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Nitric oxide donors for treating preterm labour

Kirsten Duckitt, Steve Thornton, Oliver P O'Donovan, Therese Dowswell

Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD002860.

Editor’s comment: Prof. Jim Thornton: Nitric oxide donors don’t work for preterm labour
The latest Cochrane review of nitric oxide donors for this indication includes data from 12 trials involving 1227 women. This is more than twice the number (5 trials involving 466 women) included in the previous review. The conclusion that they are ineffective is consequently more robust.

Abstract

Background

A number of tocolytics have been advocated for the treatment of threatened preterm labour in order to delay birth. The rationale is that a delay in birth may be associated with improved neonatal morbidity or mortality. Nitric oxide donors, such as nitroglycerin, have been used to relax the uterus. This review addresses their efficacy, adverse effects and influence on neonatal outcome.

Objectives

To determine whether nitric oxide donors administered in threatened preterm labour are associated with a delay in birth, adverse effects or improved neonatal outcome.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013).

Selection criteria

Randomised controlled trials of nitric oxide donors administered for tocolysis.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data.

Main results

Twelve trials, including a total of 1227 women at risk of preterm labour, contributed data to this updated review. The methodological quality of trials was mixed; trials comparing nitric oxide donors with other types of tocolytics were not blinded and this may have had an impact on findings.

Three studies compared nitric oxide donors (glyceryl trinitrate (GTN)) with placebo. There was no significant evidence that nitric oxide donors prolonged pregnancy beyond 48 hours (average risk ratio (RR) 1.19, 95% confidence interval (CI) 0.74 to 1.90, two studies, 186 women), and although for most adverse effects there was no significant difference between groups, women in the active treatment group in one study were at higher risk of experiencing a headache. For infant outcomes there was no significant evidence that nitric oxide donors reduced the risk of neonatal death or serious morbidity (stillbirth RR 0.36, 95% CI 0.01 to 8.59, one study, 153 infants; neonatal death RR 0.43, 95% CI 0.06 to 2.89, two studies, 186 infants). One study, using a composite outcome, reported a reduced risk of serious adverse outcomes for infants in the GTN group which approached statistical significance (RR 0.29, 95% CI 0.08 to 1.00, 153 infants). Overall, these studies were underpowered to identify differences between groups for most outcomes.

When nitric oxide donors were compared with other tocolytic drugs there was no significant evidence that nitric oxide donors performed better than other tocolytics (betamimetics, magnesium sulphate, a calcium channel blocker or a combination of tocolytics) in terms of pregnancy prolongation, although nitric oxide donors appeared to be associated with a reduction in most adverse effects, apart from headache. There was no significant difference between groups for infant morbidity or mortality outcomes.

Authors' conclusions

There is currently insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labour.

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Commentaries by Editor Prof. Jim Thornton