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Concomitant use of glucocorticoids: a comparison of two metaanalyses on antibiotic treatment in preterm premature rupture of membranes |
Leitich H, Egarter C, Reisenberger K, Kaider A, Berghammer P |
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Authors' objectives To investigate whether the demonstrated beneficial effects of antibiotics on maternal and neonatal morbidity are altered when glucocorticoids are part of the treatment of pre-term premature rupture of membranes.
Searching The authors searched 18 medical databases, including MEDLINE (from 1966 to October 1996) and EMBASE (from 1974 to October 1996). The search terms were: 'preterm' or 'preterm premature rupture', 'amniotic' or 'fetal/foetal membrane', 'amnion' or 'amniotic sac', and 'antibiotic', 'antimicrobial therapy' or 'treatment'. The original published report had to be written in English.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs). Two studies used a randomised, double-blind, placebo-controlled design and three were randomised and non-blinded. The length of treatment (administration of antibiotics) varied in each study, ranging from: every 6 hours, every 6 hours for 24 hours, every 8 hours until delivery, to every 6 hours for 72 hours.
Specific interventions included in the reviewAntibiotics including oral cephalexin, oral erythromycin, intravenous ampicillin and intravenous piperacillin. Glucocorticoids and tocolytics.
Participants included in the reviewThe patients were pregnant women with pre-term premature rupture of membranes, defined as premature rupture of the fetal membranes before 37 weeks' gestation. The participants had single pregnancies (with the exception of one study) between 20 and 35 weeks. The mean gestational age on admission ranged from 29.2 to 30.4 weeks. Most patients remained hospitalised throughout the treatment.
Outcomes assessed in the reviewThe neonatal outcomes assessed were: neonatal death, sepsis, hyaline membrane disease, respiratory distress syndrome, intraventricular haemorrhage, and necrotising enterocolitus. The maternal outcomes included chorioamnionitis and postpartum endometritis. The secondary outcomes were mean latency periods, mean birth weights, and mean durations of maternal and neonatal hospitalisation.
How were decisions on the relevance of primary studies made?To determine whether the studies met the inclusion criteria, the authors scanned all abstracts from the computer printouts, the full-text reports, the references from each retrieved report, and the review articles.
Assessment of study quality The authors compared the following selected standards for clinical trials: baseline similarity between study groups, randomisation process, blindness, use of placebo, and assessment of patient compliance.The authors do not state how the papers were assessed for validity, or how many of the authors performed the validity assessment.
Data extraction The authors do not state how the data were extracted for the review, or how many of the authors performed the data extraction.
The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each study separately.
Methods of synthesis How were the studies combined?The ORs and 95% CIs were calculated for the combined studies using a fixed-effect model. Logistic regression analyses were performed for each outcome to determine more precisely the influence of concomitant glucocorticoids on the effect of antibiotic treatment. As a first step, univariate analyses were performed to estimate the effect of antibiotic treatment in all studies combined, and in each of the two subgroups of studies with and without glucocorticoid treatment. Second, multivariate analyses were carried out to test the interaction between both treatments.
How were differences between studies investigated?The authors performed a chi-squared test for homogeneity, using a p-value of less than 0.05 to indicate significance. In addition, the following features were compared in order to assess whether the studies analysed were clinically homogeneous: patient inclusion and exclusion criteria; the baseline similarity of patients between studies; characteristics of management, including administration of antibiotics, glucocorticoids, tocolytics, and other treatments; management of patients with positive cultures; and neonatal management.
Results of the review Five studies with a total of 509 participants were included in the meta-analysis of antibiotic treatment with concomitant glucocorticoids. Seven studies with a total of 657 participants were included in the comparison of antibiotic treatment with or without concomitant glucocorticoids.
1. Meta-analysis of antibiotic treatment with concomitant glucocorticoids.
The assumption of statistical homogeneity was not violated in any outcome included. Antibiotic treatment had no significant effect on chorioamnionitis, postpartum endometritis, or on any of the neonatal outcomes included.
Secondary outcomes: a combined result for secondary outcomes was not calculated because the outcomes were either incomplete or reported inconsistently. Information regarding pregnancy prolongation was available in 4 of the 5 studies. In one study, the mean rupture-to-delivery interval was significantly longer in the antibiotics group (11.4 versus 6.1 days); in another, no significant difference was found. In 2 studies, the mean latency periods were unavailable, but the percentage of pregnancies prolonged beyond 5 or 7 days was significantly larger in the antibiotic groups than in the control groups. The birth weights and duration of maternal and neonatal hospitalisation did not differ significantly between the antibiotic and control groups in any of the 3 studies that reported them.
2. Comparison of antibiotic treatment with or without concomitant glucocorticoids.
Significant heterogeneity was detected for the outcome of chorioamnionitis (chi-squared 16.99, d.f.=6, p<0.01) but not for postpartum endometritis. The combined OR was 0.38 (95% CI: 0.26, 0.55, p<0.01) for chorioamnionitus and 0.50 (95% CI: 0.26, 0.96, p<0.05) for postpartum endometritis; this suggested that antibiotic treatment without concomitant use of glucocorticoids significantly reduced the odds of these outcomes by 62 and 50%, respectively. Secondary outcomes: the latency periods were reported in all studies, either as mean rupture-to-delivery, mean treatment-to-delivery, or mean or median study entry-to-delivery intervals. The difference between the antibiotic and control groups was significant in 3 studies and non significant in 3 other studies. In one study, the mean study entry-to-delivery intervals did not differ significantly, but the percentage of pregnancies prolonged for more than 7 days was significantly larger in the antibiotic group. The mean birth weights in the antibiotic and control groups were available in 6 of the 7 studies. The difference between both groups was significant in one study and not significant in the remaining 5 studies. The median or mean durations of maternal hospitalisation were significantly different between the antibiotic and control groups in one study, but did not differ significantly in another. The mean durations of neonatal hospitalisation or intensive care did not differ significantly in 3 studies. In one study, the percentage of neonates hospitalised for more than 30 days was significantly lower in the antibiotic group.
When the results of both meta-analyses were compared, a significant reduction in chorioamnionitis, postpartum endometritis, neonatal sepsis, and intraventricular haemorrhage was observed with antibiotic treatment alone, whereas antibiotic treatment with concomitant glucocorticoids showed no significant effect on any primary outcome included.
3. Logistic regression analyses.
Univariate and multivariate analyses were performed for the outcomes of chorioamnionitis, postpartum endometritis, neonatal sepsis, and intraventricular haemorrhage. There was a significant effect of antibiotic treatment over all studies of both meta-analyses; an even stronger and significant effect in the subgroup of studies without concomitant glucocorticoid treatment; and no significant effect in the subgroup of studies with concomitant glucocorticoid treatment. The ORs comparing antibiotic plus glucocorticoid versus antibiotic treatment ranged from 1.32 to 3.34; this suggested a higher risk for each of the 4 outcomes with antibiotic plus glucocorticoid than for antibiotic treatment alone.
Authors' conclusions The beneficial effects of antibiotic treatment in pre-term premature rupture of membranes may be diminished when glucocorticoids are used concomitantly. The authors state that this conclusion relies on the validity of both meta-analyses, and on the assumption that glucocorticoid treatment and no other confounding factors explain the different results of antibiotic with and without glucocorticoid treatment.
CRD commentary The authors presented a well-defined review question. The inclusion criteria were clearly stated. Sufficient details of the primary studies were presented. The primary studies were combined appropriately.
The search was fairly thorough but could have been extended to include an attempt to locate unpublished literature; the possibility of publication bias cannot be ruled out. A validity assessment of the included trials was undertaken, but the authors do not state what they did with this information. The authors stated that although the assumption of statistical homogeneity was only violated for one outcome, the question of clinical homogeneity was more difficult to answer. Some studies allowed the inclusion of twins, and differences existed in gestational age on admission. There were also variations in the choice of antibiotic(s), the duration of therapy, and the management of patients with positive cervical cultures. There were only a small number of studies included in these meta-analyses. The results and conclusions of this review need to be interpreted with caution given these limitations.
Implications of the review for practice and research The authors state that the results of this study do not allow them to make clear treatment recommendations for cases of pre-term premature rupture of membranes. Whereas glucocorticoids seem to be essential at gestational ages less than 34 weeks to decrease infant mortality from lung immaturity and intraventricular haemorrhage, antibiotic treatment may be important to prevent foetal and maternal infections. There are, therefore, indications for both therapies. However, an additive beneficial effect concerning foetal outcome could not be demonstrated. On the contrary, the proven effects of antibiotic treatment may be diminished when glucocorticoids are used concomitantly. The use of sequential instead of concomitant antibiotic and glucocorticoid therapy, and the careful selection of patients who are likely to benefit from both therapies (possibly on the basis of infection parameters), may help to further improve foetal outcome. The authors state that there is a need for more prospective studies stratifying treatment groups with and without antibiotics or glucocorticoids.
Funding Austrian Ministry of Science.
Bibliographic details Leitich H, Egarter C, Reisenberger K, Kaider A, Berghammer P. Concomitant use of glucocorticoids: a comparison of two metaanalyses on antibiotic treatment in preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 1998; 178(5): 899-908 Indexing Status Subject indexing assigned by NLM MeSH Anti-Bacterial Agents /administration & Chorioamnionitis /prevention & Double-Blind Method; Drug Therapy, Combination; Endometritis /prevention & Female; Fetal Membranes, Premature Rupture /complications /drug therapy; Gestational Age; Glucocorticoids /administration & Humans; Infant, Newborn; Logistic Models; MEDLINE; Placebos; Pregnancy; Sepsis /prevention & control; control; control; dosage /therapeutic use; dosage /therapeutic use AccessionNumber 11998000990 Date bibliographic record published 30/11/1999 Date abstract record published 30/11/1999 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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