	Intervention group: 2.5 mg intravaginal PGE2, with 2nd dose if labour not established 24 hrs later Comparison group: placebo gel, with 2nd dose after 24 hrs if labour was not established
Outcomes	Change in cervix after 48hrs.
Notes	Information from brief abstract.
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	Described as “randomized”.
Allocation concealment?	Unclear	No information.
Blinding? Women	Yes	Described as double-blind trial with placebo gel.
Blinding? Clinical staff	Yes
Blinding? Outcome assessor	Unclear	No information.
Incomplete outcome data addressed? All outcomes	Unclear	Little information on methods. It appeared that all women were available at follow up

Methods	RCT with block randomisation.
Participants	Setting: outpatient clinic in North Carolina USA. 56 women randomised Inclusion criteria: primiparous women at term (39 weeks and 4 days to 41 weeks) with singleton, cephalic, pregnancy and Bishop score < 7 Exclusion criteria: cannot tolerate acupuncture, uncertain dates, breech presentation, placenta praevia, contraindication to vaginal delivery
Interventions	Cervical examination and ultrasound at recruitment. Intervention group: acupuncture + routine care on 3 of 4 consecutive days, visits also included fetal monitoring, treatment by trained acupuncturist to hands, legs and lower back and low voltage stimulation Comparison group: routine care with follow up after 3 or 4 days
Outcomes	Vaginal delivery not achieved in 24 hrs, additional induction agents required. CS, mean time to delivery
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer generated sequence in balanced blocks of 2 or 4.
Allocation concealment?	Yes	Sealed, opaque, sequentially numbered envelopes.
Blinding? Women	No	Blinding not feasible.
Blinding? Clinical staff	No
Blinding? Outcome assessor	No
Incomplete outcome data addressed? All outcomes	Unclear	Data were available for all women randomised but denominators were not clear for some outcomes
Free of other bias?	Unclear	Women receiving acupuncture attended for 3 additional visits where other interventions occurred as well as acupuncture that may have affected outcomes

Methods	RCT 2-arm parallel group design (dose comparison study).
Participants	52 women attending a large teaching hospital and scheduled for induction of labour Inclusion criteria: singleton, cephalic presentation, not in active labour, gestational age > 40 weeks (confirmed by menstrual dates and ultrasound before 20 weeks) Exclusion criteria: previous CS, FHR abnormalities, contraindication to prostaglandin or vaginal delivery
Interventions	Intervention group: 50 mcg oral misoprostol. Comparison group: 25 mcg misoprostol. Prior to randomisation women received an ultrasound to assess fetal growth and AFV and a fetal NST was carried out. In both groups medication was administered by a nurse and in the absence of labour or contraindications the dose was repeated after 3 days to a max of 3 doses over 9 days. Women returned to hospital every 3 days unless labour started or there was any reduction in fetal kicks
Outcomes	Days to delivery, uterine hyperstimulation, further induction agents required, CS, Apgar score < 6 at 5 min, NICU admission, meconium staining, perinatal death
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Computer generated sequence.
Allocation concealment?	Yes	Coded drug boxes.
Blinding? Women	Unclear	Tablets were described as indistinguishable but they were cut from larger tablets (1/4 or 1/8)
Blinding? Outcome assessor	Yes	Described as blind.
Incomplete outcome data addressed? All outcomes	Unclear	There were some inconsistencies in the figures; while 49 women seem to have been randomised there were 52 in the results tables

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agents required	2	150	Risk Ratio (M-H, Fixed, 95% CI)	0.52 [0.27, 0.99]
2 Serious neonatal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
3 Serious maternal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
4 Vaginal delivery not achieved in 24/48 hrs	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
5 Uterine hyperstimulation (FHR changes unclear)	4	244	Risk Ratio (M-H, Fixed, 95% CI)	3.76 [0.64, 22.24]
6 Uterine hyperstimulation (without FHR changes)	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
7 Caesarean section	4	288	Risk Ratio (M-H, Fixed, 95% CI)	0.80 [0.49, 1.31]
8 Assisted (instrumental) vaginal delivery	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
9 Oxytocin augmentation	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
10 Epidural	1	100	Risk Ratio (M-H, Fixed, 95% CI)	0.83 [0.62, 1.12]
11 Maternal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
12 Uterine rupture	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
13 Serious maternal complication	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
14 Chorioamnionitis	2	180	Risk Ratio (M-H, Fixed, 95% CI)	0.37 [0.15, 0.90]
15 Endometritis	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
16 Maternal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
17 Perinatal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
18 Apgar score < 7 at 5 minutes	2	180	Risk Ratio (M-H, Fixed, 95% CI)	0.45 [0.07, 2.93]
19 NICU admission	3	230	Risk Ratio (M-H, Fixed, 95% CI)	0.32 [0.10, 1.03]
20 Neonatal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
21 Neonatal infection	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
22 Interval from intervention to delivery	0	0	Mean Difference (IV, Fixed, 95% CI)	Not estimable
23 Cervix unchanged at follow up	1	36	Risk Ratio (M-H, Fixed, 95% CI)	0.13 [0.03, 0.47]
24 “Spontaneous labour” within 48 hours	1	58	Risk Ratio (M-H, Fixed, 95% CI)	6.43 [2.12, 19.48]
25 Admitted to hospital for labour	1	100	Risk Ratio (M-H, Fixed, 95% CI)	2.7 [1.47, 4.97]
26 Gestational age at delivery (weeks)	1	100	Mean Difference (IV, Fixed, 95% CI)	−0.60 [−0.99, −0.21]
27 Gestational age on admission (days)	1	80	Mean Difference (IV, Fixed, 95% CI)	−2.0 [−4.17, 0.17]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agent required (induction with oxytocin or other means)	3	445	Risk Ratio (M-H, Fixed, 95% CI)	0.98 [0.74, 1.32]
2 Additional induction agents required (further prostaglandin required)	1	90	Risk Ratio (M-H, Fixed, 95% CI)	0.61 [0.22, 1.67]
3 Serious neonatal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
4 Serious maternal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
5 Delivery not achieved in 48-72 hrs	1	43	Risk Ratio (M-H, Fixed, 95% CI)	0.83 [0.68, 1.02]
6 Uterine rupture	1	294	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
7 Uterine hyperstimulation (with FHR changes)	4	488	Risk Ratio (M-H, Fixed, 95% CI)	2.66 [0.63, 11.25]
8 Uterine hyperstimulation (without FHR changes)	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
9 Postpartum haemorrhage (> 500 ml)	1	61	Risk Ratio (M-H, Fixed, 95% CI)	3.10 [0.13, 73.16]
10 Caesarean section	7	674	Risk Ratio (M-H, Fixed, 95% CI)	0.90 [0.72, 1.12]
11 Assisted (instrumental) vaginal delivery	4	538	Risk Ratio (M-H, Fixed, 95% CI)	1.29 [0.85, 1.96]
12 Oxytocin augmentation	1	84	Risk Ratio (M-H, Fixed, 95% CI)	0.67 [0.40, 1.12]
13 Epidural	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
14 Maternal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
15 Serious maternal complication	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
16 Chorioamnionitis	3	468	Risk Ratio (M-H, Fixed, 95% CI)	2.03 [0.66, 6.18]
17 Endometritis	2	174	Risk Ratio (M-H, Fixed, 95% CI)	1.60 [0.27, 9.37]
18 Maternal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
19 Perinatal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
20 Apgar score < 7 at 5 minutes	4	515	Risk Ratio (M-H, Fixed, 95% CI)	0.82 [0.42, 1.60]
21 NICU admission	3	215	Risk Ratio (M-H, Fixed, 95% CI)	1.61 [0.43, 6.05]
22 Neonatal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
23 Neonatal infection	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
24 Interval from intervention to delivery (days)	2	133	Std. Mean Difference (IV, Fixed, 95% CI)	−0.20 [−0.55, 0.14]
25 Cervix unchanged after 24/48 hrs	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
26 Maternal side effects	2	384	Risk Ratio (M-H, Fixed, 95% CI)	0.59 [0.13, 2.77]
27 Gestational age at delivery (weeks)	2	156	Mean Difference (IV, Random, 95% CI)	−0.06 [−0.35, 0.23]
28 Induction for gestational age > 42 weeks	2		Risk Ratio (M-H, Fixed, 95% CI)	Totals not selected
29 Delivery within 48 hours of treatment (all deliveries)	1	61	Risk Ratio (M-H, Fixed, 95% CI)	3.1 [1.29, 7.47]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agents required	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
2 Serious neonatal morbidity or death	1	77	Risk Ratio (M-H, Fixed, 95% CI)	0.34 [0.01, 8.14]
3 Serious maternal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
4 Vaginal delivery not achieved in 24/48 hrs	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
5 Uterine hyperstimulation (with FHR changes)	3	265	Risk Ratio (M-H, Fixed, 95% CI)	1.97 [0.43, 9.00]
6 Uterine hyperstimulation (without FHR changes)	2	137	Risk Ratio (M-H, Fixed, 95% CI)	3.64 [0.15, 85.97]
7 Caesarean section	4	325	Risk Ratio (M-H, Fixed, 95% CI)	0.94 [0.61, 1.46]
8 Assisted (instrumental) vaginal delivery	2	145	Risk Ratio (M-H, Fixed, 95% CI)	0.91 [0.50, 1.67]
9 Oxytocin augmentation	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
10 Epidural	1	50	Risk Ratio (M-H, Fixed, 95% CI)	0.98 [0.77, 1.26]
11 Maternal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
12 Uterine rupture	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
13 Serious maternal complication	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
14 Chorioamnionitis	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
15 Endometritis	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
16 Maternal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
17 Perinatal death	1	77	Risk Ratio (M-H, Fixed, 95% CI)	0.34 [0.01, 8.14]
18 Apgar score < 7 at 5 minutes	3	248	Risk Ratio (M-H, Fixed, 95% CI)	0.21 [0.01, 4.25]
19 NICU admission	4	325	Risk Ratio (M-H, Fixed, 95% CI)	0.89 [0.54, 1.47]
20 Neonatal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
21 Neonatal infection	1	68	Risk Ratio (M-H, Fixed, 95% CI)	0.30 [0.07, 1.36]
22 Cervix unchanged after 24/48 hrs	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
23 Gestational age at labour	1	77	Mean Difference (IV, Fixed, 95% CI)	−0.80 [−1.05, −0.55]
24 Oxytocin dose used (mU)	1	72	Mean Difference (IV, Fixed, 95% CI)	1508.70 [−2357.55, 5374.95]
25 Number of medication dose	1	60	Mean Difference (IV, Fixed, 95% CI)	−0.44 [−0.49, −0.39]
26 Number of patients requiring dosing on day 2	1	60	Risk Ratio (M-H, Fixed, 95% CI)	0.61 [0.43, 0.87]
27 Number of patients requiring induction on day 3	1	60	Risk Ratio (M-H, Fixed, 95% CI)	0.13 [0.04, 0.38]
28 Days to admission (all)	1	77	Mean Difference (IV, Fixed, 95% CI)	−2.90 [−4.99, −0.81]
29 Days to admission (nulliparous)	1	41	Mean Difference (IV, Fixed, 95% CI)	−3.20 [−6.44, 0.04]
30 Days to admission (parous)	1	36	Mean Difference (IV, Fixed, 95% CI)	−3.10 [−6.24, 0.04]
31 Days to PROM	1	77	Mean Difference (IV, Fixed, 95% CI)	−2.5 [−4.14, −0.86]
32 Interval from intervention to vaginal delivery	1	50	Mean Difference (IV, Fixed, 95% CI)	−1.4 [−3.51, 0.71]
33 Days to delivery (all)	1	68	Mean Difference (IV, Fixed, 95% CI)	−1.90 [−3.74, −0.06]
34 Days to delivery (subgroups by parity)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
34.1 Nulliparous women	1	39	Mean Difference (IV, Fixed, 95% CI)	−3.0 [−5.42, −0.58]
34.2 Parous women	1	29	Mean Difference (IV, Fixed, 95% CI)	−0.60 [−3.51, 2.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agents required (oxytocin)	1	49	Risk Ratio (M-H, Fixed, 95% CI)	2.26 [0.22, 23.33]
2 Uterine hyperstimulation	1	49	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
3 NICU admission	1	49	Risk Ratio (M-H, Fixed, 95% CI)	0.57 [0.05, 5.83]
4 Caesarean section	1	49	Risk Ratio (M-H, Fixed, 95% CI)	0.94 [0.33, 2.68]
5 Interval from treatment to delivery (in days, all deliveries)	1	49	Mean Difference (IV, Fixed, 95% CI)	1.5 [1.19, 1.81]

Methods	RCT, 3-arm trial.
Participants	Setting: not clear (outpatient setting). 136 women randomised. Inclusion criteria: women at term (37 weeks’ gestation), Bishop score < 6, candidates for vaginal delivery with uncomplicated pregnancy Exclusion criteria: women with diabetes or serious pregnancy complications including hypertension, or chronic medical conditions
Interventions	Intervention group (1): PGE2 0.5 mg intracervical. Intervention group (2): vaginal oestrogen cream (estradiol) 4 mg Comparison group: inert lubricant vaginal jelly. Women were assessed weekly until an indication for delivery arose. Medication was repeated weekly
Outcomes	Mode of delivery, use of oxytocin, condition of newborn.
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Random number tables.
Allocation concealment?	Yes	Opaque, sequentially numbered envelopes.
Blinding? Women	Yes	Placebo controlled.
Blinding? Clinical staff	Unclear	Interventions not identical.
Incomplete outcome data addressed? All outcomes	Yes	136 women were randomised, 8 were excluded after randomisation

Methods	RCT. 3-arm trial.
Participants	Setting: California, USA, women attending a naval medical centre 70 women included in the analysis (2 of 3 treatment arms included, total recruited 105 women) Inclusion criteria: women with “post dates” pregnancy - gestational age 41 weeks confirmed by menstrual dates and pre-20 weeks ultrasound. Uncomplicated pregnancy. Bishop score < 5 Exclusion criteria: women with any contraindication to vaginal delivery
Interventions	(1 intervention group had daily membrane stripping; this group has not been included in the analysis in this review.) Intervention group: intracervical PGE2 0.5 mg, daily for 3 days Comparison group: gentle cervical examination, daily for 3 days Women were instructed to return to hospital is they had bleeding, membrane rupture, regular contractions of reduction in fetal movements. Once Bishop score = 8 or women reached 42 weeks they were admitted to hospital for induction
Outcomes	Induced at 42 weeks, CS, instrumental delivery. Apgar score < 7 at 5 min, admission to NICU
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Random number tables.
Allocation concealment?	Yes	Sealed, opaque, sequentially numbered envelopes.
Blinding? Women	No	Not feasible.
Blinding? Clinical staff	No
Blinding? Outcome assessor	Unclear	Outcome assessment of cervical changes were reported to be blind
Incomplete outcome data addressed? All outcomes	Yes	No apparent loss to follow up.

Methods	Placebo controlled RCT.
Participants	Setting: outpatient clinic in Memphis, USA. 100 women recruited. Inclusion criteria: gestation 38-40 weeks with Bishop score < 7 Exclusion criteria: non-reactive NST, oligohydramnios (AFI < 5.0 cm) macrosomia (> 4000 g or 10th centile), medical indication for delivery, more than 1 previous CS
Interventions	All women underwent NST, AFV and ultrasound assessment. Intervention group: 2 mg intravaginal PGE2 for 5 consecutive days Comparison group: identical placebo for 5 consecutive days. After each dose women were monitored for 30 min to rule out labour or fetal distress. Women were reviewed twice weekly (NST and AFV)
Outcomes	Other induction agents required, uterine hyperstimulation, CS, epidural, chorioamnionitis, Apgar score, NICU admission, gestational age at delivery
Notes
*Risk of bias*
Item	Authors’ judgement	Description
Adequate sequence generation?	Yes	Random number table. Permuted blocks with variable block size. The randomisation schedule was kept in pharmacy
Allocation concealment?	Yes	Coded drug boxes prepared by pharmacy.
Blinding? Women	Yes	Placebo controlled trial.
Blinding? Clinical staff	Yes
Incomplete outcome data addressed? All outcomes	Yes	State that “no post randomisation exclusions were allowed”. All women included in the analysis
Free of other bias?	Yes	No baseline imbalance apparent.

Study	Reason for exclusion
Adewole 1993	This study examined breast stimulation and used a crossover design. Women were allocated to either breast stimulation versus no stimulation; after 3 days, if labour had not started women crossed over into the other study group
Damania 1988	Very little information was provided on study methods. It was not clear that this was a RCT
Damania 1992	In this study breast stimulation was compared with an oxytocin infusion. It was not clear that women in the oxytocin group were discharged home
Di Lieto 1989	This study used a crossover design.
Doany 1997	In this study intravaginal PGE2 with or without membrane sweeping was compared with placebo with or without membrane sweeping. Complex interventions or interventions involving membrane sweeping are not included in this review
Dorfman 1987	In this study women received a range of homeopathic herbal preparations versus placebo. The intervention was to prepare women for childbirth generally rather than to induce labour
Elliott 1984	This study focused on breast stimulation and used a crossover design
Evans 1983	It was not clear that this was a RCT: “the assignment [of medication] to patients was by consecutive entry into either of the studies”. The paper described findings for two separate studies both examining the use of intracervical porcine ovarian relaxin. The first study appeared to be conducted in hospital and women receiving medication were compared with a control group. In the “outpatient study” there was no control group; women received either 2 mg or 4 mg of relaxin 5-7 days before scheduled induction; no outcomes were reported relevant for inclusion in the review
Garry 2000	This study compared castor oil with no treatment, women were alternately allocated to groups; otherwise there was little information on methods
Griffin 2003	This study was reported in a brief abstract and insufficient information was available on methods and results to include the study. We contacted the study author and further data are not available
Herabutya 1992	This study examined intracervical prostaglandin. Little information was provided on study methods. Women “randomized” to the intervention group received intracervical PGE2 and then monitored for 4-6 hrs, some had a repeat dose after 6hrs, some had a repeat dose the next day and if labour did not start on the third day these women were admitted to hospital for amniotomy and oxytocin infusion. It was not clear what happened to women in the control group other than that they had weekly fetal monitoring; these women were not admitted unless there were signs of abnormality or until they reached 44 weeks’ gestation. The management of women in the two groups was so different that results are difficult to interpret
Kadar 1990	This study focused on nipple stimulation. Group allocation was by a quasi-randomised method; there were serious protocol violations and analysis was not by randomisation group making results very difficult to interpret
Kaul 2004	This study focused on membrane sweeping. This intervention is not included in this review
Krammer 1995	This study was reported in a very brief abstract. No original data were presented in the results
Magann 1999	This study compared PGE2 and membrane sweeping. Membrane sweeping is not included in this review
Manidakis 1999	This study was reported in a brief abstract. It was not clear that it was a RCT. We were unable to find contact details for the author to obtain further information
Moghtadaei 2007	This study focused on extra-amniotic saline infusion, an intervention rarely used nowadays. It was not clear that this intervention was carried out in an outpatient setting
Ohel 1996	This quasi randomised trial compared women receiving vaginal PGE2 with expectant management. Analysis was not by randomisation group. Of 96 cases randomised to PGE2 26 preferred expectant management and were therefore omitted from the analysis. As there was no intention to treat analysis results of this study were very difficult to interpret
Rayburn 1988	In this study some of the women included in the study were admitted to hospital rather that being treated as outpatients. No separate results were available for women in the outpatient group
Rijnders 2007	In this study the same method of inducing labour was used in both groups, 1 group was treated in hospital and 1 at home
Salamalekis 2000	In this study membrane sweeping was compared with oxytocin for labour induction. It was not clear that women were discharged home after interventions and membrane sweeping is not included in this review
Salmon 1986	This study focused on breast stimulation and used a crossover design. Women were allocated to either breast stimulation versus no stimulation; after three days, if labour had not started women crossed over into the other study group
Spallicci 2007	The intervention in this trial was an intracervical injection of hyalurodinase. This intervention is no longer used in clinical practice
Voss 1996	It was not clear that this intervention was carried out in an outpatient setting or that women were discharged home after treatment
Ziaei 2003	This study compared dexamethasone with oxytocin. it was not clear that the intervention was carried out in an outpatient setting

Methods	Double blind RCT.
Participants	30 women at term (40-41 weeks) with a Bishop score < 7.
Interventions	Intervention: (2 groups) 200 mcg or 100 mcg of oral misoprostol Comparison group: placebo. FHR and uterine monitoring for 2 hrs after medication. Procedure was repeated after three days if labour did not start until 42 weeks
Outcomes	Interval to delivery, CS, Induction at 42 weeks, hyperstimulation, Apgar scores
Notes	This study was reported in a brief abstract and the data was described as “preliminary”. We attempted to contact authors for further information (8th September 2009)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine hyperstimulation (with or without FHR changes)	1	64	Risk Ratio (M-H, Fixed, 95% CI)	0.26 [0.03, 2.73]
2 Caesarean section	1	84	Risk Ratio (M-H, Fixed, 95% CI)	0.89 [0.38, 2.08]
3 Apgar score < 7 after 5 minutes	1	84	Risk Ratio (M-H, Fixed, 95% CI)	0.33 [0.01, 7.96]
4 Admission to NICU	1	84	Risk Ratio (M-H, Fixed, 95% CI)	1.25 [0.36, 4.33]
5 Vaginal delivery not achieved within 48 hours	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
6 Interval from administration to admission (hours)	1	75	Mean Difference (IV, Fixed, 95% CI)	2.5 [2.22, 2.78]
7 Labour or SROM during ripening	1	83	Risk Ratio (M-H, Fixed, 95% CI)	0.31 [0.14, 0.69]
8 Delivery within 24 hours	1	83	Risk Ratio (M-H, Fixed, 95% CI)	0.90 [0.75, 1.07]
9 Delivery within 48 hours (cumulative)	1	83	Risk Ratio (M-H, Fixed, 95% CI)	0.93 [0.81, 1.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Caesarean section	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
2 Chorioamnionitis	1	38	Risk Ratio (M-H, Fixed, 95% CI)	1.65 [0.43, 6.38]
3 Additional induction agents required	1	40	Risk Ratio (M-H, Fixed, 95% CI)	0.47 [0.21, 1.07]
4 Uterine hyperstimulation (FHR changes unclear)	1	40	Risk Ratio (M-H, Fixed, 95% CI)	0.61 [0.06, 6.21]
5 Time from first dose to active labor (hours)	1	40	Mean Difference (IV, Fixed, 95% CI)	−34.98 [−61.23, −8.73]
6 Total doses of medication	1	40	Mean Difference (IV, Fixed, 95% CI)	−0.51 [−0.92, −0.10]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agents required	4	311	Risk Ratio (M-H, Random, 95% CI)	0.59 [0.37, 0.95]
2 Serious neonatal morbidity or death	1	36	Risk Ratio (M-H, Fixed, 95% CI)	1.56 [0.07, 35.67]
3 Serious maternal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
4 Vaginal delivery not achieved in 24/48 hrs	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
5 Uterine hyperstimulation (with FHR changes)	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
6 Uterine hyperstimulation (without FHR changes)	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
7 Caesarean section	5	343	Risk Ratio (M-H, Fixed, 95% CI)	0.88 [0.62, 1.25]
8 Assisted (instrumental) vaginal delivery	5	343	Risk Ratio (M-H, Fixed, 95% CI)	1.35 [0.93, 1.97]
9 Oxytocin augmentation	2	116	Risk Ratio (M-H, Fixed, 95% CI)	0.89 [0.63, 1.26]
10 Epidural	1	112	Risk Ratio (M-H, Fixed, 95% CI)	0.87 [0.73, 1.03]
11 Maternal death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
12 Uterine scar separation	1	32	Risk Ratio (M-H, Fixed, 95% CI)	1.0 [0.07, 14.64]
13 Serious maternal complication	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
14 Chorioamnionitis	1	32	Risk Ratio (M-H, Fixed, 95% CI)	2.0 [0.20, 19.91]
15 Endometritis	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
16 Maternal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
17 Perinatal death	1	32	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
18 Apgar score < 7 at 5 minutes	2	119	Risk Ratio (M-H, Fixed, 95% CI)	1.56 [0.07, 35.67]
19 NICU admission	2	163	Risk Ratio (M-H, Fixed, 95% CI)	0.93 [0.31, 2.79]
20 Neonatal antibiotics	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
21 Neonatal infection	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
22 Labour or ripe cervix in 48 hours	1	36	Risk Ratio (M-H, Fixed, 95% CI)	2.0 [1.00, 4.00]
23 Cervix unchanged after 24/48 hrs	2	119	Risk Ratio (M-H, Fixed, 95% CI)	0.36 [0.20, 0.63]
24 Spontaneous labour within 72 hours	1	80	Risk Ratio (M-H, Fixed, 95% CI)	1.46 [0.68, 3.10]
25 Spontaneous labour within 48 hrs	1	83	Risk Ratio (M-H, Fixed, 95% CI)	2.05 [1.27, 3.30]
26 Total dose of oxytocin in vaginal delivery (IM)	1	76	Mean Difference (IV, Fixed, 95% CI)	−2.07 [−3.21, −0.93]
27 Total dose of oxytocin in CS (IM)	1	36	Mean Difference (IV, Fixed, 95% CI)	−1.97 [−3.37, −0.57]
28 Oxytocin requirements (IU)	1	32	Mean Difference (IV, Fixed, 95% CI)	−2.56 [−4.01, −1.11]
29 Interval between day 1 and start of labour (hours)	1	32	Mean Difference (IV, Fixed, 95% CI)	−22.15 [−35.96, −8.34]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Vaginal delivery not achieved in 24/48 hrs	1	238	Risk Ratio (M-H, Fixed, 95% CI)	0.97 [0.83, 1.15]
2 Additional induction agents required	3	559	Risk Ratio (M-H, Fixed, 95% CI)	0.83 [0.74, 0.92]
3 Serious maternal morbidity or death	0	0	Risk Ratio (M-H, Fixed, 95% CI)	Not estimable
4 Maternal satisfaction (women would recommend procedure)	1	193	Risk Ratio (M-H, Fixed, 95% CI)	1.01 [0.94, 1.08]
5 Maternal satisfaction (various questions, low score= satisfied, high score = dissatisfied, score out of 10)	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
5.1 How do you think your labour went? (easy/very difficult)	1	227	Mean Difference (IV, Fixed, 95% CI)	−0.34 [−0.94, 0.26]
5.2 What do you think about home treatment? (extremely good/not at all good)	1	227	Mean Difference (IV, Fixed, 95% CI)	0.61 [0.03, 1.19]
5.3 How painful was the treatment at home? (not at all/very)	1	227	Mean Difference (IV, Fixed, 95% CI)	0.58 [−0.00, 1.16]
5.4 How anxious were you being at home taking the treatment? (not at all/very)	1	227	Mean Difference (IV, Fixed, 95% CI)	0.11 [−0.39, 0.61]
5.5 Would you have the same treatment at home again? (definitely/definitely not)	1	227	Mean Difference (IV, Fixed, 95% CI)	0.62 [−0.02, 1.26]
5.6 Would you advise a friend to have the same treatment at home? (definitely/definitely not)	1	227	Mean Difference (IV, Fixed, 95% CI)	0.41 [−0.17, 0.99]
6 Postpartum haemorrhage (> 500 ml)	3	256	Risk Ratio (M-H, Fixed, 95% CI)	1.19 [0.89, 1.59]
7 Caesarean section	3	652	Risk Ratio (M-H, Fixed, 95% CI)	1.03 [0.81, 1.31]
8 Assisted (instrumental) vaginal delivery	1	350	Risk Ratio (M-H, Fixed, 95% CI)	0.85 [0.61, 1.18]
9 Oxytocin augmentation	1	254	Risk Ratio (M-H, Fixed, 95% CI)	1.07 [0.88, 1.30]
10 Epidural	1	350	Risk Ratio (M-H, Fixed, 95% CI)	0.94 [0.82, 1.09]
11 Cervix unchanged after 48 hrs	1	257	Risk Ratio (M-H, Fixed, 95% CI)	0.83 [0.70, 0.97]
12 Maternal side effect - headache	3	522	Risk Ratio (M-H, Fixed, 95% CI)	5.41 [3.85, 7.60]
13 Maternal side effect - nausea	2	420	Risk Ratio (M-H, Fixed, 95% CI)	2.06 [1.22, 3.50]
14 Admitted in established labour within 24 hours	1	200	Risk Ratio (M-H, Fixed, 95% CI)	2.75 [1.29, 5.88]
15 Uterine hyperstimulation (with FHR changes)	1	102	Risk Ratio (M-H, Fixed, 95% CI)	0.2 [0.01, 4.07]
16 Side effects: severe headache	1	220	Risk Ratio (M-H, Fixed, 95% CI)	21.21 [2.91, 154.65]
17 Total cost of care package (GB £)	1	350	Mean Difference (IV, Fixed, 95% CI)	11.98 [−105.34, 129.30]
18 Perinatal death	1	350	Risk Ratio (M-H, Fixed, 95% CI)	0.33 [0.01, 7.94]
19 Apgar score < 7 at 5 minutes 3	3	256	Risk Ratio (M-H, Fixed, 95% CI)	1.21 [0.35, 4.17]
20 NICU admission	3	652	Risk Ratio (M-H, Fixed, 95% CI)	1.17 [0.72, 1.92]
21 Interval from admission to vaginal delivery (hours)	1	128	Mean Difference (IV, Fixed, 95% CI)	−0.70 [−6.11, 4.71]
22 Neonatal infection	1	200	Risk Ratio (M-H, Fixed, 95% CI)	1.0 [0.26, 3.89]
23 Bishop score > 6 or active labour at 36 hours	1	102	Risk Ratio (M-H, Fixed, 95% CI)	3.8 [1.54, 9.40]
24 Time in hours from admission to delivery (all women)	1	102	Mean Difference (IV, Fixed, 95% CI)	−6.67 [−9.56, −3.78]
25 Onset of labour within 24 hours	1	200	Risk Ratio (M-H, Fixed, 95% CI)	2.75 [1.29, 5.88]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Additional induction agents required	1	56	Risk Ratio (M-H, Fixed, 95% CI)	0.6 [0.31, 1.17]
2 Caesarean section	1	56	Risk Ratio (M-H, Fixed, 95% CI)	0.43 [0.17, 1.11]

PERMALINK

Different methods for the induction of labour in outpatient settings

Therese Dowswell

Anthony J Kelly

Stefania Livio

Jane E Norman

Zarko Alfirevic

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors’ conclusions

BACKGROUND

Introduction

Cervical ripening and induction of labour in outpatient settings

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

Measures of effectiveness

Complications

Detailed definitions for outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

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

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Other potential sources of bias

Effects of interventions

Induction of labour in outpatient settings: 28 studies with 2616 women

(1) Vaginal prostaglandin (PGE2) versus expectant management or placebo: five studies, 335 women

Primary outcomes

Secondary outcomes

Additional outcomes

(2) Intracervical prostaglandin (PGE2) versus expectant management or placebo: seven studies, 678 women

Primary outcomes

Secondary outcomes

Additional outcomes

(3) Vaginal misoprostol versus placebo: four studies, 274 women

Primary outcomes

Secondary outcomes

(1) Vaginal prostaglandin (PGE₂) versus expectant management or placebo: five studies, 335 women

(2) Intracervical prostaglandin (PGE₂) versus expectant management or placebo: seven studies, 678 women

(5) Intracervical PGE₂ versus vaginal misoprostol: one study, 84 women