Antibiotics for preterm rupture of membranes (Review)

Kenyon S, Boulvain M, Neilson JP

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 8
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Antibiotics for preterm rupture of membranes (Review)

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Analysis 1.1. Comparison 1 Any antibiotic versus placebo, Outcome 1 Maternal death. . . . . . . . . . . . 46
Analysis 1.3. Comparison 1 Any antibiotic versus placebo, Outcome 3 Perinatal death/death before discharge. . . . 47
Analysis 1.4. Comparison 1 Any antibiotic versus placebo, Outcome 4 Neonatal infection including pneumonia. . . 49
Analysis 1.5. Comparison 1 Any antibiotic versus placebo, Outcome 5 Neonatal necrotising enterocolitis. . . . . 51
Analysis 1.6. Comparison 1 Any antibiotic versus placebo, Outcome 6 Oxygen treatment > 36 weeks postconceptual age. 53
Analysis 1.7. Comparison 1 Any antibiotic versus placebo, Outcome 7 Major cerebral abnormality on ultrasound before
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Analysis 1.8. Comparison 1 Any antibiotic versus placebo, Outcome 8 Birth before 37 weeks gestation. . . . . . 56
Analysis 1.9. Comparison 1 Any antibiotic versus placebo, Outcome 9 Major adverse drug reaction. . . . . . . 56
Analysis 1.10. Comparison 1 Any antibiotic versus placebo, Outcome 10 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 1.11. Comparison 1 Any antibiotic versus placebo, Outcome 11 Chorioamnionitis. . . . . . . . . . 57
Analysis 1.12. Comparison 1 Any antibiotic versus placebo, Outcome 12 Caesarean section. . . . . . . . . . 58
Analysis 1.15. Comparison 1 Any antibiotic versus placebo, Outcome 15 Birth within 48 hours of randomisation. . 59
Analysis 1.16. Comparison 1 Any antibiotic versus placebo, Outcome 16 Birth within 7 days of randomisation. . . 60
Analysis 1.17. Comparison 1 Any antibiotic versus placebo, Outcome 17 Birthweight. . . . . . . . . . . . 61
Analysis 1.18. Comparison 1 Any antibiotic versus placebo, Outcome 18 Birthweight < 2500 g. . . . . . . . 62
Analysis 1.19. Comparison 1 Any antibiotic versus placebo, Outcome 19 Neonatal intensive care. . . . . . . . 62
Analysis 1.20. Comparison 1 Any antibiotic versus placebo, Outcome 20 Days in neonatal intensive care unit. . . 63
Analysis 1.21. Comparison 1 Any antibiotic versus placebo, Outcome 21 Positive neonatal blood culture. . . . . 63
Analysis 1.22. Comparison 1 Any antibiotic versus placebo, Outcome 22 Neonatal respiratory distress syndrome. . 64
Analysis 1.23. Comparison 1 Any antibiotic versus placebo, Outcome 23 Treatment with surfactant. . . . . . . 65
Analysis 1.24. Comparison 1 Any antibiotic versus placebo, Outcome 24 Number of babies requiring ventilation. . 65
Analysis 1.25. Comparison 1 Any antibiotic versus placebo, Outcome 25 Number of babies requiring oxygen therapy. 66
Analysis 1.26. Comparison 1 Any antibiotic versus placebo, Outcome 26 Neonatal oxygenation > 28 days. . . . . 66
Analysis 1.27. Comparison 1 Any antibiotic versus placebo, Outcome 27 Neonatal encephalopathy. . . . . . . 67
Analysis 1.28. Comparison 1 Any antibiotic versus placebo, Outcome 28 Serious childhood disability at approximately 2
years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 2.3. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 3 Major adverse drug reaction. . . . . 68
Analysis 2.4. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 4 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Analysis 2.6. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 6 Caesarean section. . . . . . . . . 69
Analysis 2.9. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 9 Birth within 48 hours of randomisation. 69
Antibiotics for preterm rupture of membranes (Review) i
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.10. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 10 Birth within 7 days of randomisation. 70
Analysis 2.11. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 11 Birth before 37 weeks gestation. . . 70
Analysis 2.12. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 12 Birthweight. . . . . . . . . . 71
Analysis 2.13. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 13 Birthweight < 2500 g. . . . . . . 71
Analysis 2.14. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 14 Neonatal intensive care. . . . . . 72
Analysis 2.17. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 17 Positive neonatal blood culture. . . 72
Analysis 2.18. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 18 Neonatal necrotising enterocolitis. . . 73
Analysis 2.19. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 19 Neonatal respiratory distress syndrome. 73
Analysis 2.20. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 20 Treatment with surfactant. . . . . 74
Analysis 2.21. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 21 Number of babies requiring ventilation. 74
Analysis 2.22. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 22 Number of babies requiring oxygen
therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Analysis 2.23. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 23 Neonatal oxygenation > 28 days. . . 75
Analysis 2.24. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 24 Oxygen treatment > 36 weeks postconceptual
age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Analysis 2.26. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 26 Major cerebral abnormality on ultrasound
before discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Analysis 2.27. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 27 Perinatal death/death before discharge. 77
Analysis 2.28. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 28 Serious childhood disability at approximately
2 years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Analysis 4.1. Comparison 4 Antibiotics versus no antibiotic, Outcome 1 Perinatal death/death before discharge. . . 78
Analysis 5.4. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 4 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Analysis 5.5. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 5 Chorioamnionitis. . . . . . . . . 80
Analysis 5.6. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 6 Caesarean section. . . . . . . . . 80
Analysis 5.9. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 9 Birth within 48 hours of randomisation. 81
Analysis 5.10. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 10 Birth within 7 days of randomisation. 81
Analysis 5.14. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 14 Neonatal intensive care. . . . . . 82
Analysis 5.18. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 18 Neonatal necrotising enterocolitis. . 82
Analysis 5.19. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 19 Neonatal respiratory distress syndrome. 83
Analysis 5.26. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 26 Neonatal intraventricular haemorrhage. 83
Analysis 5.27. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 27 Perinatal death/death before discharge. 84
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Antibiotics for preterm rupture of membranes (Review) ii

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Antibiotics for preterm rupture of membranes

Sara Kenyon1 , Michel Boulvain2 , James P Neilson3

1 School of Health and Population Sciences, University of Birmingham, Edgbaston, UK. 2 Dpartement de Gyncologie et dObsttrique,

Unit de Dveloppement en Obsttrique, Maternit Hpitaux Universitaires de Genve, Genve 14, Switzerland. 3 School of Repro-
ductive and Developmental Medicine, Division of Perinatal and Reproductive Medicine, The University of Liverpool, Liverpool, UK

Contact address: Sara Kenyon, School of Health and Population Sciences, University of Birmingham, Public Health Building, Edg-
baston, B15 2TT, UK. [email protected].

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 8, 2010.
Review content assessed as up-to-date: 6 July 2010.

Citation: Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews
2010, Issue 8. Art. No.: CD001058. DOI: 10.1002/14651858.CD001058.pub2.

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 strategy
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (29 April 2010).
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 6800 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
Antibiotics for preterm rupture of membranes (Review) 1
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 childrens health at seven years of age (ORACLE Children Study) and found antibiotics seemed to have little
effect on the health of children.

Authors conclusions

The decision to prescribe antibiotics for women with PROM is not clearcut. Benefits in some short-term outcomes (prolongation of
pregnancy, infection, less abnormal cerebral ultrasound before discharge from hospital) should be balanced against a lack of evidence
of benefit for others, including perinatal mortality, and longer term outcomes. If antibiotics are prescribed it is unclear which would
be the antibiotic of choice.

Co-amoxiclav should be avoided in women at risk of preterm delivery due to increased risk of neonatal necrotising enterocolitis.

PLAIN LANGUAGE SUMMARY

Antibiotics for preterm rupture of membranes

Certain antibiotics given to women with early broken waters 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 6800 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). The longer term (at seven years of age) antibiotics seem to have little effect on the health of
children. It is not clear whether antibiotics should be prescribed for women whose waters break early, and if they are, which would be
the antibiotic of choice.

BACKGROUND The causes of PROM are multifactorial. Infection appears to have

an important role, either as a cause or as a consequence of PROM.
The rate of preterm birth is 5% to 9% of all births in Europe, Some organisms may produce collagenases, mucinases and pro-
and 12% to 13% in the USA; the rates in both continents are teases which weaken the amnion and chorion and may lead to
increasing, partly due to the higher number of multiple births PROM. On the other hand, infection may occur secondary to
associated with assisted conceptions (Goldenberg 2008). About membrane rupture. Ascending infection may lead to occult de-
30% to 35% of preterm births are the result of maternal or fetal ciduitis, intra-amniotic infection or fetal infection.
disease, but 40% to 45% of premature births result from sponta-
neous preterm labour (SPL) and 25% to 30% from preterm rup- A possible mechanism for the link between infection and
ture of the membranes (PROM). For families struggling to cope preterm delivery is bacterial stimulation of the biosynthesis of
with having a baby in special care, this will be one of the most prostaglandins, either directly via phospholipase A2 and C (Bejar
difficult, emotional and stressful times of their lives (Taylor 2001) 1981), or indirectly via substances such as interleukin-1, tumour
whatever the longer term outcome. The sequelae of preterm birth necrosis factor and platelet activating factor, all of which may be
also pose significant challenges. Children born preterm are at in- found in infected amniotic fluid (Yoon 2000).
creased risk of major disabilities, such as cerebral palsy, with the
risk increasing with decreasing gestation at birth (Marlow 2005). There is increasing evidence that, in addition to preterm birth,
Many preterm children without disability develop important be- perinatal infection is an independent antecedent of other disabil-
havioural and educational difficulties (Saigal 2008).The preven- ity, particularly cerebral palsy and chronic lung disease (Dammann
tion of preterm birth and reduction of associated disability are 2005). One theory was that perinatal prescription of antibiotics
therefore important health priorities. could prevent neurological and respiratory disability by two mech-
Antibiotics for preterm rupture of membranes (Review) 2
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
anisms, either by prolonging pregnancy, or by preventing or elim- We excluded studies where outcomes for over 20% of participants
inating infection, or both. In contrast, it was also thought pos- were not reported.
sible 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 Types of participants
neurological damage (Dammann 1997) and chronic lung disease Women with preterm (less than 37 weeks) rupture of the mem-
(Kotecha 1996). branes.
In addition to a generic effect of antibiotics, there may, in the-
ory, be differences in the effects of different antibiotics. For exam-
ple, macrolide antibiotics such as clindamycin and erythromycin, Types of interventions
which reduce bacterial virulence, may have advantages over the Comparison of:
beta lactam antibiotics (co-amoxiclav, cephalosporins) which, by any antibiotic versus placebo.
destroying bacteria, release endotoxins and prostaglandins and
may worsen outcomes (McGregor 1997). Thus, separate compar- We planned to undertake subgroup comparisons for the primary
isons of these antibiotics are included in the review. outcome as follows:
all penicillins (excluding co-amoxiclav) versus placebo;
The use of antibiotics for women with preterm labour with intact beta lactam (including co-amoxiclav) antibiotics versus
membranes is addressed by another review (King 2002). placebo;
macrolide (including erythromycin) antibiotics versus
placebo.
OBJECTIVES
Additional comparisons:
To assess the effects of administering antibiotics to women with beta lactam (including co-amoxiclav) antibiotics co-
preterm rupture of membranes on fetal and neonatal morbidity amoxiclav versus macrolide antibiotics (including erythromycin);
and mortality, maternal infectious morbidity and mortality, and all penicillins (except co-amoxiclav) versus macrolide
long-term childhood development. antibiotics (including erythromycin).

Antibiotic versus no antibiotic (including non-placebo

controlled trials) - perinatal death only.
METHODS Subgroup comparison of non-placebo controlled trials
only.
Different treatment regimens of same antibiotic.
Criteria for considering studies for this review

Types of outcome measures

Types of studies
We considered all randomised controlled comparisons of antibi-
Primary outcomes
otic administration versus placebo, given to women with preterm
rupture of membranes, for inclusion in this review. We also in- Maternal death.
cluded comparisons of different antibiotics. For the unambiguous Serious maternal morbidity:
and important outcome of perinatal death alone, we included tri- septicaemia;
als in the review that were randomised but not placebo controlled. need for intensive care;
We excluded trials that used inappropriate methods of randomisa- organ failure, need for ventilation;
tion. We included trials where the method of randomisation was need for hysterectomy.
not specified in detail in the expectation that their inclusion in Perinatal death or death before discharge from hospital.
this review would encourage the authors to make available further Perinatal morbidity:
information on the method of randomisation. We excluded tri- neonatal infection including pneumonia;
als where non-randomised cohorts were amalgamated with ran- necrotising enterocolitis;
domised participants if the results of the randomised participants oxygen treatment greater than 36 weeks
were not reported separately. We included trials in which postran- postconceptual age;
domisation exclusions occurred provided there was no evidence major cerebral abnormality on ultrasound prior to
that these occurred preferentially in one or other arm of the trials. discharge.

Antibiotics for preterm rupture of membranes (Review) 3

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Secondary outcomes Trials identified through the searching activities described above
Major maternal adverse drug reaction. are each assigned to a review topic (or topics). The Trials Search
Maternal infection after delivery prior to discharge. Co-ordinator searches the register for each review using the topic
Chorioamnionitis (infection of the womb). list rather than keywords.
Caesarean section. We did not apply any language restrictions.
Days from randomisation to birth.
Days from birth to discharge from hospital.
Birth within 48 hours. Data collection and analysis
Birth within seven days.
For the methods used when assessing the trials identified in the
Birth before 37 weeks.
previous version of this review, see Appendix 1.
Birthweight.
For this update, we used the following methods when assess-
Birthweight less than 2500 grams.
ing the reports identified by the updated search (Amon 1988b;
Need for intensive care.
Beazley 1998; Bergstrom 1991; Cardamakis 1990; Christmas
Days in neonatal intensive care unit.
1990; Fuhr 2006; Gilbert 2005; Gordon 1974; Halis 2001; Hauth
1997; Hnat 2005; Kenyon 2008a; Kenyon 2008c; Kim 2008;
Positive neonatal blood culture.
Lockwood 1993b; Morales 1988; Ogasawara 1996; Ogasawara
1997; Ogasawara 1999; Owen 1993b; Sanchez-Ramos 1990;
Respiratory distress syndrome.
Svare 1997b; Thurnau 1997).
Treatment with surfactant.
Days of ventilation.
Days of oxygen therapy. Selection of studies
Oxygen treatment greater than 28 days.
Two review authors (S Kenyon (SK) and M Boulvain (MB)) inde-
pendently assessed for inclusion all the potential studies we identi-
Neonatal encephalopathy.
fied as a result of the search strategy. We resolved any disagreement
through discussion or, if required, we consulted the third review
Long-term health outcomes (as defined by trial authors) after at
author (JP Neilson (JPN)).
least two years.

Data extraction and management

Search methods for identification of studies We designed a form to extract data. For eligible studies, SK and
MB review authors extracted the data using the agreed form. We
resolved discrepancies through discussion or, if required, we con-
Electronic searches sulted the third review author (JPN). We entered data into Review
We searched the Cochrane Pregnancy and Childbirth Groups Tri- Manager software (RevMan 2008) and checked for accuracy.
als Register by contacting the Trials Search Co-ordinator (29 April When information regarding any of the above was unclear, we
2010). attempted to contact authors of the original reports asking them
The Cochrane Pregnancy and Childbirth Groups Trials Register to provide further details.
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. quarterly searches of the Cochrane Central Register of Assessment of risk of bias in included studies
Controlled Trials (CENTRAL); Two review authors (SK and MB) independently assessed risk of
2. weekly searches of MEDLINE; bias for each study using the criteria outlined in the Cochrane
3. handsearches of 30 journals and the proceedings of major Handbook for Systematic Reviews of Interventions (Higgins 2009).
conferences; We resolved any disagreement by discussion or by involving the
4. weekly current awareness alerts for a further 44 journals third review author (JPN).
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE,
the list of handsearched journals and conference proceedings, and (1) Sequence generation (checking for possible selection
the list of journals reviewed via the current awareness service can bias)
be found in the Specialized Register section within the edito- We describe for each included study the method used to generate
rial information about the Cochrane Pregnancy and Childbirth the allocation sequence in sufficient detail to allow an assessment
Group. of whether it should produce comparable groups.

Antibiotics for preterm rupture of membranes (Review) 4

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
We assessed the method as: to outcomes. We decided a cut-off for exclusion of a study for the
adequate (any truly random process, e.g. random number level of missing data at 20%. Where sufficient information has
table; computer random number generator); been reported, or can be supplied by the trial authors, we have
inadequate (any non-random process, e.g. odd or even date planned to re-include missing data in the analyses which we un-
of birth; hospital or clinic record number); or dertake. We assessed methods as:
unclear. adequate;
inadequate:
unclear.
(2) Allocation concealment (checking for possible selection
bias)
We describe for each included study the method used to conceal (5) Selective reporting bias
the allocation sequence in sufficient detail and determine whether We have described for each included study how we investigated
intervention allocation could have been foreseen in advance of, or the possibility of selective outcome reporting bias and what we
during recruitment, or changed after assignment. found.
We assessed the methods as: We assessed the methods as:
adequate (e.g. telephone or central randomisation; adequate (where it is clear that all of the studys pre-
consecutively numbered sealed opaque envelopes); specified outcomes and all expected outcomes of interest to the
inadequate (open random allocation; unsealed or non- review have been reported);
opaque envelopes, alternation; date of birth); inadequate (where not all the studys pre-specified outcomes
unclear. 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
(3) Blinding (checking for possible performance bias) outcome that would have been expected to have been reported);
We have described for each included study the methods used, if unclear.
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 (6) Other sources of bias
blinding could not have affected the results. We assessed blinding We describe for each included study any important concerns we
separately for different outcomes or classes of outcomes. have about other possible sources of bias.
We assessed the methods as: We assessed whether each study was free of other problems that
adequate, inadequate or unclear for participants; could put it at risk of bias:
adequate, inadequate or unclear for personnel; yes;
adequate, inadequate or unclear for outcome assessors. no;
unclear.

(4) Incomplete outcome data (checking for possible attrition

bias through withdrawals, dropouts, protocol deviations) (7) Overall risk of bias
We have described for each included study, and for each outcome We made explicit judgements about whether studies are at high risk
or class of outcomes, the completeness of data including attrition of bias, according to the criteria given in the Handbook (Higgins
and exclusions from the analysis. We have stated whether attri- 2009). With reference to (1) to (6) above, we assessed the likely
tion and exclusions were reported, the numbers included in the magnitude and direction of the bias and whether we considered
analysis at each stage (compared with the total randomised par- it is likely to impact on the findings (Figure 1). We considered
ticipants), reasons for attrition or exclusion where reported, and this to be unlikely and therefore, have not undertaken sensitivity
whether missing data were balanced across groups or were related analyses.

Antibiotics for preterm rupture of membranes (Review) 5

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 1. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies.

have synthesised the relevant information. We would have con-

sidered it reasonable to combine the results from both if there was
Measures of treatment effect
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.
Dichotomous data
We would have also acknowledged heterogeneity in the randomi-
For dichotomous data, we present results as summary risk ratio sation unit and performed a separate meta-analysis.
with 95% confidence intervals.

Crossover trials
Continuous data
If we had identified any crossover trials on this topic, and deemed
For continuous data, we use the mean difference if outcomes are such trials eligible for inclusion, we would have included them in
measured in the same way between trials. We use the standardised the analyses with parallel group trials, using methods described by
mean difference to combine trials that measure the same outcome, Elbourne 2002.
but use different methods.

Multiarm studies
Unit of analysis issues For the subgroup comparisons undertaken, to avoid double count-
ing, we divided out data from the shared group approximately
evenly among the comparisons as described in the Handbook
Cluster-randomised trials 16.5.4 (Higgins 2009).
We would have included cluster-randomised trials in the analy-
ses along with individually randomised trials. Their sample sizes
would have been adjusted using the methods described in the Dealing with missing data
Handbook using an estimate of the intracluster correlation co-ef- For included studies, we have noted levels of attrition. We planned
ficient (ICC) derived from the trial (if possible), or from another to explore the impact of including studies with high levels of miss-
source. If ICCs from other sources are used, we would have re- ing data in the overall assessment of treatment effect by using sen-
ported this and conducted sensitivity analyses to investigate the sitivity analysis.
effect of variation in the ICC. If we had identified both cluster- For all outcomes we have carried out analyses, as far as possible, on
randomised trials and individually-randomised trials, we would an intention-to-treat basis, i.e. we attempted to include all partici-

Antibiotics for preterm rupture of membranes (Review) 6

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
pants randomised to each group in the analyses. The denominator Assessment of reporting biases
for each outcome in each trial was the number randomised minus
any participants whose outcomes are known to be missing. 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
Assessment of heterogeneity we thought the missing data likely to introduce serious bias, we
We used the I and Tau statistic to measure heterogeneity among planned to explore the impact of including such studies in the
the trials in each analysis. We performed subgroup analysis to overall assessment of results by a sensitivity analysis. Funnel plots
obtain meta-analysis results for more clinically comparable studies, for primary outcomes only show no evidence of publication bias:
to reduce heterogeneity where it existed. 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.

Antibiotics for preterm rupture of membranes (Review) 7

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 3. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.4 Neonatal infection
including pneumonia.

Antibiotics for preterm rupture of membranes (Review) 8

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 4. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.5 Neonatal necrotising
enterocolitis.

Antibiotics for preterm rupture of membranes (Review) 9

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 5. Funnel plot of comparison: 1 Any antibiotic versus placebo, outcome: 1.7 Major cerebral
abnormality on ultrasound before discharge.

Higgins 2009). With reference to (1) to (6) above, we assessed

Data synthesis
the likely magnitude and direction of the bias and whether we
We carried out statistical analysis using the Review Manager soft- considered it is likely to impact on the findings (Figure 1). We
ware (RevMan 2008). As we suspected clinical or methodological considered this to be unlikely and therefore, have not undertaken
heterogeneity between studies sufficient to suggest that treatment sensitivity analyses.
effects may differ between trials, we used random-effects meta-
analysis.

Subgroup analysis and investigation of heterogeneity RESULTS

For fixed-effect meta-analyses, we would have conducted planned
subgroup analyses classifying whole trials by interaction tests as Description of studies
described by Deeks 2001. As we used random-effects meta-analy- See: Characteristics of included studies; Characteristics of excluded
ses we assessed differences between subgroups by inspection of the studies.
subgroups confidence intervals; non-overlapping confidence in- The search identified 49 trials; we have included 22 in the review,
tervals indicating a statistically significant difference in treatment involving more than 6800 women and their babies, and excluded
effect between the subgroups. 26. Of the trials included, the majority were small with the ex-
ception of Kenyon 2001, which randomised 4826 women, and
Mercer 1997, which randomised 614 women. Women were re-
Sensitivity analysis cruited between 20 and 37 weeks of gestation and inclusion cri-
We made explicit judgements about whether studies were at high teria varied from clinicians definition of PROM to amniocentesis
risk of bias, according to the criteria given in the Handbook ( being done as part of an infection screen (Mercer 1992). The ma-

Antibiotics for preterm rupture of membranes (Review) 10

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
jority of women were not in active labour. Ten trials tested broad losses to follow up or exclusions were available from two trials (Cox
spectrum penicillins either alone or in combination (Cox 1995; 1995; Johnston 1990). The protocols were only available for one
Ernest 1994; Fuhr 2006; Grable 1996; Johnston 1990; Kenyon study (Kenyon 2001) to allow assessment of selective reporting.
2001; Kurki 1992; Lockwood 1993a; Mercer 1997; Svare 1997a). Lack of information which would allow fuller assessment may
Five trials tested macrolide antibiotics (erythromycin) either alone reflect changes in reporting of trials.
or in combination (Garcia 1995; Kenyon 2001; McGregor 1991;
Mercer 1992; Mercer 1997) and one tested clindamycin and gen-
tamycin (Ovalle Salas 1997). The duration of treatment varied
Effects of interventions
between two doses (Kurki 1992) and 10 days (Kenyon 2001) with
five trials opting for a maximum of seven days of treatment (Fuhr We included 22 trials involving more than 6800 women and their
2006; McGregor 1991; Mercer 1997; Ovalle Salas 1997; Svare babies.
1997a). Four trials treated women until delivery (Ernest 1994; We adopted a random-effects model, as we expected heterogeneity
Garcia 1995; Johnston 1990; Mercer 1992). In four of the tri- due to variability in participant characteristics, different antibi-
als, women were treated with oral antibiotic alone (Garcia 1995; otics, year of the study and different countries etc.
Kenyon 2001; McGregor 1991; Mercer 1992). In three of the tri-
als, women were treated with intravenous antibiotic alone (Fuhr
2006; Kurki 1992; Lockwood 1993a). In six of the trials, women Any antibiotic versus placebo
were treated with a combination of intravenous and oral antibiotics We included 16 trials included in the review, which randomised
(Cox 1995; Ernest 1994; Johnston 1990; Mercer 1997; Ovalle more than 6300 women and their babies. The use of antibiotics
Salas 1997; Svare 1997a). following preterm rupture of membranes (PROM) is associated
The six non-placebo controlled but randomised studies, which with a statistically significant reduction in chorioamnionitis (risk
contributed data to the outcome measure perinatal death alone, ratio (RR) 0.66, 95% confidence interval (CI) 0.46 to 0.96; Tau
were: Amon 1988a; Camli 1997; Christmas 1992; Magwali 1999; = 0.14, I = 45%) (11 trials/1559 women). There were no reports
Morales 1989; Owen 1993a. of major adverse drug reactions. There was a significant reduction
Two trials compared three versus five days of ampicillin (Lewis in the numbers of babies born within 48 hours (RR 0.71, 95% CI
2003; Segel 2003). 0.58 to 0.87; Tau = 0.03, I = 50%) (seven trials/5927 babies)
Outcomes were divided into primary and secondary. Primary out- and seven days (RR 0.79, 95% CI 0.71 to 0.89; Tau = 0.01,
comes, as listed above, were chosen based on importance and abil- I = 65%) (seven trials/5965 babies) of randomisation. Neonatal
ity to predict longer term neonatal morbidity. Additional out- infection (RR 0.67, 95% CI 0.52 to 0.85) (12 trials/1680 babies)
come measures chosen included maternal infection, prolongation was statistically significantly reduced in the babies whose mothers
of pregnancy and measures of neonatal mortality and morbidity. received antibiotics. Only one trial (Kenyon 2001) assessed the
One study had undertaken follow up past discharge from hos- use of surfactant and it found a statistically significant reduction
pital (Kurki 1992) but the results are not reported by treatment (RR 0.83, 95% CI 0.72 to 0.96) (one trial/4809 babies) as was
group but rather by duration of membrane rupture. One study has the numbers of babies requiring oxygen therapy overall (RR 0.88,
undertaken long-term follow up at seven years of age in the UK 95% CI 0.81 to 0.96) (one trial/4809 babies). The babies in the
(Kenyon 2001). The study evaluated functional impairment, be- treatment groups spent 5.05 days less in neonatal intensive care
haviour, respiratory symptoms, hospital admissions, convulsions (mean difference (MD) -5.05, 95% CI -9.77 to -0.33) (three trials/
and other specific medical conditions. These are the only data on 225 babies) and their birthweight was greater by 54 g (MD 53.83,
long-term follow up from any of the included trials. Seven-year 95% CI 7.06 to 100.60) (12 trials/6374 babies). There was a
assessment was not specifically a prespecified outcome, but is cap- significant reduction in the number of babies with an abnormal
tured under the outcome of long-term health after at least two cerebral ultrasound scan prior to discharge from hospital (RR 0.81,
years. 95% CI 0.68 to 0.98; Tau = 0.00, I = 0%) (12 trials/6289 babies).
For details of included and excluded studies, see Characteristics of Long-term follow up at seven years of age has been completed by
included studies and Characteristics of excluded studies. 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).
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, Subgroup comparisons
Fuhr 2006, Magwali 1999, Morales 1989 and Ovalle Salas 1997. These were undertaken for the primary outcomes only and show
All trials had matched placebos and were blinded apart from the no evidence of differences in treatment effects between the sub-
six non-placebo controlled studies described above. No detail on groups, with the exception of necrotising enterocolitis, where there

Antibiotics for preterm rupture of membranes (Review) 11

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
is a strong suggestion that this is increased with beta lactum antibi- in neonatal necrotising enterocolitis found in the co-amoxiclav
otics (including co-amoxiclav) (RR 4.72, 95% CI 1.57 to 14.23). 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 en-
Additional comparisons terocolitis is abnormal microbial colonisation of the intestinal tract
by one or several species unhindered by competitors. Co-amox-
iclav, because of its large spectrum may influence such colonisa-
Erythromycin versus co-amoxiclav
tion. Furthermore, the immature gut is sensitive to bacterial tox-
We included one trial (Kenyon 2001), involving 2415 women, ins, resulting in mucosal damage and the initiation of necrotising
which focused on this comparison. Delivery within 48 hours was enterocolitis.
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. Particularly in the light of UK MRC ORACLEs finding of re-
There was no significant difference in any index of neonatal mor- duced abnormal cerebral ultrasound scans before discharge from
bidity except for necrotising enterocolitis, which was statistically hospital, it is important that long-term follow up is undertaken.
significantly less frequent after erythromycin (RR 0.46, 95% CI The UK MRC ORACLE Children Study followed up children
0.23 to 0.94). Long-term follow up has been completed by one born to women with PROM randomised within the UK to the
study (Kenyon 2001) and showed little effect on the health of chil- MRC ORACLE trial at seven years of age and found no evidence
dren (RR 0.89, 95% CI 0.79 to 1.01) (one trial/1612 children). 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
Perinatal mortality alone ORACLE trial (Kenyon 2008b) and found evidence of harm. 1 .
No statistically significant reduction in perinatal mortality prior The prescription of erythromycin (with or without co-amoxiclav)
to discharge from hospital could be found when additional data was associated with a statistically significant increase in the pro-
were included from the six studies that were randomised but not portions of children with any level of functional impairment from
placebo controlled (RR 0.87, 95% CI 0.72 to 1.05) (19 trials/ 38 to 42%. Similarly, there was a statistically significant increase
6982 babies). Subgroup comparison of this group alone also shows in the proportions of children with cerebral palsy from 1.7% to
no statistical difference. 3.3% associated with erythromycin and from 1.9% to 3.2% with
co-amoxiclav. There was a suggestion that more children who de-
veloped CP had been born to mothers who had received both an-
Differing regimens
tibiotics. In the light of these findings, it is important to be certain
Two trials (Lewis 2003; Segel 2003) compared three versus seven about the diagnosis of ruptured membranes before prescribing an-
day regimens of ampicillin treatment (130 women). From the tibiotics.
limited available outcome data, there was no obvious disadvantage
to the three day regimen.

AUTHORS CONCLUSIONS

DISCUSSION Implications for practice

This review shows that routine antibiotic administration to The decision to prescribe antibiotics for women with PROM is
women with PROM reduces some markers of maternal and neona- not clearcut. Antibiotic administration following PROM is asso-
tal morbidity. This does not translate into a statistically significant ciated with a delay in delivery and a reduction in some markers
reduction in perinatal mortality. Most trials, however, report fewer of neonatal morbidity (prolongation of pregnancy, infection, less
deaths in the treatment group and the summary result shows a abnormal cerebral ultrasound before discharge from hospital) and
trend towards a beneficial effect. We included all randomised tri- yet in the longer term follow up at seven years of age showed no
als in the evaluation of perinatal death as this outcome is unlikely evidence of either benefit or harm. Benefits in some short-term
to be influenced by knowledge of the treatment allocation. Such outcomes should be balanced against a lack of evidence of bene-
a reduction in major markers of maternal and neonatal morbid- fit for others, including perinatal mortality, and longer term out-
ity when antibiotics are administered makes a reduction in death comes. If antibiotics are prescribed, it is unclear which would be
possible, even if the result was statistically non-significant from the antibiotic of choice.
pooling of available data.
Co-amoxiclav should be avoided in women at risk of preterm de-
By far the largest trial included is UK MRC ORACLE (Kenyon livery because of the increased risk of neonatal necrotising entero-
2001), which randomised 4826 women. The significant increase colitis.

Antibiotics for preterm rupture of membranes (Review) 12

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Implications for research We acknowledge assistance with the review from Riccardo Pfis-
ter, Justus Hofmeyr, David Taylor, Ann Blackburn and Rebecca
In the future there is the possibility that comparative studies may
Smyth.
be conducted should there be developments in the pharmacology
of antibiotics. As part of the pre-publication editorial process, this 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
Groups international panel of consumers and the Groups Statis-
ACKNOWLEDGEMENTS tical Adviser.

REFERENCES

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Camli 1997 {published data only} Johnston 1990 {published data only}
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Segel SY, Miles AM, Clothier B, Parry S, Macones GA. Duration Dunlop PDM, Crowley PA, Lamont RF, Hawkins DF. Preterm
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Carroll 2000 {published data only} sulbactam. Obstetrics & Gynecology 1995;86(3):3925.
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(1 Pt 2):S53. 83551.
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Meis PJ, et al.Perinatal outcomes in women with preterm rupture
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of vaginal bleeding. American Journal of Obstetrics and Gynecology RevMan 2008
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al.Childhood outcomes after prescription of antibiotics to pregnant Obstetricians; 1990 Jan 23-27; Houston, Texas, USA. 1990:18.
women with spontaneous preterm labour: 7-year follow-up of the Svare 1997b
ORACLE II trial. Lancet 2008;372(9646):131927. Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen N, Borch-
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Kenyon S, Brocklehurst P, Jones D, Marlow N, Salt A, Taylor D. treatment in threatening preterm delivery. Acta Obstetricia et
MRC ORACLE children study. Long term outcomes following Gynecologica Scandinavica 1997;76(167:1):86.
prescription of antibiotics to pregnant women with either Taylor 2001
spontaneous preterm labour or preterm rupture of the membranes. Taylor HG, Klein N, Minich NM, Hack M. Long-term family
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labour with intact membranes. Cochrane Database of Systematic Thurnau 1997
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Lockwood 1993b relationship among inflammatory lesions of the umbilical cord
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sodium in preterm membrane rupture. American Journal of Obstetrics and Gynecology 2000;183(5):11249.
Obstetrics and Gynecology 1993;168(1 Pt 2):378.
References to other published versions of this review
Marlow 2005
Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and Crowley 1995
developmental disability at six years of age after extremely preterm Crowley P. Antibiotics for preterm prelabour rupture of
birth. New England Journal of Medicine 2005;352(1):919. membranes. [revised 05 May 1994]. In: Enkin MW, Keirse
[PUBMED: 15635108] MJNC, Renfrew MJ, Neilson JP, Crowther C (eds.) Pregnancy and

Antibiotics for preterm rupture of membranes (Review) 17

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 Childbirth Module. In: The Cochrane Pregnancy and Childbirth
Database [database on disk and CDROM]. The Cochrane
Collaboration; Issue 2, Oxford: Update Software; 1995.
Kenyon 2001
Kenyon S, Boulvain M. Antibiotics for preterm premature rupture
of membranes. Cochrane Database of Systematic Reviews 2001, Issue
3.
Kenyon 2003
Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture
of membranes. Cochrane Database of Systematic Reviews 2003, Issue
2. [DOI: 10.1002/14651858.CD001058]
Kenyon 2004
Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture
of the membranes: a systematic review. Obstetrics & Gynecology
2004;104(5 Pt 1):10517.

Indicates the major publication for the study

Antibiotics for preterm rupture of membranes (Review) 18

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Amon 1988a

Methods Randomised trial. No mention of method of randomisation. Not placebo controlled or

blinded.

Participants 82 women treatment 43 control 39. Inclusions: 20-34 weeks pregnant. PPROM con-
firmed by sterile speculum. Singleton pregnancy only.

Interventions Treatment group: ampicillin 1 gm IV every 6 hours for 24 hours. Maintained on oral
500 mg ampicillin 6 hourly until delivery. In labour they were recommenced on 1 gm
intravenous ampicillin.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Unclear No information given.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information available.

Camli 1997

Methods Randomised trial - no mention of the method of randomisation.

Participants 31 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.

Antibiotics for preterm rupture of membranes (Review) 19

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Camli 1997 (Continued)

Interventions Treatment group oral ampicillin 1 gm 4 x daily.

No placebo arm or tocolysis used.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Unclear No information given.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information available.

Christmas 1992

Methods Randomised trial. Using sequentially numbered sealed envelopes. Not placebo controlled
or blinded. The control group received IV fluids without antibiotics for first 24 hours.

Participants 94 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.

Interventions Treatment: 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.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Antibiotics for preterm rupture of membranes (Review) 20

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Christmas 1992 (Continued)

Adequate sequence generation? Unclear No information given.

Allocation concealment? Yes Using sequentially numbered sealed en-

velopes.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Cox 1995

Methods Randomised controlled trial.

Participants 62 women PPROM between 24 and 29 weeks pregnant. Not stated whether multiple
pregnancy included.

Interventions Co-amoxiclav 3 gm 6 hourly for 4 doses then co-amoxiclav 500 mg 6 hourly for 5 days
or matching placebo.

Outcomes Prolongation of pregnancy.

Neonatal mortality and morbidity.

Notes Data 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

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Unclear No information given.

Blinding? Yes Stated as double blind study.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Antibiotics for preterm rupture of membranes (Review) 21

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cox 1995 (Continued)

Free of other bias? Unclear No information given.

Ernest 1994

Methods Randomised 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.

Participants 148 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.

Interventions 4 hourly IV 1 million units benzylpenicillin for 12-24 hours - oral 250 mg penicillin
twice daily before delivery or a matched placebo.

Outcomes Latency 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

Item Authors judgement Description

Adequate sequence generation? Yes Table of random numbers.

Allocation concealment? Yes Stated that nurses were not involved in the
preparation or release of either antibiotic or
placebo.

Blinding? Yes Patients and staff blinded.

All outcomes

Incomplete outcome data addressed? Yes Data excluded for 4 women who were
All outcomes treated with antibiotics outside the proto-
col.

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Antibiotics for preterm rupture of membranes (Review) 22

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Fuhr 2006

Methods Randomised 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 gm given 3 x day for 7 days or placebo.

All women given corticosteroids and tocolytics IV.

Outcomes Prolongation 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

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Unclear No information given.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appears complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Garcia 1995

Methods Randomised 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.

Antibiotics for preterm rupture of membranes (Review) 23

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Garcia 1995 (Continued)

Interventions Erythromycin 500 mg 6 hourly orally until delivery. Matched placebo given until delivery.

Outcomes Maternal 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

Item Authors judgement Description

Adequate sequence generation? Yes Computer generated.

Allocation concealment? Unclear No information given.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Grable 1996

Methods 60 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.

Participants 60 women randomised. Inclusions <= 35 weeks with documented PPROM.

Exclusions: digital examination of cx, non-reassuring stress test, presence of chorioam-
nionitis, abruptio placenta, pre-eclampsia, multiple pregnancy and penicillin allergy.

Interventions IV ampicillin 2 gm every 6 hours for 24 hours followed by 500 mg oral ampicillin until
delivery or discharge. Matched placebos.

Outcomes Maternal morbidity. Neonatal mortality and morbidity.

Notes Study divided into GBS positive and negative patients. Unclear whether clinician knew
of positive culture.

Risk of bias

Item Authors judgement Description

Antibiotics for preterm rupture of membranes (Review) 24

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Grable 1996 (Continued)

Adequate sequence generation? Yes Randomisation based on random numbers

tables with blocks providing 1:1 ratio and
balancing every 6 women.

Allocation concealment? Yes Randomisation and preparation of drugs

conducted in pharmacy.

Blinding? Yes Double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appears complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Johnston 1990

Methods Randomised double-blind placebo controlled trial. Randomisation table generated by

consecutive coin toss, the randomisation schedule kept in pharmacy.

Participants 85 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.

Interventions IV 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.

Outcomes Not 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.

Notes Single 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.

Antibiotics for preterm rupture of membranes (Review) 25

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Johnston 1990 (Continued)

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Randomisation table generated by consec-

utive coin toss.

Allocation concealment? Yes The randomisation schedule kept in phar-

macy.

Blinding? Yes Randomisation schedule stated as not be-

All outcomes ing available to clinicians.

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Kenyon 2001

Methods Randomised 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).

Interventions Co-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 impair-
ment (severe, moderate or mild). Other outcomes included death, behaviour (using the
Strengths and Difficulties questionnaire) prespecified questions on respiratory symp-
toms, hospital admissions, convulsions, other prespecified medical conditions and de-
mographic data. Educational attainment was evaluated for children in England using
data from National Cirriculum Tests at 7 years of age (Key Stage 1).

Notes Multicentre 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

Antibiotics for preterm rupture of membranes (Review) 26

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kenyon 2001 (Continued)

affected. Consumers involved in drawing up of protocol and information for women.

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes By computer using randomly generated

blocks of 4.

Allocation concealment? Yes Sequentially numbered drug boxes of iden-

tical appearance.

Blinding? Yes Stated that clinicians remained blind to

All outcomes 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 addressed? Yes 2 women lost to follow up and 15 protocol
All outcomes violations.
In the follow up study outcome data were
determined for 75% of eligible children.

Free of selective reporting? Yes No selective reporting.

Protocol published for follow up study.

Free of other bias? Yes The study appears to be free of other

sources of bias.

Kurki 1992

Methods Randomised double blind placebo controlled trial.

Participants 101 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.

Interventions 2 doses of IV penicillin (5 mu) or matched placebo.

Outcomes Prolongation of pregnancy. Infection, neonatal morbidity and mortality. Long-term de-
velopment at 2 years.

Notes Department 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

Antibiotics for preterm rupture of membranes (Review) 27

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kurki 1992 (Continued)

reported.

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Yes Stated as being by sealed envelope.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Lewis 2003

Methods Randomised 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.

Participants 84 singleton pregnancies were randomised between 24-34 weeks gestation. Exclusions
included known infection, absence of cervical cerclage, not penicillin allergic. Corticos-
teroids given to all participants.

Interventions Ampicillin-sulbactam 3 g intravenously every six hours for either 3 or 7 days.

Outcomes Primary outcome was latency period between membrane rupture and delivery. Infection
and neonatal morbidity and mortality.

Notes 3 study sites in Tennessee USA.

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Randomised using table of arbitrary num-

bers in blocks of 10.

Allocation concealment? Yes Indicator cards placed in sealed envelopes

which were sequentially numbered and
stored on an area away from the enrolment
site

Antibiotics for preterm rupture of membranes (Review) 28

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lewis 2003 (Continued)

Blinding? Yes Stated that all carers were unaware of the

All outcomes randomisation process.

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Lockwood 1993a

Methods Randomised double blind placebo controlled trial.

Participants 75 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 ill-
ness, 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.

Interventions Piperacillin 3 gm IV 6 hourly 72 hours or placebo.

Outcomes Prolongation of pregnancy.

Neonatal outcomes.

Notes Recruitment 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

Item Authors judgement Description

Adequate sequence generation? Yes Computer-generated randomisation se-

quence.

Allocation concealment? Yes Same deposited in pharmacy.

Blinding? Yes Stated all healthcare providers were blinded

All outcomes to allocation.

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Antibiotics for preterm rupture of membranes (Review) 29

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lockwood 1993a (Continued)

Free of other bias? Unclear No information given.

Magwali 1999

Methods Randomised trial not placebo controlled. Randomisation by opening sealed consecutive
opaque envelopes in admission room.

Participants 171 women randomised 84 in treatment group 87 in no treatment group. Inclusion

PROM 26-36 weeks gestation drainage of liquor confirmed by sterile speculum. Ex-
clusions: clinical signs of chorioamnionitis, multiple pregnancy, those with any con-
traindication to continuing the pregnancy and those who had just completed a course
of antibiotics for another reason.

Interventions Co-amoxiclav for 5 days. No mention of daily frequency or mg of drugs.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Yes Stated as being by sealed envelope.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Minimal loss to follow up - 2 in the treat-
All outcomes ment and 1 in the no treatment group.

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information available.

McGregor 1991

Methods Randomised double blind placebo controlled trial.

Computer-generated random number list. Sequentially numbered bottles.

Participants 65 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 deliv-
ery (fetal distress, prolapsed cord, pregnancy-induced hypertension, abruptio placentae)
Antibiotics for preterm rupture of membranes (Review) 30
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
McGregor 1991 (Continued)

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.

Interventions Erythromycin 333 mg 3 x daily or placebo 7 days or until active labour started.

Outcomes Prolongation 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 Blancos paper has ever been published.

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Computer-generated random number list.

Allocation concealment? Yes Sequentially numbered bottles.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appears complete after 10 exclusions.
All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information available.

Mercer 1992

Methods Randomised double blind placebo controlled trial.

Computerised random number tables. Administered by the pharmacy.
Stratified at 30 weeks. gestational age.

Participants Inclusions: 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.

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mercer 1992 (Continued)

Interventions Oral 333 mg erythromycin. 8 hourly from randomisation to delivery with matched
placebo.

Outcomes Not clearly stated.

Prolongation of pregnancy. Reduction of infectious morbidity.

Notes Single 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

Item Authors judgement Description

Adequate sequence generation? Yes Computerised random number tables.

Allocation concealment? Yes Administered by the pharmacy.

Blinding? Yes States that all involved remained blind to

All outcomes treatment allocation.

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Mercer 1997

Methods Randomised double blind placebo controlled trial. Urn randomisation scheme (a pro-
cedure to increase the likelihood of obtaining an equal number of subjects in each arm)
, stratified by centre.

Participants 614 women with PPROM at 24-32 weeks gestation. Inclusion criteria: membrane rup-
ture within 36 hours of randomisation; cervical dilatation 3 cm or less on usual exami-
nation; < 5 contractions in 6 minutes.
Exclusion criteria: non-reassuring, fetal testing; vaginal bleeding; maternal or fetal indi-
cation for delivery, cervical cerclage in place, antibiotics within the last 5 days, corticos-
teroids 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 crite-
rion.
Tocolysis and corticosteroids were prohibited after randomisation.

Antibiotics for preterm rupture of membranes (Review) 32

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mercer 1997 (Continued)

Interventions Ampicillin 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.

Outcomes Composite 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 necrotising enterocolitis, 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.

Notes 11 centres - USA.

February 1992-January 1995.
1867 women screened.
804 eligible.
614 agreed to participate.
29 twin gestations.
Group B Strep positive: 118/614.
3 women lost to follow up.

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes Urn randomisation scheme (a procedure

to increase the likelihood of obtaining an
equal number of subjects in each arm),
stratified by centre.

Allocation concealment? Yes Treatment given by pharmacy.

Blinding? Yes States all involved remained blinded to

All outcomes treatment allocation.

Incomplete outcome data addressed? Yes Only 3 withdrawals (2 in placebo and 1 in

All outcomes treatment arm).

Free of selective reporting? Unclear No protocol available.

Free of other bias? Unclear No information given.

Morales 1989

Methods Randomised 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.

Antibiotics for preterm rupture of membranes (Review) 33

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Morales 1989 (Continued)

Participants Randomised: 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.

Interventions 2 g IV ampicillin every 6 hours until results of cervical cultures negative.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Yes States as sealed envelopes into 1 of 4 groups.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Ovalle Salas 1997

Methods Randomised double blind placebo controlled trial. No comment as to method of ran-
domisation.

Participants 88 women.
Inclusions: women with PPROM 24-34 weeks, PPROM diagnosed with sterile specu-
lum-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, docu-
mented 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).

Antibiotics for preterm rupture of membranes (Review) 34

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ovalle Salas 1997 (Continued)

Interventions Clindamycin 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.

Outcomes Prolongation of pregnancy, maternal infection related morbidity, birthweight, neonatal

morbidity and admission to neonatal intensive care unit.

Notes November 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

Item Authors judgement Description

Adequate sequence generation? Unclear No information given.

Allocation concealment? Unclear No information given.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete with 1 loss to follow
All outcomes up.

Free of selective reporting? Unclear Protocol not available.

Free of other bias? No Trial stopped after intermediate evaluation

showed treatment group had better out-
come.

Owen 1993a

Methods Randomised not placebo controlled. Randomised using sealed opaque envelopes deter-
mined by computer algorithm.

Participants 118 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.

Interventions IV 1 gm 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

Antibiotics for preterm rupture of membranes (Review) 35

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Owen 1993a (Continued)

delivery or diagnosis of chorioamnionitis.

Outcomes Death only included.

Notes

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Yes By computer algorithm.

Allocation concealment? Yes Sealed opaque envelope.

Blinding? No Not blinded.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete - 1 woman lost to
All outcomes follow up in control group.

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Segel 2003

Methods Randomised 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.

Participants 48 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.

Interventions For 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.

Outcomes Primary outcome of prolongation of pregnancy for at least 7 days. Secondary outcomes
included rated of chorioamnionitis, postpartum endometritis and neonatal morbidity
and mortality.

Notes Study took place between September 1999 - December 2001, Pennsylvania USA.

Risk of bias

Antibiotics for preterm rupture of membranes (Review) 36

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Segel 2003 (Continued)

Item Authors judgement Description

Adequate sequence generation? Yes Computer-generated random number ta-

ble in blocks of 4.

Allocation concealment? Yes Study medicine given by pharmacy in iden-

tical packs.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information given.

Svare 1997a

Methods Randomised double blind placebo controlled trial. Block randomisation done using
computer-generated numbers.

Participants 67 women randomised. 26 + 0 - 33 + 6 rupture of membranes, leakage of amniotic fluid

at vaginal speculum examination. Preceding onset of uterine contractions. Singleton
pregnancies.

Interventions Ampicillin 2 gm 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.

Outcomes Latency period from admission - delivery. Gestational age at delivery. Preterm delivery
less than 37/40 maternal - neonatal infection birthweight.

Notes October 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

Item Authors judgement Description

Adequate sequence generation? Yes Block randomisation done using com-

puter-generated numbers.

Antibiotics for preterm rupture of membranes (Review) 37

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Svare 1997a (Continued)

Allocation concealment? Unclear No information available.

Blinding? Yes Stated as double blind trial.

All outcomes

Incomplete outcome data addressed? Yes Data appear complete.

All outcomes

Free of selective reporting? Unclear Protocol not available.

Free of other bias? Unclear No information available

cx: cervix
EDD: expected date of delivery
GBS:
GP: group
IM: intramuscular
IUCD: intrauterine contraceptive device
IUGR: intrauterine growth retardation
IV: intravenous
IVH: intraventricular haemorrhage
L/S:
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

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Almeida 1996 Joint 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 1991 Random allocation to 2 management protocols (conservative versus induction).

Blanco 1993 Abstract only - data requested.

Following comments received during the publication of this review in 2004 we have written to Brian Mercer
who included this data in a Lancet review in 1995 and James McGregor who was listed as an author.

Antibiotics for preterm rupture of membranes (Review) 38

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Cardamakis 1990 Abstract only - study randomised but no mention of whether blinded. Comparison of ampicillin versus ceftri-
axone (doses not given). Minimal data expressed as P values.

Carroll 2000 Abstract only containing no usable data (P values only).

Debodinance 1990 Randomised trial of antibiotic treatment (mezlocillin) for women with PPROM. Not placebo controlled and
no clinical outcomes reported. Mortality data requested from author.

Dunlop 1986 Study 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 1990 Study which 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 1974 Participants 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.

Halis 2001 Abstract containing no usable data. GBS prophylaxis also given for carriers.

Julien 2002 Study compared antibiotic versus placebo only after 48 hour intravenous antibiotic treatment to all.

Kim 2008 Study was nether randomised or placebo controlled.

Lebherz 1963 Double blind randomised controlled trial of 1912 women but no mention of gestation at recruitment.

Lewis 1995 Study comparing treatment of women with PROM at 25 to 35 weeks gestation in a randomised blinded
trial comparing ampicillin-sulbactam with ampicillin: ie 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 1993a Comparative study; not placebo controlled.

Matsuda 1993b Prospective study, not randomised, of conservative versus aggressive management of women with PPROM.
Aggressive management: IV antibiotics + tocolytics. Conservative management consisted of bedrest only.

Antibiotics for preterm rupture of membranes (Review) 39

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Mbu 1998 Allocation by alternation.

McCaul 1992 Double 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 womens data; in the meantime, excluded.

Norri 1991 Abstract only - does not say whether study was placebo controlled nor could any publication be found.

Ogasawara 1996 Abstract only - data in further publication.

Ogasawara 1997 Randomised 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 1999 Randomised 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 2002 Randomised 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 1993 Comparison 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.

GBS:
IV: intravenous
PPROM: preterm prelabour rupture of membranes
PROM: premature rupture of membranes
RDS: respiratory distress syndrome
SPL:

Antibiotics for preterm rupture of membranes (Review) 40

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Any antibiotic versus placebo

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Maternal death 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only
1.1 Any antibiotic versus 3 763 Risk Ratio (M-H, Random, 95% CI) Not estimable
placebo
1.2 All penicillin (excluding 1 85 Risk Ratio (M-H, Random, 95% CI) Not estimable
co-amoxiclav) versus placebo
1.3 Beta lactum (including co- 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
amoxiclav) versus placebo
1.4 Macrolide (including 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
erythromycin) versus placebo
1.5 Other antibiotic versus 2 678 Risk Ratio (M-H, Random, 95% CI) Not estimable
placebo
2 Serious maternal morbidity 0 Risk Ratio (M-H, Random, 95% CI) Subtotals only
2.1 Any antibiotic versus 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
placebo
2.2 All penicillin (excluding 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
co-amoxiclav) versus placebo
2.3 Beta lactum (including co- 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
amoxiclav) versus placebo
2.4 Macrolide (including 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
erythromycin) versus placebo
2.5 Other antibiotic versus 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
placebo
3 Perinatal death/death before 12 Risk Ratio (M-H, Random, 95% CI) Subtotals only
discharge
3.1 Any antibiotic versus 12 6301 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.76, 1.14]
placebo
3.2 All penicillin (excluding 4 332 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.31, 1.97]
co-amoxiclav) versus placebo
3.3 Beta lactum (including 2 1880 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.15, 2.56]
co-amoxiclav) versus placebo
3.4 Macrolide (including 4 2138 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.43, 1.60]
erythromycin) versus placebo
3.5 Other antibiotic versus 3 762 Risk Ratio (M-H, Random, 95% CI) 1.13 [0.68, 1.88]
placebo
4 Neonatal infection including 12 Risk Ratio (M-H, Random, 95% CI) Subtotals only
pneumonia
4.1 Any antibiotic versus 12 1680 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.52, 0.85]
placebo
4.2 All penicillin (excluding 5 521 Risk Ratio (M-H, Random, 95% CI) 0.30 [0.13, 0.68]
co-amoxiclav) versus placebo
4.3 Beta lactum (including 1 62 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.88]
co-amoxiclav) versus placebo
Antibiotics for preterm rupture of membranes (Review) 41
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 4.4 Macrolide (including 3 334 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.45, 1.37]
erythromycin) versus placebo
4.5 Other antibiotic versus 3 763 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.53, 0.95]
placebo
5 Neonatal necrotising 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
enterocolitis
5.1 Any antibiotic versus 11 6229 Risk Ratio (M-H, Random, 95% CI) 1.09 [0.65, 1.83]
placebo
5.2 All penicillin (excluding 3 262 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.25, 2.97]
co-amoxiclav) versus placebo
5.3 Beta lactum (including 2 1880 Risk Ratio (M-H, Random, 95% CI) 4.72 [1.57, 14.23]
co-amoxiclav) versus placebo
5.4 Macrolide (including 3 2076 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.45, 1.69]
erythromycin) versus placebo
5.5 Other antibiotic versus 4 823 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.54, 1.47]
placebo
6 Oxygen treatment > 36 weeks 1 Risk Ratio (M-H, Random, 95% CI) Subtotals only
postconceptual age
6.1 Any antibiotic versus 1 4809 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.70, 1.17]
placebo
6.2 All penicillin (excluding 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
co-amoxiclav) versus placebo
6.3 Beta lactum (including 1 1818 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.63, 1.36]
co-amoxiclav) versus placebo
6.4 Macrolide (including 1 1803 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.61, 1.32]
erythromycin) versus placebo
6.5 Other antibiotic versus 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
placebo
7 Major cerebral abnormality on 12 Risk Ratio (M-H, Random, 95% CI) Subtotals only
ultrasound before discharge
7.1 Any antibiotic versus 12 6289 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.68, 0.98]
placebo
7.2 All penicillin (excluding 3 262 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.25, 0.96]
co-amoxiclav) versus placebo
7.3 Beta lactum (including 2 1880 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.52, 1.16]
co-amoxiclav) versus placebo
7.4 Macrolide (including 4 2136 Risk Ratio (M-H, Random, 95% CI) 0.93 [0.60, 1.44]
erythromycin) versus placebo
7.5 Other antibiotic versus 4 823 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.45, 1.64]
placebo
8 Birth before 37 weeks gestation 3 4931 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.98, 1.03]
9 Major adverse drug reaction 3 5487 Risk Ratio (M-H, Random, 95% CI) Not estimable
10 Maternal infection after 4 5547 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.80, 1.02]
delivery prior to discharge
11 Chorioamnionitis 11 1559 Risk Ratio (M-H, Random, 95% CI) 0.66 [0.46, 0.96]
12 Caesarean section 11 6317 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.88, 1.05]
13 Days from birth till discharge 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
of mother
14 Days from randomisation to 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
birth

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Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15 Birth within 48 hours of 7 5927 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.58, 0.87]
randomisation
16 Birth within 7 days of 7 5965 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.71, 0.89]
randomisation
17 Birthweight 12 6374 Mean Difference (IV, Random, 95% CI) 53.83 [7.06, 100.60]
18 Birthweight < 2500 g 2 4876 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.96, 1.04]
19 Neonatal intensive care 4 5023 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.84, 1.13]
20 Days in neonatal intensive care 3 225 Mean Difference (IV, Random, 95% CI) -5.05 [-9.77, -0.33]
unit
21 Positive neonatal blood culture 3 4961 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.63, 0.99]
22 Neonatal respiratory distress 12 6287 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.83, 1.09]
syndrome
23 Treatment with surfactant 1 4809 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.72, 0.96]
24 Number of babies requiring 2 4924 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.80, 1.02]
ventilation
25 Number of babies requiring 1 4809 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.81, 0.96]
oxygen therapy
26 Neonatal oxygenation > 28 3 5487 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.61, 1.03]
days
27 Neonatal encephalopathy 1 60 Risk Ratio (M-H, Random, 95% CI) Not estimable
28 Serious childhood disability at 1 3171 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.91, 1.12]
approximately 2 years

Comparison 2. Erythromycin versus co-amoxiclav

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Maternal death 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
2 Serious maternal morbidity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
3 Major adverse drug reaction 1 2395 Risk Ratio (M-H, Random, 95% CI) Not estimable
4 Maternal infection after delivery 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.87, 1.20]
prior to discharge
5 Chorioamnionitis 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
6 Caesarean section 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.90, 1.16]
7 Days from randomisation to 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
birth
8 Days from birth till discharge of 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
mother
9 Birth within 48 hours of 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.14 [1.02, 1.28]
randomisation
10 Birth within 7 days of 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.06 [0.99, 1.13]
randomisation
11 Birth before 37 weeks gestation 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.96, 1.03]
12 Birthweight 1 2395 Mean Difference (IV, Random, 95% CI) 19.0 [-41.92, 79.92]
13 Birthweight < 2500 g 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.95, 1.05]
14 Neonatal intensive care 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.95, 1.05]
15 Days in neonatal intensive care 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
unit
Antibiotics for preterm rupture of membranes (Review) 43
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16 Neonatal infection including 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
pneumonia
17 Positive neonatal blood culture 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.62, 1.15]
18 Neonatal necrotising 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.46 [0.23, 0.94]
enterocolitis
19 Neonatal respiratory distress 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.99 [0.84, 1.16]
syndrome
20 Treatment with surfactant 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.81, 1.19]
21 Number of babies requiring 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.86, 1.17]
ventilation
22 Number of babies requiring 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.87, 1.10]
oxygen therapy
23 Neonatal oxygenation > 28 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.66, 1.12]
days
24 Oxygen treatment > 36 weeks 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.70, 1.34]
postconceptual age
25 Neonatal encephalopathy 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
26 Major cerebral abnormality on 1 2395 Risk Ratio (M-H, Random, 95% CI) 1.10 [0.74, 1.63]
ultrasound before discharge
27 Perinatal death/death before 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.66, 1.23]
discharge
28 Serious childhood disability at 1 1612 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.79, 1.01]
approximately 2 years

Comparison 4. Antibiotics versus no antibiotic

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Perinatal death/death before 18 Risk Ratio (M-H, Random, 95% CI) Subtotals only
discharge
1.1 New Subgroup 18 6872 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.74, 1.08]
1.2 Antibiotics versus no 6 571 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.41, 1.14]
treatment (no placebo)

Comparison 5. 3 versus 7 day ampicillin regimens

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Maternal death 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
2 Serious maternal morbidity 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
3 Major adverse drug reaction 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
4 Maternal infection after delivery 1 84 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.36, 4.33]
prior to discharge
5 Chorioamnionitis 1 84 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.33, 1.63]
Antibiotics for preterm rupture of membranes (Review) 44
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6 Caesarean section 1 84 Risk Ratio (M-H, Random, 95% CI) 1.18 [0.72, 1.91]
7 Days from randomisation to 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
birth
8 Days from birth till discharge of 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
mother
9 Birth within 48 hours of 1 84 Risk Ratio (M-H, Random, 95% CI) 1.14 [0.46, 2.87]
randomisation
10 Birth within 7 days of 1 84 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.70, 1.42]
randomisation
11 Birth before 37 weeks gestation 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
12 Birthweight 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
13 Birthweight < 2500 g 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
14 Neonatal intensive care 1 84 Risk Ratio (M-H, Random, 95% CI) 1.0 [0.84, 1.19]
15 Days in neonatal intensive care 0 0 Mean Difference (IV, Random, 95% CI) Not estimable
unit
16 Neonatal infection including 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
pneumonia
17 Positive neonatal blood culture 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
18 Neonatal necrotising 2 130 Risk Ratio (M-H, Random, 95% CI) 0.43 [0.07, 2.86]
enterocolitis
19 Neonatal respiratory distress 2 130 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.62, 1.49]
syndrome
20 Treatment with surfactant 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
21 Number of babies requiring 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
ventilation
22 Number of babies requiring 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
oxygen therapy
23 Neonatal oxygenation > 28 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
days
24 Oxygen treatment > 36 weeks 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
postconceptual age
25 Neonatal encephalopathy 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
26 Neonatal intraventricular 2 130 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.04, 3.12]
haemorrhage
27 Perinatal death/death before 2 130 Risk Ratio (M-H, Random, 95% CI) 0.40 [0.05, 2.94]
discharge
28 Serious childhood disability at 0 0 Risk Ratio (M-H, Random, 95% CI) Not estimable
approximately 2 years

Antibiotics for preterm rupture of membranes (Review) 45

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.1. Comparison 1 Any antibiotic versus placebo, Outcome 1 Maternal death.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 1 Maternal death

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Johnston 1990 0/40 0/45 0.0 [ 0.0, 0.0 ]

Mercer 1997 0/299 0/312 0.0 [ 0.0, 0.0 ]

Svare 1997a 0/30 0/37 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 369 394 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Test for overall effect: Z = 0.0 (P < 0.00001)
2 All penicillin (excluding co-amoxiclav) versus placebo
Johnston 1990 0/40 0/45 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 40 45 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
3 Beta lactum (including co-amoxiclav) versus placebo
Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
4 Macrolide (including erythromycin) versus placebo
Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
5 Other antibiotic versus placebo
Mercer 1997 0/299 0/312 0.0 [ 0.0, 0.0 ]

Svare 1997a 0/30 0/37 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 329 349 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Antibiotics for preterm rupture of membranes (Review) 46

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.3. Comparison 1 Any antibiotic versus placebo, Outcome 3 Perinatal death/death before
discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 3 Perinatal death/death before discharge

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Cox 1995 1/31 5/31 1.0 % 0.20 [ 0.02, 1.61 ]

Garcia 1995 2/30 5/30 1.7 % 0.40 [ 0.08, 1.90 ]

Grable 1996 0/31 2/29 0.5 % 0.19 [ 0.01, 3.75 ]

Johnston 1990 3/40 4/45 2.1 % 0.84 [ 0.20, 3.54 ]

Kenyon 2001 226/3584 82/1225 71.2 % 0.94 [ 0.74, 1.20 ]

Kurki 1992 1/57 1/58 0.6 % 1.02 [ 0.07, 15.88 ]

Lockwood 1993a 3/37 3/35 1.8 % 0.95 [ 0.20, 4.38 ]

McGregor 1991 6/28 0/27 0.5 % 12.55 [ 0.74, 212.52 ]

Mercer 1992 6/106 10/114 4.4 % 0.65 [ 0.24, 1.71 ]

Mercer 1997 19/299 18/312 10.9 % 1.10 [ 0.59, 2.06 ]

Ovalle Salas 1997 7/42 6/43 4.2 % 1.19 [ 0.44, 3.26 ]

Svare 1997a 2/30 2/37 1.2 % 1.23 [ 0.18, 8.25 ]

Subtotal (95% CI) 4315 1986 100.0 % 0.93 [ 0.76, 1.14 ]

Total events: 276 (Treatment), 138 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 8.73, df = 11 (P = 0.65); I2 =0.0%
Test for overall effect: Z = 0.69 (P = 0.49)
2 All penicillin (excluding co-amoxiclav) versus placebo
Grable 1996 0/31 2/29 9.6 % 0.19 [ 0.01, 3.75 ]

Johnston 1990 3/40 4/45 42.0 % 0.84 [ 0.20, 3.54 ]

Kurki 1992 1/57 1/58 11.5 % 1.02 [ 0.07, 15.88 ]

Lockwood 1993a 3/37 3/35 36.9 % 0.95 [ 0.20, 4.38 ]

Subtotal (95% CI) 165 167 100.0 % 0.78 [ 0.31, 1.97 ]

Total events: 7 (Treatment), 10 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.00, df = 3 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 0.53 (P = 0.60)
3 Beta lactum (including co-amoxiclav) versus placebo
Cox 1995 1/31 5/31 28.4 % 0.20 [ 0.02, 1.61 ]

Kenyon 2001 79/1205 41/613 71.6 % 0.98 [ 0.68, 1.41 ]

0.001 0.01 0.1 1 10 100 1000

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Subtotal (95% CI) 1236 644 100.0 % 0.62 [ 0.15, 2.56 ]
Total events: 80 (Treatment), 46 (Control)
Heterogeneity: Tau2 = 0.69; Chi2 = 2.17, df = 1 (P = 0.14); I2 =54%
Test for overall effect: Z = 0.65 (P = 0.51)
4 Macrolide (including erythromycin) versus placebo
Garcia 1995 2/30 5/30 14.0 % 0.40 [ 0.08, 1.90 ]

Kenyon 2001 70/1190 41/613 54.1 % 0.88 [ 0.61, 1.28 ]

McGregor 1991 6/28 0/27 5.0 % 12.55 [ 0.74, 212.52 ]

Mercer 1992 6/106 10/114 26.9 % 0.65 [ 0.24, 1.71 ]

Subtotal (95% CI) 1354 784 100.0 % 0.83 [ 0.43, 1.60 ]

Total events: 84 (Treatment), 56 (Control)
Heterogeneity: Tau2 = 0.17; Chi2 = 4.82, df = 3 (P = 0.19); I2 =38%
Test for overall effect: Z = 0.56 (P = 0.57)
5 Other antibiotic versus placebo
Mercer 1997 19/299 18/312 66.8 % 1.10 [ 0.59, 2.06 ]

Ovalle Salas 1997 7/42 6/42 25.9 % 1.17 [ 0.43, 3.18 ]

Svare 1997a 2/30 2/37 7.2 % 1.23 [ 0.18, 8.25 ]

Subtotal (95% CI) 371 391 100.0 % 1.13 [ 0.68, 1.88 ]

Total events: 28 (Treatment), 26 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 2 (P = 0.99); I2 =0.0%
Test for overall effect: Z = 0.46 (P = 0.65)

0.001 0.01 0.1 1 10 100 1000

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 Analysis 1.4. Comparison 1 Any antibiotic versus placebo, Outcome 4 Neonatal infection including
pneumonia.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 4 Neonatal infection including pneumonia

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Cox 1995 0/31 1/31 0.6 % 0.33 [ 0.01, 7.88 ]

Ernest 1994 0/77 2/67 0.7 % 0.17 [ 0.01, 3.57 ]

Fuhr 2006 1/47 7/58 1.4 % 0.18 [ 0.02, 1.38 ]

Garcia 1995 4/30 5/30 4.1 % 0.80 [ 0.24, 2.69 ]

Johnston 1990 3/40 11/45 4.2 % 0.31 [ 0.09, 1.02 ]

Kurki 1992 0/57 1/58 0.6 % 0.34 [ 0.01, 8.15 ]

Lockwood 1993a 2/37 4/35 2.3 % 0.47 [ 0.09, 2.42 ]

McGregor 1991 1/24 1/27 0.8 % 1.13 [ 0.07, 17.02 ]

Mercer 1992 14/109 19/114 15.0 % 0.77 [ 0.41, 1.46 ]

Mercer 1997 46/299 67/312 52.7 % 0.72 [ 0.51, 1.01 ]

Ovalle Salas 1997 7/42 7/43 6.6 % 1.02 [ 0.39, 2.67 ]

Svare 1997a 7/30 16/37 10.9 % 0.54 [ 0.26, 1.14 ]

Subtotal (95% CI) 823 857 100.0 % 0.67 [ 0.52, 0.85 ]

Total events: 85 (Treatment), 141 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 6.23, df = 11 (P = 0.86); I2 =0.0%
Test for overall effect: Z = 3.22 (P = 0.0013)
2 All penicillin (excluding co-amoxiclav) versus placebo
Ernest 1994 0/77 2/67 7.3 % 0.17 [ 0.01, 3.57 ]

Fuhr 2006 1/47 7/58 15.6 % 0.18 [ 0.02, 1.38 ]

Johnston 1990 3/40 11/45 45.7 % 0.31 [ 0.09, 1.02 ]

Kurki 1992 0/57 1/58 6.6 % 0.34 [ 0.01, 8.15 ]

Lockwood 1993a 2/37 4/35 24.8 % 0.47 [ 0.09, 2.42 ]

Subtotal (95% CI) 258 263 100.0 % 0.30 [ 0.13, 0.68 ]

Total events: 6 (Treatment), 25 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.70, df = 4 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 2.88 (P = 0.0040)
3 Beta lactum (including co-amoxiclav) versus placebo
Cox 1995 0/31 1/31 100.0 % 0.33 [ 0.01, 7.88 ]

0.001 0.01 0.1 1 10 100 1000

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Subtotal (95% CI) 31 31 100.0 % 0.33 [ 0.01, 7.88 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.68 (P = 0.50)
4 Macrolide (including erythromycin) versus placebo
Garcia 1995 4/30 5/30 20.8 % 0.80 [ 0.24, 2.69 ]

McGregor 1991 1/24 1/27 4.1 % 1.13 [ 0.07, 17.02 ]

Mercer 1992 14/109 19/114 75.1 % 0.77 [ 0.41, 1.46 ]

Subtotal (95% CI) 163 171 100.0 % 0.79 [ 0.45, 1.37 ]

Total events: 19 (Treatment), 25 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.07, df = 2 (P = 0.96); I2 =0.0%
Test for overall effect: Z = 0.84 (P = 0.40)
5 Other antibiotic versus placebo
Mercer 1997 46/299 67/312 75.0 % 0.72 [ 0.51, 1.01 ]

Ovalle Salas 1997 7/42 7/43 9.5 % 1.02 [ 0.39, 2.67 ]

Svare 1997a 7/30 16/37 15.6 % 0.54 [ 0.26, 1.14 ]

Subtotal (95% CI) 371 392 100.0 % 0.71 [ 0.53, 0.95 ]

Total events: 60 (Treatment), 90 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.08, df = 2 (P = 0.58); I2 =0.0%
Test for overall effect: Z = 2.29 (P = 0.022)

0.001 0.01 0.1 1 10 100 1000

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 Analysis 1.5. Comparison 1 Any antibiotic versus placebo, Outcome 5 Neonatal necrotising enterocolitis.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 5 Neonatal necrotising enterocolitis

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Cox 1995 5/31 0/31 3.1 % 11.00 [ 0.63, 190.79 ]

Fuhr 2006 1/47 3/58 4.8 % 0.41 [ 0.04, 3.83 ]

Grable 1996 1/31 1/29 3.3 % 0.94 [ 0.06, 14.27 ]

Johnston 1990 2/40 3/45 7.2 % 0.75 [ 0.13, 4.26 ]

Kenyon 2001 55/3584 6/1225 19.2 % 3.13 [ 1.35, 7.26 ]

Lockwood 1993a 2/37 0/35 2.8 % 4.74 [ 0.24, 95.33 ]

McGregor 1991 2/26 4/27 8.2 % 0.52 [ 0.10, 2.60 ]

Mercer 1992 8/106 12/114 18.9 % 0.72 [ 0.31, 1.69 ]

Mercer 1997 24/299 27/312 27.6 % 0.93 [ 0.55, 1.57 ]

Ovalle Salas 1997 0/42 1/43 2.5 % 0.34 [ 0.01, 8.14 ]

Svare 1997a 0/30 1/37 2.5 % 0.41 [ 0.02, 9.68 ]

Subtotal (95% CI) 4273 1956 100.0 % 1.09 [ 0.65, 1.83 ]

Total events: 100 (Treatment), 58 (Control)
Heterogeneity: Tau2 = 0.18; Chi2 = 13.98, df = 10 (P = 0.17); I2 =28%
Test for overall effect: Z = 0.32 (P = 0.75)
2 All penicillin (excluding co-amoxiclav) versus placebo
Fuhr 2006 1/47 3/58 31.3 % 0.41 [ 0.04, 3.83 ]

Johnston 1990 2/40 3/45 51.5 % 0.75 [ 0.13, 4.26 ]

Lockwood 1993a 2/37 0/35 17.3 % 4.74 [ 0.24, 95.33 ]

Subtotal (95% CI) 124 138 100.0 % 0.85 [ 0.25, 2.97 ]

Total events: 5 (Treatment), 6 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.71, df = 2 (P = 0.43); I2 =0.0%
Test for overall effect: Z = 0.25 (P = 0.80)
3 Beta lactum (including co-amoxiclav) versus placebo
Cox 1995 5/31 0/31 15.0 % 11.00 [ 0.63, 190.79 ]

Kenyon 2001 24/1205 3/613 85.0 % 4.07 [ 1.23, 13.46 ]

Subtotal (95% CI) 1236 644 100.0 % 4.72 [ 1.57, 14.23 ]

Total events: 29 (Treatment), 3 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0%

0.001 0.01 0.1 1 10 100 1000

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Test for overall effect: Z = 2.76 (P = 0.0058)
4 Macrolide (including erythromycin) versus placebo
Kenyon 2001 11/1190 3/613 26.3 % 1.89 [ 0.53, 6.75 ]

McGregor 1991 2/26 4/27 16.5 % 0.52 [ 0.10, 2.60 ]

Mercer 1992 8/106 12/114 57.2 % 0.72 [ 0.31, 1.69 ]

Subtotal (95% CI) 1322 754 100.0 % 0.88 [ 0.45, 1.69 ]

Total events: 21 (Treatment), 19 (Control)
Heterogeneity: Tau2 = 0.01; Chi2 = 2.03, df = 2 (P = 0.36); I2 =2%
Test for overall effect: Z = 0.39 (P = 0.70)
5 Other antibiotic versus placebo
Grable 1996 1/31 1/29 3.4 % 0.94 [ 0.06, 14.27 ]

Mercer 1997 24/299 27/312 91.5 % 0.93 [ 0.55, 1.57 ]

Ovalle Salas 1997 0/42 1/43 2.5 % 0.34 [ 0.01, 8.14 ]

Svare 1997a 0/30 1/37 2.5 % 0.41 [ 0.02, 9.68 ]

Subtotal (95% CI) 402 421 100.0 % 0.89 [ 0.54, 1.47 ]

Total events: 25 (Treatment), 30 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.61, df = 3 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 0.47 (P = 0.64)

0.001 0.01 0.1 1 10 100 1000

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 Analysis 1.6. Comparison 1 Any antibiotic versus placebo, Outcome 6 Oxygen treatment > 36 weeks
postconceptual age.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 6 Oxygen treatment > 36 weeks postconceptual age

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Kenyon 2001 202/3584 76/1225 100.0 % 0.91 [ 0.70, 1.17 ]

Subtotal (95% CI) 3584 1225 100.0 % 0.91 [ 0.70, 1.17 ]

Total events: 202 (Treatment), 76 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.74 (P = 0.46)
2 All penicillin (excluding co-amoxiclav) versus placebo
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable
3 Beta lactum (including co-amoxiclav) versus placebo
Kenyon 2001 69/1205 38/613 100.0 % 0.92 [ 0.63, 1.36 ]

Subtotal (95% CI) 1205 613 100.0 % 0.92 [ 0.63, 1.36 ]

Total events: 69 (Treatment), 38 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.41 (P = 0.69)
4 Macrolide (including erythromycin) versus placebo
Kenyon 2001 66/1190 38/613 100.0 % 0.89 [ 0.61, 1.32 ]

Subtotal (95% CI) 1190 613 100.0 % 0.89 [ 0.61, 1.32 ]

Total events: 66 (Treatment), 38 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.56 (P = 0.57)
5 Other antibiotic versus placebo
Subtotal (95% CI) 0 0 0.0 % 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: not applicable

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Antibiotics for preterm rupture of membranes (Review) 53

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 Analysis 1.7. Comparison 1 Any antibiotic versus placebo, Outcome 7 Major cerebral abnormality on
ultrasound before discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 7 Major cerebral abnormality on ultrasound before discharge

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 Any antibiotic versus placebo

Cox 1995 7/31 8/31 0.88 [ 0.36, 2.12 ]

Fuhr 2006 0/47 2/58 0.25 [ 0.01, 5.00 ]

Garcia 1995 2/30 1/30 2.00 [ 0.19, 20.90 ]

Grable 1996 0/31 0/29 0.0 [ 0.0, 0.0 ]

Johnston 1990 5/40 14/45 0.40 [ 0.16, 1.02 ]

Kenyon 2001 142/3584 61/1225 0.80 [ 0.59, 1.07 ]

Lockwood 1993a 5/37 7/35 0.68 [ 0.24, 1.93 ]

McGregor 1991 5/26 1/27 5.19 [ 0.65, 41.50 ]

Mercer 1992 11/106 14/114 0.85 [ 0.40, 1.78 ]

Mercer 1997 57/299 68/312 0.87 [ 0.64, 1.20 ]

Ovalle Salas 1997 3/42 7/43 0.44 [ 0.12, 1.58 ]

Svare 1997a 3/30 1/37 3.70 [ 0.41, 33.77 ]

Subtotal (95% CI) 4303 1986 0.81 [ 0.68, 0.98 ]

Total events: 240 (Treatment), 184 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 9.52, df = 10 (P = 0.48); I2 =0.0%
Test for overall effect: Z = 2.13 (P = 0.033)
2 All penicillin (excluding co-amoxiclav) versus placebo
Fuhr 2006 0/47 2/58 0.25 [ 0.01, 5.00 ]

Johnston 1990 5/40 14/45 0.40 [ 0.16, 1.02 ]

Lockwood 1993a 5/37 7/35 0.68 [ 0.24, 1.93 ]

Subtotal (95% CI) 124 138 0.49 [ 0.25, 0.96 ]

Total events: 10 (Treatment), 23 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.74, df = 2 (P = 0.69); I2 =0.0%
Test for overall effect: Z = 2.08 (P = 0.037)
3 Beta lactum (including co-amoxiclav) versus placebo
Cox 1995 7/31 8/31 0.88 [ 0.36, 2.12 ]

Kenyon 2001 46/1205 31/613 0.75 [ 0.48, 1.18 ]

Subtotal (95% CI) 1236 644 0.78 [ 0.52, 1.16 ]

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Total events: 53 (Treatment), 39 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.09, df = 1 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 1.24 (P = 0.22)
4 Macrolide (including erythromycin) versus placebo
Garcia 1995 2/30 1/30 2.00 [ 0.19, 20.90 ]

Kenyon 2001 50/1190 31/613 0.83 [ 0.54, 1.29 ]

McGregor 1991 5/26 1/27 5.19 [ 0.65, 41.50 ]

Mercer 1992 11/106 14/114 0.85 [ 0.40, 1.78 ]

Subtotal (95% CI) 1352 784 0.93 [ 0.60, 1.44 ]

Total events: 68 (Treatment), 47 (Control)
Heterogeneity: Tau2 = 0.03; Chi2 = 3.36, df = 3 (P = 0.34); I2 =11%
Test for overall effect: Z = 0.32 (P = 0.75)
5 Other antibiotic versus placebo
Grable 1996 0/31 0/29 0.0 [ 0.0, 0.0 ]

Mercer 1997 57/299 68/312 0.87 [ 0.64, 1.20 ]

Ovalle Salas 1997 3/42 7/43 0.44 [ 0.12, 1.58 ]

Svare 1997a 3/30 1/37 3.70 [ 0.41, 33.77 ]

Subtotal (95% CI) 402 421 0.85 [ 0.45, 1.64 ]

Total events: 63 (Treatment), 76 (Control)
Heterogeneity: Tau2 = 0.13; Chi2 = 2.74, df = 2 (P = 0.25); I2 =27%
Test for overall effect: Z = 0.47 (P = 0.64)

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 Analysis 1.8. Comparison 1 Any antibiotic versus placebo, Outcome 8 Birth before 37 weeks gestation.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 8 Birth before 37 weeks gestation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 3049/3584 1041/1225 84.3 % 1.00 [ 0.97, 1.03 ]

McGregor 1991 28/28 27/27 13.0 % 1.00 [ 0.93, 1.07 ]

Svare 1997a 27/30 34/37 2.7 % 0.98 [ 0.84, 1.14 ]

Total (95% CI) 3642 1289 100.0 % 1.00 [ 0.98, 1.03 ]

Total events: 3104 (Treatment), 1102 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.08, df = 2 (P = 0.96); I2 =0.0%
Test for overall effect: Z = 0.03 (P = 0.98)

0.1 0.2 0.5 1 2 5 10

Analysis 1.9. Comparison 1 Any antibiotic versus placebo, Outcome 9 Major adverse drug reaction.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 9 Major adverse drug reaction

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 0/3584 0/1225 0.0 [ 0.0, 0.0 ]

Mercer 1997 0/299 0/312 0.0 [ 0.0, 0.0 ]

Svare 1997a 0/30 0/37 0.0 [ 0.0, 0.0 ]

Total (95% CI) 3913 1574 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%
Test for overall effect: Z = 0.0 (P < 0.00001)

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 Analysis 1.10. Comparison 1 Any antibiotic versus placebo, Outcome 10 Maternal infection after delivery
prior to discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 10 Maternal infection after delivery prior to discharge

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Garcia 1995 8/30 7/30 1.9 % 1.14 [ 0.47, 2.75 ]

Kenyon 2001 686/3584 262/1225 90.5 % 0.89 [ 0.79, 1.02 ]

Mercer 1997 33/299 36/312 7.3 % 0.96 [ 0.61, 1.49 ]

Svare 1997a 2/30 1/37 0.3 % 2.47 [ 0.23, 25.91 ]

Total (95% CI) 3943 1604 100.0 % 0.91 [ 0.80, 1.02 ]

Total events: 729 (Treatment), 306 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 1.06, df = 3 (P = 0.79); I2 =0.0%
Test for overall effect: Z = 1.61 (P = 0.11)

0.001 0.01 0.1 1 10 100 1000

Analysis 1.11. Comparison 1 Any antibiotic versus placebo, Outcome 11 Chorioamnionitis.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 11 Chorioamnionitis

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Ernest 1994 3/77 9/67 6.4 % 0.29 [ 0.08, 1.03 ]

Garcia 1995 3/30 1/30 2.5 % 3.00 [ 0.33, 27.23 ]

Grable 1996 4/31 8/29 7.9 % 0.47 [ 0.16, 1.39 ]

Johnston 1990 3/40 16/45 7.2 % 0.21 [ 0.07, 0.67 ]

Kurki 1992 1/50 7/51 2.9 % 0.15 [ 0.02, 1.14 ]

Lockwood 1993a 10/35 10/37 12.4 % 1.06 [ 0.50, 2.23 ]

McGregor 1991 7/28 6/27 9.4 % 1.13 [ 0.43, 2.92 ]

Mercer 1992 18/105 22/112 15.9 % 0.87 [ 0.50, 1.53 ]

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Mercer 1997 69/299 101/312 22.3 % 0.71 [ 0.55, 0.93 ]

Ovalle Salas 1997 2/42 11/45 5.2 % 0.19 [ 0.05, 0.83 ]

Svare 1997a 6/30 5/37 7.9 % 1.48 [ 0.50, 4.38 ]

Total (95% CI) 767 792 100.0 % 0.66 [ 0.46, 0.96 ]

Total events: 126 (Treatment), 196 (Control)
Heterogeneity: Tau2 = 0.14; Chi2 = 18.29, df = 10 (P = 0.05); I2 =45%
Test for overall effect: Z = 2.18 (P = 0.029)

0.01 0.1 1 10 100

Analysis 1.12. Comparison 1 Any antibiotic versus placebo, Outcome 12 Caesarean section.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 12 Caesarean section

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Ernest 1994 16/77 15/67 1.9 % 0.93 [ 0.50, 1.73 ]

Garcia 1995 5/30 6/30 0.7 % 0.83 [ 0.28, 2.44 ]

Grable 1996 9/31 4/29 0.7 % 2.10 [ 0.73, 6.10 ]

Johnston 1990 9/40 6/45 0.8 % 1.69 [ 0.66, 4.32 ]

Kenyon 2001 974/3584 357/1225 71.4 % 0.93 [ 0.84, 1.03 ]

Kurki 1992 14/50 16/51 2.1 % 0.89 [ 0.49, 1.63 ]

Lockwood 1993a 11/38 11/37 1.5 % 0.97 [ 0.48, 1.97 ]

Mercer 1992 26/105 18/112 2.6 % 1.54 [ 0.90, 2.64 ]

Mercer 1997 90/299 97/312 13.1 % 0.97 [ 0.76, 1.23 ]

Ovalle Salas 1997 20/42 21/46 3.7 % 1.04 [ 0.67, 1.63 ]

Svare 1997a 9/30 13/37 1.5 % 0.85 [ 0.42, 1.72 ]

Total (95% CI) 4326 1991 100.0 % 0.96 [ 0.88, 1.05 ]

Total events: 1183 (Treatment), 564 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 7.13, df = 10 (P = 0.71); I2 =0.0%
Test for overall effect: Z = 0.90 (P = 0.37)

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 Analysis 1.15. Comparison 1 Any antibiotic versus placebo, Outcome 15 Birth within 48 hours of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 15 Birth within 48 hours of randomisation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Grable 1996 3/31 12/29 2.8 % 0.23 [ 0.07, 0.75 ]

Johnston 1990 1/40 6/45 0.9 % 0.19 [ 0.02, 1.49 ]

Kenyon 2001 1153/3584 498/1225 36.4 % 0.79 [ 0.73, 0.86 ]

Lockwood 1993a 12/38 24/37 10.7 % 0.49 [ 0.29, 0.82 ]

Mercer 1992 37/106 57/114 19.7 % 0.70 [ 0.51, 0.96 ]

Mercer 1997 82/299 114/312 25.4 % 0.75 [ 0.59, 0.95 ]

Svare 1997a 8/30 6/37 4.1 % 1.64 [ 0.64, 4.22 ]

Total (95% CI) 4128 1799 100.0 % 0.71 [ 0.58, 0.87 ]

Total events: 1296 (Treatment), 717 (Control)
Heterogeneity: Tau2 = 0.03; Chi2 = 12.11, df = 6 (P = 0.06); I2 =50%
Test for overall effect: Z = 3.32 (P = 0.00088)

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 Analysis 1.16. Comparison 1 Any antibiotic versus placebo, Outcome 16 Birth within 7 days of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 16 Birth within 7 days of randomisation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

Fuhr 2006 17/47 32/58 5.4 % 0.66 [ 0.42, 1.02 ]

Grable 1996 17/31 21/29 6.6 % 0.76 [ 0.51, 1.12 ]

Johnston 1990 22/40 37/45 9.2 % 0.67 [ 0.49, 0.91 ]

Kenyon 2001 2067/3584 775/1225 27.4 % 0.91 [ 0.87, 0.96 ]

Lockwood 1993a 22/38 33/37 9.9 % 0.65 [ 0.48, 0.87 ]

Mercer 1992 77/106 94/114 19.8 % 0.88 [ 0.76, 1.02 ]

Mercer 1997 166/299 229/312 21.8 % 0.76 [ 0.67, 0.85 ]

Total (95% CI) 4145 1820 100.0 % 0.79 [ 0.71, 0.89 ]

Total events: 2388 (Treatment), 1221 (Control)
Heterogeneity: Tau2 = 0.01; Chi2 = 16.94, df = 6 (P = 0.01); I2 =65%
Test for overall effect: Z = 3.99 (P = 0.000067)

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 Analysis 1.17. Comparison 1 Any antibiotic versus placebo, Outcome 17 Birthweight.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 17 Birthweight

Study or subgroup Treatment Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Cox 1995 31 1282 (409) 31 1305 (413) 4.8 % -23.00 [ -227.61, 181.61 ]

Ernest 1994 77 1896 (556) 67 1808 (716) 4.6 % 88.00 [ -123.70, 299.70 ]

Garcia 1995 30 2022 (607) 30 2170 (799.7) 1.7 % -148.00 [ -507.26, 211.26 ]

Johnston 1990 40 1897 (600) 45 1587 (592) 3.2 % 310.00 [ 56.05, 563.95 ]

Kenyon 2001 3584 2103 (764) 1225 2072 (769) 38.2 % 31.00 [ -18.80, 80.80 ]

Kurki 1992 50 2124 (390) 51 2090 (516) 6.3 % 34.00 [ -144.16, 212.16 ]

Lockwood 1993a 38 1837 (759) 37 1697 (581) 2.3 % 140.00 [ -165.42, 445.42 ]

McGregor 1991 28 1638.5 (530.8) 27 1741.4 (444) 3.1 % -102.90 [ -361.17, 155.37 ]

Mercer 1992 106 1771 (653) 114 1817 (637) 6.8 % -46.00 [ -216.66, 124.66 ]

Mercer 1997 299 1549 (497) 312 1457 (508) 22.8 % 92.00 [ 12.31, 171.69 ]

Ovalle Salas 1997 42 1849 (458.4) 43 1645 (521.4) 4.7 % 204.00 [ -4.58, 412.58 ]

Svare 1997a 30 1962 (712) 37 1838 (785) 1.7 % 124.00 [ -235.02, 483.02 ]

Total (95% CI) 4355 2019 100.0 % 53.83 [ 7.06, 100.60 ]

Heterogeneity: Tau2 = 845.13; Chi2 = 12.62, df = 11 (P = 0.32); I2 =13%

Test for overall effect: Z = 2.26 (P = 0.024)

-1000 -500 0 500 1000

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 Analysis 1.18. Comparison 1 Any antibiotic versus placebo, Outcome 18 Birthweight < 2500 g.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 18 Birthweight < 2500 g

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 2581/3584 880/1225 96.9 % 1.00 [ 0.96, 1.04 ]

Svare 1997a 24/30 31/37 3.1 % 0.95 [ 0.76, 1.20 ]

Total (95% CI) 3614 1262 100.0 % 1.00 [ 0.96, 1.04 ]

Total events: 2605 (Treatment), 911 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.17, df = 1 (P = 0.68); I2 =0.0%
Test for overall effect: Z = 0.05 (P = 0.96)

0.1 0.2 0.5 1 2 5 10

Analysis 1.19. Comparison 1 Any antibiotic versus placebo, Outcome 19 Neonatal intensive care.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 19 Neonatal intensive care

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Cox 1995 31/31 28/31 28.3 % 1.11 [ 0.97, 1.26 ]

Kenyon 2001 2502/3584 880/1225 35.2 % 0.97 [ 0.93, 1.01 ]

Ovalle Salas 1997 23/42 37/43 14.5 % 0.64 [ 0.47, 0.86 ]

Svare 1997a 27/30 30/37 22.0 % 1.11 [ 0.91, 1.35 ]

Total (95% CI) 3687 1336 100.0 % 0.98 [ 0.84, 1.13 ]

Total events: 2583 (Treatment), 975 (Control)
Heterogeneity: Tau2 = 0.02; Chi2 = 13.44, df = 3 (P = 0.004); I2 =78%
Test for overall effect: Z = 0.32 (P = 0.75)

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 Analysis 1.20. Comparison 1 Any antibiotic versus placebo, Outcome 20 Days in neonatal intensive care
unit.
Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 20 Days in neonatal intensive care unit

Study or subgroup Treatment Control Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Johnston 1990 40 12.3 (35.9) 45 11.8 (21.9) 13.5 % 0.50 [ -12.33, 13.33 ]

McGregor 1991 28 9.5 (10.5) 27 14.5 (18.9) 33.8 % -5.00 [ -13.12, 3.12 ]

Ovalle Salas 1997 42 6.7 (9.12) 43 13.2 (19.7) 52.7 % -6.50 [ -13.00, 0.00 ]

Total (95% CI) 110 115 100.0 % -5.05 [ -9.77, -0.33 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.91, df = 2 (P = 0.63); I2 =0.0%

Test for overall effect: Z = 2.10 (P = 0.036)

-1000 -500 0 500 1000

Analysis 1.21. Comparison 1 Any antibiotic versus placebo, Outcome 21 Positive neonatal blood culture.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 21 Positive neonatal blood culture

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Johnston 1990 0/40 2/45 0.6 % 0.22 [ 0.01, 4.54 ]

Kenyon 2001 233/3584 100/1225 98.5 % 0.80 [ 0.64, 1.00 ]

Svare 1997a 1/30 2/37 0.9 % 0.62 [ 0.06, 6.48 ]

Total (95% CI) 3654 1307 100.0 % 0.79 [ 0.63, 0.99 ]

Total events: 234 (Treatment), 104 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.72, df = 2 (P = 0.70); I2 =0.0%
Test for overall effect: Z = 2.08 (P = 0.038)

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 Analysis 1.22. Comparison 1 Any antibiotic versus placebo, Outcome 22 Neonatal respiratory distress
syndrome.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 22 Neonatal respiratory distress syndrome

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Cox 1995 27/31 21/31 14.5 % 1.29 [ 0.97, 1.70 ]

Fuhr 2006 7/47 11/58 2.3 % 0.79 [ 0.33, 1.87 ]

Garcia 1995 7/30 6/30 1.8 % 1.17 [ 0.44, 3.06 ]

Grable 1996 6/31 9/29 2.1 % 0.62 [ 0.25, 1.53 ]

Johnston 1990 6/40 11/45 2.1 % 0.61 [ 0.25, 1.51 ]

Kenyon 2001 719/3584 266/1225 29.0 % 0.92 [ 0.82, 1.05 ]

Lockwood 1993a 23/37 20/35 9.4 % 1.09 [ 0.74, 1.59 ]

McGregor 1991 15/26 15/25 7.0 % 0.96 [ 0.61, 1.52 ]

Mercer 1992 27/106 24/114 6.4 % 1.21 [ 0.75, 1.96 ]

Mercer 1997 121/299 152/312 23.0 % 0.83 [ 0.69, 0.99 ]

Ovalle Salas 1997 4/42 13/43 1.6 % 0.32 [ 0.11, 0.89 ]

Svare 1997a 3/30 3/37 0.8 % 1.23 [ 0.27, 5.67 ]

Total (95% CI) 4303 1984 100.0 % 0.95 [ 0.83, 1.09 ]

Total events: 965 (Treatment), 551 (Control)
Heterogeneity: Tau2 = 0.01; Chi2 = 15.15, df = 11 (P = 0.18); I2 =27%
Test for overall effect: Z = 0.75 (P = 0.45)

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 Analysis 1.23. Comparison 1 Any antibiotic versus placebo, Outcome 23 Treatment with surfactant.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 23 Treatment with surfactant

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 526/3584 217/1225 100.0 % 0.83 [ 0.72, 0.96 ]

Total (95% CI) 3584 1225 100.0 % 0.83 [ 0.72, 0.96 ]

Total events: 526 (Treatment), 217 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.56 (P = 0.011)

0.1 0.2 0.5 1 2 5 10

Analysis 1.24. Comparison 1 Any antibiotic versus placebo, Outcome 24 Number of babies requiring
ventilation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 24 Number of babies requiring ventilation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 749/3584 283/1225 98.2 % 0.90 [ 0.80, 1.02 ]

Kurki 1992 8/57 9/58 1.8 % 0.90 [ 0.38, 2.18 ]

Total (95% CI) 3641 1283 100.0 % 0.90 [ 0.80, 1.02 ]

Total events: 757 (Treatment), 292 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.00, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 1.65 (P = 0.10)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 1.25. Comparison 1 Any antibiotic versus placebo, Outcome 25 Number of babies requiring
oxygen therapy.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 25 Number of babies requiring oxygen therapy

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 1125/3584 436/1225 100.0 % 0.88 [ 0.81, 0.96 ]

Total (95% CI) 3584 1225 100.0 % 0.88 [ 0.81, 0.96 ]

Total events: 1125 (Treatment), 436 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.75 (P = 0.0060)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 1.26. Comparison 1 Any antibiotic versus placebo, Outcome 26 Neonatal oxygenation > 28 days.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 26 Neonatal oxygenation > 28 days

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 299/3584 114/1225 64.3 % 0.90 [ 0.73, 1.10 ]

Mercer 1997 39/299 64/312 35.0 % 0.64 [ 0.44, 0.92 ]

Svare 1997a 0/30 1/37 0.7 % 0.41 [ 0.02, 9.68 ]

Total (95% CI) 3913 1574 100.0 % 0.79 [ 0.61, 1.03 ]

Total events: 338 (Treatment), 179 (Control)
Heterogeneity: Tau2 = 0.02; Chi2 = 2.77, df = 2 (P = 0.25); I2 =28%
Test for overall effect: Z = 1.74 (P = 0.082)

0.001 0.01 0.1 1 10 100 1000

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 Analysis 1.27. Comparison 1 Any antibiotic versus placebo, Outcome 27 Neonatal encephalopathy.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 27 Neonatal encephalopathy

Study or subgroup Treatment Control Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Garcia 1995 0/30 0/30 0.0 [ 0.0, 0.0 ]

Total (95% CI) 30 30 0.0 [ 0.0, 0.0 ]

Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Analysis 1.28. Comparison 1 Any antibiotic versus placebo, Outcome 28 Serious childhood disability at
approximately 2 years.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 28 Serious childhood disability at approximately 2 years

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 938/2375 311/796 100.0 % 1.01 [ 0.91, 1.12 ]

Total (95% CI) 2375 796 100.0 % 1.01 [ 0.91, 1.12 ]

Total events: 938 (Treatment), 311 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.21 (P = 0.83)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.3. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 3 Major adverse drug reaction.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 3 Major adverse drug reaction

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 0/1190 0/1205 0.0 [ 0.0, 0.0 ]

Total (95% CI) 1190 1205 0.0 [ 0.0, 0.0 ]

Total events: 0 (Erythromycin), 0 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Analysis 2.4. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 4 Maternal infection after delivery
prior to discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 4 Maternal infection after delivery prior to discharge

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 241/1190 239/1205 100.0 % 1.02 [ 0.87, 1.20 ]

Total (95% CI) 1190 1205 100.0 % 1.02 [ 0.87, 1.20 ]

Total events: 241 (Erythromycin), 239 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.26 (P = 0.80)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.6. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 6 Caesarean section.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 6 Caesarean section

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 335/1190 332/1205 100.0 % 1.02 [ 0.90, 1.16 ]

Total (95% CI) 1190 1205 100.0 % 1.02 [ 0.90, 1.16 ]

Total events: 335 (Erythromycin), 332 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.33 (P = 0.74)

0.1 0.2 0.5 1 2 5 10

Analysis 2.9. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 9 Birth within 48 hours of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 9 Birth within 48 hours of randomisation

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 414/1190 367/1205 100.0 % 1.14 [ 1.02, 1.28 ]

Total (95% CI) 1190 1205 100.0 % 1.14 [ 1.02, 1.28 ]

Total events: 414 (Erythromycin), 367 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 2.26 (P = 0.024)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.10. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 10 Birth within 7 days of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 10 Birth within 7 days of randomisation

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 725/1190 695/1205 100.0 % 1.06 [ 0.99, 1.13 ]

Total (95% CI) 1190 1205 100.0 % 1.06 [ 0.99, 1.13 ]

Total events: 725 (Erythromycin), 695 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 1.62 (P = 0.11)

0.1 0.2 0.5 1 2 5 10

Analysis 2.11. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 11 Birth before 37 weeks
gestation.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 11 Birth before 37 weeks gestation

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 1006/1190 1025/1205 100.0 % 0.99 [ 0.96, 1.03 ]

Total (95% CI) 1190 1205 100.0 % 0.99 [ 0.96, 1.03 ]

Total events: 1006 (Erythromycin), 1025 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.36 (P = 0.72)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.12. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 12 Birthweight.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 12 Birthweight

Study or subgroup Erythromycin Co-amoxiclav Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Kenyon 2001 1190 2102 (766) 1205 2083 (755) 100.0 % 19.00 [ -41.92, 79.92 ]

Total (95% CI) 1190 1205 100.0 % 19.00 [ -41.92, 79.92 ]

Heterogeneity: not applicable

Test for overall effect: Z = 0.61 (P = 0.54)

-100 -50 0 50 100

Analysis 2.13. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 13 Birthweight < 2500 g.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 13 Birthweight < 2500 g

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 863/1190 877/1205 100.0 % 1.00 [ 0.95, 1.05 ]

Total (95% CI) 1190 1205 100.0 % 1.00 [ 0.95, 1.05 ]

Total events: 863 (Erythromycin), 877 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.14 (P = 0.89)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.14. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 14 Neonatal intensive care.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 14 Neonatal intensive care

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 836/1190 848/1205 100.0 % 1.00 [ 0.95, 1.05 ]

Total (95% CI) 1190 1205 100.0 % 1.00 [ 0.95, 1.05 ]

Total events: 836 (Erythromycin), 848 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.06 (P = 0.95)

0.1 0.2 0.5 1 2 5 10

Analysis 2.17. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 17 Positive neonatal blood
culture.
Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 17 Positive neonatal blood culture

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 68/1190 82/1205 100.0 % 0.84 [ 0.62, 1.15 ]

Total (95% CI) 1190 1205 100.0 % 0.84 [ 0.62, 1.15 ]

Total events: 68 (Erythromycin), 82 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 1.10 (P = 0.27)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.18. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 18 Neonatal necrotising
enterocolitis.
Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 18 Neonatal necrotising enterocolitis

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 11/1190 24/1205 100.0 % 0.46 [ 0.23, 0.94 ]

Total (95% CI) 1190 1205 100.0 % 0.46 [ 0.23, 0.94 ]

Total events: 11 (Erythromycin), 24 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 2.12 (P = 0.034)

0.1 0.2 0.5 1 2 5 10

Analysis 2.19. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 19 Neonatal respiratory distress
syndrome.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 19 Neonatal respiratory distress syndrome

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 236/1190 241/1205 100.0 % 0.99 [ 0.84, 1.16 ]

Total (95% CI) 1190 1205 100.0 % 0.99 [ 0.84, 1.16 ]

Total events: 236 (Erythromycin), 241 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.10 (P = 0.92)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.20. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 20 Treatment with surfactant.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 20 Treatment with surfactant

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 176/1190 182/1205 100.0 % 0.98 [ 0.81, 1.19 ]

Total (95% CI) 1190 1205 100.0 % 0.98 [ 0.81, 1.19 ]

Total events: 176 (Erythromycin), 182 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.22 (P = 0.83)

0.1 0.2 0.5 1 2 5 10

Analysis 2.21. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 21 Number of babies requiring
ventilation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 21 Number of babies requiring ventilation

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 251/1190 254/1205 100.0 % 1.00 [ 0.86, 1.17 ]

Total (95% CI) 1190 1205 100.0 % 1.00 [ 0.86, 1.17 ]

Total events: 251 (Erythromycin), 254 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.01 (P = 0.99)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

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 Analysis 2.22. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 22 Number of babies requiring
oxygen therapy.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 22 Number of babies requiring oxygen therapy

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 370/1190 383/1205 100.0 % 0.98 [ 0.87, 1.10 ]

Total (95% CI) 1190 1205 100.0 % 0.98 [ 0.87, 1.10 ]

Total events: 370 (Erythromycin), 383 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.36 (P = 0.72)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 2.23. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 23 Neonatal oxygenation > 28
days.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 23 Neonatal oxygenation > 28 days

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 94/1190 111/1205 100.0 % 0.86 [ 0.66, 1.12 ]

Total (95% CI) 1190 1205 100.0 % 0.86 [ 0.66, 1.12 ]

Total events: 94 (Erythromycin), 111 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 1.15 (P = 0.25)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.24. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 24 Oxygen treatment > 36
weeks postconceptual age.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 24 Oxygen treatment > 36 weeks postconceptual age

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 66/1190 69/1205 100.0 % 0.97 [ 0.70, 1.34 ]

Total (95% CI) 1190 1205 100.0 % 0.97 [ 0.70, 1.34 ]

Total events: 66 (Erythromycin), 69 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.19 (P = 0.85)

0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 2.26. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 26 Major cerebral abnormality
on ultrasound before discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 26 Major cerebral abnormality on ultrasound before discharge

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 50/1190 46/1205 100.0 % 1.10 [ 0.74, 1.63 ]

Total (95% CI) 1190 1205 100.0 % 1.10 [ 0.74, 1.63 ]

Total events: 50 (Erythromycin), 46 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.48 (P = 0.63)

0.1 0.2 0.5 1 2 5 10

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 Analysis 2.27. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 27 Perinatal death/death before
discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 27 Perinatal death/death before discharge

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 70/1190 79/1205 100.0 % 0.90 [ 0.66, 1.23 ]

Total (95% CI) 1190 1205 100.0 % 0.90 [ 0.66, 1.23 ]

Total events: 70 (Erythromycin), 79 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 0.68 (P = 0.50)

0.1 0.2 0.5 1 2 5 10

Analysis 2.28. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 28 Serious childhood disability at
approximately 2 years.

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 28 Serious childhood disability at approximately 2 years

Study or subgroup Erythromycin Co-amoxiclav Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Kenyon 2001 293/788 344/824 100.0 % 0.89 [ 0.79, 1.01 ]

Total (95% CI) 788 824 100.0 % 0.89 [ 0.79, 1.01 ]

Total events: 293 (Erythromycin), 344 (Co-amoxiclav)
Heterogeneity: not applicable
Test for overall effect: Z = 1.87 (P = 0.062)

0.1 0.2 0.5 1 2 5 10

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 Analysis 4.1. Comparison 4 Antibiotics versus no antibiotic, Outcome 1 Perinatal death/death before
discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 4 Antibiotics versus no antibiotic

Outcome: 1 Perinatal death/death before discharge

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI

1 New Subgroup
Amon 1988a 2/43 6/39 1.5 % 0.30 [ 0.06, 1.41 ]

Camli 1997 3/15 4/16 2.1 % 0.80 [ 0.21, 3.00 ]

Christmas 1992 1/48 3/46 0.7 % 0.32 [ 0.03, 2.96 ]

Cox 1995 1/31 5/31 0.8 % 0.20 [ 0.02, 1.61 ]

Garcia 1995 2/30 5/30 1.5 % 0.40 [ 0.08, 1.90 ]

Grable 1996 0/31 2/29 0.4 % 0.19 [ 0.01, 3.75 ]

Johnston 1990 3/40 4/45 1.8 % 0.84 [ 0.20, 3.54 ]

Kenyon 2001 226/3584 82/1225 61.2 % 0.94 [ 0.74, 1.20 ]

Kurki 1992 1/57 1/58 0.5 % 1.02 [ 0.07, 15.88 ]

Lockwood 1993a 3/37 3/35 1.6 % 0.95 [ 0.20, 4.38 ]

Magwali 1999 8/82 11/86 4.9 % 0.76 [ 0.32, 1.80 ]

McGregor 1991 6/28 0/27 0.5 % 12.55 [ 0.74, 212.52 ]

Mercer 1992 6/106 10/114 3.8 % 0.65 [ 0.24, 1.71 ]

Mercer 1997 19/299 18/312 9.4 % 1.10 [ 0.59, 2.06 ]

Morales 1989 5/42 3/37 2.0 % 1.47 [ 0.38, 5.73 ]

Ovalle Salas 1997 7/42 6/43 3.6 % 1.19 [ 0.44, 3.26 ]

Owen 1993a 4/59 7/58 2.7 % 0.56 [ 0.17, 1.82 ]

Svare 1997a 2/30 2/37 1.0 % 1.23 [ 0.18, 8.25 ]

Subtotal (95% CI) 4604 2268 100.0 % 0.89 [ 0.74, 1.08 ]

Total events: 299 (Treatment), 172 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 12.87, df = 17 (P = 0.75); I2 =0.0%
Test for overall effect: Z = 1.18 (P = 0.24)
2 Antibiotics versus no treatment (no placebo)
Amon 1988a 2/43 6/39 11.0 % 0.30 [ 0.06, 1.41 ]

Camli 1997 3/15 4/16 15.0 % 0.80 [ 0.21, 3.00 ]

Christmas 1992 1/48 3/46 5.3 % 0.32 [ 0.03, 2.96 ]

0.001 0.01 0.1 1 10 100 1000

(Continued . . . )

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 (. . . Continued)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Magwali 1999 8/82 11/86 35.5 % 0.76 [ 0.32, 1.80 ]

Morales 1989 5/42 3/37 14.1 % 1.47 [ 0.38, 5.73 ]

Owen 1993a 4/59 7/58 19.0 % 0.56 [ 0.17, 1.82 ]

Subtotal (95% CI) 289 282 100.0 % 0.69 [ 0.41, 1.14 ]

Total events: 23 (Treatment), 34 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 2.97, df = 5 (P = 0.70); I2 =0.0%
Test for overall effect: Z = 1.45 (P = 0.15)

0.001 0.01 0.1 1 10 100 1000

Analysis 5.4. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 4 Maternal infection after delivery
prior to discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 4 Maternal infection after delivery prior to discharge

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 5/42 4/42 100.0 % 1.25 [ 0.36, 4.33 ]

Total (95% CI) 42 42 100.0 % 1.25 [ 0.36, 4.33 ]

Total events: 5 (Treatment), 4 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.35 (P = 0.73)

0.1 0.2 0.5 1 2 5 10

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 Analysis 5.5. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 5 Chorioamnionitis.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 5 Chorioamnionitis

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 8/42 11/42 100.0 % 0.73 [ 0.33, 1.63 ]

Total (95% CI) 42 42 100.0 % 0.73 [ 0.33, 1.63 ]

Total events: 8 (Treatment), 11 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.78 (P = 0.44)

0.1 0.2 0.5 1 2 5 10

Analysis 5.6. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 6 Caesarean section.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 6 Caesarean section

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 20/42 17/42 100.0 % 1.18 [ 0.72, 1.91 ]

Total (95% CI) 42 42 100.0 % 1.18 [ 0.72, 1.91 ]

Total events: 20 (Treatment), 17 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.66 (P = 0.51)

0.1 0.2 0.5 1 2 5 10

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 Analysis 5.9. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 9 Birth within 48 hours of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 9 Birth within 48 hours of randomisation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 8/42 7/42 100.0 % 1.14 [ 0.46, 2.87 ]

Total (95% CI) 42 42 100.0 % 1.14 [ 0.46, 2.87 ]

Total events: 8 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.28 (P = 0.78)

0.1 0.2 0.5 1 2 5 10

Analysis 5.10. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 10 Birth within 7 days of
randomisation.
Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 10 Birth within 7 days of randomisation

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 25/42 25/42 100.0 % 1.00 [ 0.70, 1.42 ]

Total (95% CI) 42 42 100.0 % 1.00 [ 0.70, 1.42 ]

Total events: 25 (Treatment), 25 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)

0.1 0.2 0.5 1 2 5 10

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 Analysis 5.14. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 14 Neonatal intensive care.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 14 Neonatal intensive care

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 36/42 36/42 100.0 % 1.00 [ 0.84, 1.19 ]

Total (95% CI) 42 42 100.0 % 1.00 [ 0.84, 1.19 ]

Total events: 36 (Treatment), 36 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)

0.1 0.2 0.5 1 2 5 10

Analysis 5.18. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 18 Neonatal necrotising
enterocolitis.
Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 18 Neonatal necrotising enterocolitis

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 1/42 2/42 64.0 % 0.50 [ 0.05, 5.31 ]

Segel 2003 0/23 1/23 36.0 % 0.33 [ 0.01, 7.78 ]

Total (95% CI) 65 65 100.0 % 0.43 [ 0.07, 2.86 ]

Total events: 1 (Treatment), 3 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.04, df = 1 (P = 0.84); I2 =0.0%
Test for overall effect: Z = 0.87 (P = 0.38)

0.01 0.1 1 10 100

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 Analysis 5.19. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 19 Neonatal respiratory distress
syndrome.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 19 Neonatal respiratory distress syndrome

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 14/42 15/42 55.5 % 0.93 [ 0.52, 1.68 ]

Segel 2003 10/23 10/23 44.5 % 1.00 [ 0.52, 1.93 ]

Total (95% CI) 65 65 100.0 % 0.96 [ 0.62, 1.49 ]

Total events: 24 (Treatment), 25 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 0.17 (P = 0.86)

0.1 0.2 0.5 1 2 5 10

Analysis 5.26. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 26 Neonatal intraventricular
haemorrhage.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 26 Neonatal intraventricular haemorrhage

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 0/42 1/42 49.6 % 0.33 [ 0.01, 7.96 ]

Segel 2003 0/23 1/23 50.4 % 0.33 [ 0.01, 7.78 ]

Total (95% CI) 65 65 100.0 % 0.33 [ 0.04, 3.12 ]

Total events: 0 (Treatment), 2 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.96 (P = 0.34)

0.01 0.1 1 10 100

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 Analysis 5.27. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 27 Perinatal death/death before
discharge.

Review: Antibiotics for preterm rupture of membranes

Comparison: 5 3 versus 7 day ampicillin regimens

Outcome: 27 Perinatal death/death before discharge

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Random,95% CI M-H,Random,95% CI
Lewis 2003 1/42 1/42 53.0 % 1.00 [ 0.06, 15.47 ]

Segel 2003 0/23 3/23 47.0 % 0.14 [ 0.01, 2.62 ]

Total (95% CI) 65 65 100.0 % 0.40 [ 0.05, 2.94 ]

Total events: 1 (Treatment), 4 (Control)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.94, df = 1 (P = 0.33); I2 =0.0%
Test for overall effect: Z = 0.90 (P = 0.37)

0.001 0.01 0.1 1 10 100 1000

APPENDICES

Appendix 1. Methods used to assess trials included in previous versions of this review
The following methods were used to assess Almeida 1996; Amon 1988a; Camli 1997; Christmas 1992; Cox 1995; Ernest 1994; Garcia
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.

Antibiotics for preterm rupture of membranes (Review) 84

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Antibiotics for preterm rupture of membranes (Review) 85
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
WHATS NEW
Last assessed as up-to-date: 6 July 2010.

Date Event Description

7 July 2010 New citation required and conclusions have changed The 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 2010 New 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.

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

Date Event Description

29 January 2009 Amended Author contact details edited.

20 February 2008 Amended Corrected error in dose of amoxycillin given in Char-

acteristics of included studies table for Almeida 1996a.
Converted to new review format.

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

24 January 2003 New citation required and conclusions have changed Substantive amendment

Antibiotics for preterm rupture of membranes (Review) 86

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
No sources of support supplied

INDEX TERMS

Medical Subject Headings (MeSH)

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

MeSH check words

Child; Female; Humans; Pregnancy

Antibiotics for preterm rupture of membranes (Review) 87

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.