Prevention of Preterm Birth

Jeffrey M. Denney; Jennifer F. Culhane; Robert L. Goldenberg

Disclosures

Women's Health. 2008;4(6):625-638. 

In This Article

Tocolytic Drugs

Tocolytic drugs reduce or stop uterine contractions. Some of these drugs, such as β-mimetic agents, have been thoroughly evaluated, whereas others, including magnesium sulfate, calcium-channel blockers, oxytocin antagonists, nitroglycerin and COX inhibitors, have not. In general, data from randomized trials suggest that tocolytic drugs may prolong pregnancy up to 48 h.[97] However, if a benefit is defined as a reduction in preterm delivery or even a delay in delivery for more than 1 week, the effect of tocolytic therapy appears to be minimal. Furthermore, the use of most tocolytic agents has not been associated with a reduction in neonatal mortality or respiratory distress syndrome. Magnesium sulfate, which in the USA has been a mainstay of treatment used to reduce preterm birth, was found to be ineffective in terms of preventing preterm delivery.[98] However, recent data from a trial involving 2241 women at 24 -32 weeks gestation suggests a reduction in the incidence of cerebral palsy with the use of magnesium sulfate (1.9%) versus placebo (3.5%); RR: 0.55; 95% CI: 0.32-30.95.[99]

Cochrane analysts also stated that administration of β-mimetics - ritodrine and terbutaline - may facilitate a 48 h delay in delivery in comparison with no treatment/placebo, but do so at the cost of placing both the mother and fetus/neonate at greater risk of unwanted side effects than other types of tocolytics. Specifically, use of β-mimetic agents has been associated with an increased risk of many neonatal side effects including neonatal intraventricular hemorrhage.[100,101,102] Other reviews and meta-analyses have been used to evaluate efficacy of the remaining tocolytic classes. For example, a Cochrane meta-analysis of tocolytic agents suggested that calcium-channel blockers and the oxytocin antagonist atosiban may delay delivery by 2-7 days.[103,104] COX inhibitors have been used to inhibit contractions based on their ability to block inflammatory processes triggering labor. However, their use has been associated with undesirable neonatal side effects - intraventricular hemorrhage, necrotizing enterocolitis, oligohydramnios in utero, bronchopulmonary dysplasia and patent ductus arteriosus requiring ligation. As a result of these effects, which are more common when used at or beyond 32 weeks gestation, COX inhibitors are generally used for preterm labor at earlier gestational ages in comparison with other tocolytic agents.[105,106,107,108,109]

Usage of tocolytics in Europe probably varies from that of the USA. Europeans more often employ the use of tractocile (atosiban), which is an oxytocin receptor antagonist. While atosiban has been shown to delay preterm birth up to 48 h, it has not reduced the incidence of preterm birth at less than 37 weeks any more than placebos have done. Currently in the USA, atosiban is not available for use outside of research protocols since it is not approved by the FDA.

Nevertheless, the delay in delivery afforded by some tocolytic drugs may have a benefit. Antenatal administration of corticosteroid drugs for as few as 12-24 h before delivery is associated with significant reductions in neonatal respiratory distress syndrome, intraventricular hemorrhage and mortality. Since the apparent benefit of tocolytic drugs is to delay delivery for 48 h, the combined use of tocolytic drugs and corticosteroids has become widespread. Even though this approach has not been adequately tested in randomized studies, several retrospective observational studies suggest that it improves outcome.[110]

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