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Antibiotics for preterm rupture of membranes

RHL Commentary by Coltart CEM, Festin M

1. INTRODUCTION

Preterm premature rupture of membranes (pPROM) occurs in 1%–3% of all pregnancies and is responsible for approximately one third of all preterm births (1, 2). A tenfold increase in neonatal infection has been noted in uncomplicated cases of premature rupture of membranes (PROM) compared with neonates in general (3). After membranes have been ruptured for more than 24 hours, the incidence of neonatal infection is approximately 1%, and when clinical chorioamnionitis is present, the incidence of neonatal infection increases to between 3% and 5% (4).

Preterm delivery is a risk factor for increased neonatal morbidity and mortality. One of the risk factors associated with preterm delivery is infection, which may lead to infection in utero and in the fetus. Such infections are also a common cause of low-birth-weight deliveries. The objective of this Cochrane review (5), updated in 2010, was to assess the effects of administering antibiotics to women with preterm rupture of membranes. Specifically, the review aimed to evaluate the effects of antibiotics on fetal and neonatal morbidity and mortality, maternal infectious morbidity and mortality, and long-term childhood development.

2. METHODS OF THE REVIEW

The authors of the review planned to include all randomized controlled trials comparing antibiotic treatment versus placebo for women with PROM. They compared placebo treatment to treatment with penicillin (excluding co-amoxiclav) or beta lactams (including co-amoxiclav) or macrolides. In addition, comparisons of different antibiotics were also included: beta lactam versus macrolide and penicillin versus macrolide.

The review authors searched for eligible articles electronically in the Cochrane Pregnancy and Childbirth Group’s Trials Register, which includes relevant trials from the Cochrane Central Register of controlled trials (CENTRAL) and MEDLINE. The authors also made hand searches of journals and conference proceedings and email alerts from BioMed Central. There were no language restrictions in their search.

Two review authors independently assessed the available studies for inclusion in the review and any disagreements were resolved by discussion, or if required by consulting with the third author. The data were analysed using Review Manager Software (RevMan 2008). Sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting bias were used to assess the risk of bias in the included studies.

Primary outcome measures included maternal death, serious maternal morbidity, perinatal death (or death before discharge) and perinatal morbidity (as defined by the trial authors). Secondary outcome measures included: major maternal adverse drug reaction, maternal infection after delivery prior to discharge, chorioamnionitis, caesarean section, days from randomization to birth, days from birth to discharge, birth within 48 hours, birth within 7 days, birth before 37 weeks, birth weight, birth weight less than 2500 g, need for intensive care, days in neonatal intensive care unit, positive neonatal blood culture, respiratory distress syndrome, treatment with surfactant, number of days of ventilation, number of days of oxygen therapy, oxygen treatment greater than 28 days, neonatal encephalopathy and long-term health outcomes after at least 2 years (as defined by trial authors).

3. RESULTS OF THE REVIEW

This review includes 22 trials (out of 49 identified articles) involving 6800 women and babies overall. Giving antibiotics to women with pPROM was associated with a statistically significant reduction in chorioamnionitis [relative risk [RR]: 0.66, 95% confidence interval (CI) 0.46–0.96]. There was also a statistically significant reduction in deliveries within 48 hours (RR 0.71, 95% CI 0.58–0.87) and 7 days of randomization (RR 0.79, 95% CI 0.71–0.89).

The following markers of neonatal morbidity were also reduced: neonatal infection (RR 0.67, 95% CI 0.52–0.85), use of surfactant (RR 0.83, 95% CI 0.72–0.96), the numbers of babies requiring oxygen therapy overall (RR 0.88, 95% CI 0.81–0.96) and the number of babies diagnosed with abnormal cerebral ultrasound prior to discharge from hospital (RR 0.81, 95% CI 0.68–0.98). However, there was a significant increase in cases of babies with necrotizing enterocolitis (two trials, RR 4.72, 95% CI 1.57–14.23) in babies who received co-amoxiclav antibiotics.

One study evaluated the children’s health at 7 years of age and found that antibiotic use for pPROM had little long-term effect on the health of the children.

4. DISCUSSION

The conclusions of the review are not clear-cut. Administration of antibiotics to women with PROM is associated with a delay in delivery and a reduction in some markers of neonatal morbidity (prolongation of pregnancy, infection, less abnormal cerebral ultrasound before discharge). Most trials show a trend towards a beneficial effect, although the results are not significant. However, in the long term (at 7 years' follow-up), antibiotic use for pPROM had little effect (beneficial or harmful) on the health of the children. Therefore, the use of antibiotics should be balanced between benefits in some short-term outcomes and lack of evidence of benefit for others (e.g. perinatal mortality) and longer-term outcomes. Furthermore, if antibiotics are used, it is unclear which should be the antibiotic of choice. Specifically, co-amoxiclav should be avoided in women at risk of preterm delivery because of the increased risk of neonatal necrotizing enterocolitis. This is a change in conclusions from the previous version of this review.

4.1 Applicability of the results

The studies included in this review were conducted in both developing as well as developed countries. The possible etiological agents in developed and developing countries may vary from site to site, and vigilance in identifying the agents responsible from PROM would be needed. However, bacteriological culture facilities may be lacking or may be costly in many areas in developing countries and broad-spectrum antibiotics may have to be used empirically. Because of the higher rates of neonatal infection and morbidity in developing countries, routine administration of antibiotics in these settings would have a relatively higher impact in improving clinical outcomes compared to industrialized countries.

4.2 Implementation of the interventio

The review does not provide a clear answer whether antibiotics should be used for pPROM, but it highlights the need for evaluating the risk to benefit ratio (or more accurately the benefit to lack of harm). If local protocol deems that antibiotics would be of benefit, implementation should be feasible across many health-care settings in both developed and developing countries. Several types of antibiotic are readily available, even in under-resourced settings. One of the available antibiotics can be administered to women, provided they are in a health-care facility, they present early enough after the appearance of signs of pPROM and the prescribed antibiotics can be afforded by either the woman or the health-care service.

This review highlights the risk of neonatal necrotizing enterocolitis from co-amoxiclav. The choice of antibiotics should preferably be based on the common organisms found in cultures from the genital tract of pregnant women in the country. If such information is not available, a broad-spectrum antibiotic, which is safe for pregnant women, may be used intravenously until the patient delivers. In the presence of fetal distress or signs of infection in the mother or the fetus, the clinical situation must be evaluated for immediate delivery. While antibiotics may be relatively easy to administer, it may be advisable to administer them in the hospital setting, rather than in the community, as delivery timing could be difficult to predict in women with pPROM.

For many hospitals, obtaining a supply of antibiotics may be much easier than investing in intensive care equipment for women with pPROM. For example, this is true for hospitals in rural Philippines (and in many other developing countries). This prolongation of pregnancy through the use of antibiotics can allow the mother to be transferred to a facility with better equipment for the management of such cases.

4.3 Implications for research

The authors highlight the need for further comparative studies to elucidate the best antibiotic agent. In addition, further evidence with respect to the cost–effectiveness of antibiotic use in such cases would be useful. Studies into the effectiveness of orally-administered antibiotics, compared to the parenteral route, could possibly demonstrate an easier and less costly management pathway.

To complement this review, further studies on other variables affecting pPROM would be useful – e.g. the effect of level of activity of the mother diagnosed with PROM, level of nursery care capability and resources, and the rates of survival in babies born to women with PROM in different levels of health-care facilities. The search for the ideal antibiotic for PROM should continue.

Sources of support: None

Acknowledgement: None.

References

• Mercer BM. Preterm rupture of membranes. Obstetrics Gynecology 2003; 101:178-193.
• Premature rupture of membranes. ACOG Technical Bulletin 115. Washington, DC: American College of Obstetricians and Gynecologists; 1998.
• Belady PH, Farkouh LJ, Gibbs RS. Intra-amniotic infection and premature rupture of the membranes. Clinical Perinatology 1997;24:43-57.
• Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clinal Perinatology 1991;18:361-379.
• Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database of Systematic Reviews 2010;Issue 8. Art. No.: CD001058; DOI: 10.1002/14651858.CD001058.pub2.

This document should be cited as: Coltart CEM, Festin M. Antibiotics for preterm rupture of membranes: RHL commentary (last revised: 1 December 2011). The WHO Reproductive Health Library; Geneva: World Health Organization.