Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor.

OBJECTIVE:  The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). STUDY DESIGN:  Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. RESULTS:  The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016-July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015-August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. CONCLUSION:  Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL

Amiodarone therapy for drug-refractory fetal tachycardia.

Background - Fetal tachycardia complicated by ventricular dysfunction and hydrops fetalis carries a significant risk of morbidity and mortality. Transplacental digoxin is effective therapy in a small percentage, but there is no consensus with regard to antiarrhythmic treatment if digoxin fails. This study evaluates the safety, efficacy, and outcome of amiodarone therapy for digoxin-refractory fetal tachycardia with heart failure. Methods and Results - Fetuses with incessant tachycardia and either hydrops fetalis (n = 24) or ventricular dysfunction ( n = 2) for whom digoxin monotherapy and secondary antiarrhythmic agents ( n = 13) were not effective were treated transplacentally with a loading dose of oral amiodarone for 2 to 7 days, followed by daily maintenance therapy for <1 to 15 weeks. Digoxin therapy was continued throughout gestation. Newborns were studied by transesophageal pacing or ECG monitoring to determine the mechanism of tachycardia. Three fetuses were delivered urgently in tachycardia during amiodarone loading, and 3 required additional antiarrhythmic agents for sustained cardioversion. Amiodarone or amiodarone combinations converted 14 of 15 (93%) with reentrant supraventricular tachycardia, 2 of 2 with ventricular or junctional ectopic tachycardia, and 3 of 9 (33%) with atrial flutter. Amiodarone-related adverse effects were transient in 5 infants and 8 mothers. Mean gestational age at delivery was 37 weeks, with 100% survival. Conclusions - Orally administered amiodarone is safe and effective treatment for drug-refractory fetal tachycardia, specifically reentrant supraventricular tachycardia, junctional ectopic, or ventricular tachycardia, even when accompanied by hydrops fetalis or ventricular dysfunction