Antibiotics for preterm rupture of membranes

  • Review
  • Intervention

Authors

  • Sara Kenyon,

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

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  • Michel Boulvain,

    1. Maternité Hôpitaux Universitaires de Genève, Département de Gynécologie et d'Obstétrique, Unité de Développement en Obstétrique, Genève 14, Switzerland
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  • James P Neilson

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

Background

Premature birth carries substantial neonatal morbidity and mortality. Subclinical infection is associated with preterm rupture of membranes (PROM). Prophylactic maternal antibiotic therapy might lessen infectious morbidity and delay labour, but could suppress labour without treating underlying infection.

Objectives

To evaluate the immediate and long-term effects of administering antibiotics to women with PROM before 37 weeks, on maternal infectious morbidity, neonatal morbidity and mortality, and longer-term childhood development.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013).

Selection criteria

Randomised controlled trials comparing antibiotic administration with placebo that reported clinically relevant outcomes were included as were trials of different antibiotics. Trials in which no placebo was used were included for the outcome of perinatal death alone.

Data collection and analysis

We extracted data from each report without blinding of either the results or the treatments that women received. We sought unpublished data from a number of authors.

Main results

We included 22 trials, involving 6872 women and babies.

The use of antibiotics following PROM is associated with statistically significant reductions in chorioamnionitis (average risk ratio (RR) 0.66, 95% confidence interval (CI) 0.46 to 0.96, and a reduction in the numbers of babies born within 48 hours (average RR 0.71, 95% CI 0.58 to 0.87) and seven days of randomisation (average RR 0.79, 95% CI 0.71 to 0.89). The following markers of neonatal morbidity were reduced: neonatal infection (RR 0.67, 95% CI 0.52 to 0.85), use of surfactant (RR 0.83, 95% CI 0.72 to 0.96), oxygen therapy (RR 0.88, 95% CI 0.81 to 0.96), and abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.81, 95% CI 0.68 to 0.98). Co-amoxiclav was associated with an increased risk of neonatal necrotising enterocolitis (RR 4.72, 95% CI 1.57 to 14.23).

One study evaluated the children's health at seven years of age (ORACLE Children Study) and found antibiotics seemed to have little effect on the health of children.

Authors' conclusions

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.

Plain language summary

Antibiotics for preterm rupture of membranes

Certain antibiotics given to women whose waters have broken early will improve babies' health. Babies born too soon are more likely to suffer ill health in the early days and sometimes throughout life. Early labour and birth (before 37 weeks) may be due to undetected infection as well as the waters breaking early. The review of 22 trials, involving 6872 women and their babies, found that, in the short term, certain antibiotics given to women, when their waters break early, increase the time babies stay in the womb. They reduced infection, but did not save more babies. One antibiotic (co-amoxiclav) increased the number of babies with a rare condition of inflammation of the bowel (necrotising enterocolitis). Although, in the longer term (at seven years of age) antibiotics seem to have little effect on the health of children, the short-term advantages are such that we recommend antibiotics should be given routinely.

Laički sažetak

Antibiotici za prsnuće vodenjaka prije termina

Davanje određenih antibiotika ženama s ranim prsnućem vodenjaka poboljšati će zdravlje djeteta. Djeca rođena prerano imaju veću vjerojatnost lošeg zdravlja u prvim danima, a ponekad i tijekom života. Prijevremeni trudovi i porod (prije 37. tjedna trudnoće) mogu biti posljedica neotkrivene infekcije kao i prijevremenog prsnuća vodenjaka. Cochrane sustavni pregled 22 istraživanja koja uključuju 6872 žene i njihovu djecu, pokazao je da promatrano kratkoročno neki antibiotici dani ženama kod ranijeg prsnuća vodenjaka povećavaju vrijeme ostanka ploda u maternici. Antibiotici smanjuju infekcije, ali nisu spasili veći broj djece. Jedan je antibiotik (koamoksiklav) povećao broj djece s rijetkim stanjem upale crijeva (nekrotizirajući enterokolitis). Iako se čini da dugoročno (u dobi od sedam godina) antibiotici imaju mali učinak na zdravlje djece, kratkoročne prednosti su takve da preporučujemo rutinsku primjenu antibiotika.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Katarina Vučić
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Background

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

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

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. 

Figure 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.

Figure 2.

Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.3 Perinatal death/death before discharge.

Figure 3.

Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.4 Neonatal infection including pneumonia.

Figure 4.

Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.5 Neonatal necrotising enterocolitis.

Figure 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

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

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

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

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

Download statistical data

Comparison 1. Any antibiotic versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal death3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Any antibiotic versus placebo3763Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 All penicillin (excluding co-amoxiclav) versus placebo185Risk 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 placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.5 Other antibiotic versus placebo2678Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2 Serious maternal morbidity0 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Any antibiotic versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.2 All penicillin (excluding co-amoxiclav) versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.3 Beta lactum (including co-amoxiclav) versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.4 Macrolide (including erythromycin) versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
2.5 Other antibiotic versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3 Perinatal death/death before discharge12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Any antibiotic versus placebo126301Risk Ratio (M-H, Random, 95% CI)0.93 [0.76, 1.14]
3.2 All penicillin (excluding co-amoxiclav) versus placebo4332Risk Ratio (M-H, Random, 95% CI)0.78 [0.31, 1.97]
3.3 Beta lactum (including co-amoxiclav) versus placebo21880Risk Ratio (M-H, Random, 95% CI)0.62 [0.15, 2.56]
3.4 Macrolide (including erythromycin) versus placebo42138Risk Ratio (M-H, Random, 95% CI)0.83 [0.43, 1.60]
3.5 Other antibiotic versus placebo3762Risk Ratio (M-H, Random, 95% CI)1.13 [0.68, 1.88]
4 Neonatal infection including pneumonia12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Any antibiotic versus placebo121680Risk Ratio (M-H, Random, 95% CI)0.67 [0.52, 0.85]
4.2 All penicillin (excluding co-amoxiclav) versus placebo5521Risk Ratio (M-H, Random, 95% CI)0.30 [0.13, 0.68]
4.3 Beta lactum (including co-amoxiclav) versus placebo162Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.88]
4.4 Macrolide (including erythromycin) versus placebo3334Risk Ratio (M-H, Random, 95% CI)0.79 [0.45, 1.37]
4.5 Other antibiotic versus placebo3763Risk Ratio (M-H, Random, 95% CI)0.71 [0.53, 0.95]
5 Neonatal necrotising enterocolitis11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Any antibiotic versus placebo116229Risk Ratio (M-H, Random, 95% CI)1.09 [0.65, 1.83]
5.2 All penicillin (excluding co-amoxiclav) versus placebo3262Risk Ratio (M-H, Random, 95% CI)0.85 [0.25, 2.97]
5.3 Beta lactum (including co-amoxiclav) versus placebo21880Risk Ratio (M-H, Random, 95% CI)4.72 [1.57, 14.23]
5.4 Macrolide (including erythromycin) versus placebo32076Risk Ratio (M-H, Random, 95% CI)0.88 [0.45, 1.69]
5.5 Other antibiotic versus placebo4823Risk Ratio (M-H, Random, 95% CI)0.89 [0.54, 1.47]
6 Oxygen treatment > 36 weeks' postconceptual age1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6.1 Any antibiotic versus placebo14809Risk Ratio (M-H, Random, 95% CI)0.91 [0.70, 1.17]
6.2 All penicillin (excluding co-amoxiclav) versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
6.3 Beta lactum (including co-amoxiclav) versus placebo11818Risk Ratio (M-H, Random, 95% CI)0.92 [0.63, 1.36]
6.4 Macrolide (including erythromycin) versus placebo11803Risk Ratio (M-H, Random, 95% CI)0.89 [0.61, 1.32]
6.5 Other antibiotic versus placebo00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
7 Major cerebral abnormality on ultrasound before discharge12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
7.1 Any antibiotic versus placebo126289Risk 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 placebo21880Risk 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 placebo4823Risk 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]
Analysis 1.1.

Comparison 1 Any antibiotic versus placebo, Outcome 1 Maternal death.

Analysis 1.3.

Comparison 1 Any antibiotic versus placebo, Outcome 3 Perinatal death/death before discharge.

Analysis 1.4.

Comparison 1 Any antibiotic versus placebo, Outcome 4 Neonatal infection including pneumonia.

Analysis 1.5.

Comparison 1 Any antibiotic versus placebo, Outcome 5 Neonatal necrotising enterocolitis.

Analysis 1.6.

Comparison 1 Any antibiotic versus placebo, Outcome 6 Oxygen treatment > 36 weeks' postconceptual age.

Analysis 1.7.

Comparison 1 Any antibiotic versus placebo, Outcome 7 Major cerebral abnormality on ultrasound before discharge.

Analysis 1.8.

Comparison 1 Any antibiotic versus placebo, Outcome 8 Birth before 37 weeks' gestation.

Analysis 1.9.

Comparison 1 Any antibiotic versus placebo, Outcome 9 Major adverse drug reaction.

Analysis 1.10.

Comparison 1 Any antibiotic versus placebo, Outcome 10 Maternal infection after delivery prior to discharge.

Analysis 1.11.

Comparison 1 Any antibiotic versus placebo, Outcome 11 Chorioamnionitis.

Analysis 1.12.

Comparison 1 Any antibiotic versus placebo, Outcome 12 Caesarean section.

Analysis 1.15.

Comparison 1 Any antibiotic versus placebo, Outcome 15 Birth within 48 hours of randomisation.

Analysis 1.16.

Comparison 1 Any antibiotic versus placebo, Outcome 16 Birth within 7 days of randomisation.

Analysis 1.17.

Comparison 1 Any antibiotic versus placebo, Outcome 17 Birthweight.

Analysis 1.18.

Comparison 1 Any antibiotic versus placebo, Outcome 18 Birthweight < 2500 g.

Analysis 1.19.

Comparison 1 Any antibiotic versus placebo, Outcome 19 Neonatal intensive care.

Analysis 1.20.

Comparison 1 Any antibiotic versus placebo, Outcome 20 Days in neonatal intensive care unit.

Analysis 1.21.

Comparison 1 Any antibiotic versus placebo, Outcome 21 Positive neonatal blood culture.

Analysis 1.22.

Comparison 1 Any antibiotic versus placebo, Outcome 22 Neonatal respiratory distress syndrome.

Analysis 1.23.

Comparison 1 Any antibiotic versus placebo, Outcome 23 Treatment with surfactant.

Analysis 1.24.

Comparison 1 Any antibiotic versus placebo, Outcome 24 Number of babies requiring ventilation.

Analysis 1.25.

Comparison 1 Any antibiotic versus placebo, Outcome 25 Number of babies requiring oxygen therapy.

Analysis 1.26.

Comparison 1 Any antibiotic versus placebo, Outcome 26 Neonatal oxygenation > 28 days.

Analysis 1.27.

Comparison 1 Any antibiotic versus placebo, Outcome 27 Neonatal encephalopathy.

Analysis 1.28.

Comparison 1 Any antibiotic versus placebo, Outcome 28 Serious childhood disability at 7 years.

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]
Analysis 2.3.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 3 Major adverse drug reaction.

Analysis 2.4.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 4 Maternal infection after delivery prior to discharge.

Analysis 2.6.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 6 Caesarean section.

Analysis 2.9.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 9 Birth within 48 hours of randomisation.

Analysis 2.10.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 10 Birth within 7 days of randomisation.

Analysis 2.11.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 11 Birth before 37 weeks' gestation.

Analysis 2.12.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 12 Birthweight.

Analysis 2.13.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 13 Birthweight < 2500 g.

Analysis 2.14.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 14 Neonatal intensive care.

Analysis 2.17.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 17 Positive neonatal blood culture.

Analysis 2.18.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 18 Neonatal necrotising enterocolitis.

Analysis 2.19.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 19 Neonatal respiratory distress syndrome.

Analysis 2.20.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 20 Treatment with surfactant.

Analysis 2.21.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 21 Number of babies requiring ventilation.

Analysis 2.22.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 22 Number of babies requiring oxygen therapy.

Analysis 2.23.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 23 Neonatal oxygenation > 28 days.

Analysis 2.24.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 24 Oxygen treatment > 36 weeks' postconceptual age.

Analysis 2.26.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 26 Major cerebral abnormality on ultrasound before discharge.

Analysis 2.27.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 27 Perinatal death/death before discharge.

Analysis 2.28.

Comparison 2 Erythromycin versus co-amoxiclav, Outcome 28 Serious childhood disability at 7 years.

Comparison 4. Antibiotics versus no antibiotic
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Perinatal death/death before discharge18 Risk 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]
Analysis 4.1.

Comparison 4 Antibiotics versus no antibiotic, Outcome 1 Perinatal death/death before discharge.

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]
Analysis 5.4.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 4 Maternal infection after delivery prior to discharge.

Analysis 5.5.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 5 Chorioamnionitis.

Analysis 5.6.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 6 Caesarean section.

Analysis 5.9.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 9 Birth within 48 hours of randomisation.

Analysis 5.10.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 10 Birth within 7 days of randomisation.

Analysis 5.14.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 14 Neonatal intensive care.

Analysis 5.18.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 18 Neonatal necrotising enterocolitis.

Analysis 5.19.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 19 Neonatal respiratory distress syndrome.

Analysis 5.26.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 26 Neonatal intraventricular haemorrhage.

Analysis 5.27.

Comparison 5 3 versus 7 day ampicillin regimens, Outcome 27 Perinatal death/death before discharge.

Appendices

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

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

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

History

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 performed

Search 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 2008Amended

Corrected 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

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

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

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

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Amon 1988a

MethodsRandomised trial. No mention of method of randomisation. Not placebo-controlled or blinded.
Participants82 women treatment 43 control 39. Inclusions: 20-34 weeks' pregnant. PPROM confirmed by sterile speculum. Singleton pregnancy only.
InterventionsTreatment group: ampicillin 1 g IV every 6 hours for 24 hours. Maintained on oral 500 mg ampicillin 6-hourly until delivery. In labour they were recommenced on 1 g IV ampicillin.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information available.

Camli 1997

MethodsRandomised trial - no mention of the method of randomisation.
Participants31 women with premature rupture of the membranes between 28-34 weeks gestation. PPROM confirmed by speculum. Exclusions: women who go into active labour within 24 hours or who need induction of labour. Multiple pregnancy and fetal malformations. Women with serious medical conditions or who need antibiotic treatment for a known infection. Women who have received antibiotics in the last 10 days or who are allergic to penicillin.
InterventionsTreatment group oral ampicillin 1 g 4 x daily.
No placebo arm or tocolysis used.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information available.

Christmas 1992

MethodsRandomised trial. Using sequentially numbered sealed envelopes. Not placebo-controlled or blinded. The control group received IV fluids without antibiotics for first 24 hours.
Participants94 women randomised 48 treatment, 46 control. Inclusions: singleton pregnancies 20-34 weeks with PPROM confirmed by sterile speculum.
Exclusions: penicillin allergy. Prior antibiotic therapy. Clinical evidence of intra-amniotic infection. Evidence of labour or fetal distress.
InterventionsTreatment: 24 hours IV ampicillin 2 g every 6 hours for 4 doses; gentamycin 90 mg loading dose 60 mg every 8 hours for 3 doses. Then oral amoxicillin + clavulanic acid. 500 mg 3 x day for 7 days. Control IV fluids without antibiotics for 24 hours.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Low riskUsing sequentially numbered sealed envelopes.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Cox 1995

MethodsRandomised controlled trial.
Participants62 women PPROM between 24 and 29 weeks' pregnant. Not stated whether multiple pregnancy included.
InterventionsCo-amoxiclav 3 g 6-hourly for 4 doses then co-amoxiclav 500 mg 6-hourly for 5 days or matching placebo.
OutcomesProlongation of pregnancy.
Neonatal mortality and morbidity.
NotesData extracted from abstract only. Further data requested from Dr Cox but not made available.
Study took place between May 1991 and April 1994 in Dallas, Texas.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Ernest 1994

MethodsRandomised double-blind, placebo-controlled trial. A table of random numbers was used. Drugs and placebo were prepared by research nurses. The authors specify that participants and caregivers were blinded as to group.
Participants148 women at 21-37 weeks with premature rupture of the membranes preterm confirmed with positive nitrazine test and 'ferning' of amniotic fluid or by seeing vaginal pool of amniotic fluid from os. No tocolytics or steroids given. Multiple pregnancies included.
Exclusions are not clearly stated.
Interventions4-hourly IV 1 million units benzylpenicillin for 12-24 hours - oral 250 mg penicillin twice daily before delivery or a matched placebo.
OutcomesLatency period, infection complications and neonatal
outcomes studies. Data on death not included.
Notes

Study conducted from March 2 1989 to May 29 1991, in a single site (North Carolina, USA). 148 women.
71 placebo.
77 treatment.
4 women were excluded because of protocol violation in placebo arm (antibiotics given).

Information on neonatal death not given.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers.
Allocation concealment (selection bias)Low riskStated that nurses were not involved in the preparation or release of either antibiotic or placebo.
Blinding (performance bias and detection bias)
All outcomes
Low riskPatients and staff blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData excluded for 4 women who were treated with antibiotics outside the protocol.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Fuhr 2006

MethodsRandomised double-blind, placebo-controlled trial - multicentre.
Participants

105 pregnant women with PROM between 24+0 and 32+6 weeks.

Exclusion criteria not clearly stated nor whether multiple pregnancy included.

Interventions

Metzlocillin 2 g given 3 x day for 7 days or placebo.

All women given corticosteroids and tocolytics IV.

OutcomesProlongation of pregnancy and neonatal mortality and morbidity.
Notes

5 centres in Germany - dates not given.

47 women in treatment arm and 58 in control.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Garcia-Burguillo 1995

MethodsRandomised double-blind, placebo-controlled trial.
Participants

60 singleton pregnancy women. Preterm PROM under 36 weeks' pregnant. Ruptured membranes confirmed by sterile speculum examination, ferning test and nitrazine test.
No steroids or tocolytics given after randomisation.

Exclusions: > 37/40.
Discrepancy of over 2 standard deviations between scan and dates EDD.
Bleeding.
Contractions.
Fetal distress.
Fetal malformation.
Fetal death.
Chorioamnionitis on admission.
Antibiotics given during previous 10 days.

InterventionsErythromycin 500 mg 6-hourly orally until delivery. Matched placebo given until delivery.
OutcomesMaternal morbidity. Neonatal mortality and morbidity.
Notes

60 women recruited during 1992 from single centre in Madrid, Spain.
No losses to follow-up.

Paper in Spanish and data extracted with help from Dr Pigem.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Grable 1996

Methods60 women randomised to double blind placebo controlled trial. Randomisation based on random numbers tables with blocks providing 1:1 ratio and balancing every 6 women. Randomisation conducted in pharmacy.
Participants60 women randomised. Inclusions <= 35 weeks with documented PPROM.
Exclusions: digital examination of cx, non-reassuring stress test, presence of chorioamnionitis, abruptio placenta, pre-eclampsia, multiple pregnancy and penicillin allergy.
InterventionsIV ampicillin 2 g every 6 hours for 24 hours followed by 500 mg oral ampicillin until delivery or discharge. Matched placebos.
OutcomesMaternal morbidity. Neonatal mortality and morbidity.
NotesStudy divided into GBS positive and negative patients. Unclear whether clinician knew of positive culture.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation based on random numbers tables with blocks providing 1:1 ratio and balancing every 6 women.
Allocation concealment (selection bias)Low riskRandomisation and preparation of drugs conducted in pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Johnston 1990

MethodsRandomised double-blind, placebo-controlled trial. Randomisation table generated by consecutive coin toss, the randomisation schedule kept in pharmacy.
Participants85 women randomised. Inclusions: mothers with singleton gestations between 20-34 weeks with PPROM confirmed by sterile speculum for pooling, ferning and nitrazine paper testing.
Exclusions: penicillin allergy, taking antibiotics at the time of PPROM, had fever > 100.4 degrees Fahrenheit, had signs of chorioamnionitis, were in active labour (defined by 3 or more contractions per 10-minute period for 1 hour or presented with cervical dilatation > 3 cm confirmed at the time of sterile speculum. Fetal indications for exclusion were the presence of fetal distress, defined as repetitive late deceleration or sustained bradycardia, or congenital abnormality on ultrasound.
InterventionsIV mezlocillin for 48 hours followed by oral ampicillin until delivery or matched (IV + oral) placebo.
No doses noted. After randomisation no tocolytic steroids given.
Study drugs discontinued if infection diagnosed.
OutcomesNot clearly defined other than maternal or perinatal morbidity and mortality.
Outcomes looked at included length of pregnancy, maternal infectious morbidity, mode of delivery. Neonatal outcomes - stillbirth, neonatal death, birthweight Apgar, cord pH, positive blood culture, RDS, IVH, NEC, NICU stay over 30 days.
NotesSingle centre - University Medical Centre - Jacksonville Florida.
85 women randomised.
All women had infection screen on admission. No digital examination allowed.
No comment as to losses to follow-up or recruitment period.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation table generated by consecutive coin toss.
Allocation concealment (selection bias)Low riskThe randomisation schedule kept in pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskRandomisation schedule stated as not being available to clinicians.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Kenyon 2001

MethodsRandomised double-blind, placebo-controlled trial.
Participants

4826 women under 37 weeks' pregnant with PROM. Multiple pregnancies included.

UK follow-up at 7 years of age of the 4378 children of the 4148 eligible women who joined the ORACLE trial using a parental questionnaire. Exclusions 661 women (246 due to perinatal death, 376 randomised outside UK and 39 women withdrew).

InterventionsCo-amoxiclav 375 mg QDS, erythromycin 250 mg QDS orally for 10 days or until delivery matched placebo (2 x 2 factorial design).
Outcomes

Primary outcome: neonatal death or abnormal brain scans on discharge from hospital or oxygenation at 36 weeks' postconceptual age.
Secondary outcomes include prolongation of pregnancy, neonatal infection, respiratory outcomes.

Functional impairment was assessed using the Mark III Multi-Attribute Health Status classification system. Primary outcome was defined as any level of functional impairment (severe, moderate or mild). Other outcomes included death, behaviour (using the Strengths and Difficulties questionnaire) prespecified questions on respiratory symptoms, hospital admissions, convulsions, other prespecified medical conditions and demographic data. Educational attainment was evaluated for children in England using data from National Cirriculum Tests at 7 years of age (Key Stage 1).

NotesMulticentre trial (161 centres, 135 in the UK). Randomised 4826 women. 2 women lost to follow-up and 15 women were excluded due to protocol violations. 4809 women analysed. For twin pregnancies adverse outcomes were considered present if one twin affected. Consumers involved in drawing up of protocol and information for women.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBy computer using randomly generated blocks of 4.
Allocation concealment (selection bias)Low riskSequentially numbered drug boxes of identical appearance.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Stated that clinicians remained blind to treatment allocation in all but 9 cases and that all staff and participants remained blind to treatment allocation.

For the follow-up study all participants bar 1 women and all Study staff remained blind to treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

2 women lost to follow-up and 15 protocol violations.

In the follow-up study outcome data were determined for 75% of eligible children.

Selective reporting (reporting bias)Low risk

No selective reporting.

Protocol published for follow-up study.

Other biasLow riskThe study appears to be free of other sources of bias.

Kurki 1992

MethodsRandomised double-blind, placebo-controlled trial.
Participants101 women randomised between 23-36 weeks' pregnant with visible leakage of amniotic fluid who did not go into labour within 12 hours of admission. Sterile speculum, digital examination and infection screening was performed on admission. Multiple pregnancies included.
Interventions2 doses of IV penicillin (5 mu) or matched placebo.
OutcomesProlongation of pregnancy. Infection, neonatal morbidity and mortality. Long-term development at 2 years.
NotesDepartment of Obstetrics and Gynaecology, Helsinki, Finland.
No mention of where the study was conducted. Sealed envelope randomisation.
Results in 76 women not randomised but admitted during the same period are also reported.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Low riskStated as being by sealed envelope.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Lewis 2003

MethodsRandomised trial looking at 3 or 7 days antibiotic therapy. Randomised using table of arbitrary numbers in blocks of 10. Indicator cards placed in sealed envelopes which were sequentially numbered and stored on an area away from the enrolment site.
Participants84 singleton pregnancies were randomised between 24-34 weeks' gestation. Exclusions included known infection, absence of cervical cerclage, not penicillin allergic. Corticosteroids given to all participants.
InterventionsAmpicillin-sulbactam 3 g intravenously every six hours for either 3 or 7 days.
OutcomesPrimary outcome was latency period between membrane rupture and delivery. Infection and neonatal morbidity and mortality.
Notes3 study sites in Tennessee USA.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised using table of arbitrary numbers in blocks of 10.
Allocation concealment (selection bias)Low riskIndicator cards placed in sealed envelopes which were sequentially numbered and stored on an area away from the enrolment site
Blinding (performance bias and detection bias)
All outcomes
Low riskStated that all carers were unaware of the randomisation process.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Lockwood 1993a

MethodsRandomised double-blind placebo-controlled trial.
Participants75 women randomised with a single fetus at 24-34 completed weeks (accurate gestational age), admitted with PROM. No digital examination unless active labour. Women had infection screening.
Exclusions: abruption, lethal fetal abnormalities clinical chorioamnionitis, maternal illness, diabetes, PIH, lupus, severe maternal disease, fetal growth retardation, fetal distress, cervical cerclage, active herpes. Women having received antibiotics for existing infection were also excluded.
InterventionsPiperacillin 3 g IV 6-hourly 72 hours or placebo.
OutcomesProlongation of pregnancy.
Neonatal outcomes.
NotesRecruitment in 3 centres (USA) from January 1987 to January 1992. 75 women were randomised (treatment 38, placebo 37).
3 babies (1 in the experimental group and 2 in controls) were lost to follow-up.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation sequence.
Allocation concealment (selection bias)Low riskSame deposited in pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated all healthcare providers were blinded to allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Magwali 1999

MethodsRandomised trial not placebo-controlled. Randomisation by opening sealed consecutive opaque envelopes in admission room.
Participants171 women randomised 84 in treatment group 87 in no treatment group. Inclusion PROM 26-36 weeks' gestation drainage of liquor confirmed by sterile speculum. Exclusions: clinical signs of chorioamnionitis, multiple pregnancy, those with any contraindication to continuing the pregnancy and those who had just completed a course of antibiotics for another reason.
InterventionsCo-amoxiclav for 5 days. No mention of daily frequency or mg of drugs.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Low riskStated as being by sealed envelope.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskMinimal loss to follow-up - 2 in the treatment and 1 in the no treatment group.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information available.

McGregor 1991

MethodsRandomised double-blind placebo-controlled trial.
Computer-generated random number list. Sequentially numbered bottles.
Participants65 women with singleton pregnancies.
Women between 23-34 completed weeks' gestation with PROM. Sterile speculum. No corticosteroids administered.
Exclusions: active labour, presence of maternal or fetal complication to necessitate delivery (fetal distress, prolapsed cord, pregnancy-induced hypertension, abruptio placentae) placenta praevia, cervical cerclage, known infection requiring antibiotic treatment, use of vaginal or oral antibiotics in last 2 weeks, presence of known uterine or fetal abnormality, history of vaginal bleeding in last month, serious existing maternal disease, history of allergy or intolerance to erythromycin.
InterventionsErythromycin 333 mg 3 x daily or placebo 7 days or until active labour started.
OutcomesProlongation of pregnancy. Maternal and neonatal infectious morbidity.
Notes

July 1986-June 1988 University Hospital Denver.
65 women recruited (10 excluded - 15%).
55 analysed - (28 treatment, 27 placebo).

No replies received to letter requesting breakdown between stillbirths and neonatal deaths and asking if Blanco's paper has ever been published.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random number list.
Allocation concealment (selection bias)Low riskSequentially numbered bottles.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete after 10 exclusions.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information available.

Mercer 1992

MethodsRandomised double-blind, placebo-controlled trial.
Computerised random number tables. Administered by the pharmacy.
Stratified at 30 weeks. gestational age.
ParticipantsInclusions: 220 women 20-34/6 weeks pregnant with PPROM - sterile speculum and evaluation of cervix. Amniocentesis done for infection screen. Multiple pregnancies included.
Exclusions: PPROM > 72 hours duration, cervical dilatation > 4 cm, progressive labour, vaginal bleeding, temperature 99 degrees Fahrenheit or greater, active infection requiring antibiotic therapy, antibiotic therapy within 1 week prior to admission, active hepatic disease, erythromycin allergy, cervical cerclage or medical condition requiring delivery. IUGR (< 10 centile), congenital abnormalities, evidence of fetal distress, unsuccessful tocolysis on admission for preterm labour.
InterventionsOral 333 mg erythromycin. 8-hourly from randomisation to delivery with matched placebo.
OutcomesNot clearly stated.
Prolongation of pregnancy. Reduction of infectious morbidity.
NotesSingle centre (Memphis, Tennessee, USA).
March 1989-August 1990.
Women had infection screen before randomisation.
220 randomised, (treatment 106, placebo 114) 3 lost to follow-up.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised random number tables.
Allocation concealment (selection bias)Low riskAdministered by the pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskStates that all involved remained blind to treatment allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Mercer 1997

MethodsRandomised double-blind, placebo-controlled trial. Urn randomisation scheme (a procedure to increase the likelihood of obtaining an equal number of subjects in each arm), stratified by centre.
Participants614 women with PPROM at 24-32 weeks' gestation. Inclusion criteria: membrane rupture within 36 hours of randomisation; cervical dilatation 3 cm or less on usual examination; < 5 contractions in 6 minutes.
Exclusion criteria: non-reassuring, fetal testing; vaginal bleeding; maternal or fetal indication for delivery, cervical cerclage in place, antibiotics within the last 5 days, corticosteroids within last 7 days, allergy to penicillin or erythromycin, maternal infection or medical disease, ultrasound evidence of placenta praevia, fetal weight < 10th centile for gestational age, malformation. Previous successful tocolysis was not an exclusion criterion.
Tocolysis and corticosteroids were prohibited after randomisation.
InterventionsAmpicillin 2 g 6-hourly and erythromycin 250 mg 6-hourly IV for 48 hours, then oral amoxacillin 250 mg every 8 hours and erythromycin 333 mg 8-hourly for 5 days and a matching placebo regimen.
OutcomesComposite primary outcome included pregnancies complicated by at least 1 of the following: fetal or infant death, respiratory distress, severe intraventricular haemorrhage, stage 2 or 3 NEC, or sepsis within 72 hours of birth. These perinatal morbidities were also assessed separately and pregnancy prolongation assessed.
For twin pregnancies adverse outcomes considered present if 1 twin affected.
Notes11 centres - USA.
February 1992-January 1995.
1867 women screened.
804 eligible.
614 agreed to participate.
29 twin gestations.
GBS positive: 118/614.
3 women lost to follow-up.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUrn randomisation scheme (a procedure to increase the likelihood of obtaining an equal number of subjects in each arm), stratified by centre.
Allocation concealment (selection bias)Low riskTreatment given by pharmacy.
Blinding (performance bias and detection bias)
All outcomes
Low riskStates all involved remained blinded to treatment allocation.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOnly 3 withdrawals (2 in placebo and 1 in treatment arm).
Selective reporting (reporting bias)Unclear riskNo protocol available.
Other biasUnclear riskNo information given.

Morales 1989

MethodsRandomised trial not placebo controlled. RCT of antenatal steroids + ampicillin. 4 groups - GP1 - neither, GP2 steroids only, GP3 antibiotic only, GP4 both. Randomised by using sealed envelopes into 1 of groups.
ParticipantsRandomised: 41 = GP1, 43 = GP2, 37 = GP3, 44 = GP4.
Inclusion criteria 26-34 weeks' pregnant singleton gestation. PROM confirmed by sterile speculum L/S ratio less than 2.0.
Exclusions: In labour within 12 hours of randomisation women with uterine tenderness, foul smelling lochia or fetal tachycardia on admission, women allergic to penicillin, with congenital abnormality with L/S ratio greater than 2.0 or not obtained.
Interventions2 g IV ampicillin every 6 hours until results of cervical cultures negative.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Low riskStates as sealed envelopes into 1 of 4 groups.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Ovalle-Salas 1997

MethodsRandomised double-blind, placebo-controlled trial. No comment as to method of randomisation.
Participants88 women.
Inclusions: women with PPROM 24-34 weeks, PPROM diagnosed with sterile speculum-pooling, ferning and nitrazine tests.
No digital examination performed.
Exclusions: labour, significant haemorrhage, abruptio placentae, use of antibiotics within 30 days before screening for study, fetal anomaly or death, multiple gestation, documented allergy to clindamycin or gentamicin, uterine abnormality, presence of IUCD, fetal distress, clinical chorioamnionitis, maternal medical complications necessitating delivery or any condition precluding expectant management and intrauterine growth retardation (< 10th centile for gestational age).
InterventionsClindamycin 600 mg IV every 6 hours for 48 hours + 4 mg/kg/day gentamycin IV for 48 hours followed by Clindamycin 300 mg orally every 6 hours for 5 days + gentamycin 2 mg/kg/day IM every 12 hours for 5 days.
Matching placebo.
OutcomesProlongation of pregnancy, maternal infection related morbidity, birthweight, neonatal morbidity and admission to neonatal intensive care unit.
NotesNovember 1990-September 1994. 3 sites: 2 Chile, 1 USA.
Women had infection screen.
88 women randomised
(treatment 42, control 46).
1 lost to follow-up in placebo arm.
Trial stopped after intermediate evaluation showed treatment group had better outcome.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given.
Allocation concealment (selection bias)Unclear riskNo information given.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete with 1 loss to follow-up.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasHigh riskTrial stopped after intermediate evaluation showed treatment group had better outcome.

Owen 1993a

MethodsRandomised not placebo-controlled. Randomised using sealed opaque envelopes determined by computer algorithm.
Participants118 randomised 1 lost to follow-up. 59 treatment 58 controls. Inclusions 24 to 34 weeks' gestation. PPROM confirmed by speculum. Exclusions in labour, clinical evidence of infection suspected fetal compromise, membrane rupture over 2 days, fetal abnormality, antibiotics in last 7 days, multiple pregnancy, cervical cerclage, prompt delivery required.
InterventionsIV 1 g ampicillin 6-hourly for 24 hours then 500 mg ampicillin orally every 6 hours. If allergic to penicillin 500 mg erythromycin used 6-hourly. Treatment continued with delivery or diagnosis of chorioamnionitis.
OutcomesDeath only included.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBy computer algorithm.
Allocation concealment (selection bias)Low riskSealed opaque envelope.
Blinding (performance bias and detection bias)
All outcomes
High riskNot blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete - 1 woman lost to follow-up in control group.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Segel 2003

MethodsRandomised double-blind, placebo-controlled trial of 3 or 7 days treatment. Pharmacy provided randomisation with a computer-generated random number table in blocks of 4.
Participants48 women randomised: 24 in each arm-analysis on 23 in each arm. Women 24-33 weeks with clinically confirmed ruptured membranes. Exclusions included penicillin allergy, active labour, suspected infection, multiple pregnancy, known medical maternal or fetal problems and exposure to antibiotics within 1 week before admission.
InterventionsFor first 48 hours all women received parenteral ampicillin 2 g every 6 hours. Women were then randomly selected to receive either 3 or 7 days oral ampicillin. Women allocated the 3-day course received a matching placebo.
OutcomesPrimary outcome of prolongation of pregnancy for at least 7 days. Secondary outcomes included rated of chorioamnionitis, postpartum endometritis and neonatal morbidity and mortality.
NotesStudy took place between September 1999 - December 2001, Pennsylvania USA.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random number table in blocks of 4.
Allocation concealment (selection bias)Low riskStudy medicine given by pharmacy in identical packs.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information given.

Svare 1997a

  1. a

    cx: cervix
    EDD: expected date of delivery
    GBS: group B Streptococcus
    GP: group
    IM: intramuscular
    IUCD: intrauterine contraceptive device
    IUGR: intrauterine growth retardation
    IV: intravenous
    IVH: intraventricular haemorrhage
    L/S: lecithin/sphingomyelin
    NEC: necrotising enterocolitis
    NICU: neonatal intensive care unit
    PIH: pregnancy induced hypertension
    PPROM: preterm prelabour rupture of membranes
    PROM: premature rupture of membranes
    QDS: four times per day
    RCT: randomised controlled trial
    RDS: respiratory distress syndrome

MethodsRandomised double-blind, placebo-controlled trial. Block randomisation done using computer-generated numbers.
Participants67 women randomised. 26 + 0 - 33 + 6 rupture of membranes, leakage of amniotic fluid at vaginal speculum examination. Preceding onset of uterine contractions. Singleton pregnancies.
InterventionsAmpicillin 2 g IV 6-hourly. 24 hours - pivampicillin 500 g orally 8-hourly for 7 days plus IV metronidazole 500 mg every 8 hours for 24 hours, followed by metronidazole 400 mg orally every 8 hours for 7 days or identical placebo.
OutcomesLatency period from admission - delivery. Gestational age at delivery. Preterm delivery less than 37/40 maternal - neonatal infection birthweight.
NotesOctober 1991-April 1994. 6 centres around Copenhagen.
67 women randomised.
30 antibiotics.
37 placebo.
Data sent from Mr Svare and extracted from PhD thesis.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock randomisation done using computer-generated numbers.
Allocation concealment (selection bias)Unclear riskNo information available.
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind trial.
Incomplete outcome data (attrition bias)
All outcomes
Low riskData appear complete.
Selective reporting (reporting bias)Unclear riskProtocol not available.
Other biasUnclear riskNo information available

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    GBS: group B Streptococcus
    IV: intravenous
    PPROM: preterm prelabour rupture of membranes
    PROM: premature rupture of membranes
    RDS: respiratory distress syndrome
    SPL: spontaneous preterm labour

Almeida 1996Joint venture between Mozambique (where women were recruited), Sweden and Norway.
Data (apart from birthweight and caesarean section rates in the paper) supplied additionally by authors but numbers of women different from paper. Author written to for clarification but no response received.
Bergstrom 1991Random allocation to 2 management protocols (conservative versus induction).
Blanco 1993Abstract only - data requested.
Following comments received during the publication of this review in 2004, we wrote to Brian Mercer who included these data in a Lancet review in 1995 and James McGregor who was listed as an author.
Cardamakis 1990Abstract only - study randomised but no mention of whether blinded. Comparison of ampicillin versus ceftriaxone (doses not given). Minimal data expressed as P values.
Carroll 2000Abstract only containing no usable data (P values only).
Debodinance 1990Randomised trial of antibiotic treatment (mezlocillin) for women with PPROM. Not placebo-controlled and no clinical outcomes reported. Mortality data requested from author.
Dunlop 1986Study of 48 women with PPROM 26 to 34 weeks of pregnancy, given either oral ritodrine or cephalexin or both or neither (factorial design) - not placebo-controlled. No concealment of allocation for some participants (Latin Square method).
Fortunato 1990Study that investigated active versus passive management of women with PPROM. 55 women were recruited when admitted and given antibiotics. The control group were women who presented with PPROM. 1985-1987 before use of active protocol. Excluded as not double-blinded, randomised or controlled.
Gordon 1974Participants allocated to treatment or no treatment group on the arbitrary basis of the last digit of the admission number (unsatisfactory concealment of allocation). No mention of blinding.
Haas 2010This was a trial registration. The trial did not take place and no results are available.
Halis 2001Abstract containing no usable data. GBS prophylaxis also given for carriers.
Hernandez 2011Study comparing two macrolide antibiotics: i.e. comparison of similar antibiotics - so excluded as this antibiotic comparison was not included in this review.
Julien 2002Study compared antibiotic versus placebo only after 48 hour intravenous antibiotic treatment to all.
Kim 2008Study was neither randomised nor placebo-controlled.
Kwak 2013Study comparing a beta-lactam antibiotic with the same antibiotic plus macrolide. This antibiotic comparison was not included in this review.
Lebherz 1963Double-blind randomised controlled trial of 1912 women but no mention of gestation at recruitment.
Lewis 1995Study comparing treatment of women with PROM at 25 to 35 weeks' gestation in a randomised blinded trial comparing ampicillin-sulbactam with ampicillin: i.e. comparison of similar antibiotics - so excluded as this antibiotic comparison was not included in this review.
Lewis 1996

This is a randomised trial of corticosteroids in women with PPROM after a minimum of 12 hours ampicillin sulbactam.

77 women were enrolled. No statistically significant difference in latency period was noted. Neonatal and maternal infectious morbidity were similar. A significant reduction in the incidence of RDS, 18.4% versus 43.6%, was observed in the steroid group.

Lovett 1997

Double-blind, placebo-controlled trial of 112 women with PPROM 23 to 25 weeks' gestation to receive ampicillin/sulbactam or ampicillin or placebo.

Excluded because of a high rate of exclusions (52/164: 32%). Further information has been requested from the authors.

Matsuda 1993aComparative study; not placebo-controlled.
Matsuda 1993bProspective study, not randomised, of conservative versus aggressive management of women with PPROM. Aggressive management: IV antibiotics + tocolytics. Conservative management consisted of bedrest only.
Mbu 1998Allocation by alternation.
McCaul 1992Double-blind, placebo-controlled trial of 84 women with PPROM (19 to 34 weeks' pregnant) who received ampicillin or placebo. 112 randomised - 12 non-compliant so excluded and 26 removed from study (does not add up). Letter sent to Mr McCaul to get excluded women's data; in the meantime, excluded.
Norri 1991Abstract only - does not say whether study was placebo-controlled nor could any publication be found.
Ogasawara 1996Abstract only - data in further publication.
Ogasawara 1997Randomised prospective study of 51 women with either PROM or SPL. Not placebo-controlled and all women were given IV ampicillin 2 g every 6 hours until GBS status known.
Ogasawara 1999Randomised, double-blind, placebo-controlled trial of 60 women between 22 and 34 weeks pregnant with either PROM or SPL. All women were given IV ampicillin 2 g every 6 hours until GBS status known
Ovalle 2002Randomised placebo-controlled study looking at chorioamnionitis. No clear details of method of randomisation. 100 women recruited -71 analysed-excluded as large number lost to follow-up.
Spitzer 1993Comparison of neonatal infection rates in 2 groups of women, with PPROM. Both groups were treated with tocolytic and steroid therapy. The first group was given antibiotic therapy continuously from onset of PPROM until delivery. The second group received antibiotic therapy for the first 3 days after PPROM and for a 3-day period around each successive dose of corticosteroids. The study was neither randomised, nor placebo-controlled or blinded.

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