TOCOX - A randomised, double-blind, placebo-controlled trial of rofecoxib (a COX-2-specific prostaglandin inhibitor) for the prevention of preterm delivery in women at high risk

Objective To assess the safety and efficacy of the long term prophylactic use of rofecoxib (a COX-2-specific inhibitor) in women at high risk of preterm delivery. Design A randomised, double-blind, placebo-controlled trial. Setting Queen Charlotte's and Chelsea Hospital, London and Guys and St Thomas' Hospitals, London. Population Ninety-eight singleton pregnancies at high risk of preterm labour. Methods Treatment from 16 to 32 weeks. Weekly ultrasound surveillance. Main outcome measures Fetal renal function and ductus arteriosus blood flow changes. Preterm delivery rates and neonatal outcome. Results Rofecoxib caused a reduction in hourly fetal urine production rates (-34%, 95% CI -13 to -50%, P = 0.004) and amniotic fluid index (-2.2, 95% CI -3.2 to -1.2, P < 0.001). This effect did not increase with time on treatment and reversed in all cases on discontinuation of treatment. Rofecoxib had an effect on the ductus arteriosus, increasing maximum systolic velocity (0.1 m/s, 95% CI 0.03-0.16, P = 0.02) and minimum diastolic velocity (0.007 m/s, 95% CI 0.0007-0.013, P = 0.03). This effect increased with time on treatment but was reversed with discontinuation of treatment and had no long term clinical sequelae. There was no difference in preterm delivery rates <30 weeks (28% on placebo vs 33% on rofecoxib, Mantel-Haensel [M-H]-adjusted risk 1.11, 95% CI 0.67-1.87). There were more deliveries <37 weeks in those on rofecoxib (40% vs 67%, M-H-adjusted risk 1.59, 95% CI 1.09-2.32). Rates of preterm prelabour rupture of membranes (PPROM) were higher in those on rofecoxib (RR 2.5, 95% CI 1.3-4.7). Conclusion Rofecoxib has a significant but reversible effect on fetal renal function and the ductus arteriosus. It does not reduce the incidence of early preterm delivery <30 weeks and is associated with an increased risk of delivery before 37 weeks in women at high risk.