Abstract
Background
Relaxin is a protein hormone composed of two amino acid chains. The role played by relaxin in human pregnancy and parturition is unclear. Its use and involvement as a cervical ripening agent has been debated since the 1950s. Because the main source of human relaxin is the corpus luteum of pregnancy much of the early work on induction of labour has focused on porcine or bovine preparations. With the advent of DNA recombinant technology human relaxin has become available for evaluation. Relaxin is thought to have a promoting effect on cervical ripening. Due to a possible inhibitory effect on human myometrial activity, relaxin may not be associated with the concomitant increase in the rate of uterine hyperstimulation seen with other induction agents. This is one of a series of reviews of methods of cervical ripening and labour induction using a standardised methodology.
Objectives
To determine the effects of relaxin (purified porcine and recombinant human) for third trimester cervical ripening or induction of labour in comparison with other methods of induction.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2003) and bibliographies of relevant papers. We updated this search on 13 August 2009 and added the results to the awaiting classification section.
Selection criteria
Clinical trials comparing relaxin used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods.
Data collection and analysis
A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two‐stage method of data extraction.
Main results
Nine studies were considered; five have been excluded and four included examining a total of 267 women. There were no reported cases of uterine hyperstimulation with fetal heart rate (FHR) changes in any of the studies. There was no evidence of a difference between the rate of caesarean section in those women given relaxin compared with placebo (15.3% versus 14.2%; relative risk (RR) 0.79, 95% confidence interval (CI) 0.42 to 1.50, 4 trials, 257 women). There was a reduction in the risk of the cervix remaining unfavourable or unchanged with induction with relaxin (21.9% versus 49.3%; RR 0.45, 95% CI 0.28 to 0.72, 3 trials, 371 women). There were no reported cases of uterine hyperstimulation without FHR changes.
Authors' conclusions
The place of relaxin, either purified porcine or recombinant human, as an induction or cervical priming agent is unclear. Further trials are needed to estimate the true effect of relaxin within current clinical practice.
[Note: The three citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
Plain language summary
Relaxin for cervical ripening and induction of labour
Not enough evidence that relaxin helps ripen the cervix and induce labour.
Relaxin is a hormone secreted by the placenta in the final stages of pregnancy to ripen the neck of the uterus (cervix) and prepare it for labour. It is used to induce labour and is either made from genetically combined human relaxin or from animal preparations. The role of relaxin treatment remains unclear but it is possible that it may relax the muscle tissue of the uterus and therefore not work as well as other methods of induction. The review of trials found there was not enough research to show the true effect of relaxin. More research is needed.
Background
Sometimes it is necessary to bring on labour artificially because of safety concerns for the mother or baby. This review is one of a series of reviews of methods of labour induction using a standardised protocol. For more detailed information on the rationale for this methodological approach, please refer to the currently published 'generic' protocol (Hofmeyr 2000). The generic protocol describes how a number of standardised reviews will be combined to compare various methods of preparing the cervix of the uterus and inducing labour.
Relaxin is a protein hormone composed of two amino acid chains. The role played by relaxin in human pregnancy and parturition is unclear. Its use and involvement as a cervical ripening agent has been debated since the 1950s. Because the main source of human relaxin is the corpus luteum of pregnancy much of the early work on induction of labour has focused on porcine or bovine preparations. With the advent of DNA recombinant technology human relaxin has become available for evaluation. Relaxin is thought to have a promoting effect on cervical ripening. Due to a possible inhibitory effect on human myometrial activity, relaxin may not be associated with the concomitant increase in the rate of uterine hyperstimulation seen with other induction agents.
Objectives
To determine the effects of relaxin (both purified porcine and recombinant human) for third trimester cervical ripening or induction of labour in comparison with other methods of induction.
Methods
Criteria for considering studies for this review
Types of studies
Clinical trials comparing relaxin (both purified porcine and recombinant human) for cervical ripening or labour induction, with other methods listed above it on a predefined list of methods of labour induction (see 'Methods of the review'); the trials included some form of random allocation to either group; and they reported one or more of the prestated outcomes.
Types of participants
Pregnant women due for third trimester induction of labour, carrying a viable fetus.
Types of interventions
Relaxin (both purified porcine and recombinant human) compared with other methods of cervical ripening or induction of labour above it on a predefined list of methods of induction (see 'Methods of review').
Types of outcome measures
Clinically relevant outcomes for trials of methods of cervical ripening/labour induction have been prespecified by two authors of labour induction reviews (Justus Hofmeyr and Zarko Alfirevic). Differences were settled by discussion.
Five primary outcomes were chosen as being most representative of the clinically important measures of effectiveness and complications:
(1) vaginal delivery not achieved within 24 hours (or period specified by trial authors); (2) uterine hyperstimulation with fetal heart rate (FHR) changes; (3) caesarean section; (4) serious neonatal morbidity or perinatal death (e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood); (5) serious maternal morbidity or death (e.g. uterine rupture, admission to intensive care unit, septicaemia).
Perinatal and maternal morbidity and mortality are composite outcomes. This is not an ideal solution because some components are clearly less severe than others. It is possible for one intervention to cause more deaths but less severe morbidity. However, in the context of labour induction at term this is unlikely. All these events will be rare, and a modest change in their incidence will be easier to detect if composite outcomes are presented. The incidence of individual components will be explored as secondary outcomes (see below).
Secondary outcomes relate to measures of effectiveness, complications and satisfaction:
Measures of effectiveness: (6) cervix unfavourable/unchanged after 12 to 24 hours; (7) oxytocin augmentation.
Complications: (8) uterine hyperstimulation without FHR changes; (9) uterine rupture; (10) epidural analgesia; (11) instrumental vaginal delivery; (12) meconium stained liquor; (13) Apgar score less than seven at five minutes; (14) neonatal intensive care unit admission; (15) neonatal encephalopathy; (16) perinatal death; (17) disability in childhood; (18) maternal side effects (all); (19) maternal nausea; (20) maternal vomiting; (21) maternal diarrhoea; (22) other maternal side‐effects; (23) postpartum haemorrhage (as defined by the trial authors); (24) serious maternal complications (e.g. intensive care unit admission, septicaemia but excluding uterine rupture); (25) maternal death.
Measures of satisfaction: (26) woman not satisfied; (27) caregiver not satisfied.
'Uterine rupture' includes all clinically significant ruptures of unscarred or scarred uteri. Trivial scar dehiscence noted incidentally at the time of surgery is excluded.
Additional outcomes may appear in individual primary reviews, but will not contribute to the secondary reviews.
While all the above outcomes will be sought, only those with data appear in the analysis tables.
The terminology of uterine hyperstimulation is problematic (Curtis 1987). In the reviews we will use the term 'uterine hyperstimulation without FHR changes' to include uterine tachysystole (more than five contractions per 10 minutes for at least 20 minutes) and uterine hypersystole/hypertonus (a contraction lasting at least two minutes) and 'uterine hyperstimulation with FHR changes' to denote uterine hyperstimulation syndrome (tachysystole or hypersystole with fetal heart rate changes such as persistent decelerations, tachycardia or decreased short term variability). However, due to varied reporting there is the possibility of subjective bias in interpretation of these outcomes. Also it is not always clear from trials if these outcomes are reported in a mutually exclusive manner.
Outcomes were included in the analysis: if reasonable measures were taken to minimise observer bias; and data were available for analysis according to original allocation.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2003).
We updated this search on 13 August 2009 and added the results to Studies awaiting classification.
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
The original search was performed simultaneously for all reviews of methods of inducing labour, as outlined in the generic protocol for these reviews (Hofmeyr 2000).
The reference lists of trial reports and reviews were searched by hand.
We did not apply any language restrictions.
Data collection and analysis
A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. Many methods have been studied, examining the effects of these methods when induction of labour was undertaken in a variety of clinical groups e.g. restricted to primiparous women or those with ruptured membranes. Most trials are intervention‐driven, comparing two or more methods in various categories of women. Clinicians and parents need the data arranged according to the clinical characteristics of the women undergoing induction of labour, to be able to choose which method is best for a particular clinical scenario. To extract these data from several hundred trial reports in a single step would be very difficult. We developed a two‐stage method of data extraction. The initial data extraction was done in a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data was then extracted from the primary reviews into a series of secondary reviews, arranged by the clinical characteristics of the women undergoing induction of labour.
To avoid duplication of data in the primary reviews, the labour induction methods were listed in a specific order, from one to 25. Each primary review included comparisons between one of the methods (from two to 25) with only those methods above it on the list. Thus, the review of intravenous oxytocin (4) included only comparisons with intracervical prostaglandins (3), vaginal prostaglandins (2) or placebo (1). Methods identified in the future will be added to the end of the list. The current list is as follows:
(1) placebo/no treatment; (2) vaginal prostaglandins; (3) intracervical prostaglandins; (4) intravenous oxytocin; (5) amniotomy; (6) intravenous oxytocin with amniotomy; (7) vaginal misoprostol; (8) oral misoprostol; (9) mechanical methods including extra‐amniotic Foley catheter; (10) membrane sweeping; (11) extra‐amniotic prostaglandins; (12) intravenous prostaglandins; (13) oral prostaglandins; (14) mifepristone; (15) oestrogens with or without amniotomy; (16) corticosteroids; (17) relaxin; (18) hyaluronidase; (19) castor oil, bath, and/or enema; (20) acupuncture; (21) breast stimulation; (22) sexual intercourse; (23) homoeopathic methods; (24) nitric oxide; (25) buccal or sublingual misoprostol (26) other methods for induction of labour.
The primary reviews were analysed by the following subgroups: (1) previous caesarean section or not; (2) nulliparity or multiparity; (3) membranes intact or ruptured; (4) cervix favourable, unfavourable or undefined.
The secondary reviews will include all methods of labour induction for each of the categories of women for which subgroup analysis has been done in the primary reviews. There will thus be six secondary reviews, of methods of labour induction in the following groups of women:
(1) nulliparous, intact membranes (unfavourable cervix, favourable cervix, cervix not defined); (2) nulliparous, ruptured membranes (unfavourable cervix, favourable cervix, cervix not defined); (3) multiparous, intact membranes (unfavourable cervix, favourable cervix, cervix not defined); (4) multiparous, ruptured membranes (unfavourable cervix, favourable cervix, cervix not defined); (5) previous caesarean section, intact membranes (unfavourable cervix, favourable cervix, cervix not defined); (6) previous caesarean section, ruptured membranes (unfavourable cervix, favourable cervix, cervix not defined).
Each time a primary review is updated with new data, those secondary reviews which include data which have changed, will also be updated.
The trials included in the primary reviews were extracted from an initial set of trials covering all interventions used in induction of labour (see above for details of search strategy). The data extraction process was conducted centrally. This was co‐ordinated from the Clinical Effectiveness Support Unit (CESU) at the Royal College of Obstetricians and Gynaecologists, UK, in co‐operation with The Pregnancy and Childbirth Group of The Cochrane Collaboration. This process allowed the data extraction process to be standardised across all the reviews.
The trials were initially reviewed on eligibility criteria, using a standardised form and the basic selection criteria specified above. Following this, data were extracted to a standardised data extraction form which was piloted for consistency and completeness. The pilot process involved the researchers at the CESU and previous reviewers in the area of induction of labour.
Information was extracted regarding the methodological quality of trials on a number of levels. This process was completed without consideration of trial results. Assessment of selection bias examined the process involved in the generation of the random sequence and the method of allocation concealment separately. These were then judged as adequate or inadequate using the criteria described in Table 1 for the purpose of the reviews.
1. Methodological quality of trials.
| Methodological item | Adequate | Inadequate |
| Generation of random sequence | Computer generated sequence, random number tables, lot drawing, coin tossing, shuffling cards, throwing dice. | Case number, date of birth, date of admission, alternation. |
| Concealment of allocation | Central randomisation, coded drug boxes, sequentially sealed opaque envelopes. | Open allocation sequence, any procedure based on inadequate generation. |
Performance bias was examined with regards to whom was blinded in the trials i.e. patient, caregiver, outcome assessor or analyst. In many trials the caregiver, assessor and analyst were the same party. Details of the feasibility and appropriateness of blinding at all levels was sought.
Predefined sub‐group analyses are: previous caesarean section or not; nulliparity or multiparity; membranes intact or ruptured, and cervix unfavourable, favourable or undefined. Only those outcomes with data appear in the analysis tables.
Individual outcome data were included in the analysis if they met the prestated criteria in 'Types of outcome measures'. Included trial data were processed as described in the Cochrane Reviewers' Handbook (Clarke 2002). Data extracted from the trials were analysed on an intention to treat basis (when this was not done in the original report, re‐analysis is performed if possible). Where data were missing, clarification is sought from the original authors. If the attrition was such that it might significantly affect the results, these data were excluded from the analysis. This decision rested with the reviewers of primary reviews and is clearly documented. If missing data become available, they will be included in the analyses.
Data were extracted from all eligible trials to examine how issues of quality influence effect size in a sensitivity analysis. In trials where reporting was poor, methodological issues were reported as unclear or clarification sought.
Due to the large number of trials, double data extraction was not feasible and agreement between the three data extractors was therefore assessed on a random sample of trials.
Once the data had been extracted, they were distributed to individual reviewers for entry onto the Review Manager computer software (RevMan 2003), checked for accuracy, and analysed as above using the RevMan software. For dichotomous data, relative risks and 95% confidence intervals were calculated, and in the absence of heterogeneity, results were pooled using a fixed effects model.
The predefined criteria for sensitivity analysis included all aspects of quality assessment as mentioned above, including aspects of selection, performance and attrition bias.
Primary analysis was limited to the prespecified outcomes and sub‐group analyses. In the event of differences in unspecified outcomes or sub‐groups being found, these were analysed post hoc, but clearly identified as such to avoid drawing unjustified conclusions.
Results
Description of studies
In total nine studies were considered for inclusion in the review. Five were excluded and four included.
(Three reports from an updated search in July 2009 have been added to Characteristics of studies awaiting classification.)
Excluded studies One of the excluded trials was unpublished (Chou 1991), and there was insufficient information to include this trial. One trial (Decker 1958) reported on induction of labour for women of less than 36 weeks gestation and included data on women with an intrauterine death. This trial was excluded on eligibility grounds. The remaining three trials (Dill 1958; Nesbitt 1961; Evans 1983) did not report on any of the prespecified outcomes in a format that allowed data to be extracted in a dichotomous format.
Included studies Two trials compared purified porcine relaxin with placebo (MacLennan 1980; Maclennan 1986). Both used a single 1 to 2 mg dose, although one study administered the relaxin into the vagina (MacLennan 1980) and the other intracervically (Maclennan 1986). The two remaining trials (Bell 1993; Brennand 1997) compared vaginal recombinant human relaxin with placebo. One trial used a fixed dose of 1.5 mg of relaxin (Bell 1993), the other (Brennand 1997) used a dose ranging regime of 1 mg, 2 mg or 4 mg of relaxin. Due to the small volume of data available no attempt was made to examine the effect of various doses of relaxin.
Risk of bias in included studies
Randomisation and concealment One trial (Brennand 1997) comparing human recombinant relaxin with placebo employed central randomisation. The other trial examining the effect of human relaxin (Bell 1993) used computer generated lists of random numbers but it appears that the allocation was from an open list. The other two trials (MacLennan 1980; Maclennan 1986) were unclear on both the method of generation of the random sequence or the allocation concealment method used.
Blinding All four trials included a placebo arm in the trial, and all made specific reference to the fact that both patient and investigator were blinded to the treatment given.
Effects of interventions
In total, nine studies were considered; five have been excluded and four included examining a total of 267 women.
The initial analysis compared any relaxin formulation with placebo. We also performed a further analysis in two subgroups according to the type of relaxin used i.e. purified porcine or recombinant human relaxin. However, there was no significant difference between the two subgroups for any of the reported outcomes, as reflected by lack of statistical heterogeneity for all reported outcomes. Hence all data have therefore been reported together regardless of the preparation.
Results presented refer to the 'all women' group and unless stated no difference was seen in any of the predefined sub‐groups. Primary outcomes There were no reported cases of uterine hyperstimulation with fetal heart rate (FHR) changes in any of the studies. There was no evidence of a difference between the rate of caesarean section in those women given relaxin compared with placebo (15.3% versus 14.2%; relative risk (RR) 0.79, 95% confidence interval (CI) 0.42 to 1.50, 4 trials, 257 women). Two trials reported no cases of neonatal mortality or morbidity; overall there were insufficient data to comment on this outcome or the other outcome of maternal mortality or morbidity.
Secondary outcomes Compared with placebo there was a reduction in the risk of the cervix remaining unfavourable or unchanged following relaxin administration (21.9% versus 49.3%; RR 0.45, 95% CI 0.28 to 0.72, 3 trials, 371 women). Oxytocin augmentation was not reduced with relaxin in comparison with placebo (53.7% versus 70.6%; RR 0.83, 95% CI 0.65 to 1.06, 3 trials, 196 women). There was some apparent heterogeneity between these studies and the trial by MacLennan 1980, which used porcine relaxin differed from the othere two trials which used recombinant human relaxin. however the numbers included are too small to make any major conclusions. There were no reported cases of uterine hyperstimulation without FHR changes in the two trials reporting this outcome. The use of epidural analgesia or the rate of instrumental delivery was not different between cases induced with relaxin in comparison with placebo. There were insufficient data to comment on other neonatal outcomes. Postpartum hemorrhage was reported in one trial and there was no significant difference between relaxin in comparison with placebo.
Discussion
Outcomes Currently available data do not show any significant difference between relaxin and placebo for induction of labour. The only perceived benefit of relaxin in comparison to placebo is an improvement in cervical favourability.
Sensitivity analysis One of the included trials administered relaxin via an intracervical route (Maclennan 1986). This may alter the action/efficacy of relaxin in comparison to vaginal administration. Removal of this trial from the results did not statistically alter any of the results and hence we felt it justified to include this trial alongside the other three trials where relaxin was administered vaginally. Any perceived difference of effect between vaginal and intracervical relaxin could only realistically be detected with much larger numbers of trial participants.
Authors' conclusions
Implications for practice.
The place of relaxin, either purified porcine or recombinant human, as an induction or cervical priming agent is unclear and its use outside of clinical trials should be discouraged.
Implications for research.
Further trials are needed to estimate the true effect of relaxin on clinically relevant outcomes for the woman and her infant.
[Note: The three citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
What's new
| Date | Event | Description |
|---|---|---|
| 13 August 2009 | Amended | Search updated. Three reports added to Studies awaiting classification (Critchley 1994; Karpovich 2006; Weiss 2009). |
History
Protocol first published: Issue 2, 2000 Review first published: Issue 2, 2001
| Date | Event | Description |
|---|---|---|
| 4 November 2008 | Amended | Converted to new review format. |
Acknowledgements
We would like to thank Jim Neilson, Zarko Alfirevic and Justus Hofmeyr for their advice and patience during the development of this review and Caroline Crowther for her patience and attention to detail during the final production of the review .
Data and analyses
Comparison 1. Relaxin versus placebo/no treatment (all women).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2 Uterine hyperstimulation with FHR changes | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Caesarean section | 4 | 267 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.42, 1.50] |
| 4 Serious neonatal morbidity/perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Cervix unfavourable/unchanged after 24 hours | 3 | 171 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.45 [0.28, 0.72] |
| 7 Oxytocin augmentation | 3 | 196 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.65, 1.06] |
| 8 Uterine hyperstimulation without FHR changes | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Epidural analgesia | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.56, 1.34] |
| 11 Instrumental delivery | 3 | 196 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.76, 1.86] |
| 13 Apgar score < 7 at 5 minutes | 1 | 71 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 16 Perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Postpartum haemorrhage | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.05, 3.59] |
1.2. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 2 Uterine hyperstimulation with FHR changes.
1.3. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 3 Caesarean section.
1.4. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 4 Serious neonatal morbidity/perinatal death.
1.6. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 6 Cervix unfavourable/unchanged after 24 hours.
1.7. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 7 Oxytocin augmentation.
1.8. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 8 Uterine hyperstimulation without FHR changes.
1.10. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 10 Epidural analgesia.
1.11. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 11 Instrumental delivery.
1.13. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 13 Apgar score < 7 at 5 minutes.
1.16. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 16 Perinatal death.
1.19. Analysis.
Comparison 1 Relaxin versus placebo/no treatment (all women), Outcome 19 Postpartum haemorrhage.
Comparison 2. Relaxin versus placebo/no treatment (all women, unfavourable cervix).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2 Uterine hyperstimulation with FHR changes | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Caesarean section | 3 | 207 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.45, 1.73] |
| 4 Serious neonatal morbidity/perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Cervix unfavourable/unchanged after 24 hours | 2 | 111 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.60 [0.34, 1.04] |
| 7 Oxytocin augmentation | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.76, 1.36] |
| 8 Uterine hyperstimulation without FHR changes | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Epidural analgesia | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.49, 1.95] |
| 11 Instrumental delivery | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.63 [0.73, 3.64] |
| 13 Apgar score < 7 at 5 minutes | 1 | 71 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 16 Perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Postpartum haemorrhage | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.05, 3.59] |
2.2. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 2 Uterine hyperstimulation with FHR changes.
2.3. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 3 Caesarean section.
2.4. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 4 Serious neonatal morbidity/perinatal death.
2.6. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 6 Cervix unfavourable/unchanged after 24 hours.
2.7. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 7 Oxytocin augmentation.
2.8. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 8 Uterine hyperstimulation without FHR changes.
2.10. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 10 Epidural analgesia.
2.11. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 11 Instrumental delivery.
2.13. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 13 Apgar score < 7 at 5 minutes.
2.16. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 16 Perinatal death.
2.19. Analysis.
Comparison 2 Relaxin versus placebo/no treatment (all women, unfavourable cervix), Outcome 19 Postpartum haemorrhage.
Comparison 3. Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2 Uterine hyperstimulation with FHR changes | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Caesarean section | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.97 [0.42, 2.23] |
| 4 Serious neonatal morbidity/perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Cervix unfavourable/unchanged after 24 hours | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.25, 1.46] |
| 7 Oxytocin augmentation | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.76, 1.36] |
| 8 Uterine hyperstimulation without FHR changes | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 10 Epidural analgesia | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.49, 1.95] |
| 11 Instrumental delivery | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.63 [0.73, 3.64] |
| 16 Perinatal death | 2 | 136 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 19 Postpartum haemorrhage | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.41 [0.05, 3.59] |
3.2. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 2 Uterine hyperstimulation with FHR changes.
3.3. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 3 Caesarean section.
3.4. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 4 Serious neonatal morbidity/perinatal death.
3.6. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 6 Cervix unfavourable/unchanged after 24 hours.
3.7. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 7 Oxytocin augmentation.
3.8. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 8 Uterine hyperstimulation without FHR changes.
3.10. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 10 Epidural analgesia.
3.11. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 11 Instrumental delivery.
3.16. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 16 Perinatal death.
3.19. Analysis.
Comparison 3 Relaxin versus placebo/no treatment (all women, intact membranes, unfavourable cervix), Outcome 19 Postpartum haemorrhage.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Bell 1993.
| Methods | Open allocation from computer generated randomised number list. | |
| Participants | 40 women requiring induction of labour. Inclusion criteria: uncomplicated singleton pregnancy, gestation longer than 40 weeks, cephalic presentation, unscarred uterus. Exclusion criteria: abnormal placental location, antepartum haemorrhage, ruptured membranes, Calder score > 6, fetal malformation, fetal growth retardation, reduced amniotic fluid volume, macrosomia. |
|
| Interventions | 1.5 mg vaginal recombinant human relaxin in methycellulose gel (n = 18) or inert gel (n = 22). Baseline Calder score at instillation followed by re‐evaluation at 15 hours. Both groups then had amniotomy and oxytocin. |
|
| Outcomes | Presence of contractions, change in Calder score, rates of spontaneous labour, hyperstimulation, mode of delivery, oxytocin augmentation, epidural analgesia, perinatal mortality and postpartum haemorrhage. | |
| Notes | Multicentre trial; Royal Women's Hospital, Melbourne, Queen Victoria Hospital, Adelaide and Monash Medical Centre, Clayton, Australia. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
Brennand 1997.
| Methods | Central randomisation with coded drug boxes. | |
| Participants | 96 women requiring induction of labour. Inclusion criteria: singleton pregnancy, at least 37 weeks gestation, cephalic presentation, Bishops score < 4. Exclusion criteria: uterine scar, ruptured membranes, abnormal placentation, placental abruption, significant systemic disease, growth retardation, fetal malformation, macrosomia, oligo or polyhydramnios. |
|
| Interventions | 1.0 mg (n = 23), 2.0 mg (n = 25) or 4.0 mg (n = 25) vaginal recombinant human relaxin in methycellulose gel or placebo gel (n = 23). Instillation following baseline Bishops score. Re‐evaluation at 15 hours, followed by administration of vaginal prostaglandin gel (2 mg). Further 1‐2 mg vaginal gel administered at 6 hours, amniotomy once 3 cm dilated. |
|
| Outcomes | Change in Bishops score, labour duration, spontaneous labour, mode of delivery, oxytocin augmentation, perinatal mortality. | |
| Notes | 3 relaxin arms analysed as one versus placebo. Glasgow Royal Maternity Hospital, UK. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
MacLennan 1980.
| Methods | 'Randomised double blind'. | |
| Participants | 60 women requiring induction of labour. Inclusion criteria: singleton pregnancy, cephalic presentation, unscarred uterus, maternal height over 150 cm. |
|
| Interventions | 2.0 mg vaginal purified porcine relaxin diluted in water (n = 30) or placebo (n = 30). Instillation following baseline cervical assessment. Re‐examined following morning. Subsequent method of induction not specified. |
|
| Outcomes | Change in Bishops score, mode of delivery, epidural analgesia, Apgar scores and hyperstimulation rates. | |
| Notes | Queen Victoria Hospital, Adelaide, Australia. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Maclennan 1986.
| Methods | 'Randomly allocated'. | |
| Participants | 54 patients requiring induction of labour. Inclusion criteria: singleton pregnancy, cephalic presentation, unscarred uterus, maternal height over 150 cm, modified Bishops score < 7. |
|
| Interventions | 1.0 mg (n = 25) or 2.0 mg (n = 23) intracervical purified porcine relaxin or placebo (n = 23). Instillation following baseline Bishops score. Re‐examined following morning. Subsequent method of induction not specified. |
|
| Outcomes | Change in Bishops score, mode of delivery, epidural analgesia, Apgar scores. | |
| Notes | Queen Victoria Hospital, Adelaide, Australia. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Chou 1991 | Unpublished trial. Planned comparison of human relaxin gel for cervical ripening and induction of labour. Recruitment began 1991. Unpublished to date. |
| Decker 1958 | Comparison of 20 mg subcutaneous injection of relaxin with placebo. Trial included all women less than 36 weeks gestation and 3 cases of IUD. Not possible to separate out data. |
| Dill 1958 | Comparison of intravenous bovine relaxin with placebo. Method of allocation probably non‐random. No primary outcomes reported. |
| Evans 1983 | Two trials reported. First trial relaxin with oxytocin, hence not relevant to this review. Second trial comparison of either 2 mg or 4 mg intracervical relaxin with placebo, in an outpatient setting. No outcomes reported in dichotomous format. |
| Nesbitt 1961 | Comparison of 40 mg intravenous relaxin with placebo. No outcomes reported in dichotomous format. |
IUD = Intrauterine death
Contributions of authors
Anthony J Kelly and Josephine Kavanagh performed the data extraction. Anthony J Kelly, Josephine Kavanagh and Jane Thomas drafted the review.
Sources of support
Internal sources
Clinical Effectiveness Support Unit, Royal College of Obstetricians and Gynaecologists, UK.
External sources
No sources of support supplied
Declarations of interest
None known.
Edited (no change to conclusions)
References
References to studies included in this review
Bell 1993 {published data only}
- Bell RJ, Permezel M, MacLennan A, Hughes C, Healy D, Brennecke S. A randomized, double‐blind, placebo controlled trial of the safety of vaginal recombinant human relaxin for cervical ripening. Obstetrics & Gynecology 1993;82:328‐33. [PubMed] [Google Scholar]
Brennand 1997 {published data only}
- Brennand JE, Calder AA, Leitch CR, Greer IA, Chou MM, MacKenzie IZ. Recombinant human relaxin as a cervical ripening agent. British Journal of Obstetrics and Gynaecology 1997;104:775‐80. [DOI] [PubMed] [Google Scholar]
MacLennan 1980 {published data only}
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Maclennan 1986 {published data only}
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References to studies excluded from this review
Chou 1991 {unpublished data only}
- Chou MM. Double‐blind randomized trial of human relaxin gel for cervical ripening and induction of labour. Personal communication 1991.
Decker 1958 {published data only}
- Decker WH, Thwaite W, Bordat S, Kayser R, Harami T, Campbell J. Some effects of relaxin in obstetrics. Obstetrics & Gynecology 1958;12:37‐46. [DOI] [PubMed] [Google Scholar]
Dill 1958 {published data only}
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Evans 1983 {published data only}
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References to studies awaiting assessment
Critchley 1994 {published data only}
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Weiss 2009 {published data only}
- Weiss G, Teichman S, Stewart D, Nader D, Wood S, Unemori E. A randomized, double‐blind, placebo‐controlled trial of relaxin for cervical ripening in post‐delivery date pregnancies. Annals of the New York Academy of Sciences 2009;1160:385‐6. [DOI] [PubMed] [Google Scholar]
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