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Antibiotics for preterm rupture of membranes

  1. Sara Kenyon1,*,
  2. Michel Boulvain2,
  3. James P Neilson3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 2 DEC 2013

Assessed as up-to-date: 26 NOV 2013

DOI: 10.1002/14651858.CD001058.pub3


How to Cite

Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001058. DOI: 10.1002/14651858.CD001058.pub3.

Author Information

  1. 1

    University of Birmingham, School of Health and Population Sciences, Edgbaston, UK

  2. 2

    Maternité Hôpitaux Universitaires de Genève, Département de Gynécologie et d'Obstétrique, Unité de Développement en Obstétrique, Genève 14, Switzerland

  3. 3

    The University of Liverpool, Department of Women's and Children's Health, Liverpool, UK

*Sara Kenyon, School of Health and Population Sciences, University of Birmingham, Public Health Building, Edgbaston, B15 2TT, UK. s.kenyon@bham.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 2 DEC 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The rate of preterm birth is 5% to 9% of all births in Europe, and 12% to 13% in the USA; the rates in both continents are increasing, partly due to the higher number of multiple births associated with assisted conceptions (Goldenberg 2008). About 30% to 35% of preterm births are the result of maternal or fetal disease, but 40% to 45% of premature births result from spontaneous preterm labour (SPL) and 25% to 30% from preterm rupture of the membranes (PROM). Once the membranes have ruptured prematurely, 50% of women will go into labour within 24 to 48 hours and 70% to 90% within seven days (Dale 1989). For families struggling to cope with having a baby in special care, this will be one of the most difficult, emotional and stressful times of their lives (Taylor 2001), whatever the longer-term outcome. The sequelae of preterm birth also pose significant challenges. Children born preterm are at increased risk of major disabilities, such as cerebral palsy, with the risk increasing with decreasing gestation at birth (Costeloe 2012; Marlow 2005). Many preterm children without disability develop important behavioural and educational difficulties (Saigal 2008).The prevention of preterm birth and reduction of associated disability are therefore important health priorities.

The causes of PROM are multifactorial. Infection appears to have an important role, either as a cause or as a consequence of PROM. Some organisms may produce collagenases, mucinases and proteases, which weaken the amnion and chorion and may lead to PROM. On the other hand, infection may occur secondary to membrane rupture. Ascending infection may lead to occult deciduitis, intra-amniotic infection or fetal infection.

A possible mechanism for the link between infection and preterm delivery is bacterial stimulation of the biosynthesis of prostaglandins, either directly via phospholipase A2 and C (Bejar 1981), or indirectly via substances such as interleukin-1, tumour necrosis factor and platelet activating factor, all of which may be found in infected amniotic fluid (Yoon 2000).

There is increasing evidence that, in addition to preterm birth, perinatal infection is an independent antecedent of other disability, particularly cerebral palsy and chronic lung disease (Dammann 2005; Romero 2007). One theory was that perinatal prescription of antibiotics could prevent neurological and respiratory disability by two mechanisms, either by prolonging pregnancy, or by preventing or eliminating infection, or both. In contrast, it was also thought possible that prolongation of pregnancy might increase rather than decrease disability by continuing fetal exposure to inflammatory cytokines, which have already been implicated in the genesis of neurological damage (Dammann 1997; Wu 2002) and chronic lung disease (Kotecha 1996; Speer 2003). 

In addition to a generic effect of antibiotics, there may, in theory, be differences in the effects of different antibiotics. For example, macrolide antibiotics such as clindamycin and erythromycin, which reduce bacterial virulence, may have advantages over the beta lactam antibiotics (co-amoxiclav, cephalosporins) which, by destroying bacteria, release endotoxins and prostaglandins and may worsen outcomes (McGregor 1997). Thus, separate comparisons of these antibiotics are included in the review.

The use of antibiotics for women with preterm labour with intact membranes is addressed by another review (King 2002).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To assess the effects of administering antibiotics to women with preterm rupture of membranes on fetal and neonatal morbidity and mortality, maternal infectious morbidity and mortality, and long-term childhood development.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We considered all randomised controlled comparisons of antibiotic administration versus placebo, given to women with preterm rupture of membranes, for inclusion in this review. We also included comparisons of different antibiotics. For the unambiguous and important outcome of perinatal death alone, we included trials in the review that were randomised but not placebo-controlled. We excluded trials that used inappropriate methods of randomisation. We included trials where the method of randomisation was not specified in detail in the expectation that their inclusion in this review would encourage the authors to make available further information on the method of randomisation. We excluded trials where non-randomised cohorts were amalgamated with randomised participants if the results of the randomised participants were not reported separately. We included trials in which post-randomisation exclusions occurred, provided there was no evidence that these occurred preferentially in one or other arm of the trials. We excluded studies where outcomes for over 20% of participants were not reported.

 

Types of participants

Women with preterm (less than 37 weeks) rupture of the membranes.

 

Types of interventions

Comparison of:

  • any antibiotic versus placebo.

We planned to undertake subgroup comparisons for the primary outcome as follows:

  • all penicillins (excluding co-amoxiclav) versus placebo;
  • beta lactam (including co-amoxiclav) antibiotics versus placebo;
  • macrolide (including erythromycin) antibiotics versus placebo.

Additional comparisons:

  • beta lactam (including co-amoxiclav) antibiotics versus macrolide antibiotics (including erythromycin);
  • all penicillins (except co-amoxiclav) versus macrolide antibiotics (including erythromycin).

  • Antibiotic versus no antibiotic (including non-placebo controlled trials) - perinatal death only:
    • Subgroup comparison of non-placebo controlled trials only.
  • Different treatment regimens of same antibiotic.

 

Types of outcome measures

 

Primary outcomes

  • Maternal death.
  • Serious maternal morbidity:
    • septicaemia;
    • need for intensive care;
    • organ failure, need for ventilation;
    • need for hysterectomy.
  • Perinatal death or death before discharge from hospital.
  • Perinatal morbidity:
    • neonatal infection including pneumonia;
    • necrotising enterocolitis;
    • oxygen treatment greater than 36 weeks' postconceptual age;
    • major cerebral abnormality on ultrasound prior to discharge.

 

Secondary outcomes

  • Major maternal adverse drug reaction.
  • Maternal infection after delivery prior to discharge.
  • Chorioamnionitis (infection of the womb).
  • Caesarean section.
  • Days from randomisation to birth.
  • Days from birth to discharge from hospital.
  • Birth within 48 hours.
  • Birth within seven days.
  • Birth before 37 weeks.
  • Birthweight.
  • Birthweight less than 2500 g.
  • Need for intensive care.
  • Days in neonatal intensive care unit.
  • Positive neonatal blood culture.
  • Respiratory distress syndrome.
  • Treatment with surfactant.
  • Days of ventilation.
  • Days of oxygen therapy.
  • Oxygen treatment greater than 28 days.
  • Neonatal encephalopathy.
  • Long-term health outcomes (as defined by trial authors) after at least two years.

 

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 (30 September 2013).

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

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

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

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

We did not apply any language restrictions.

 

Data collection and analysis

For the methods used when assessing the trials identified in a previous version of this review (Kenyon 2003), see Appendix 1.

For the previous update (Kenyon 2010), we used the following methods when assessing the reports identified by the updated search (Amon 1988b; Beazley 1998; Bergstrom 1991; Cardamakis 1990; Christmas 1990; Fuhr 2006; Gilbert 2005; Gordon 1974; Halis 2001; Hauth 1997; Hnat 2005; Kenyon 2008a; Kenyon 2008c; Kim 2008; Lockwood 1993b; Morales 1988; Ogasawara 1996; Ogasawara 1997; Ogasawara 1999; Owen 1993b; Sanchez-Ramos 1990; Svare 1997b; Thurnau 1997). For this update, we would have used the following methods if we had identified new studies for inclusion.

 

Selection of studies

Two review authors (S Kenyon (SK) and M Boulvain (MB)) independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third review author (JP Neilson (JPN)).

 

Data extraction and management

We designed a form to extract data. For eligible studies, review authors SK and MB extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted the third review author (JPN). We entered data into Review Manager software (RevMan 2011) and checked for accuracy.

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

 

Assessment of risk of bias in included studies

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

 

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

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

We assessed the method as:

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

 

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

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

We assessed the methods as:

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

 

(3) Blinding (checking for possible performance bias)

We describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We judged studies at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

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

 

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

We describe 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. We decided a cut-off for exclusion of a study for the level of missing data at 20%. Where sufficient information has been reported, or can be supplied by the trial authors, we planned to re-include missing data in the analyses which we undertake. We assessed methods as:

  • low risk of bias;
  • high risk of bias:
  • unclear risk of bias. 

 

(5) Selective reporting bias

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

We assessed the methods as:

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

 

(6) Other sources of bias

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

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

  • 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 Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings (Figure 1). We considered this to be unlikely and, therefore, have not undertaken sensitivity analyses. 

 FigureFigure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

 

Measures of treatment effect

 

Dichotomous data

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

 

Continuous data

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

 

Unit of analysis issues

 

Cluster-randomised trials

We would have included cluster-randomised trials in the analyses along with individually-randomised trials. Their sample sizes would have been adjusted using the methods described in the Cochrane Handbook (Higgins 2011) 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 had been used, we would have reported this and conducted sensitivity analyses to investigate the effect of variation in the ICC. If we had identified both cluster-randomised trials and individually-randomised trials, we would have synthesised the relevant information. We would have considered it reasonable to combine the results from both if there was little heterogeneity among the study designs and the interaction between the effect of intervention and the choice of randomisation unit was considered to be unlikely.

We would have also acknowledged heterogeneity in the randomisation unit and performed a separate meta-analysis.

 

Cross-over trials

If we had identified any cross-over trials on this topic, and deemed such trials eligible for inclusion, we would have included them in the analyses with parallel group trials, using methods described by Elbourne 2002.

 

Multi-arm studies

For the subgroup comparisons undertaken, to avoid double counting, we divided out data from the shared group approximately evenly among the comparisons as described in theCochrane Handbook (Higgins 2011).

 

Dealing with missing data

For included studies, we 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 are known to be missing.

 

Assessment of heterogeneity

We used the I² and Tau² statistic to measure heterogeneity among the trials in each analysis. We performed subgroup analysis to obtain meta-analysis results for more clinically comparable studies, to reduce heterogeneity where it existed.

 

Assessment of reporting biases

Where we suspected reporting bias (see ‘Selective reporting bias’ above), we attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and we thought the missing data likely to introduce serious bias, we planned to explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. Funnel plots for primary outcomes only show no evidence of publication bias: Figure 2,Figure 3; Figure 4; Figure 5.

 FigureFigure 2. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.3 Perinatal death/death before discharge.
 FigureFigure 3. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.4 Neonatal infection including pneumonia.
 FigureFigure 4. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.5 Neonatal necrotising enterocolitis.
 FigureFigure 5. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.7 Major cerebral abnormality on ultrasound before discharge.

 

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011). As we suspected clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we used random-effects meta-analysis.

 

Subgroup analysis and investigation of heterogeneity

We conducted planned subgroup analyses classifying whole trials by interaction tests available in RevMan 2011.

 

Sensitivity analysis

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings (Figure 1). We considered this to be unlikely and therefore, have not undertaken sensitivity analyses. 

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

The search identified 51 trials. We included 22 trials in the review, involving 6872 women and their babies, and excluded 29. Of the trials included, the majority were small with the exception of Kenyon 2001, which randomised 4826 women, and Mercer 1997, which randomised 614 women. Women were recruited between 20 and 37 weeks of gestation and inclusion criteria varied from clinicians definition of PROM to amniocentesis being carried out as part of an infection screen (Mercer 1992). The majority of women were not in active labour. Ten trials tested broad spectrum penicillins either alone or in combination (Cox 1995; Ernest 1994; Fuhr 2006; Grable 1996; Johnston 1990; Kenyon 2001; Kurki 1992; Lockwood 1993a; Mercer 1997; Svare 1997a). Five trials tested macrolide antibiotics (erythromycin) either alone or in combination (Garcia-Burguillo 1995; Kenyon 2001; McGregor 1991; Mercer 1992; Mercer 1997) and one tested clindamycin and gentamycin (Ovalle-Salas 1997). The duration of treatment varied between two doses (Kurki 1992) and 10 days (Kenyon 2001) with five trials opting for a maximum of seven days of treatment (Fuhr 2006; McGregor 1991; Mercer 1997; Ovalle-Salas 1997; Svare 1997a). Four trials treated women until delivery (Ernest 1994; Garcia-Burguillo 1995; Johnston 1990; Mercer 1992). In four of the trials, women were treated with oral antibiotic alone (Garcia-Burguillo 1995; Kenyon 2001; McGregor 1991; Mercer 1992). In three of the trials, women were treated with intravenous antibiotic alone (Fuhr 2006; Kurki 1992; Lockwood 1993a). In six of the trials, women were treated with a combination of intravenous and oral antibiotics (Cox 1995; Ernest 1994; Johnston 1990; Mercer 1997; Ovalle-Salas 1997; Svare 1997a).

The six non-placebo controlled but randomised studies, which contributed data to the outcome measure perinatal death alone, were: Amon 1988a; Camli 1997; Christmas 1992; Magwali 1999; Morales 1989; Owen 1993a.

Two trials compared three versus five days of ampicillin (Lewis 2003; Segel 2003).

Outcomes were divided into primary and secondary. Primary outcomes, as listed above, were chosen based on importance and ability to predict longer term neonatal morbidity. Additional outcome measures chosen included maternal infection, prolongation of pregnancy and measures of neonatal mortality and morbidity. One study had undertaken follow-up past discharge from hospital (Kurki 1992) but the results are not reported by treatment group but rather by duration of membrane rupture. One study has undertaken long-term follow-up at seven years of age in the UK (Kenyon 2001). The study evaluated functional impairment, behaviour, respiratory symptoms, hospital admissions, convulsions and other specific medical conditions. These are the only data on long-term follow-up from any of the included trials. Seven-year assessment was not specifically a prespecified outcome, but is captured under the outcome of long-term health after at least two years.

For details of included and excluded studies, see Characteristics of included studies and Characteristics of excluded studies.

 

Risk of bias in included studies

The method of randomisation was described in all trials with the exception of Amon 1988a, Camli 1997, Cox 1995, Kurki 1992, Fuhr 2006, Magwali 1999, Morales 1989 and Ovalle-Salas 1997. All trials had matched placebos and were blinded apart from the six non-placebo controlled studies described above. No detail on losses to follow-up or exclusions were available from two trials (Cox 1995; Johnston 1990). The protocols were only available for one study (Kenyon 2001) to allow assessment of selective reporting. Lack of information that would allow fuller assessment may reflect changes in reporting of trials.

 

Effects of interventions

We included 22 trials involving 6872 women and their babies.

We adopted a random-effects model, as we expected heterogeneity due to variability in participant characteristics, different antibiotics, year of the study and different countries etc.

 

Any antibiotic versus placebo

We included 16 trials in this comparison, which randomised more than 6300 women and their babies.

 

Primary Outcomes

No maternal deaths occurred in the three trials reporting this outcome, and there were no data reported on serious maternal morbidity.

There was no significant difference between groups in perinatal death (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.76 to 1.14, 12 trials, data for 6301 babies). Neonatal infection (RR 0.67, 95% CI 0.52 to 0.85) (12 trials/1680 babies) was statistically significantly reduced in the babies whose mothers received antibiotics. Only one trial (Kenyon 2001) assessed the use of surfactant and it found a statistically significant reduction (RR 0.83, 95% CI 0.72 to 0.96) (one trial/4809 babies) as was the numbers of babies requiring oxygen therapy overall (RR 0.88, 95% CI 0.81 to 0.96) (one trial/4809 babies). There were no clear differences between groups for other neonatal outcomes including neonatal respiratory distress syndrome (RR 0.95, 95% CI 0.83 to 1.09), necrotising enterocolitis (RR 1.09, 95% CI 0.65 to 1.83), and the number of babies requiring ventilation (RR 0.90, 95% CI 0.80 to 1.02). There was a significant reduction in the number of babies with an abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.81, 95% CI 0.68 to 0.98; Tau² = 0.00, I² = 0%) (12 trials/6289 babies).

 

Secondary Outcomes

Thre was no evidence of any difference between groups for birth before 37 weeks' gestation and there were no reports of major adverse drug reactions. The use of antibiotics following preterm rupture of membranes (PROM) was associated with a statistically significant reduction in chorioamnionitis (RR 0.66, 95% CI 0.46 to 0.96; Tau² = 0.14, I² = 45%) (11 trials/1559 women). The rate of caesarean section was similar in the two groups (RR 0.96, 95% CI 0.88 to 1.05). The mean maternal length of hospital stay and the interval between randomisation and the birth were not reported in any of the trials included in this comparison.

There was a significant reduction in the numbers of babies born within 48 hours (RR 0.71, 95% CI 0.58 to 0.87; Tau² = 0.03, I² = 50%) (seven trials/5927 babies) and seven days (RR 0.79, 95% CI 0.71 to 0.89; Tau² = 0.01, I² = 65%) (seven trials/5965 babies) of randomisation. The babies in the treatment groups spent 5.05 days less in neonatal intensive care (mean difference (MD) -5.05, 95% CI -9.77 to -0.33) (three trials/225 babies) and their birthweight was greater by 54 g (MD 53.83, 95% CI 7.06 to 100.60) (12 trials/6374 babies).

Long-term follow-up at seven years of age has been completed by one study (ORACLE - Kenyon 2008a) and showed that antibiotics seemed to have little effect on the health of the children (RR 1.01, 95% CI 0.91 to 1.12) (one trial/3171 children).

 

Subgroup comparisons

These were undertaken for the primary outcomes only and show no evidence of differences in treatment effects between the subgroups, with the exception of necrotising enterocolitis, where there is a strong suggestion that this is increased with beta lactum antibiotics (including co-amoxiclav) (RR 4.72, 95% CI 1.57 to 14.23).

 

Additional comparisons

 

Erythromycin versus co-amoxiclav

We included one trial (Kenyon 2001), involving 2415 women that focused on this comparison. Delivery within 48 hours was less common after co-amoxiclav (RR 1.14, 95% CI 1.02 to 1.28) but the difference was not statistically significant at seven days (RR 1.06, 95% CI 0.99 to 1.13). There was no significant difference in any index of neonatal morbidity except for necrotising enterocolitis, which was statistically significantly less frequent after erythromycin (RR 0.46, 95% CI 0.23 to 0.94). Long-term follow-up has been completed by one study (Kenyon 2001) and showed little effect on the health of children (RR 0.89, 95% CI 0.79 to 1.01) (one trial/1612 children).

 

Perinatal mortality alone

No statistically significant reduction in perinatal mortality prior to discharge from hospital could be found when additional data were included from the six studies that were randomised but not placebo controlled (RR 0.89, 95% CI 0.74 to 1.08) (18 trials/6872 babies). Subgroup comparison of this group alone also shows no statistical difference.

 

Differing regimens

Two trials (Lewis 2003; Segel 2003) compared three versus seven-day regimens of ampicillin treatment (130 women). From the limited available outcome data, there was no obvious disadvantage to the three-day regimen.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

This review shows that routine antibiotic administration to women with PROM reduces some markers of maternal and neonatal morbidity. This does not translate into a statistically significant reduction in perinatal mortality. Most trials, however, report fewer deaths in the treatment group and the summary result shows a trend towards a beneficial effect. We included all randomised trials in the evaluation of perinatal death as this outcome is unlikely to be influenced by knowledge of the treatment allocation. Such a reduction in major markers of maternal and neonatal morbidity when antibiotics are administered makes a reduction in death possible, even if the result was statistically non-significant from pooling of available data.

By far the largest trial included is the UK MRC ORACLE (Kenyon 2001), which randomised 4826 women. The significant increase in neonatal necrotising enterocolitis found in the co-amoxiclav arm of this trial is plausible since co-amoxiclav is known to select for Enterobacter, Citrobacter and Pseudomonas (Hoy 2001). One suggested mechanism of pathogenesis of neonatal necrotising enterocolitis is abnormal microbial colonisation of the intestinal tract by one or several species unhindered by competitors. Co-amoxiclav, because of its large spectrum may influence such colonisation. Furthermore, the immature gut is sensitive to bacterial toxins, resulting in mucosal damage and the initiation of necrotising enterocolitis.

Particularly in the light of the UK MRC ORACLE's finding of reduced abnormal cerebral ultrasound scans before discharge from hospital, it is important that long-term follow-up is undertaken. The UK MRC ORACLE Children Study followed up children, who were born to women with PROM randomised within the UK to the MRC ORACLE trial, at seven years of age and found no evidence of either benefit or harm. This same study also assessed long-term outcomes in children born to women with spontaneous preterm labour (SPL) and intact membranes randomised to the original ORACLE trial (Kenyon 2008b) and found evidence of harm. The prescription of erythromycin (with or without co-amoxiclav) was associated with a statistically significant increase in the proportions of children with any level of functional impairment from 38% to 42%. Similarly, there was a statistically significant increase in the proportions of children with cerebral palsy from 1.7% to 3.3% associated with erythromycin and from 1.9% to 3.2% with co-amoxiclav. There was a suggestion that more children who developed cerebral palsy had been born to mothers who had received both antibiotics. In the light of these findings, it is important to be certain about the diagnosis of ruptured membranes before prescribing antibiotics.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Routine prescription of antibiotics for women with preterm rupture of the membranes is associated with prolongation of pregnancy and improvements in a number of short-term neonatal morbidities, but no significant reduction in perinatal mortality. Despite lack of evidence of longer term benefit in childhood, the advantages on short-term morbidities are such that we would recommend antibiotics are routinely prescribed. The antibiotic of choice is not clear but co-amoxiclav should be avoided in women due to increased risk of neonatal necrotising enterocolitis.

 
Implications for research

In the future there is the possibility that comparative studies may be conducted should there be developments in the pharmacology of antibiotics.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

We acknowledge assistance with the review from Therese Dowswell, Riccardo Pfister, Justus Hofmeyr, David Taylor, Ann Blackburn and Rebecca Smyth.

Therese Dowswell's work was financially supported by the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization. The named authors alone are responsible for the views expressed in this publication.

As part of the pre-publication editorial process, the review has been commented on by two peers (an editor and referee who is external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Any antibiotic versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Maternal death3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Any antibiotic versus placebo
3763Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 All penicillin (excluding co-amoxiclav) versus placebo
185Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   1.3 Beta lactum (including co-amoxiclav) versus placebo 
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   1.4 Macrolide (including erythromycin) versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.5 Other antibiotic versus placebo
2678Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

2 Serious maternal morbidity0Risk Ratio (M-H, Random, 95% CI)Subtotals only

   2.1 Any antibiotic versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.2 All penicillin (excluding co-amoxiclav) versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.3 Beta lactum (including co-amoxiclav) versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.4 Macrolide (including erythromycin) versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.5 Other antibiotic versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Perinatal death/death before discharge12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Any antibiotic versus placebo
126301Risk Ratio (M-H, Random, 95% CI)0.93 [0.76, 1.14]

    3.2 All penicillin (excluding co-amoxiclav) versus placebo
4332Risk Ratio (M-H, Random, 95% CI)0.78 [0.31, 1.97]

    3.3 Beta lactum (including co-amoxiclav) versus placebo
21880Risk Ratio (M-H, Random, 95% CI)0.62 [0.15, 2.56]

    3.4 Macrolide (including erythromycin) versus placebo
42138Risk Ratio (M-H, Random, 95% CI)0.83 [0.43, 1.60]

    3.5 Other antibiotic versus placebo
3762Risk Ratio (M-H, Random, 95% CI)1.13 [0.68, 1.88]

 4 Neonatal infection including pneumonia12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Any antibiotic versus placebo
121680Risk Ratio (M-H, Random, 95% CI)0.67 [0.52, 0.85]

    4.2 All penicillin (excluding co-amoxiclav) versus placebo
5521Risk Ratio (M-H, Random, 95% CI)0.30 [0.13, 0.68]

    4.3 Beta lactum (including co-amoxiclav) versus placebo
162Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.88]

    4.4 Macrolide (including erythromycin) versus placebo
3334Risk Ratio (M-H, Random, 95% CI)0.79 [0.45, 1.37]

    4.5 Other antibiotic versus placebo
3763Risk Ratio (M-H, Random, 95% CI)0.71 [0.53, 0.95]

 5 Neonatal necrotising enterocolitis11Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Any antibiotic versus placebo
116229Risk Ratio (M-H, Random, 95% CI)1.09 [0.65, 1.83]

    5.2 All penicillin (excluding co-amoxiclav) versus placebo
3262Risk Ratio (M-H, Random, 95% CI)0.85 [0.25, 2.97]

    5.3 Beta lactum (including co-amoxiclav) versus placebo
21880Risk Ratio (M-H, Random, 95% CI)4.72 [1.57, 14.23]

    5.4 Macrolide (including erythromycin) versus placebo
32076Risk Ratio (M-H, Random, 95% CI)0.88 [0.45, 1.69]

    5.5 Other antibiotic versus placebo
4823Risk Ratio (M-H, Random, 95% CI)0.89 [0.54, 1.47]

 6 Oxygen treatment > 36 weeks' postconceptual age1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Any antibiotic versus placebo
14809Risk Ratio (M-H, Random, 95% CI)0.91 [0.70, 1.17]

   6.2 All penicillin (excluding co-amoxiclav) versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Beta lactum (including co-amoxiclav) versus placebo
11818Risk Ratio (M-H, Random, 95% CI)0.92 [0.63, 1.36]

    6.4 Macrolide (including erythromycin) versus placebo
11803Risk Ratio (M-H, Random, 95% CI)0.89 [0.61, 1.32]

   6.5 Other antibiotic versus placebo
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 7 Major cerebral abnormality on ultrasound before discharge12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    7.1 Any antibiotic versus placebo
126289Risk Ratio (M-H, Random, 95% CI)0.81 [0.68, 0.98]

    7.2 All penicillin (excluding co-amoxiclav) versus placebo 
3262Risk Ratio (M-H, Random, 95% CI)0.49 [0.25, 0.96]

    7.3 Beta lactum (including co-amoxiclav) versus placebo
21880Risk Ratio (M-H, Random, 95% CI)0.78 [0.52, 1.16]

    7.4 Macrolide (including erythromycin) versus placebo 
42136Risk Ratio (M-H, Random, 95% CI)0.93 [0.60, 1.44]

    7.5 Other antibiotic versus placebo
4823Risk Ratio (M-H, Random, 95% CI)0.85 [0.45, 1.64]

 8 Birth before 37 weeks' gestation34931Risk Ratio (M-H, Random, 95% CI)1.00 [0.98, 1.03]

 9 Major adverse drug reaction35487Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 10 Maternal infection after delivery prior to discharge45547Risk Ratio (M-H, Random, 95% CI)0.91 [0.80, 1.02]

 11 Chorioamnionitis111559Risk Ratio (M-H, Random, 95% CI)0.66 [0.46, 0.96]

 12 Caesarean section116317Risk Ratio (M-H, Random, 95% CI)0.96 [0.88, 1.05]

13 Days from birth till discharge of mother00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

14 Days from randomisation to birth00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 15 Birth within 48 hours of randomisation75927Risk Ratio (M-H, Random, 95% CI)0.71 [0.58, 0.87]

 16 Birth within 7 days of randomisation75965Risk Ratio (M-H, Random, 95% CI)0.79 [0.71, 0.89]

 17 Birthweight126374Mean Difference (IV, Random, 95% CI)53.83 [7.06, 100.60]

 18 Birthweight < 2500 g24876Risk Ratio (M-H, Random, 95% CI)1.00 [0.96, 1.04]

 19 Neonatal intensive care45023Risk Ratio (M-H, Random, 95% CI)0.98 [0.84, 1.13]

 20 Days in neonatal intensive care unit3225Mean Difference (IV, Random, 95% CI)-5.05 [-9.77, -0.33]

 21 Positive neonatal blood culture34961Risk Ratio (M-H, Random, 95% CI)0.79 [0.63, 0.99]

 22 Neonatal respiratory distress syndrome126287Risk Ratio (M-H, Random, 95% CI)0.95 [0.83, 1.09]

 23 Treatment with surfactant14809Risk Ratio (M-H, Random, 95% CI)0.83 [0.72, 0.96]

 24 Number of babies requiring ventilation24924Risk Ratio (M-H, Random, 95% CI)0.90 [0.80, 1.02]

 25 Number of babies requiring oxygen therapy14809Risk Ratio (M-H, Random, 95% CI)0.88 [0.81, 0.96]

 26 Neonatal oxygenation > 28 days35487Risk Ratio (M-H, Random, 95% CI)0.79 [0.61, 1.03]

 27 Neonatal encephalopathy160Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 28 Serious childhood disability at 7 years13171Risk Ratio (M-H, Random, 95% CI)1.01 [0.91, 1.12]

 
Comparison 2. Erythromycin versus co-amoxiclav

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Maternal death00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

2 Serious maternal morbidity00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Major adverse drug reaction12395Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Maternal infection after delivery prior to discharge12395Risk Ratio (M-H, Random, 95% CI)1.02 [0.87, 1.20]

5 Chorioamnionitis00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 6 Caesarean section12395Risk Ratio (M-H, Random, 95% CI)1.02 [0.90, 1.16]

7 Days from randomisation to birth00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

8 Days from birth till discharge of mother00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 9 Birth within 48 hours of randomisation12395Risk Ratio (M-H, Random, 95% CI)1.14 [1.02, 1.28]

 10 Birth within 7 days of randomisation12395Risk Ratio (M-H, Random, 95% CI)1.06 [0.99, 1.13]

 11 Birth before 37 weeks' gestation12395Risk Ratio (M-H, Random, 95% CI)0.99 [0.96, 1.03]

 12 Birthweight12395Mean Difference (IV, Random, 95% CI)19.0 [-41.92, 79.92]

 13 Birthweight < 2500 g12395Risk Ratio (M-H, Random, 95% CI)1.00 [0.95, 1.05]

 14 Neonatal intensive care12395Risk Ratio (M-H, Random, 95% CI)1.00 [0.95, 1.05]

15 Days in neonatal intensive care unit00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

16 Neonatal infection including pneumonia00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 17 Positive neonatal blood culture12395Risk Ratio (M-H, Random, 95% CI)0.84 [0.62, 1.15]

 18 Neonatal necrotising enterocolitis12395Risk Ratio (M-H, Random, 95% CI)0.46 [0.23, 0.94]

 19 Neonatal respiratory distress syndrome12395Risk Ratio (M-H, Random, 95% CI)0.99 [0.84, 1.16]

 20 Treatment with surfactant12395Risk Ratio (M-H, Random, 95% CI)0.98 [0.81, 1.19]

 21 Number of babies requiring ventilation12395Risk Ratio (M-H, Random, 95% CI)1.00 [0.86, 1.17]

 22 Number of babies requiring oxygen therapy12395Risk Ratio (M-H, Random, 95% CI)0.98 [0.87, 1.10]

 23 Neonatal oxygenation > 28 days12395Risk Ratio (M-H, Random, 95% CI)0.86 [0.66, 1.12]

 24 Oxygen treatment > 36 weeks' postconceptual age12395Risk Ratio (M-H, Random, 95% CI)0.97 [0.70, 1.34]

25 Neonatal encephalopathy00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 26 Major cerebral abnormality on ultrasound before discharge12395Risk Ratio (M-H, Random, 95% CI)1.10 [0.74, 1.63]

 27 Perinatal death/death before discharge12395Risk Ratio (M-H, Random, 95% CI)0.90 [0.66, 1.23]

 28 Serious childhood disability at 7 years11612Risk Ratio (M-H, Random, 95% CI)0.89 [0.79, 1.01]

 
Comparison 4. Antibiotics versus no antibiotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death/death before discharge18Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Antibiotics versus no antibiotics (all studies)
186872Risk Ratio (M-H, Random, 95% CI)0.89 [0.74, 1.08]

    1.2 Antibiotics versus no treatment (no placebo)
6571Risk Ratio (M-H, Random, 95% CI)0.69 [0.41, 1.14]

 
Comparison 5. 3 versus 7 day ampicillin regimens

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

1 Maternal death00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

2 Serious maternal morbidity00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

3 Major adverse drug reaction00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 4 Maternal infection after delivery prior to discharge184Risk Ratio (M-H, Random, 95% CI)1.25 [0.36, 4.33]

 5 Chorioamnionitis184Risk Ratio (M-H, Random, 95% CI)0.73 [0.33, 1.63]

 6 Caesarean section184Risk Ratio (M-H, Random, 95% CI)1.18 [0.72, 1.91]

7 Days from randomisation to birth00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

8 Days from birth till discharge of mother00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 9 Birth within 48 hours of randomisation184Risk Ratio (M-H, Random, 95% CI)1.14 [0.46, 2.87]

 10 Birth within 7 days of randomisation184Risk Ratio (M-H, Random, 95% CI)1.0 [0.70, 1.42]

11 Birth before 37 weeks' gestation00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

12 Birthweight00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

13 Birthweight < 2500 g00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 14 Neonatal intensive care184Risk Ratio (M-H, Random, 95% CI)1.0 [0.84, 1.19]

15 Days in neonatal intensive care unit00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

16 Neonatal infection including pneumonia00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

17 Positive neonatal blood culture00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 18 Neonatal necrotising enterocolitis2130Risk Ratio (M-H, Random, 95% CI)0.43 [0.07, 2.86]

 19 Neonatal respiratory distress syndrome2130Risk Ratio (M-H, Random, 95% CI)0.96 [0.62, 1.49]

20 Treatment with surfactant00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

21 Number of babies requiring ventilation00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

22 Number of babies requiring oxygen therapy00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

23 Neonatal oxygenation > 28 days00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

24 Oxygen treatment > 36 weeks' postconceptual age00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

25 Neonatal encephalopathy00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 26 Neonatal intraventricular haemorrhage2130Risk Ratio (M-H, Random, 95% CI)0.33 [0.04, 3.12]

 27 Perinatal death/death before discharge2130Risk Ratio (M-H, Random, 95% CI)0.40 [0.05, 2.94]

28 Serious childhood disability at 7 years00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Methods used to assess trials included in a previous version of this review (published 2003, Issue 2).

The following methods were used to assess Almeida 1996; Amon 1988a; Camli 1997; Christmas 1992; Cox 1995; Ernest 1994; Garcia-Burguillo 1995; Grable 1996; Johnston 1990; Kenyon 2001; Kurki 1992; Lewis 2003; Lockwood 1993a; Magwali 1999; McGregor 1991; Mercer 1992; Mercer 1997; Morales 1989; Ovalle-Salas 1997; Owen 1993a; Segel 2003; Svare 1997a.

All trials identified by the methods described in the search strategy were scrutinised by the reviewers. We processed included trial data as described in Alderson 2004. We evaluated trials under consideration for inclusion and methodological quality. There was no blinding of authorship. We assigned quality scores for concealment of allocation to each trial, using the criteria described in section six of the Cochrane Reviewers' Handbook (Alderson 2004): A = adequate; B = unclear; C = inadequate; D = not used.

We excluded trials that proved on closer examination not to be true randomised trials. We analysed outcomes on an intention-to-treat basis.

We extracted and double entered data. Wherever possible, we sought unpublished data from the investigator. Where outcomes were published in the form of percentages or graphs, the number of events were calculated. Where maternal outcomes were presented, numerators and denominators were calculated based on the number of mothers. Babies from multiple pregnancies have been treated as a single unit, with the worst outcome among the babies included in analyses. Of the 22 trials included, 12 only randomised singletons. Of the seven remaining, two did not state whether multiples were included. Of the five trials that included multiples, two specified how they had analysed the data (Kenyon 2001; Mercer 1997) and both used the worst outcomes in any baby.

We tested for heterogeneity between trial results using a standard Chi-squared test. For dichotomous data, we calculated the relative risk and for continuous variables, the weighted mean difference; in both cases, we reported 95% confidence intervals.

 

Feedback

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Shapiro, March 2003

 

Summary

The ORACLE study accounts for the vast majority of women included in this review, 4826 out of around 6000 women. ORACLE did not have a stopping rule, so that one cannot gauge why the study was stopped when it was. Were repeated statistical tests done? The impression, unfortunately, is that the study may have been stopped when a significant result was obtained. If so, this makes the "significant" conclusions untenable.

 

Reply

Thank you for your comments. The Medical Research Council (UK) ORACLE Trial had both a Steering Group and a Data Monitoring Committee. The Data Monitoring Committee agreed terms of reference before the start of the Study. These were documented in the trial protocol, as follows:
"The independent Data Monitoring Committee (chairman: Professor Adrian Grant, Aberdeen; members: Professor Forrester Cockburn, Glasgow; Mr Richard Gray, Oxford; Professor Charles Rodeck, London) will conduct interim analyses of morbidity and mortality among all trial participants. The Trial Director and Steering Group will be informed if at any time the randomised comparisons in this study have provided both (i) proof beyond reasonable doubt of a difference in a major endpoint between the study and control groups, and (ii) evidence that would be expected to alter substantially the choice of treatment for patients whose doctors are, in the light of the evidence from the other randomised trials, substantially uncertain whether to recommend antibiotics. Exact criteria of "proof beyond reasonable doubt" are not specified, but members of the committee have expressed sympathy with the view that it should generally involve a difference of at least three standard deviations in a major endpoint. Using this criterion has the practical advantage that the exact number of interim analyses is of little importance, and so no fixed schedule is proposed."

The Committee met annually throughout trial recruitment, and for the last time in June 1999. At that time the conditions for discontinuation had not been met so it was decided to carry on until funding ceased. Recruitment closed on 31st May 2000, as this allowed time for the last women to deliver, data to be chased and cleaned, analysis to be undertaken and reports prepared for publication.

[Summary of response from Sara Kenyon, May 2003]

 

Contributors

Summary of comment from Mervyn Shapiro, March 2003.

 

Stones, February 2008, 20 February 2008

 

Summary

In 'Characteristics of included studies' for Almeida 1996a the dose of amoxycillin is given as 75 g where it should be 0.75 g or perhaps 750 mg for clarity.

[Summary of feedback from William Stones, February 2008]

 

Reply

Thank you for bringing this to our attention. We have corrected the error.

[Reply from Sara Kenyon, February 2008]

 

Contributors

Feedback: William Stones

Reply: Sara Kenyon

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 26 November 2013.


DateEventDescription

17 December 2013AmendedWe have added graph labels for all comparisons. There are no implications for the text of the review.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 2, 1998
Review first published: Issue 2, 1998


DateEventDescription

9 October 2013New search has been performedSearch updated 30 September 2013. Four new trial reports identified; none eligible for inclusion. Recommendation to give antibiotics routinely in these circumstances made clearer in conclusions.

9 October 2013New citation required but conclusions have not changedReview updated.

7 July 2010New citation required and conclusions have changedThe decision to prescribe antibiotics for women with PROM is now not clearcut, and if antibiotics are prescribed it is unclear which would be the antibiotic of choice.

29 April 2010New search has been performedSearch updated. 23 new trial reports identified.

Fourteen new reports of trials already included have been added, including follow-up data at seven years from the largest included trial (Kenyon 2001). One new trial has been added (Fuhr 2006).

Nine new trials have been excluded and a trial that was previously included has now been excluded (Almeida 1996).

Outcomes were divided into primary and secondary and subgroup comparisons undertaken to look at the effect of different antibiotics for primary outcomes only.

29 January 2009AmendedAuthor contact details edited.

20 February 2008Feedback has been incorporatedFeedback from William Stones added along with reply from the author.

20 February 2008AmendedCorrected error in dose of amoxycillin given in 'Characteristics of included studies' table for Almeida 1996a.

Converted to new review format.

24 January 2003New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Sara Kenyon assessed the relevant trials, abstracted the data and wrote the text of the review. Michel Boulvain and Jim Neilson checked the extracted data and helped write the review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Sara Kenyon was the Co-ordinator of the ORACLE Trial and led the ORACLE Children Study, both of which are included in this review.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • University of Liverpool, UK.
  • University of Geneva, Switzerland.
  • Leicester Royal Infirmary, UK.
  • University of Birmingham, UK.

 

External sources

  • UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization, Switzerland.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Secondary outcome "Serious childhood disability at approximately two years" changed to "Serious childhood disability at seven years".

 

Index terms

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Medical Subject Headings (MeSH)

Amoxicillin-Potassium Clavulanate Combination [adverse effects]; Anti-Bacterial Agents [adverse effects; *therapeutic use]; Chorioamnionitis [prevention & control]; Developmental Disabilities [prevention & control]; Fetal Membranes, Premature Rupture [*drug therapy]; Infant, Premature; Length of Stay; Macrolides [therapeutic use]; Perinatal Mortality; Pregnancy Complications, Infectious [mortality; prevention & control]; Premature Birth [prevention & control]; Randomized Controlled Trials as Topic

MeSH check words

Child; Female; Humans; Infant, Newborn; Pregnancy

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Amon 1988a {published data only}
  • Amon E, Lewis S, Sibai BM, Moretti M. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Proceedings of 8th Annual Meeting of the Society of Perinatal Obstetricians; 1988 Feb 3-6; Las Vegas, Nevada, USA. 1988:51.
  • Amon E, Lewis SV, Sibai BM, Villar MA, Arheart KL. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. American Journal of Obstetrics and Gynecology 1988;159:539-43.
Camli 1997 {published data only}
  • Camli L, Mavunagacioglu S, Bostanci A, Camli S, Soylu F. Antibiotherapy in preterm premature rupture of membrane. Does it affect the latent period and infectious morbidity?. Jinekoloji Ve Obstetrik Dergisi 1997;11:138-42.
Christmas 1992 {published data only}
  • Christmas JT, Cox SM, Andrew W, Dax J, Leveno KJ, Gilstrap LC. Expectant management of preterm ruptured membranes: effects of antimicrobial therapy. Obstetrics & Gynecology 1992;80:759-62.
  • Christmas JT, Cox SM, Gilstrap LC, Leveno KJ, Andrews W, Dax J. Expectant management of preterm ruptured membranes: effects of antimicrobial therapy on interval to delivery. Proceedings of 10th Annual Meeting of Society of Perinatal Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. 1990:19.
Cox 1995 {published data only}
  • Cox SM, Leveno KJ, Sherman ML, Travis L, De Plama R. Ruptured membranes at 24 to 29 weeks: a randomized double blind trial of antimicrobials versus placebo. American Journal of Obstetrics and Gynecology 1995;172:412.
Ernest 1994 {published data only}
  • Ernest JM, Givner LB. A prospective, randomized, placebo-controlled trial of penicillin in preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 1994;170(2):516-21.
Fuhr 2006 {published data only}
  • Fuhr NA, Becker C, van Baalen A, Bauer K, Hopp H. Antibiotic therapy for preterm premature rupture of membranes - results of a multicenter study. Journal of Perinatal Medicine 2006;34(3):203-6.
Garcia-Burguillo 1995 {published data only}
  • Garcia-Burguillo A, Hernandez-Garcia JM, de la Fuente P. Erythromycin prophylaxis in preterm pregnancies with rupture of amniotic membranes [Profilaxis con eritromicina en gestaciones pretermino con rotura prematura de las membranas amnioticas]. Clinica e Investigacion en Ginecologia y Obstetricia 1995;23(3):96-100.
Grable 1996 {published data only}
  • Grable IA, Garcia PM, Perry D, Socol ML. Group B streptococcus and preterm premature rupture of membranes: a randomized, double-blind clinical trial of antepartum ampicillin. American Journal of Obstetrics and Gynecology 1996;175:1036-42.
Johnston 1990 {published data only}
  • Johnston MM, Sanchez-Ramos L, Vaughan AJ, Todd MW, Benrubi GI. Antibiotic therapy in preterm premature rupture of membranes: a randomized, prospective, double-blind trial. American Journal of Obstetrics and Gynecology 1990;163(3):743-7.
  • Sanchez-Ramos L, Johnston M, Vaughn A, Benrubi GI, Todd M. High dose antibiotic therapy in preterm premature rupture of the membranes: a double blind, randomized, prospective study. Proceedings of 10th Annual Meeting of Society of Perinatal Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. 1990:18.
Kenyon 2001 {published data only}
  • Gilbert RE, Pike K, Kenyon SL, Tarnow-Mordi W, Taylor DJ. The effect of prepartum antibiotics on the type of neonatal bacteraemia: insights from the MRC ORACLE trials. BJOG: an international journal of obstetrics and gynaecology 2005;112(6):830-2.
  • Jones DR, Pike K, Kenyon S, Pike L, Henderson B, Brocklehurst P, et al. Routine educational outcome measures in health studies: Key Stage 1 in the ORACLE Children Study follow-up of randomised trial cohorts. Archives of Disease in Childhood 2011;96(1):25-9.
  • Kenyon S, Brocklehurst P, Jones D, Marlow N, Salt A, Taylor D. MRC ORACLE children study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes. BMC Pregnancy & Childbirth 2008;8:14.
  • Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008;372(9646):1310-8.
  • Kenyon S, Taylor DJ, Tarnow-Mordi W. ORACLE-antibiotics for preterm prelabour rupture of the membranes: short and long term outcomes. Acta Paediatrica Supplement 2002;91(437):12-5.
  • Kenyon SL, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE 1 randomised trial. Lancet 2001;357:979-88.
Kurki 1992 {published data only}
  • Kurki T, Hallman M, Zilliacus R, Teramo K, Ylikorkala O. Premature rupture of the membranes; effect of penicillin prophylaxis and long-term outcome of the children. American Journal of Perinatology 1992;9:11-6.
Lewis 2003 {published data only}
  • Lewis DF, Adair CD, Robichaux AG, Jaekle RK, Moore JA, Evans AT, et al. Antibiotic therapy in preterm premature rupture of membranes: are seven days necessary? A preliminary randomized clinical trial. American Journal of Obstetrics and Gynecology 2003;188(6):1413-6.
Lockwood 1993a {published data only}
  • Lockwood CJ, Costigan K, Ghidini A, Wein R, Cetrulo C, Alvarez M, et al. Double-blind, placebo-controlled trial of piperacillin sodium in preterm membrane rupture. American Journal of Obstetrics and Gynecology 1993;168(1 Pt 2):378.
  • Lockwood CJ, Costigan K, Ghidini A, Wein R, Chien D, Brown BL, et al. Double-blind, placebo-controlled trial of piperacillin prophylaxis in preterm membrane rupture. American Journal of Obstetrics and Gynecology 1993;169:970-6.
Magwali 1999 {published data only}
  • Magwali TL, Cipato T, Majoko F, Rusakaniko S, Mujaji C. Prophylactic augmentin in prelabour preterm rupture of the membranes. International Journal of Gynecology & Obstetrics 1999;65:261-5.
McGregor 1991 {published data only}
  • McGregor JA, French JI. Double-blind, randomized, placebo controlled, prospective evaluation of the efficacy of short course erythromycin in prolonging gestation among women with preterm rupture of membranes. Proceedings of 9th Annual Meeting of the Society of Perinatal Obstetricians; 1989 Feb 1-4; New Orleans, Louisiana, USA. 1989.
  • McGregor JA, French JI, Seo K. Antimicrobial therapy in preterm premature rupture of membranes: results of a prospective, double-blind, placebo-controlled trial of erythromycin. American Journal of Obstetrics and Gynecology 1991;165:632-40.
Mercer 1992 {published data only}
  • Mercer BM, Moretti ML, Prevost RR, Sibai BM. Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients. American Journal of Obstetrics and Gynecology 1992;166:794-802.
Mercer 1997 {published data only}
  • Beazley D. Impact of amnionitis and antepartum antibiotic treatment on neonatal outcome after PPROM. American Journal of Obstetrics and Gynecology 1998;178(1 Pt 2):S15.
  • Hauth JC. The NICHD-MFMU antibiotic treatment of PROM study: correlation with acute placental inflammation and prenatal morbidity. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S53.
  • Hnat MD, Mercer BM, Thurnau G, Goldenberg R, Thom EA, Meis PJ, et al. Perinatal outcomes in women with preterm rupture of membranes between 24 and 32 weeks of gestation and a history of vaginal bleeding. American Journal of Obstetrics and Gynecology 2005;193:164-8.
  • Mercer B. The NICHD-MFMU antibiotic treatment of PPROM study: evaluation of factors associated with successful outcome. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S8.
  • Mercer B, Miodovnik M, Thurnau G, Goldenberg R, Das A, Merenstein G, et al. A multicentre randomized controlled trial of antibiotic therapy versus placebo therapy after preterm premature rupture of the membranes. American Journal of Obstetrics and Gynecology 1996;174(1 Pt 2):304.
  • Mercer BM, Crouse DT, Goldenberg RL, Miodovnik M, Mapp DC, Meis PJ, et al. The antibiotic treatment of PPROM study: systemic maternal and fetal markers and perinatal outcomes. American Journal of Obstetrics and Gynecology 2012;206(2):145.e1-9.
  • Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. JAMA 1997;278:989-95.
  • Ramsey P. Preterm premature rupture of membranes (PPROM): latency and neonatal outcome. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S113.
  • Thurnau G. The NICHD-MFMU antibiotic treatment of PROM study: impact of initial amniotic fluid volume on pregnancy outcome. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S53.
Morales 1989 {published data only}
  • Morales WJ, Angel JL, Knuppel RA. Comparison of various parameters as predictors of chorioamnionitis in preterm patients with premature rupture of membranes. Southern Medical Journal 1988;81:40.
  • Morales WJ, Angel JL, O'Brien WF, Knuppel RA. Use of ampicillin and corticosteroids in premature rupture of membranes: a randomized study. Obstetrics & Gynecology 1989;73(5):721-6.
Ovalle-Salas 1997 {published data only}
  • Ovalle A, Martinez M, Gomez R, Valderrama O, Lira P, Rubio R, et al. Preterm premature rupture of membranes: a prospective randomized placebo controlled trial of antibiotic treatment. American Journal of Obstetrics and Gynecology 1996;174(1 Pt 2):401.
  • Ovalle A, Martinez M, Kakarieka E, Rubio R, Valderrama O, Villablanca E, et al. Antibiotic administration in patients with preterm premature rupture of membranes reduces the rate of histological chorioamnionitis. American Journal of Obstetrics and Gynecology 1999;180(1 Pt 2):S83.
  • Ovalle-Salas A, Gomez R, Martinez MA, Rubio R, Fuentes A, Valderrama O, et al. Antibiotic therapy in patients with preterm premature rupture of membranes: a prospective, randomized, placebo-controlled study with microbiological assessment of the amniotic cavity and lower genital tract. Prenatal and Neonatal Medicine 1997;2:213-22.
Owen 1993a {published data only}
  • Owen J, Groome LJ, Hauth JC. Randomised trial of prophylactic therapy after preterm amnion rupture. American Journal of Obstetrics and Gynecology 1993;169(4):976-81.
  • Owen J, Groome LJ, Hauth JC. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. American Journal of Obstetrics and Gynecology 1993;168(1 Pt 2):379.
Segel 2003 {published data only}
  • Segel S, Miles A, Clothier B, Parry S, Macones G. Optimal duration of antibiotic therapy after PPROM. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S72.
  • Segel SY, Miles AM, Clothier B, Parry S, Macones GA. Duration of antibiotic therapy after preterm premature rupture of fetal membranes. American Journal of Obstetrics and Gynecology 2003;189:799-802.
Svare 1997a {published data only}
  • Svare J. Preterm delivery and subclinical uro-genital infection [thesis]. Denmark: Department of Obstetrics and Gynaecology Rigshospitalet, University of Copenhagen, 1997.
  • Svare J, Langhoff-Roos J, Andersen LF, Baggesen NK, Christensen HB, Heisterberg L, et al. Antibiotic treatment in preterm labor or preterm premature rupture of the membranes - a randomized controlled double-blind trial. Acta Obstetricia et Gynecologica Scandinavica Supplement 1996;75(Suppl 162):36.
  • Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen N, Borch-Christensen H, Heisterberg L, et al. Ampicillin-metronidazole treatment in threatening preterm delivery. Acta Obstetricia et Gynecologica Scandinavica 1997;76(167:1):86.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Almeida 1996 {published data only}
  • Almeida L, Schmauch A, Bergstrom S. A randomised study on the impact of peroral amoxicillin in women with prelabour rupture of membranes preterm. Gynecologic and Obstetric Investigation 1996;41:82-4.
Bergstrom 1991 {published data only}
  • Bergstrom S. A prospective study on the perinatal outcome in Mozambican pregnant women with preterm rupture of membranes using two different methods of clinical management. Gynecologic & Obstetric Investigation 1991;32:217-9.
Blanco 1993 {published data only}
  • Blanco J, Iams J, Artal R, Baker J, Hibbard J, McGregor J, et al. Multicenter double-blind prospective random trial of ceftizoxime vs placebo in women with preterm premature ruptured membranes (pPROM). American Journal of Obstetrics and Gynecology 1993;168:378.
Cardamakis 1990 {published data only}
  • Cardamakis E, Minaretzis D, Papageorgiou J, Karaiskakis P, Kioses E, Michalas S. Premature rupture of the membranes. II. Chemioprophylaxis. Proceedings of 12th European Congress of Perinatal Medicine; 1990 Sept 11-14; Lyon, France. 1990:45.
Carroll 2000 {published data only}
  • Carroll E, Heywood P, Besinger R, Muraskas J, Fisher S, Gianopoulos JG. A prospective randomized double blind trial of ampicillin with and without sulbactam in preterm premature rupture of the membranes [abstract]. American Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S61.
Debodinance 1990 {published data only}
  • Debodinance P, Parmentier D, Devulder G, Closset P, Querleu D, Crepin G. Can one reduce the risk of neonatal infection after premature rupture of membranes? [Peut-on reduire le risque infectieux neonatal dans les ruptures prematurees des membranes?]. Journal de Gynecologie, Obstetrique et Biologie de la Reproduction 1990;19:533-7.
Dunlop 1986 {published data only}
Fortunato 1990 {published data only}
  • Fortunato SJ, Welt SI, Eggleston M, Cole J, Bryant EC, Dodson MG. Prolongation of the latency period in preterm premature rupture of the membranes using prophylactic antibiotics and tocolysis. Journal of Perinatology 1990;3:252-6.
Gordon 1974 {published data only}
  • Gordon M, Weingold AB. Treatment of patients with premature rupture of the fetal membranes: (a) prior to 32 weeks; (b) after 32 weeks. Premature rupture of the membranes - a rational approach to management. In: Reid DE, Christian CD editor(s). Controversy in Obstetrics & Gynecology II. Philadelphia: WB Saunders Company, 1974:42-4.
Haas 2010 {published data only}
  • Haas D. Preterm premature rupture of membranes: erythromycin versus azithromycin a randomized trial comparing their efficacy to prolong latency (PEACE trial). http://clinicaltrials.gov/show/NCT01556334 (accessed 25 June 2012) 2010.
Halis 2001 {published data only}
  • Halis, Ragosch, Hundertmark, Weitzel, Hopp. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes - a randomized controlled trial. 11th European Congress of Clinical Microbiology and Infectious Diseases; 2001 April 1-4; Istanbul, Turkey. 2001.
Hernandez 2011 {published data only}
  • Hernandez y Ballinas A, Lopez Faran JA, Gamez Guevara C. [Comparison of maternal and perinatal outcomes in the conservative treatment preterm premature membrane rupture between the use of erythromycin and clindamycin]. [Spanish]. Ginecologia y Obstetricia de Mexico 2011;79(7):403-10.
Julien 2002 {published data only}
  • Julien S, Khandelwal M, Olasewere T. Randomised trial comparing long term versus short term antibiotic prophylaxis in preterm premature rupture of membranes (PPROM). American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S66.
Kim 2008 {published data only}
  • Kim YH, Song TB, Kim CH, Kim JW, Cho MY, Yang SY, et al. Changes of lipid peroxidation and protein carbonyls formation by antibiotic therapy in the maternal venous plasma of preterm premature rupture of membranes. 55th Annual Meeting of the Society of Gynecologic Investigation; 2008 March 26-29; San Diego, USA 2008:Abstract no: 398.
Kwak 2013 {published data only}
  • Kwak HM, Shin MY, Cha HH, Choi SJ, Lee JH, Kim JS, et al. The efficacy of cefazolin plus macrolide (erythromycin or clarithromycin) versus cefazolin alone in neonatal morbidity and placental inflammation for women with preterm premature rupture of membranes. Placenta 2013;34(4):346-52.
Lebherz 1963 {published data only}
  • Lebherz TB, Hellman LP, Madding R, Anctil A, Arje SL. Double-blind study of premature rupture of the membranes. American Journal of Obstetrics and Gynecology 1963;87(2):218-25.
Lewis 1995 {published data only}
  • Lewis DF, Fontenot MT, Brooks GG, Wise R, Perkins MB, Heymann AR. Latency period after preterm premature rupture of membranes: a comparison of ampicillin with and without sulbactam. Obstetrics & Gynecology 1995;86(3):392-5.
Lewis 1996 {published data only}
  • Lewis DF, Brody K, Edwards MS, Brouillette RM, Burlison S, London S. Preterm premature ruptured membranes: a randomized trial of steroids after treatment with antibiotics. Obstetrics & Gynecology 1996;88(5):801-5.
Lovett 1997 {published data only}
  • Lovett S, Weiss J, Diogo M, Williams P, Garite T. A prospective randomized clinical trial of antibiotic therapy for preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 1996;174:306.
  • Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ. A prospective, double-blind, randomized, controlled clinical trial of ampicillin-sulbactam for preterm premature rupture of membranes in women receiving antenatal corticosteroid therapy. American Journal of Obstetrics and Gynecology 1997;176(5):1030-8.
Matsuda 1993a {published data only}
  • Matsuda Y, Ikenoue T, Ibara S, Sameshima H, Kuraya K, Hokanishi H. The efficacy of prophylactic antibiotic and tocolytic therapy for premature rupture of the membranes. Acta Obstetricia et Gynecologica Japonica 1993;45(10):1109-14.
Matsuda 1993b {published data only}
  • Matsuda Y, Ikenoue T, Hokanishi H. Premature rupture of the membranes - aggressive versus conservative approach: effect of tocolytic and antibiotic therapy. Gynecologic and Obstetric Investigation 1993;36:102-7.
Mbu 1998 {published data only}
  • Mbu RE, Tchio R, Leke RG, Tamba NE, Njoh N. Premature rupture of membranes: maternal and fetal outcome in the absence of antibiotic prophylaxis [Rupture prematuree des membranes: devenir maternal et foetal en l'absence de la prophylaxie antibiotique]. African Journal of Reproductive Health 1998;2:26-31.
McCaul 1992 {published data only}
  • McCaul JF, Perry KG, Moore JL, Martin RW, Bucovaz ET, Morrison JC. Adjunctive antibiotic treatment of women with preterm rupture of membranes or preterm labor. International Journal of Gynecology & Obstetrics 1992;38:19-24.
Norri 1991 {published data only}
  • Norri L, Yla-Outinen A, Tuimala R. Prophylactic antibiotics in premature rupture of membranes. Proceedings of 13th World Congress of Gynaecology and Obstetrics (FIGO);1991 September; Singapore. 1991:80.
Ogasawara 1996 {published data only}
  • Ogasawara KK, Goodwin TM. The efficacy of treating ureaplasma urealyticum in patients with preterm labor or preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 1996;174(1 Pt 2):401.
Ogasawara 1997 {published data only}
Ogasawara 1999 {published data only}
  • Ogasawara KK, Goodwin TM. Efficacy of azithromycin in reducing lower genital ureaplasma urealyticum colonization in women at risk for preterm delivery. Journal of Maternal Fetal Medicine 1999;8:12-6.
Ovalle 2002 {published data only}
  • Ovalle A, Martinez MA, Kakarieka E, Gomez R, Rubio R, Valderrama O, et al. Antibiotic administration in patients with preterm premature rupture of the membranes reduces the rate of histological chorioamnionitis: a prospective, randomised, controlled study. Journal of Maternal-Fetal & Neonatal Medicine 2002;12:35-41.
Spitzer 1993 {published data only}
  • Spitzer D, Zajc M, Gregg A, Steiner H, Staudach A. Antepartum antibiotic therapy and subsequent neonatal morbidity in patients with preterm premature rupture of the membranes. International Journal of Experimental and Clinical Chemotherapy 1993;6(1):35-8.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Alderson 2004
  • Alderson P, Green S, Higgins JPT, editors. Cochrane Reviewers' Handbook 4.2.2 [updated March 2004]. The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
Amon 1988b
  • Amon E, Lewis S, Sibai BM, Moretti M. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Proceedings of 8th Annual Meeting of the Society of Perinatal Obstetricians; 1988 Feb 3-6; Las Vegas, Nevada, USA. 1988:51.
Beazley 1998
  • Beazley D. Impact of amnionitis and antepartum antibiotic treatment on neonatal outcome after PPROM. American Journal of Obstetrics and Gynecology 1998;178(1 Pt 2):S15.
Bejar 1981
Christmas 1990
  • Christmas JT, Cox SM, Gilstrap LC, Leveno KJ, Andrews W, Dax J. Expectant management of preterm ruptured membranes: effects of antimicrobial therapy on interval to delivery. Proceedings of 10th Annual Meeting of Society of Perinatal Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. 1990:19.
Costeloe 2012
  • Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper ES. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICURE studies). BMJ 2012;345:e7976.
Dale 1989
  • Dale PO, Tanbo T, Bendvold E, Moe N. Duration of the latency period in preterm premature rupture of the membranes. Maternal and neonatal consequences of expectant management. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1989;30:257-62.
Dammann 1997
Dammann 2005
Elbourne 2002
Gilbert 2005
Goldenberg 2008
Hauth 1997
  • Hauth JC. The NICHD-MFMU antibiotic treatment of PROM study: correlation with acute placental inflammation and prenatal morbidity. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S53.
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hnat 2005
  • Hnat MD, Mercer BM, Thurnau G, Goldenberg R, Thom EA, Meis PJ, et al. Perinatal outcomes in women with preterm rupture of membranes between 24 and 32 weeks of gestation and a history of vaginal bleeding. American Journal of Obstetrics and Gynecology 2005;193:164-8.
Hoy 2001
Kenyon 2008a
  • Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008;372(9646):1310-8.
Kenyon 2008b
  • Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008;372(9646):1319-27.
Kenyon 2008c
  • Kenyon S, Brocklehurst P, Jones D, Marlow N, Salt A, Taylor D. MRC ORACLE children study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes. BMC Pregnancy & Childbirth 2008;8:14.
King 2002
  • King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database of Systematic Reviews 2002, Issue 4. [DOI: 10.1002/14651858.CD000246]
Kotecha 1996
Lockwood 1993b
  • Lockwood CJ, Costigan K, Ghidini A, Wein R, Cetrulo C, Alvarez M, et al. Double-blind, placebo-controlled trial of piperacillin sodium in preterm membrane rupture. American Journal of Obstetrics and Gynecology 1993;168(1 Pt 2):378.
Marlow 2005
  • Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. New England Journal of Medicine 2005;352(1):9-19. [PUBMED: 15635108]
McGregor 1997
  • McGregor J, French J. Evidence-based prevention of preterm birth and rupture of membranes: infection and inflammation. Journal of the Society of Obstetricians and Gynaecologists of Canada 1997;19:835-51.
Morales 1988
  • Morales WJ, Angel JL, Knuppel RA. Comparison of various parameters as predictors of chorioamnionitis in preterm patients with premature rupture of membranes. Southern Medical Journal 1988;81:40.
Owen 1993b
  • Owen J, Groome LJ, Hauth JC. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. American Journal of Obstetrics and Gynecology 1993;168(1 Pt 2):379.
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Romero 2007
  • Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutrition Reviews 2007;65:S194-202.
Saigal 2008
Sanchez-Ramos 1990
  • Sanchez-Ramos L, Johnston M, Vaughn A, Benrubi GI, Todd M. High dose antibiotic therapy in preterm premature rupture of the membranes: a double blind, randomized, prospective study. Proceedings of 10th Annual Meeting of Society of Perinatal Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. 1990:18.
Speer 2003
  • Speer CP. Inflammation and bronchopulmonary dysplasia. Seminars in Neonatology 2003;8 No. 1:29-38.
Svare 1997b
  • Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen N, Borch-Christensen H, Heisterberg L, et al. Ampicillin-metronidazole treatment in threatening preterm delivery. Acta Obstetricia et Gynecologica Scandinavica 1997;76(167:1):86.
Taylor 2001
  • Taylor HG, Klein N, Minich NM, Hack M. Long-term family outcomes for children with very low birth weights. Archives of Pediatrics & Adolescent Medicine 2001;155(2):155-61. [PUBMED: 11177090]
Thurnau 1997
  • Thurnau G. The NICHD-MFMU antibiotic treatment of PROM study: impact of initial amniotic fluid volume on pregnancy outcome. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S53.
Wu 2002
Yoon 2000
  • Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kin CJ, et al. The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis. American Journal of Obstetrics and Gynecology 2000;183(5):1124-9.

References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. Additional references
  23. References to other published versions of this review
Crowley 1995
  • Crowley P. Antibiotics for preterm prelabour rupture of membranes. [revised 05 May 1994]. In: Enkin MW, Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds.) Pregnancy and Childbirth Module. In: The Cochrane Pregnancy and Childbirth Database [database on disk and CDROM]. The Cochrane Collaboration; Issue 2, Oxford: Update Software; 1995.
Kenyon 2001
  • Kenyon S, Boulvain M. Antibiotics for preterm premature rupture of membranes. Cochrane Database of Systematic Reviews 2001, Issue 3.
Kenyon 2003
  • Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD001058]
Kenyon 2004
Kenyon 2010