The relationship between antenatal indomethacin as a tocolytic drug and neonatal outcomes: a retrospective cohort study

Abstract

Introduction

Preterm birth is associated with increased mortality and morbidity. Tocolytic drugs, such as indomethacin, are often used to postpone preterm delivery. Indomethacin has been proven to be more effective than other tocolytic agents in terms of delaying birth but is often prescribed with caution because of its potential association with adverse neonatal outcomes. We aim to study the effects of antenatal indomethacin on neonatal outcomes after controlling for potential confounders, as compared to nifedipine and/or atosiban.

Methods

In this cohort study, we performed a retrospective analysis of maternal and neonatal data. Women were included if they received indomethacin, nifedipine or atosiban as a tocolytic drug for imminent preterm labor and gave birth at a gestational age (GA) between 23^5/7 and 32^0/7weeks, between 2010 and 2015. Main outcome measures were: neonatal death, necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), patent ductus arteriosus (PDA) and its treatment.

Results

Four hundred seventy-four women, delivering 610 infants were investigated. The incidence of the following adverse neonatal outcomes were significantly higher after indomethacin use: neonatal death (p = .017), NEC (p = .026), SIP (p = .008), PDA (p = .000) and PDA ligation (p = .000). However, these associations showed to be nonsignificant after adjusting for confounders (adjusted odds ratio neonatal mortality 1.6 (0.7–3.8)), NEC 1.6 (0.6–4.4), SIP 2.8 (0.3–30.0), PDA 1.1 (0.6–2.2) and PDA ligation 2.2 (0.7–6.5).

Conclusions

The presumed association between antenatal indomethacin exposure and several adverse neonatal outcomes may be based upon indication bias. Taking important confounding factors, such as GA at birth and neonatal birth weight into account, antenatal indomethacin exposure does not result in a higher incidence of adverse neonatal outcomes. However, there may be a higher risk for spontaneous intestinal perforation.

Keywords:

• Indomethacin
• neonatal outcomes
• preterm birth
• tocolytic drugs

Acknowledgments

We thank Jeanne Dieleman for her assistance during the analyses.

Disclosure statement

The authors received no financial support and declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

Contribution to authorship

JR and PJvRH were responsible for the design and conception of the research question and designed the protocol. JR undertook literature search. JR, BW, SL and IT did study selection and data extraction. JR, LJ, BW and SL did statistical analyses – with additional input from JD – and designed tables and figures. The initial draft of the manuscript was prepared by JR, with additional input from IT, LJ, PJvRH and HN.