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Am Fam Physician. 2002;65(2):282-285

Because indomethacin is a prostaglandin synthetase inhibitor, it acts as a tocolytic agent and is as effective as other conventional agents in delaying delivery. Because of its efficacy and benign side effect profile compared with other tocolytic drugs, indomethacin is often regarded as a first-line agent for the treatment of intraventricular hemorrhage. Two reports have linked indomethacin to an increased risk of intraventricular hemorrhage in neonates, but the patients in both studies had multiple risk factors. Suarez and colleagues studied the independent association of indomethacin with neonatal intraventricular hemorrhage.

In a case-control study, the authors evaluated neonates who developed intraventricular hemorrhage during the two years since indomethacin became widely used as a first-line tocolytic agent. Cranial ultrasonography is routinely performed on days 7 to 10 of life in all infants born at 32 weeks' gestation or younger. Neonates delivered at older gestational ages were scanned if clinically indicated. The 56 identified infants with intraventricular hemorrhage were matched with four control infants of approximately the same gestational age admitted to the special care nursery at the same time but without evidence of intraventricular hemorrhage. Data extracted from the charts of the infants with intraventricular hemorrhage and the control infants included maternal characteristics, antepartum and intrapartum information (including use of tocolysis), and neonatal events.

FactorsAdjusted OR95% CI
RDS6.21.7, 22.2
Chorioamnionitis3.31.5, 7.1
Vaginal delivery2.61.2, 5.5
Combination tocolysis*2.00.8, 4.8
Indomethacin only*1.30.5, 3.3
Magnesium only*0.90.3, 2.8
Gestational age0.70.6, 0.9

The 56 infants with intraventricular hemorrhage and 224 control infants were similar in maternal age, parity, gender, and exposure to betamethasone. The infants with intraventricular hemorrhage were more likely than the control infants to have been exposed to chorioamnionitis and to be born vaginally at an early gestational age and a lower birth weight. Initial univariate statistical analysis of various tocolytic regimens associated exposure to indomethacin with increased risk of intraventricular hemorrhage. Conversely, multivariable logistic regression controlling for known risk factors for intraventricular hemorrhage revealed that indomethacin tocolysis alone or in combination with magnesium sulfate was not independently associated with intraventricular hemorrhage (see accompanying table). Vaginal delivery, early gestational age at delivery, the presence of chorioamnionitis, and respiratory distress syndrome were associated with intraventricular hemorrhage.

The authors conclude that indomethacin tocolysis is not associated with an increased risk of intraventricular hemorrhage. They attribute the previous association to confounding factors in very high-risk pregnancies and advocate the wider use of indomethacin as a first-line tocolytic agent.

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