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
2013, Issue 12
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Antibiotics for preterm rupture of membranes (Review)

Copyright © 2013 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Analysis 1.1. Comparison 1 Any antibiotic versus placebo, Outcome 1 Maternal death. . . . . . . . . . . . 48
Analysis 1.3. Comparison 1 Any antibiotic versus placebo, Outcome 3 Perinatal death/death before discharge. . . . 49
Analysis 1.4. Comparison 1 Any antibiotic versus placebo, Outcome 4 Neonatal infection including pneumonia. . . 51
Analysis 1.5. Comparison 1 Any antibiotic versus placebo, Outcome 5 Neonatal necrotising enterocolitis. . . . . 53
Analysis 1.6. Comparison 1 Any antibiotic versus placebo, Outcome 6 Oxygen treatment > 36 weeks’ postconceptual age. 55
Analysis 1.7. Comparison 1 Any antibiotic versus placebo, Outcome 7 Major cerebral abnormality on ultrasound before
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 1.8. Comparison 1 Any antibiotic versus placebo, Outcome 8 Birth before 37 weeks’ gestation. . . . . . 58
Analysis 1.9. Comparison 1 Any antibiotic versus placebo, Outcome 9 Major adverse drug reaction. . . . . . . 59
Analysis 1.10. Comparison 1 Any antibiotic versus placebo, Outcome 10 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Analysis 1.11. Comparison 1 Any antibiotic versus placebo, Outcome 11 Chorioamnionitis. . . . . . . . . . 61
Analysis 1.12. Comparison 1 Any antibiotic versus placebo, Outcome 12 Caesarean section. . . . . . . . . . 62
Analysis 1.15. Comparison 1 Any antibiotic versus placebo, Outcome 15 Birth within 48 hours of randomisation. . 63
Analysis 1.16. Comparison 1 Any antibiotic versus placebo, Outcome 16 Birth within 7 days of randomisation. . . 64
Analysis 1.17. Comparison 1 Any antibiotic versus placebo, Outcome 17 Birthweight. . . . . . . . . . . . 65
Analysis 1.18. Comparison 1 Any antibiotic versus placebo, Outcome 18 Birthweight < 2500 g. . . . . . . . 66
Analysis 1.19. Comparison 1 Any antibiotic versus placebo, Outcome 19 Neonatal intensive care. . . . . . . . 66
Analysis 1.20. Comparison 1 Any antibiotic versus placebo, Outcome 20 Days in neonatal intensive care unit. . . 67
Analysis 1.21. Comparison 1 Any antibiotic versus placebo, Outcome 21 Positive neonatal blood culture. . . . . 68
Analysis 1.22. Comparison 1 Any antibiotic versus placebo, Outcome 22 Neonatal respiratory distress syndrome. . 69
Analysis 1.23. Comparison 1 Any antibiotic versus placebo, Outcome 23 Treatment with surfactant. . . . . . . 70
Analysis 1.24. Comparison 1 Any antibiotic versus placebo, Outcome 24 Number of babies requiring ventilation. . 70
Analysis 1.25. Comparison 1 Any antibiotic versus placebo, Outcome 25 Number of babies requiring oxygen therapy. 71
Analysis 1.26. Comparison 1 Any antibiotic versus placebo, Outcome 26 Neonatal oxygenation > 28 days. . . . . 72
Analysis 1.27. Comparison 1 Any antibiotic versus placebo, Outcome 27 Neonatal encephalopathy. . . . . . . 72
Analysis 1.28. Comparison 1 Any antibiotic versus placebo, Outcome 28 Serious childhood disability at 7 years. . . 73
Analysis 2.3. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 3 Major adverse drug reaction. . . . . 74
Analysis 2.4. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 4 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Analysis 2.6. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 6 Caesarean section. . . . . . . . . 75
Analysis 2.9. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 9 Birth within 48 hours of randomisation. 75
Analysis 2.10. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 10 Birth within 7 days of randomisation. 76
Antibiotics for preterm rupture of membranes (Review) i
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.11. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 11 Birth before 37 weeks’ gestation. . . 76
Analysis 2.12. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 12 Birthweight. . . . . . . . . . 77
Analysis 2.13. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 13 Birthweight < 2500 g. . . . . . . 78
Analysis 2.14. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 14 Neonatal intensive care. . . . . . 78
Analysis 2.17. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 17 Positive neonatal blood culture. . . 79
Analysis 2.18. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 18 Neonatal necrotising enterocolitis. . . 79
Analysis 2.19. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 19 Neonatal respiratory distress syndrome. 80
Analysis 2.20. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 20 Treatment with surfactant. . . . . 80
Analysis 2.21. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 21 Number of babies requiring ventilation. 81
Analysis 2.22. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 22 Number of babies requiring oxygen
therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Analysis 2.23. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 23 Neonatal oxygenation > 28 days. . . 82
Analysis 2.24. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 24 Oxygen treatment > 36 weeks’ postconceptual
age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis 2.26. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 26 Major cerebral abnormality on ultrasound
before discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis 2.27. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 27 Perinatal death/death before discharge. 84
Analysis 2.28. Comparison 2 Erythromycin versus co-amoxiclav, Outcome 28 Serious childhood disability at 7 years. 85
Analysis 4.1. Comparison 4 Antibiotics versus no antibiotic, Outcome 1 Perinatal death/death before discharge. . . 86
Analysis 5.4. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 4 Maternal infection after delivery prior to
discharge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Analysis 5.5. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 5 Chorioamnionitis. . . . . . . . . 88
Analysis 5.6. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 6 Caesarean section. . . . . . . . . 88
Analysis 5.9. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 9 Birth within 48 hours of randomisation. 89
Analysis 5.10. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 10 Birth within 7 days of randomisation. 89
Analysis 5.14. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 14 Neonatal intensive care. . . . . . 90
Analysis 5.18. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 18 Neonatal necrotising enterocolitis. . 90
Analysis 5.19. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 19 Neonatal respiratory distress syndrome. 91
Analysis 5.26. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 26 Neonatal intraventricular haemorrhage. 92
Analysis 5.27. Comparison 5 3 versus 7 day ampicillin regimens, Outcome 27 Perinatal death/death before discharge. 93
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 96
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Antibiotics for preterm rupture of membranes (Review) ii

Copyright © 2013 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 Département de Gynécologie et d’Obstétrique,

Unité de Développement en Obstétrique, Maternité Hôpitaux Universitaires de Genève, Genève 14, Switzerland. 3 Department of
Women’s and Children’s Health, 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: Edited (no change to conclusions), published in Issue 12, 2013.
Review content assessed as up-to-date: 26 November 2013.

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

Copyright © 2013 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 methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 September 2013).
Selection criteria
Randomised controlled trials comparing antibiotic administration with placebo that reported clinically relevant outcomes were included
as were trials of different antibiotics. Trials in which no placebo was used were included for the outcome of perinatal death alone.
Data collection and analysis
We extracted data from each report without blinding of either the results or the treatments that women received. We sought unpublished
data from a number of authors.
Main results
We included 22 trials, involving 6872 women and babies.
The use of antibiotics following PROM is associated with statistically significant reductions in chorioamnionitis (average risk ratio
(RR) 0.66, 95% confidence interval (CI) 0.46 to 0.96, and a reduction in the numbers of babies born within 48 hours (average RR
0.71, 95% CI 0.58 to 0.87) and seven days of randomisation (average RR 0.79, 95% CI 0.71 to 0.89). The following markers of
neonatal morbidity were reduced: neonatal infection (RR 0.67, 95% CI 0.52 to 0.85), use of surfactant (RR 0.83, 95% CI 0.72 to
0.96), oxygen therapy (RR 0.88, 95% CI 0.81 to 0.96), and abnormal cerebral ultrasound scan prior to discharge from hospital (RR
Antibiotics for preterm rupture of membranes (Review) 1
Copyright © 2013 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 children’s health at seven years of age (ORACLE Children Study) and found antibiotics seemed to have little
effect on the health of children.

Authors’ conclusions

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

PLAIN LANGUAGE SUMMARY

Antibiotics for preterm rupture of membranes

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

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

The rate of preterm birth is 5% to 9% of all births in Europe, and an important role, either as a cause or as a consequence of PROM.
12% to 13% in the USA; the rates in both continents are increas- Some organisms may produce collagenases, mucinases and pro-
ing, partly due to the higher number of multiple births associated teases, which weaken the amnion and chorion and may lead to
with assisted conceptions (Goldenberg 2008). About 30% to 35% PROM. On the other hand, infection may occur secondary to
of preterm births are the result of maternal or fetal disease, but membrane rupture. Ascending infection may lead to occult de-
40% to 45% of premature births result from spontaneous preterm ciduitis, intra-amniotic infection or fetal infection.
labour (SPL) and 25% to 30% from preterm rupture of the mem- A possible mechanism for the link between infection and
branes (PROM). Once the membranes have ruptured prematurely, preterm delivery is bacterial stimulation of the biosynthesis of
50% of women will go into labour within 24 to 48 hours and prostaglandins, either directly via phospholipase A2 and C (Bejar
70% to 90% within seven days (Dale 1989). For families strug- 1981), or indirectly via substances such as interleukin-1, tumour
gling to cope with having a baby in special care, this will be one necrosis factor and platelet activating factor, all of which may be
of the most difficult, emotional and stressful times of their lives found in infected amniotic fluid (Yoon 2000).
(Taylor 2001), whatever the longer-term outcome. The sequelae
of preterm birth also pose significant challenges. Children born There is increasing evidence that, in addition to preterm birth,
preterm are at increased risk of major disabilities, such as cerebral perinatal infection is an independent antecedent of other disabil-
palsy, with the risk increasing with decreasing gestation at birth ity, particularly cerebral palsy and chronic lung disease (Dammann
(Costeloe 2012; Marlow 2005). Many preterm children without 2005; Romero 2007). One theory was that perinatal prescription
disability develop important behavioural and educational difficul- of antibiotics could prevent neurological and respiratory disability
ties (Saigal 2008).The prevention of preterm birth and reduction by two mechanisms, either by prolonging pregnancy, or by pre-
of associated disability are therefore important health priorities. venting or eliminating infection, or both. In contrast, it was also
Antibiotics for preterm rupture of membranes (Review) 2
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
thought possible that prolongation of pregnancy might increase Types of participants
rather than decrease disability by continuing fetal exposure to in- Women with preterm (less than 37 weeks) rupture of the mem-
flammatory cytokines, which have already been implicated in the branes.
genesis of neurological damage (Dammann 1997; Wu 2002) and
chronic lung disease (Kotecha 1996; Speer 2003).
Types of interventions
In addition to a generic effect of antibiotics, there may, in the-
ory, be differences in the effects of different antibiotics. For exam- Comparison of:
ple, macrolide antibiotics such as clindamycin and erythromycin, • any antibiotic versus placebo.
which reduce bacterial virulence, may have advantages over the We planned to undertake subgroup comparisons for the primary
beta lactam antibiotics (co-amoxiclav, cephalosporins) which, by outcome as follows:
destroying bacteria, release endotoxins and prostaglandins and • all penicillins (excluding co-amoxiclav) versus placebo;
may worsen outcomes (McGregor 1997). Thus, separate compar- • beta lactam (including co-amoxiclav) antibiotics versus
isons of these antibiotics are included in the review. placebo;
• macrolide (including erythromycin) antibiotics versus
The use of antibiotics for women with preterm labour with intact
placebo.
membranes is addressed by another review (King 2002).
Additional comparisons:
• beta lactam (including co-amoxiclav) antibiotics versus
OBJECTIVES macrolide antibiotics (including erythromycin);
• all penicillins (except co-amoxiclav) versus macrolide
To assess the effects of administering antibiotics to women with antibiotics (including erythromycin).
preterm rupture of membranes on fetal and neonatal morbidity
and mortality, maternal infectious morbidity and mortality, and • Antibiotic versus no antibiotic (including non-placebo
long-term childhood development. controlled trials) - perinatal death only:
◦ Subgroup comparison of non-placebo controlled trials
only.
• Different treatment regimens of same antibiotic.
METHODS

Types of outcome measures

Criteria for considering studies for this review
Primary outcomes
• Maternal death.
Types of studies • Serious maternal morbidity:
We considered all randomised controlled comparisons of antibi- ◦ septicaemia;
otic administration versus placebo, given to women with preterm ◦ need for intensive care;
rupture of membranes, for inclusion in this review. We also in- ◦ organ failure, need for ventilation;
cluded comparisons of different antibiotics. For the unambiguous ◦ need for hysterectomy.
and important outcome of perinatal death alone, we included tri- • Perinatal death or death before discharge from hospital.
als in the review that were randomised but not placebo-controlled. • Perinatal morbidity:
We excluded trials that used inappropriate methods of randomisa- ◦ neonatal infection including pneumonia;
tion. We included trials where the method of randomisation was ◦ necrotising enterocolitis;
not specified in detail in the expectation that their inclusion in ◦ oxygen treatment greater than 36 weeks’
this review would encourage the authors to make available further postconceptual age;
information on the method of randomisation. We excluded tri- ◦ major cerebral abnormality on ultrasound prior to
als where non-randomised cohorts were amalgamated with ran- discharge.
domised participants if the results of the randomised participants
were not reported separately. We included trials in which post-ran-
domisation exclusions occurred, provided there was no evidence Secondary outcomes
that these occurred preferentially in one or other arm of the trials. • Major maternal adverse drug reaction.
We excluded studies where outcomes for over 20% of participants • Maternal infection after delivery prior to discharge.
were not reported. • Chorioamnionitis (infection of the womb).

Antibiotics for preterm rupture of membranes (Review) 3

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 • Caesarean section. Data collection and analysis
• Days from randomisation to birth.
For the methods used when assessing the trials identified in a
• Days from birth to discharge from hospital.
previous version of this review (Kenyon 2003), see Appendix 1.
• Birth within 48 hours.
For the previous update (Kenyon 2010), we used the follow-
• Birth within seven days.
ing methods when assessing the reports identified by the up-
• Birth before 37 weeks.
dated search (Amon 1988b; Beazley 1998; Bergstrom 1991;
• Birthweight.
Cardamakis 1990; Christmas 1990; Fuhr 2006; Gilbert 2005;
• Birthweight less than 2500 g.
Gordon 1974; Halis 2001; Hauth 1997; Hnat 2005; Kenyon
• Need for intensive care.
2008a; Kenyon 2008c; Kim 2008; Lockwood 1993b; Morales
• Days in neonatal intensive care unit.
1988; Ogasawara 1996; Ogasawara 1997; Ogasawara 1999; Owen
• Positive neonatal blood culture.
1993b; Sanchez-Ramos 1990; Svare 1997b; Thurnau 1997). For
• Respiratory distress syndrome.
this update, we would have used the following methods if we had
• Treatment with surfactant.
identified new studies for inclusion.
• Days of ventilation.
• Days of oxygen therapy.
• Oxygen treatment greater than 28 days. Selection of studies
• Neonatal encephalopathy.
Two review authors (S Kenyon (SK) and M Boulvain (MB)) inde-
• Long-term health outcomes (as defined by trial authors)
pendently assessed for inclusion all the potential studies we identi-
after at least two years.
fied as a result of the search strategy. We resolved any disagreement
through discussion or, if required, we consulted the third review
author (JP Neilson (JPN)).

Search methods for identification of studies

Data extraction and management
We designed a form to extract data. For eligible studies, review
authors SK and MB extracted the data using the agreed form. We
Electronic searches
resolved discrepancies through discussion or, if required, we con-
We searched the Cochrane Pregnancy and Childbirth Group’s sulted the third review author (JPN). We entered data into Review
Trials Register by contacting the Trials Search Co-ordinator (30 Manager software (RevMan 2011) and checked for accuracy.
September 2013). When information regarding any of the above was unclear, we
The Cochrane Pregnancy and Childbirth Group’s Trials Register attempted to contact authors of the original reports asking them
is maintained by the Trials Search Co-ordinator and contains trials to provide further details.
identified from:
1. monthly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL); Assessment of risk of bias in included studies
2. weekly searches of MEDLINE; Two review authors (SK and MB) independently assessed risk of
3. weekly searches of Embase; bias for each study using the criteria outlined in the Cochrane
4. handsearches of 30 journals and the proceedings of major Handbook for Systematic Reviews of Interventions (Higgins 2011).
conferences; We resolved any disagreement by discussion or by involving the
5. 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, MEDLINE and
Embase, the list of handsearched journals and conference pro- (1) Sequence generation (checking for possible selection
ceedings, and the list of journals reviewed via the current aware- bias)
ness service can be found in the ‘Specialized Register’ section We describe for each included study the method used to generate
within the editorial information about the Cochrane Pregnancy the allocation sequence in sufficient detail to allow an assessment
and Childbirth Group. of whether it should produce comparable groups.
Trials identified through the searching activities described above We assessed the method as:
are each assigned to a review topic (or topics). The Trials Search • low risk of bias (any truly random process, e.g. random
Co-ordinator searches the register for each review using the topic number table; computer random number generator);
list rather than keywords. • high risk of bias (any non-random process, e.g. odd or even
We did not apply any language restrictions. date of birth; hospital or clinic record number);

Antibiotics for preterm rupture of membranes (Review) 4

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 • unclear risk of bias. been reported, or can be supplied by the trial authors, we planned
to re-include missing data in the analyses which we undertake. We
assessed methods as:
(2) Allocation concealment (checking for possible selection • low risk of bias;
bias) • high risk of bias:
We describe for each included study the method used to conceal • unclear risk of bias.
the allocation sequence in sufficient detail and determine whether
intervention allocation could have been foreseen in advance of, or
(5) Selective reporting bias
during recruitment, or changed after assignment.
We assessed the methods as: We describe for each included study how we investigated the pos-
• low risk of bias (e.g. telephone or central randomisation; sibility of selective outcome reporting bias and what we found.
consecutively numbered sealed opaque envelopes); We assessed the methods as:
• high risk of bias (open random allocation; unsealed or non- • low risk of bias (where it is clear that all of the study’s pre-
opaque envelopes, alternation; date of birth); specified outcomes and all expected outcomes of interest to the
• unclear risk of bias. review have been reported);
• high risk of bias (where not all the study’s pre-specified
outcomes have been reported; one or more reported primary
(3) Blinding (checking for possible performance bias) outcomes were not pre-specified; outcomes of interest are
reported incompletely and so cannot be used; study fails to
We describe for each included study the methods used, if any, to include results of a key outcome that would have been expected
blind study participants and personnel from knowledge of which to have been reported);
intervention a participant received. We judged studies at low risk • unclear risk of bias.
of bias if they were blinded, or if we judge that the lack of blinding
could not have affected the results. We assessed blinding separately
for different outcomes or classes of outcomes. (6) Other sources of bias
We assessed the methods as: We describe for each included study any important concerns we
• low, high or unclear risk of bias for participants; have about other possible sources of bias.
• low, high or unclear risk of bias for personnel; We assessed whether each study was free of other problems that
• low, high or unclear risk of bias for outcome assessors. could put it at risk of bias:
• yes;
• no;
(4) Incomplete outcome data (checking for possible attrition • unclear.
bias through withdrawals, dropouts, protocol deviations)
We describe for each included study, and for each outcome or
class of outcomes, the completeness of data including attrition (7) Overall risk of bias
and exclusions from the analysis. We have stated whether attri- We made explicit judgements about whether studies are at high risk
tion and exclusions were reported, the numbers included in the of bias, according to the criteria given in the Cochrane Handbook
analysis at each stage (compared with the total randomised par- (Higgins 2011). With reference to (1) to (6) above, we assessed
ticipants), reasons for attrition or exclusion where reported, and the likely magnitude and direction of the bias and whether we
whether missing data were balanced across groups or were related considered it is likely to impact on the findings (Figure 1). We
to outcomes. We decided a cut-off for exclusion of a study for the considered this to be unlikely and, therefore, have not undertaken
level of missing data at 20%. Where sufficient information has sensitivity analyses.

Antibiotics for preterm rupture of membranes (Review) 5

Copyright © 2013 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.

results from both if there was little heterogeneity among the study
designs and the interaction between the effect of intervention and
Measures of treatment effect
the choice of randomisation unit was considered to be unlikely.
We would have also acknowledged heterogeneity in the randomi-
sation unit and performed a separate meta-analysis.
Dichotomous data
For dichotomous data, we present results as summary risk ratio
with 95% confidence intervals. Cross-over trials
If we had identified any cross-over trials on this topic, and deemed
Continuous data such trials eligible for inclusion, we would have included them in
the analyses with parallel group trials, using methods described by
For continuous data, we use the mean difference if outcomes are
Elbourne 2002.
measured in the same way between trials. We use the standardised
mean difference to combine trials that measure the same outcome,
but use different methods. Multi-arm studies
For the subgroup comparisons undertaken, to avoid double count-
Unit of analysis issues ing, we divided out data from the shared group approximately
evenly among the comparisons as described in theCochrane Hand-
book (Higgins 2011).
Cluster-randomised trials
We would have included cluster-randomised trials in the analy-
ses along with individually-randomised trials. Their sample sizes Dealing with missing data
would have been adjusted using the methods described in the For included studies, we noted levels of attrition. We planned to
Cochrane Handbook (Higgins 2011) using an estimate of the in- explore the impact of including studies with high levels of missing
tracluster correlation co-efficient (ICC) derived from the trial (if data in the overall assessment of treatment effect by using sensi-
possible), or from another source. If ICCs from other sources had tivity analysis.
been used, we would have reported this and conducted sensitiv- For all outcomes we have carried out analyses, as far as possible, on
ity analyses to investigate the effect of variation in the ICC. If an intention-to-treat basis, i.e. we attempted to include all partici-
we had identified both cluster-randomised trials and individually- pants randomised to each group in the analyses. The denominator
randomised trials, we would have synthesised the relevant infor- for each outcome in each trial was the number randomised minus
mation. We would have considered it reasonable to combine the any participants whose outcomes are known to be missing.

Antibiotics for preterm rupture of membranes (Review) 6

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Assessment of heterogeneity Where we suspected reporting bias (see ‘Selective reporting bias’
We used the I² and Tau² statistic to measure heterogeneity among above), we attempted to contact study authors asking them to
the trials in each analysis. We performed subgroup analysis to provide missing outcome data. Where this was not possible, and
obtain meta-analysis results for more clinically comparable studies, we thought the missing data likely to introduce serious bias, we
to reduce heterogeneity where it existed. planned to explore the impact of including such studies in the
overall assessment of results by a sensitivity analysis. Funnel plots
for primary outcomes only show no evidence of publication bias:
Assessment of reporting biases 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 © 2013 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 © 2013 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 © 2013 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.

RESULTS
Data synthesis
We carried out statistical analysis using the Review Manager soft-
ware (RevMan 2011). As we suspected clinical or methodological Description of studies
heterogeneity between studies sufficient to suggest that treatment The search identified 51 trials. We included 22 trials in the review,
effects may differ between trials, we used random-effects meta- involving 6872 women and their babies, and excluded 29. Of
analysis. the trials included, the majority were small with the exception of
Kenyon 2001, which randomised 4826 women, and Mercer 1997,
which randomised 614 women. Women were recruited between
Subgroup analysis and investigation of heterogeneity
20 and 37 weeks of gestation and inclusion criteria varied from
We conducted planned subgroup analyses classifying whole trials clinicians definition of PROM to amniocentesis being carried out
by interaction tests available in RevMan 2011. as part of an infection screen (Mercer 1992). The majority of
women were not in active labour. Ten trials tested broad spectrum
penicillins either alone or in combination (Cox 1995; Ernest
Sensitivity analysis 1994; Fuhr 2006; Grable 1996; Johnston 1990; Kenyon 2001;
We made explicit judgements about whether studies were at high Kurki 1992; Lockwood 1993a; Mercer 1997; Svare 1997a). Five
risk of bias, according to the criteria given in the Cochrane Hand- trials tested macrolide antibiotics (erythromycin) either alone or in
book (Higgins 2011). With reference to (1) to (6) above, we as- combination (Garcia-Burguillo 1995; Kenyon 2001; McGregor
sessed the likely magnitude and direction of the bias and whether 1991; Mercer 1992; Mercer 1997) and one tested clindamycin and
we considered it was likely to impact on the findings (Figure 1). gentamycin (Ovalle-Salas 1997). The duration of treatment varied
We considered this to be unlikely and therefore, have not under- between two doses (Kurki 1992) and 10 days (Kenyon 2001) with
taken sensitivity analyses. five trials opting for a maximum of seven days of treatment (Fuhr

Antibiotics for preterm rupture of membranes (Review) 10

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2006; McGregor 1991; Mercer 1997; Ovalle-Salas 1997; Svare We adopted a random-effects model, as we expected heterogeneity
1997a). Four trials treated women until delivery (Ernest 1994; due to variability in participant characteristics, different antibi-
Garcia-Burguillo 1995; Johnston 1990; Mercer 1992). In four of otics, year of the study and different countries etc.
the trials, women were treated with oral antibiotic alone (Garcia-
Burguillo 1995; Kenyon 2001; McGregor 1991; Mercer 1992). In
three of the trials, women were treated with intravenous antibiotic Any antibiotic versus placebo
alone (Fuhr 2006; Kurki 1992; Lockwood 1993a). In six of the We included 16 trials in this comparison, which randomised more
trials, women were treated with a combination of intravenous and than 6300 women and their babies.
oral antibiotics (Cox 1995; Ernest 1994; Johnston 1990; Mercer
1997; Ovalle-Salas 1997; Svare 1997a).
The six non-placebo controlled but randomised studies, which Primary Outcomes
contributed data to the outcome measure perinatal death alone, No maternal deaths occurred in the three trials reporting this out-
were: Amon 1988a; Camli 1997; Christmas 1992; Magwali 1999; come, and there were no data reported on serious maternal mor-
Morales 1989; Owen 1993a. bidity.
Two trials compared three versus five days of ampicillin (Lewis There was no significant difference between groups in perinatal
2003; Segel 2003). death (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.76
Outcomes were divided into primary and secondary. Primary out- to 1.14, 12 trials, data for 6301 babies). Neonatal infection (RR
comes, as listed above, were chosen based on importance and abil- 0.67, 95% CI 0.52 to 0.85) (12 trials/1680 babies) was statistically
ity to predict longer term neonatal morbidity. Additional out- significantly reduced in the babies whose mothers received antibi-
come measures chosen included maternal infection, prolongation otics. Only one trial (Kenyon 2001) assessed the use of surfactant
of pregnancy and measures of neonatal mortality and morbidity. and it found a statistically significant reduction (RR 0.83, 95%
One study had undertaken follow-up past discharge from hos- CI 0.72 to 0.96) (one trial/4809 babies) as was the numbers of
pital (Kurki 1992) but the results are not reported by treatment babies requiring oxygen therapy overall (RR 0.88, 95% CI 0.81
group but rather by duration of membrane rupture. One study has to 0.96) (one trial/4809 babies). There were no clear differences
undertaken long-term follow-up at seven years of age in the UK between groups for other neonatal outcomes including neonatal
(Kenyon 2001). The study evaluated functional impairment, be- respiratory distress syndrome (RR 0.95, 95% CI 0.83 to 1.09),
haviour, respiratory symptoms, hospital admissions, convulsions necrotising enterocolitis (RR 1.09, 95% CI 0.65 to 1.83), and the
and other specific medical conditions. These are the only data on number of babies requiring ventilation (RR 0.90, 95% CI 0.80 to
long-term follow-up from any of the included trials. Seven-year 1.02). There was a significant reduction in the number of babies
assessment was not specifically a prespecified outcome, but is cap- with an abnormal cerebral ultrasound scan prior to discharge from
tured under the outcome of long-term health after at least two hospital (RR 0.81, 95% CI 0.68 to 0.98; Tau² = 0.00, I² = 0%)
years. (12 trials/6289 babies).
For details of included and excluded studies, see Characteristics of
included studies and Characteristics of excluded studies.
Secondary Outcomes
Thre was no evidence of any difference between groups for birth
Risk of bias in included studies before 37 weeks’ gestation and there were no reports of major
The method of randomisation was described in all trials with the adverse drug reactions. The use of antibiotics following preterm
exception of Amon 1988a, Camli 1997, Cox 1995, Kurki 1992, rupture of membranes (PROM) was associated with a statistically
Fuhr 2006, Magwali 1999, Morales 1989 and Ovalle-Salas 1997. significant reduction in chorioamnionitis (RR 0.66, 95% CI 0.46
All trials had matched placebos and were blinded apart from the to 0.96; Tau² = 0.14, I² = 45%) (11 trials/1559 women). The
six non-placebo controlled studies described above. No detail on rate of caesarean section was similar in the two groups (RR 0.96,
losses to follow-up or exclusions were available from two trials (Cox 95% CI 0.88 to 1.05). The mean maternal length of hospital stay
1995; Johnston 1990). The protocols were only available for one and the interval between randomisation and the birth were not
study (Kenyon 2001) to allow assessment of selective reporting. reported in any of the trials included in this comparison.
Lack of information that would allow fuller assessment may reflect There was a significant reduction in the numbers of babies born
changes in reporting of trials. within 48 hours (RR 0.71, 95% CI 0.58 to 0.87; Tau² = 0.03, I² =
50%) (seven trials/5927 babies) and seven days (RR 0.79, 95% CI
0.71 to 0.89; Tau² = 0.01, I² = 65%) (seven trials/5965 babies) of
randomisation. The babies in the treatment groups spent 5.05 days
Effects of interventions less in neonatal intensive care (mean difference (MD) -5.05, 95%
We included 22 trials involving 6872 women and their babies. CI -9.77 to -0.33) (three trials/225 babies) and their birthweight

Antibiotics for preterm rupture of membranes (Review) 11

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
was greater by 54 g (MD 53.83, 95% CI 7.06 to 100.60) (12 This review shows that routine antibiotic administration to
trials/6374 babies). women with PROM reduces some markers of maternal and neona-
Long-term follow-up at seven years of age has been completed by tal morbidity. This does not translate into a statistically significant
one study (ORACLE - Kenyon 2008a) and showed that antibiotics reduction in perinatal mortality. Most trials, however, report fewer
seemed to have little effect on the health of the children (RR 1.01, deaths in the treatment group and the summary result shows a
95% CI 0.91 to 1.12) (one trial/3171 children). trend towards a beneficial effect. We included all randomised tri-
als in the evaluation of perinatal death as this outcome is unlikely
to be influenced by knowledge of the treatment allocation. Such
Subgroup comparisons a reduction in major markers of maternal and neonatal morbid-
These were undertaken for the primary outcomes only and show ity when antibiotics are administered makes a reduction in death
no evidence of differences in treatment effects between the sub- possible, even if the result was statistically non-significant from
groups, with the exception of necrotising enterocolitis, where there pooling of available data.
is a strong suggestion that this is increased with beta lactum antibi- By far the largest trial included is the UK MRC ORACLE (Kenyon
otics (including co-amoxiclav) (RR 4.72, 95% CI 1.57 to 14.23). 2001), which randomised 4826 women. The significant increase
in neonatal necrotising enterocolitis found in the co-amoxiclav
arm of this trial is plausible since co-amoxiclav is known to select
Additional comparisons for Enterobacter, Citrobacter and Pseudomonas (Hoy 2001). One
suggested mechanism of pathogenesis of neonatal necrotising en-
terocolitis is abnormal microbial colonisation of the intestinal tract
Erythromycin versus co-amoxiclav by one or several species unhindered by competitors. Co-amox-
We included one trial (Kenyon 2001), involving 2415 women that iclav, because of its large spectrum may influence such colonisa-
focused on this comparison. Delivery within 48 hours was less tion. Furthermore, the immature gut is sensitive to bacterial tox-
common after co-amoxiclav (RR 1.14, 95% CI 1.02 to 1.28) but ins, resulting in mucosal damage and the initiation of necrotising
the difference was not statistically significant at seven days (RR enterocolitis.
1.06, 95% CI 0.99 to 1.13). There was no significant difference Particularly in the light of the UK MRC ORACLE’s finding of
in any index of neonatal morbidity except for necrotising entero- reduced abnormal cerebral ultrasound scans before discharge from
colitis, which was statistically significantly less frequent after ery- hospital, it is important that long-term follow-up is undertaken.
thromycin (RR 0.46, 95% CI 0.23 to 0.94). Long-term follow- The UK MRC ORACLE Children Study followed up children,
up has been completed by one study (Kenyon 2001) and showed who were born to women with PROM randomised within the
little effect on the health of children (RR 0.89, 95% CI 0.79 to UK to the MRC ORACLE trial, at seven years of age and found
1.01) (one trial/1612 children). no evidence of either benefit or harm. This same study also as-
sessed long-term outcomes in children born to women with spon-
taneous preterm labour (SPL) and intact membranes randomised
Perinatal mortality alone
to the original ORACLE trial (Kenyon 2008b) and found evidence
No statistically significant reduction in perinatal mortality prior of harm. The prescription of erythromycin (with or without co-
to discharge from hospital could be found when additional data amoxiclav) was associated with a statistically significant increase
were included from the six studies that were randomised but not in the proportions of children with any level of functional impair-
placebo controlled (RR 0.89, 95% CI 0.74 to 1.08) (18 trials/ ment from 38% to 42%. Similarly, there was a statistically signif-
6872 babies). Subgroup comparison of this group alone also shows icant increase in the proportions of children with cerebral palsy
no statistical difference. from 1.7% to 3.3% associated with erythromycin and from 1.9%
to 3.2% with co-amoxiclav. There was a suggestion that more
children who developed cerebral palsy had been born to mothers
Differing regimens who had received both antibiotics. In the light of these findings, it
Two trials (Lewis 2003; Segel 2003) compared three versus seven- is important to be certain about the diagnosis of ruptured mem-
day regimens of ampicillin treatment (130 women). From the branes before prescribing antibiotics.
limited available outcome data, there was no obvious disadvantage
to the three-day regimen.
AUTHORS’ CONCLUSIONS

Implications for practice

DISCUSSION Routine prescription of antibiotics for women with preterm rup-

Antibiotics for preterm rupture of membranes (Review) 12

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ture of the membranes is associated with prolongation of preg- Dowswell, Riccardo Pfister, Justus Hofmeyr, David Taylor, Ann
nancy and improvements in a number of short-term neonatal mor- Blackburn and Rebecca Smyth.
bidities, but no significant reduction in perinatal mortality. De-
Therese Dowswell’s work was financially supported by the UNDP/
spite lack of evidence of longer term benefit in childhood, the ad-
UNFPA/UNICEF/WHO/World Bank Special Programme of Re-
vantages on short-term morbidities are such that we would recom-
search, Development and Research Training in Human Reproduc-
mend antibiotics are routinely prescribed. The antibiotic of choice
tion (HRP), Department of Reproductive Health and Research
is not clear but co-amoxiclav should be avoided in women due to
(RHR), World Health Organization. The named authors alone
increased risk of neonatal necrotising enterocolitis.
are responsible for the views expressed in this publication.
Implications for research As part of the pre-publication editorial process, the review has been
commented on by two peers (an editor and referee who is external
In the future there is the possibility that comparative studies may
to the editorial team), a member of the Pregnancy and Childbirth
be conducted should there be developments in the pharmacology
Group’s international panel of consumers and the Group’s Statis-
of antibiotics.
tical Adviser.
The National Institute for Health Research (NIHR) is the largest
single funder of the Cochrane Pregnancy and Childbirth Group.
The views and opinions expressed therein are those of the authors
ACKNOWLEDGEMENTS
and do not necessarily reflect those of the NIHR, NHS or the
We acknowledge assistance with the review from Therese Department of Health.

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42–4. S, London S. Preterm premature ruptured membranes: a
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Haas D. Preterm premature rupture of membranes: Obstetrics & Gynecology 1996;88(5):801–5.
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comparing their efficacy to prolong latency (PEACE trial). Lovett S, Weiss J, Diogo M, Williams P, Garite T. A
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Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ.
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Hernandez 2011 {published data only} Matsuda Y, Ikenoue T, Ibara S, Sameshima H, Kuraya K,
Hernandez y Ballinas A, Lopez Faran JA, Gamez Guevara Hokanishi H. The efficacy of prophylactic antibiotic and
C. [Comparison of maternal and perinatal outcomes in tocolytic therapy for premature rupture of the membranes.
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rupture between the use of erythromycin and clindamycin]. 1109–14.
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Julien 2002 {published data only} the membranes - aggressive versus conservative approach:
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trial comparing long term versus short term antibiotic Obstetric Investigation 1993;36:102–7.
prophylaxis in preterm premature rupture of membranes Mbu 1998 {published data only}
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2002;187(6 Pt 2):S66. Premature rupture of membranes: maternal and fetal
Kim 2008 {published data only} outcome in the absence of antibiotic prophylaxis [Rupture
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et al.Changes of lipid peroxidation and protein carbonyls l’absence de la prophylaxie antibiotique]. African Journal of
formation by antibiotic therapy in the maternal venous Reproductive Health 1998;2:26–31.
plasma of preterm premature rupture of membranes. 55th McCaul 1992 {published data only}
Annual Meeting of the Society of Gynecologic Investigation; McCaul JF, Perry KG, Moore JL, Martin RW, Bucovaz ET,
2008 March 26-29; San Diego, USA 2008:Abstract no: Morrison JC. Adjunctive antibiotic treatment of women
398. with preterm rupture of membranes or preterm labor.
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al.The efficacy of cefazolin plus macrolide (erythromycin or Norri 1991 {published data only}
clarithromycin) versus cefazolin alone in neonatal morbidity Norri L, Yla-Outinen A, Tuimala R. Prophylactic antibiotics
and placental inflammation for women with preterm in premature rupture of membranes. Proceedings of 13th
premature rupture of membranes. Placenta 2013;34(4): World Congress of Gynaecology and Obstetrics (FIGO);
346–52. 1991 September; Singapore. 1991:80.
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Ogasawara 1996 {published data only} Perinatal Obstetricians; 1990 Jan 23-27; Houston, Texas,
Ogasawara KK, Goodwin TM. The efficacy of treating USA. 1990:19.
ureaplasma urealyticum in patients with preterm labor Costeloe 2012
or preterm premature rupture of membranes. American Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow
Journal of Obstetrics and Gynecology 1996;174(1 Pt 2):401. N, Draper ES. Short term outcomes after extreme preterm
Ogasawara 1997 {published data only} birth in England: comparison of two birth cohorts in 1995
Ogasawara KK, Goodwin TM. The efficacy of prophylactic and 2006 (the EPICURE studies). BMJ 2012;345:e7976.
erythromycin in preventing vertical transmission of Dale 1989
ureaplasma urealyticum. American Journal of Perinatology Dale PO, Tanbo T, Bendvold E, Moe N. Duration of
1997;14(4):233–7. the latency period in preterm premature rupture of the
Ogasawara 1999 {published data only} membranes. Maternal and neonatal consequences of
Ogasawara KK, Goodwin TM. Efficacy of azithromycin in expectant management. European Journal of Obstetrics,
reducing lower genital ureaplasma urealyticum colonization Gynecology, and Reproductive Biology 1989;30:257–62.
in women at risk for preterm delivery. Journal of Maternal Dammann 1997
Fetal Medicine 1999;8:12–6. Dammann O, Leviton A. Maternal intrauterine infection,
Ovalle 2002 {published data only} cytokines, and brain damage in the preterm newborn.
Ovalle A, Martinez MA, Kakarieka E, Gomez R, Rubio R, Pediatric Research 1997;42(1):1–8.
Valderrama O, et al.Antibiotic administration in patients Dammann 2005
with preterm premature rupture of the membranes reduces Dammann O, Leviton A, Gappa M, Dammann CE.
the rate of histological chorioamnionitis: a prospective, Lung and brain damage in preterm newborns, and their
randomised, controlled study. Journal of Maternal-Fetal & association with gestational age, prematurity subgroup,
Neonatal Medicine 2002;12:35–41. infection/inflammation and long term outcome. BJOG: an
international journal of obstetrics and gynaecology 2005;112
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(Suppl 1):4–9.
Spitzer D, Zajc M, Gregg A, Steiner H, Staudach A.
Antepartum antibiotic therapy and subsequent neonatal Elbourne 2002
morbidity in patients with preterm premature rupture of Elbourne DR, Altman DG, Higgins JPT, Curtin F,
the membranes. International Journal of Experimental and Vaillancourt JM. Meta-analyses involving cross-over trials:
Clinical Chemotherapy 1993;6(1):35–8. methodological issues. International Journal of Epidemiology
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Additional references Gilbert 2005
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Alderson P, Green S, Higgins JPT, editors. Cochrane neonatal bacteraemia: insights from the MRC ORACLE
Reviewers’ Handbook 4.2.2 [updated March 2004]. The trials. BJOG: an international journal of obstetrics and
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Amon E, Lewis S, Sibai BM, Moretti M. Ampicillin Epidemiology and causes of preterm birth. Lancet 2008;
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Meeting of the Society of Perinatal Obstetricians; 1988 Feb
Hauth JC. The NICHD-MFMU antibiotic treatment
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Beazley 1998 inflammation and prenatal morbidity. American Journal of
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Bejar 1981 Systematic Reviews of Interventions Version 5.1.0 [updated
Bejar R, Curbelo V, Davi SC, Gluck L. Premature labour March 2011]. The Cochrane Collaboration, 2011.
bacterial sources of phospholipase. Obstetrics & Gynecology Available from www.cochrane-handbook.org.
1981;57:479. Hnat 2005
Christmas 1990 Hnat MD, Mercer BM, Thurnau G, Goldenberg R, Thom
Christmas JT, Cox SM, Gilstrap LC, Leveno KJ, Andrews EA, Meis PJ, et al.Perinatal outcomes in women with
W, Dax J. Expectant management of preterm ruptured preterm rupture of membranes between 24 and 32 weeks
membranes: effects of antimicrobial therapy on interval to of gestation and a history of vaginal bleeding. American
delivery. Proceedings of 10th Annual Meeting of Society of Journal of Obstetrics and Gynecology 2005;193:164–8.

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Hoy 2001 rupture. American Journal of Obstetrics and Gynecology
Hoy CM. The role of infection in necrotising enterocolitis. 1993;168(1 Pt 2):379.
Reviews in Medical Microbiology 2001;12:121–9. RevMan 2011
Kenyon 2008a The Nordic Cochrane Centre, The Cochrane Collaboration.
Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Salt A, et al.Childhood outcomes after prescription of Cochrane Centre, The Cochrane Collaboration, 2011.
antibiotics to pregnant women with preterm rupture of Romero 2007
the membranes: 7-year follow-up of the ORACLE I trial. Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation
Lancet 2008;372(9646):1310–8. in pregnancy: its roles in reproductive physiology, obstetrical
Kenyon 2008b complications, and fetal injury. Nutrition Reviews 2007;65:
Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, S194–202.
Salt A, et al.Childhood outcomes after prescription of Saigal 2008
antibiotics to pregnant women with spontaneous preterm Saigal S, Doyle LW. An overview of mortality and sequelae
labour: 7-year follow-up of the ORACLE II trial. Lancet of preterm birth from infancy to adulthood. Lancet 2008;
2008;372(9646):1319–27. 371(9608):261–9. [PUBMED: 18207020]
Kenyon 2008c Sanchez-Ramos 1990
Kenyon S, Brocklehurst P, Jones D, Marlow N, Salt A, Sanchez-Ramos L, Johnston M, Vaughn A, Benrubi GI,
Taylor D. MRC ORACLE children study. Long term Todd M. High dose antibiotic therapy in preterm premature
outcomes following prescription of antibiotics to pregnant rupture of the membranes: a double blind, randomized,
women with either spontaneous preterm labour or preterm prospective study. Proceedings of 10th Annual Meeting
rupture of the membranes. BMC Pregnancy & Childbirth of Society of Perinatal Obstetricians; 1990 Jan 23-27;
2008;8:14. Houston, Texas, USA. 1990:18.
King 2002 Speer 2003
King J, Flenady V. Prophylactic antibiotics for inhibiting Speer CP. Inflammation and bronchopulmonary dysplasia.
preterm labour with intact membranes. Cochrane Database Seminars in Neonatology 2003;8 No. 1:29–38.
of Systematic Reviews 2002, Issue 4. [DOI: 10.1002/
14651858.CD000246] Svare 1997b
Svare J, Langhoff-Roos J, Andersen LF, Kryger-Baggesen
Kotecha 1996
N, Borch-Christensen H, Heisterberg L, et al.Ampicillin-
Kotecha S. Cytokines in chronic lung disease of prematurity.
metronidazole treatment in threatening preterm delivery.
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Lockwood 1993b
Taylor 2001
Lockwood CJ, Costigan K, Ghidini A, Wein R, Cetrulo
Taylor HG, Klein N, Minich NM, Hack M. Long-term
C, Alvarez M, et al.Double-blind, placebo-controlled trial
family outcomes for children with very low birth weights.
of piperacillin sodium in preterm membrane rupture.
Archives of Pediatrics & Adolescent Medicine 2001;155(2):
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155–61. [PUBMED: 11177090]
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Marlow 2005 Thurnau 1997
Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic Thurnau G. The NICHD-MFMU antibiotic treatment
and developmental disability at six years of age after of PROM study: impact of initial amniotic fluid volume
extremely preterm birth. New England Journal of Medicine on pregnancy outcome. American Journal of Obstetrics and
2005;352(1):9–19. [PUBMED: 15635108] Gynecology 1997;176(1 Pt 2):S53.

McGregor 1997 Wu 2002

McGregor J, French J. Evidence-based prevention of Wu YW. Systematic review of chorioamnionitis and cerebral
preterm birth and rupture of membranes: infection and palsy. Mental Retardation and Developmental Disabilities
inflammation. Journal of the Society of Obstetricians and Research Reviews 2002;8(1):25–9.
Gynaecologists of Canada 1997;19:835–51. Yoon 2000
Morales 1988 Yoon BH, Romero R, Park JS, Kim M, Oh SY, Kin CJ,
Morales WJ, Angel JL, Knuppel RA. Comparison of various et al.The relationship among inflammatory lesions of the
parameters as predictors of chorioamnionitis in preterm umbilical cord (funisitis), umbilical cord plasma interleukin
patients with premature rupture of membranes. Southern 6 concentration, amniotic fluid infection, and neonatal
Medical Journal 1988;81:40. sepsis. American Journal of Obstetrics and Gynecology 2000;
183(5):1124–9.
Owen 1993b
Owen J, Groome LJ, Hauth JC. Randomized trial of References to other published versions of this review
prophylactic antibiotic therapy after preterm amnion

Antibiotics for preterm rupture of membranes (Review) 18

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Crowley 1995 preterm rupture of membranes. Cochrane Database
Crowley P. Antibiotics for preterm prelabour rupture of of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/
membranes. [revised 05 May 1994]. In: Enkin MW, 14651858.CD001058]
Keirse MJNC, Renfrew MJ, Neilson JP, Crowther C (eds.) Kenyon 2004
Pregnancy and Childbirth Module. In: The Cochrane Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm
Pregnancy and Childbirth Database [database on disk and rupture of the membranes: a systematic review. Obstetrics
CDROM]. The Cochrane Collaboration; Issue 2, Oxford: & Gynecology 2004;104(5 Pt 1):1051–7. [DOI: 10.1002/
Update Software; 1995. 14651858.CD001058]
Kenyon 2001 Kenyon 2010
Kenyon S, Boulvain M. Antibiotics for preterm premature Kenyon S, Boulvain M, Neilson JP. Antibiotics for
rupture of membranes. Cochrane Database of Systematic preterm rupture of membranes. Cochrane Database
Reviews 2001, Issue 3. of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/
Kenyon 2003 14651858.CD001058.pub2]
Kenyon S, Boulvain M, Neilson JP. Antibiotics for ∗
Indicates the major publication for the study

Antibiotics for preterm rupture of membranes (Review) 19

Copyright © 2013 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 g IV every 6 hours for 24 hours. Maintained on oral
500 mg ampicillin 6-hourly until delivery. In labour they were recommenced on 1 g IV
ampicillin

Outcomes Death only included.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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) 20

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Camli 1997 (Continued)

Interventions Treatment group oral ampicillin 1 g 4 x daily.

No placebo arm or tocolysis used.

Outcomes Death only included.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Antibiotics for preterm rupture of membranes (Review) 21

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Christmas 1992 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Low risk Using sequentially numbered sealed en-
velopes.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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 g 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection Low risk Stated as double blind study.
bias)

Antibiotics for preterm rupture of membranes (Review) 22

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cox 1995 (Continued)

All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Table of random numbers.

bias)

Allocation concealment (selection bias) Low risk Stated that nurses were not involved in the
preparation or release of either antibiotic or
placebo

Blinding (performance bias and detection Low risk Patients and staff blinded.
bias)
All outcomes

Antibiotics for preterm rupture of membranes (Review) 23

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ernest 1994 (Continued)

Incomplete outcome data (attrition bias) Low risk Data excluded for 4 women who were
All outcomes treated with antibiotics outside the proto-
col

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk No information given.

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 g 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk No information given.

Antibiotics for preterm rupture of membranes (Review) 24

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Garcia-Burguillo 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.

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

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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk No information given.

Antibiotics for preterm rupture of membranes (Review) 25

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 g 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Randomisation based on random numbers
bias) tables with blocks providing 1:1 ratio and
balancing every 6 women

Allocation concealment (selection bias) Low risk Randomisation and preparation of drugs
conducted in pharmacy

Blinding (performance bias and detection Low risk Double-blind trial.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Antibiotics for preterm rupture of membranes (Review) 26

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Johnston 1990 (Continued)

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.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Randomisation table generated by consec-
bias) utive coin toss.

Allocation concealment (selection bias) Low risk The randomisation schedule kept in phar-
macy.

Blinding (performance bias and detection Low risk Randomisation schedule stated as not be-
bias) ing available to clinicians
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Antibiotics for preterm rupture of membranes (Review) 27

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kenyon 2001 (Continued)

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

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk By computer using randomly generated
bias) blocks of 4.

Allocation concealment (selection bias) Low risk Sequentially numbered drug boxes of iden-
tical appearance.

Blinding (performance bias and detection Low risk Stated that clinicians remained blind to
bias) treatment allocation in all but 9 cases and
All outcomes that all staff and participants remained
blind to treatment allocation
For the follow-up study all participants bar
1 women and all Study staff remained blind
to treatment allocation

Incomplete outcome data (attrition bias) Low risk 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

Selective reporting (reporting bias) Low risk No selective reporting.

Protocol published for follow-up study.

Antibiotics for preterm rupture of membranes (Review) 28

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kenyon 2001 (Continued)

Other bias Low risk 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
reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Low risk Stated as being by sealed envelope.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk No information given.

Antibiotics for preterm rupture of membranes (Review) 29

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Randomised using table of arbitrary num-
bias) bers in blocks of 10.

Allocation concealment (selection bias) Low risk Indicator cards placed in sealed envelopes
which were sequentially numbered and
stored on an area away from the enrolment
site

Blinding (performance bias and detection Low risk Stated that all carers were unaware of the
bias) randomisation process
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Antibiotics for preterm rupture of membranes (Review) 30

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lockwood 1993a (Continued)

were also excluded

Interventions Piperacillin 3 g 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated randomisation se-

bias) quence.

Allocation concealment (selection bias) Low risk Same deposited in pharmacy.

Blinding (performance bias and detection Low risk Stated all healthcare providers were blinded
bias) to allocation.
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Antibiotics for preterm rupture of membranes (Review) 31

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Magwali 1999 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Low risk Stated as being by sealed envelope.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Minimal loss to follow-up - 2 in the treat-
All outcomes ment and 1 in the no treatment group

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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)
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 Blanco’s paper has ever been published

Risk of bias

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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
McGregor 1991 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random number list.
bias)

Allocation concealment (selection bias) Low risk Sequentially numbered bottles.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete after 10 exclusions.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

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

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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mercer 1992 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computerised random number tables.
bias)

Allocation concealment (selection bias) Low risk Administered by the pharmacy.

Blinding (performance bias and detection Low risk States that all involved remained blind to
bias) treatment allocation
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

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 NEC, or sepsis within 72 hours of birth. These perinatal morbidities were
also assessed separately and pregnancy prolongation assessed.
For twin pregnancies adverse outcomes considered present if 1 twin affected

Notes 11 centres - USA.

February 1992-January 1995.
1867 women screened.

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Mercer 1997 (Continued)

804 eligible.
614 agreed to participate.
29 twin gestations.
GBS positive: 118/614.
3 women lost to follow-up.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Urn randomisation scheme (a procedure
bias) to increase the likelihood of obtaining an
equal number of subjects in each arm),
stratified by centre

Allocation concealment (selection bias) Low risk Treatment given by pharmacy.

Blinding (performance bias and detection Low risk States all involved remained blinded to
bias) treatment allocation
All outcomes

Incomplete outcome data (attrition bias) Low risk Only 3 withdrawals (2 in placebo and 1 in
All outcomes treatment arm).

Selective reporting (reporting bias) Unclear risk No protocol available.

Other bias Unclear risk 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

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

Antibiotics for preterm rupture of membranes (Review) 35

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Morales 1989 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Low risk States as sealed envelopes into 1 of 4 groups.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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)

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

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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Ovalle-Salas 1997 (Continued)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information given.

bias)

Allocation concealment (selection bias) Unclear risk No information given.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete with 1 loss to follow-
All outcomes up.

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias High risk 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 g ampicillin 6-hourly for 24 hours then 500 mg ampicillin orally every 6 hours.
If allergic to penicillin 500 mg erythromycin used 6-hourly. Treatment continued with
delivery or diagnosis of chorioamnionitis

Outcomes Death only included.

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk By computer algorithm.

bias)

Antibiotics for preterm rupture of membranes (Review) 37

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Owen 1993a (Continued)

Allocation concealment (selection bias) Low risk Sealed opaque envelope.

Blinding (performance bias and detection High risk Not blinded.

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete - 1 woman lost to
All outcomes follow-up in control group

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random number ta-
bias) ble in blocks of 4.

Allocation concealment (selection bias) Low risk Study medicine given by pharmacy in iden-
tical packs.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Antibiotics for preterm rupture of membranes (Review) 38

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Segel 2003 (Continued)

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Other bias Unclear risk 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 g IV 6-hourly. 24 hours - pivampicillin 500 g orally 8-hourly for 7 days
plus IV metronidazole 500 mg every 8 hours for 24 hours, followed by metronidazole
400 mg orally every 8 hours for 7 days or identical placebo

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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Block randomisation done using com-
bias) puter-generated numbers.

Allocation concealment (selection bias) Unclear risk No information available.

Blinding (performance bias and detection Low risk Stated as double-blind trial.
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk Data appear complete.
All outcomes

Selective reporting (reporting bias) Unclear risk Protocol not available.

Antibiotics for preterm rupture of membranes (Review) 39

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Svare 1997a (Continued)

Other bias Unclear risk No information available

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

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 wrote to Brian Mercer who
included these data in a Lancet review in 1995 and James McGregor who was listed as an author

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

Antibiotics for preterm rupture of membranes (Review) 40

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

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 that investigated active versus passive management of women with PPROM. 55 women were recruited
when admitted and given antibiotics. The control group were women who presented with PPROM. 1985-
1987 before use of active protocol. Excluded as not double-blinded, randomised or controlled

Gordon 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

Haas 2010 This was a trial registration. The trial did not take place and no results are available

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

Hernandez 2011 Study comparing two macrolide antibiotics: i.e. comparison of similar antibiotics - so excluded as this antibiotic
comparison was not included in this review

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

Kim 2008 Study was neither randomised nor placebo-controlled.

Kwak 2013 Study comparing a beta-lactam antibiotic with the same antibiotic plus macrolide. This antibiotic comparison
was not included in this review

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: i.e. comparison of similar antibiotics - so excluded as this
antibiotic comparison was not included in this review

Lewis 1996 This is a randomised trial of corticosteroids in women with PPROM after a minimum of 12 hours ampicillin
sulbactam
77 women were enrolled. No statistically significant difference in latency period was noted. Neonatal and
maternal infectious morbidity were similar. A significant reduction in the incidence of RDS, 18.4% versus 43.
6%, was observed in the steroid group

Lovett 1997 Double-blind, placebo-controlled trial of 112 women with PPROM 23 to 25 weeks’ gestation to receive
ampicillin/sulbactam or ampicillin or placebo
Excluded because of a high rate of exclusions (52/164: 32%). Further information has been requested from the
authors

Matsuda 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

Mbu 1998 Allocation by alternation.

Antibiotics for preterm rupture of membranes (Review) 41

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

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 women’s 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 randomisa-
tion. 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: group B Streptococcus

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

Antibiotics for preterm rupture of membranes (Review) 42

Copyright © 2013 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) 0.0 [0.0, 0.0]
placebo
1.2 All penicillin (excluding 1 85 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
co-amoxiclav) versus placebo
1.3 Beta lactum (including co- 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
amoxiclav) versus placebo
1.4 Macrolide (including 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
erythromycin) versus placebo
1.5 Other antibiotic versus 2 678 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
placebo
2.2 All penicillin (excluding 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
co-amoxiclav) versus placebo
2.3 Beta lactum (including co- 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
amoxiclav) versus placebo
2.4 Macrolide (including 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
erythromycin) versus placebo
2.5 Other antibiotic versus 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 43
Copyright © 2013 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) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
of mother
14 Days from randomisation to 0 0 Mean Difference (IV, Random, 95% CI) 0.0 [0.0, 0.0]
birth

Antibiotics for preterm rupture of membranes (Review) 44

Copyright © 2013 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) 0.0 [0.0, 0.0]
28 Serious childhood disability at 1 3171 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.91, 1.12]
7 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) 0.0 [0.0, 0.0]
2 Serious maternal morbidity 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3 Major adverse drug reaction 1 2395 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
birth
8 Days from birth till discharge of 0 0 Mean Difference (IV, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
unit
Antibiotics for preterm rupture of membranes (Review) 45
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16 Neonatal infection including 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
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]
7 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 Antibiotics versus no 18 6872 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.74, 1.08]
antibiotics (all studies)
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) 0.0 [0.0, 0.0]
2 Serious maternal morbidity 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3 Major adverse drug reaction 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
4 Maternal infection after delivery 1 84 Risk Ratio (M-H, Random, 95% CI) 1.25 [0.36, 4.33]
prior to discharge
Antibiotics for preterm rupture of membranes (Review) 46
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5 Chorioamnionitis 1 84 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.33, 1.63]
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) 0.0 [0.0, 0.0]
birth
8 Days from birth till discharge of 0 0 Mean Difference (IV, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
12 Birthweight 0 0 Mean Difference (IV, Random, 95% CI) 0.0 [0.0, 0.0]
13 Birthweight < 2500 g 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
unit
16 Neonatal infection including 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
pneumonia
17 Positive neonatal blood culture 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
21 Number of babies requiring 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
ventilation
22 Number of babies requiring 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
oxygen therapy
23 Neonatal oxygenation > 28 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
days
24 Oxygen treatment > 36 weeks’ 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
postconceptual age
25 Neonatal encephalopathy 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
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) 0.0 [0.0, 0.0]
7 years

Antibiotics for preterm rupture of membranes (Review) 47

Copyright © 2013 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 Antibiotic Placebo Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 0 (Placebo)
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 (Antibiotic), 0 (Placebo)
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 (Antibiotic), 0 (Placebo)
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 (Antibiotic), 0 (Placebo)
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 (Antibiotic), 0 (Placebo)
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 antibiotic Favours placebo

Antibiotics for preterm rupture of membranes (Review) 48

Copyright © 2013 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Any antibiotic versus placebo
Cox 1995 1/31 5/31 1.0 % 0.20 [ 0.02, 1.61 ]

Garcia-Burguillo 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 (Antibiotic), 138 (Placebo)
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 (Antibiotic), 10 (Placebo)
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

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours placebo
(Continued . . . )

Antibiotics for preterm rupture of membranes (Review) 49

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 (. . .Continued)
Study or subgroup Antibiotic Placebo Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
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 ]

Subtotal (95% CI) 1236 644 100.0 % 0.62 [ 0.15, 2.56 ]

Total events: 80 (Antibiotic), 46 (Placebo)
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-Burguillo 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 (Antibiotic), 56 (Placebo)
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 (Antibiotic), 26 (Placebo)
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

Favours antibiotic Favours placebo

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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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-Burguillo 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 (Antibiotic), 141 (Placebo)
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 (Antibiotic), 25 (Placebo)
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)

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours placebo
(Continued . . . )

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Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 (. . .Continued)
Study or subgroup Antibiotic Placebo Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
3 Beta lactum (including co-amoxiclav) versus placebo
Cox 1995 0/31 1/31 100.0 % 0.33 [ 0.01, 7.88 ]

Subtotal (95% CI) 31 31 100.0 % 0.33 [ 0.01, 7.88 ]

Total events: 0 (Antibiotic), 1 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.68 (P = 0.50)
4 Macrolide (including erythromycin) versus placebo
Garcia-Burguillo 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 (Antibiotic), 25 (Placebo)
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 (Antibiotic), 90 (Placebo)
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

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 58 (Placebo)
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 (Antibiotic), 6 (Placebo)
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 ]

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours placebo
(Continued . . . )

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 (. . .Continued)
Study or subgroup Antibiotic Placebo Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Total events: 29 (Antibiotic), 3 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0%
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 (Antibiotic), 19 (Placebo)
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 (Antibiotic), 30 (Placebo)
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

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 76 (Placebo)
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 (Antibiotic), 0 (Placebo)
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 (Antibiotic), 38 (Placebo)
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 (Antibiotic), 38 (Placebo)
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 (Antibiotic), 0 (Placebo)
Heterogeneity: not applicable
Test for overall effect: not applicable

0.1 0.2 0.5 1 2 5 10

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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 Antibiotic Placebo Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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-Burguillo 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 (Antibiotic), 184 (Placebo)
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 (Antibiotic), 23 (Placebo)
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 ]

0.01 0.1 1 10 100

Favours antibiotic Favours placebo
(Continued . . . )

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 (. . .Continued)
Study or subgroup Antibiotic Placebo Risk Ratio Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Kenyon 2001 46/1205 31/613 0.75 [ 0.48, 1.18 ]

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

Total events: 53 (Antibiotic), 39 (Placebo)
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-Burguillo 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 (Antibiotic), 47 (Placebo)
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 (Antibiotic), 76 (Placebo)
Heterogeneity: Tau2 = 0.13; Chi2 = 2.74, df = 2 (P = 0.25); I2 =27%
Test for overall effect: Z = 0.47 (P = 0.64)

0.01 0.1 1 10 100

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 1102 (Placebo)
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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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 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 Antibiotic Placebo Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 0 (Placebo)

Heterogeneity: Tau2 = ; Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Garcia-Burguillo 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 (Antibiotic), 306 (Placebo)
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)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours placebo

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 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Ernest 1994 3/77 9/67 6.4 % 0.29 [ 0.08, 1.03 ]

Garcia-Burguillo 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 ]

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 (Antibiotic), 196 (Placebo)
Heterogeneity: Tau2 = 0.14; Chi2 = 18.29, df = 10 (P = 0.05); I2 =45%
Test for overall effect: Z = 2.18 (P = 0.029)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours antibiotic Favours placebo

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 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

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

Garcia-Burguillo 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 (Antibiotic), 564 (Placebo)
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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 717 (Placebo)
Heterogeneity: Tau2 = 0.03; Chi2 = 12.11, df = 6 (P = 0.06); I2 =50%
Test for overall effect: Z = 3.32 (P = 0.00088)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 1221 (Placebo)
Heterogeneity: Tau2 = 0.01; Chi2 = 16.94, df = 6 (P = 0.01); I2 =65%
Test for overall effect: Z = 3.99 (P = 0.000067)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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

Mean Mean
Study or subgroup Antibiotic Placebo Difference Weight 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-Burguillo 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)
Test for subgroup differences: Not applicable

-1000 -500 0 500 1000

Favours placebo Favours antibiotic

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 911 (Placebo)
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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 975 (Placebo)
Heterogeneity: Tau2 = 0.02; Chi2 = 13.44, df = 3 (P = 0.004); I2 =78%
Test for overall effect: Z = 0.32 (P = 0.75)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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

Mean Mean
Study or subgroup Antibiotic Placebo Difference Weight 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)
Test for subgroup differences: Not applicable

-1000 -500 0 500 1000

Favours antibiotic Favours placebo

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 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 104 (Placebo)
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)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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-Burguillo 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 (Antibiotic), 551 (Placebo)
Heterogeneity: Tau2 = 0.01; Chi2 = 15.15, df = 11 (P = 0.18); I2 =27%
Test for overall effect: Z = 0.75 (P = 0.45)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 217 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 2.56 (P = 0.011)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 292 (Placebo)
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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 436 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 2.75 (P = 0.0060)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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 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 Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 179 (Placebo)
Heterogeneity: Tau2 = 0.02; Chi2 = 2.77, df = 2 (P = 0.25); I2 =28%
Test for overall effect: Z = 1.74 (P = 0.082)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours placebo

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 Antibiotic Placebo Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Garcia-Burguillo 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 (Antibiotic), 0 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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 Analysis 1.28. Comparison 1 Any antibiotic versus placebo, Outcome 28 Serious childhood disability at 7
years.

Review: Antibiotics for preterm rupture of membranes

Comparison: 1 Any antibiotic versus placebo

Outcome: 28 Serious childhood disability at 7 years

Study or subgroup Antibiotic Placebo Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (Antibiotic), 311 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.21 (P = 0.83)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours placebo

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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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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

Mean Mean
Study or subgroup Erythromycin Co-amoxiclav Difference Weight 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)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours co-amoxiclav Favours erythromycin

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 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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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 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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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 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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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 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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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 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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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

Review: Antibiotics for preterm rupture of membranes

Comparison: 2 Erythromycin versus co-amoxiclav

Outcome: 28 Serious childhood disability at 7 years

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

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours erythromycin Favours co-amoxiclav

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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 Antibiotic No antibiotic Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Antibiotics versus no antibiotics (all studies)
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-Burguillo 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 (Antibiotic), 172 (No antibiotic)
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 ]

0.001 0.01 0.1 1 10 100 1000

Favours antibiotic Favours no antibiotic
(Continued . . . )

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 (. . . Continued)
Study or subgroup Antibiotic No antibiotic Risk Ratio Weight Risk Ratio
M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Christmas 1992 1/48 3/46 5.3 % 0.32 [ 0.03, 2.96 ]

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 (Antibiotic), 34 (No antibiotic)
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

Favours antibiotic Favours no antibiotic

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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 4 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.35 (P = 0.73)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 11 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.78 (P = 0.44)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 17 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.66 (P = 0.51)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 7 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.28 (P = 0.78)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 25 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 36 (7 day)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 3 (7 day)
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)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours 3 day Favours 7 day

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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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 25 (7 day)
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)
Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10

Favours 3 day Favours 7 day

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 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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 2 (7 day)
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)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours 3 day Favours 7 day

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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 3 day 7 day Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI 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 (3 day), 4 (7 day)
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)
Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours 3 day Favours 7 day

APPENDICES

Appendix 1. Methods used to assess trials included in a previous version of this review (published
2003, Issue 2).
The following methods were used to assess Almeida 1996; Amon 1988a; Camli 1997; Christmas 1992; Cox 1995; Ernest 1994;
Garcia-Burguillo 1995; Grable 1996; Johnston 1990; Kenyon 2001; Kurki 1992; Lewis 2003; Lockwood 1993a; Magwali 1999;
McGregor 1991; Mercer 1992; Mercer 1997; Morales 1989; Ovalle-Salas 1997; Owen 1993a; Segel 2003; Svare 1997a.
All trials identified by the methods described in the search strategy were scrutinised by the reviewers. We processed included trial data as
described in Alderson 2004. We evaluated trials under consideration for inclusion and methodological quality. There was no blinding
of authorship. We assigned quality scores for concealment of allocation to each trial, using the criteria described in section six of the
Cochrane Reviewers’ Handbook (Alderson 2004): A = adequate; B = unclear; C = inadequate; D = not used.
We excluded trials that proved on closer examination not to be true randomised trials. We analysed outcomes on an intention-to-treat
basis.
We extracted and double entered data. Wherever possible, we sought unpublished data from the investigator. Where outcomes were
published in the form of percentages or graphs, the number of events were calculated. Where maternal outcomes were presented,
numerators and denominators were calculated based on the number of mothers. Babies from multiple pregnancies have been treated as
a single unit, with the worst outcome among the babies included in analyses. Of the 22 trials included, 12 only randomised singletons.
Of the seven remaining, two did not state whether multiples were included. Of the five trials that included multiples, two specified
how they had analysed the data (Kenyon 2001; Mercer 1997) and both used the worst outcomes in any baby.
We tested for heterogeneity between trial results using a standard Chi-squared test. For dichotomous data, we calculated the relative
risk and for continuous variables, the weighted mean difference; in both cases, we reported 95% confidence intervals.
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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
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WHAT’S NEW
Last assessed as up-to-date: 26 November 2013.

Date Event Description

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

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

Date Event Description

9 October 2013 New search has been performed Search updated 30 September 2013. Four new trial re-
ports identified; none eligible for inclusion. Recom-
mendation to give antibiotics routinely in these circum-
stances made clearer in conclusions

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

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 pre-
scribed 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

29 January 2009 Amended Author contact details edited.

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

Antibiotics for preterm rupture of membranes (Review) 95

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(Continued)

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.

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

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

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

SOURCES OF SUPPORT

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

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

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

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

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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

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