Two trials of antenatal thyrotrophin‐releasing hormone for fetal maturation: stopping before the due date

Abstract

A complete list of those participating in these trials may be found on pages 904-WS.Objectives To determine whether the addition of antenatal thyrotrophin-releasing hormone (TRH) to corticosteroids, given to women at risk of preterm delivery, would decrease the risk of death and severe morbidity associated with prematurity.Design 'Itvo concurrent multicentre, double blind, randomised, placebo-controlled trials were designed with a common core dataset to be analysed as a single large pragmatic trial.Setting Hospital maternity units.Populations Pregnant women at risk of preterm delivery who had been prescribed a course of corticosteroids to enhance fetal maturation.Interventions Antenatal administration of TRH 400 pg every eight hours for four doses versus matching placebo.Main outcome measures Primary: death of the baby or chronic lung disease (defined as oxygen dependency at 28 days after birth). Secondary: other measures of respiratory morbidity, in particular respiratory distress syndrome. Other measures of short term neonatal morbidity including intraventricular haemorrhage and necrotising enterocolitis. Measures of maternal side effects. ResultsThe antenatal TRH trial was halted early on the basis of external evidence. Overall a total of 225 women were recruited who delivered 275 babies. The primary outcome of death or chronic lung disease occurred in 33 babies in the TRH group and 43 babies in the placebo group (RR 0.8, 95% CI 0.5-1.2). There were no other differences between the two groups. Stratified analysis did not reveal any differences between the two groups depending on how long before the time of delivery the mother had received the TRH or placebo.Conclusions These trials are too small to provide convincing evidence of the effect of antenatal TRH on neonatal outcome. When added to the existing systematic review and meta-analysis, however, these data should provide evidence on which subsequent practice can be based. The process by which the trials were monitored and stopped is of relevance to future trials.

Role of external evidence in monitoring clinical trials: experience from a perinatal trial

“…The antenatal thyrotropin releasing hormone trial was set up to evaluate the use of thyrotropin releasing hormone combined with corticosteroids in women at risk of preterm labour 6. When the study was being planned, six randomised controlled trials of thyrotropin releasing hormone had already been performed and had been combined in a systematic review and meta-analysis 7.…”

How should randomised trials including multiple pregnancies be analysed?

“…Some trials, although, recruit a substantial proportion of women multiple pregnancies. For example, in the Antenatal TRH trial, 1 nearly 20% (44/225) of the women recruited had multiple pregnancies, and they contributed 34% (94/275) of the babies in the trial. Even where multiples make up only a relatively small percentage of the trial's population, it is common to analyse single and multiple pregnancies separately in subgroup analyses.…”