Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes

Objective

The objective of the study was to determine whether indomethacin used as a tocolytic agent is associated with adverse neonatal outcomes.

Study Design

We used published guidelines of the Metaanalysis of Observational Studies in Epidemiology Group (MOOSE) to perform the metaanalysis. The search strategy used included computerized bibliographic searches of MEDLINE (1966-2005), PubMed (1966-2005), abstracts published in Obstetrics and Gynecology (1991-2005), abstracts published in Pediatric Research (1991-2005), and references of published manuscripts. Study inclusion criteria were publication in English, more than 30 deliveries less than 37 weeks’ gestation, and meeting diagnostic criteria for individual neonatal outcomes. Exclusion criteria included case reports, case series, and multiple publications from the same author. Metaanalysis was performed using random effects model if there were more than 2 observational studies for a specific outcome. Eggers test was performed to exclude publication bias. Sensitivity analysis was performed to evaluate the effect of antenatal steroid exposure, gestation, and recent antenatal indomethacin exposure (duration of 48 hours or more between the last dose and delivery).

Results

Fifteen retrospective cohort studies and 6 case-controlled studies met inclusion criteria. Antenatal indomethacin was associated with an increased risk of periventricular leukomalacia (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-3.1). Recent exposure to antenatal indomethacin was associated with necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2). Antenatal indomethacin was not associated with intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, and mortality.

Conclusion

Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing enterocolitis in premature infants and therefore should be used judiciously for tocolysis.

Key words: antenatal indomethacin, metaanalysis of observational studies, necrotizing enterocolitis, periventricular leukomalacia, premature infants