Introduction: Pre-eclampsia contributes to maternal and fetal morbidity and mortality all over the world. Endothelial dysfunction is postulated to be the crux of the pathogenesis. Recent meta-analysis of aspirin trials showed aspirin to be effective when started early in pregnancy (at ≤ 16-week gestation). We aimed to study the effect of low-dose prophylactic isosorbide mononitrate (ISMN) 20 mg/day on the incidence of hypertensive diseases in high-risk women receiving standard aspirin prophylaxis.
Methods: Design: Randomized double-blind placebo-controlled parallel-arm superiority trial. Setting: Antenatal clinic of a tertiary teaching hospital, South India. Participants and methods: One hundred women fulfilling NICE guideline criteria for aspirin prophylaxis recruited at 12-16 weeks were randomized to receive either 20 mg/day of ISMN or placebo, in addition to 75 mg/day of oral aspirin from recruitment till delivery. Main outcome measure: Rate of hypertensive disorder of pregnancy (HDP). Sample Size: One hundred women (50 in each arm) to detect a decrease of HDP from 20% in the placebo group to 5% in the ISMN group with a power of 80% and at 0.05.
Results: One hundred women (50 in each arm) participated and completed the trial. Intention to treat analysis of these 100 women showed that the groups were comparable in terms of age, BMI, parity, and vascular indices (such as mean arterial pressure, uterine artery pulsatility index, flow-mediated vasodilatation index, brachial-ankle pulse wave velocity, Ankle-Brachial Index, brachial arterial stiffness index, and ankle arterial stiffness index). The rate of hypertensive disorders (gestational hypertension, pre-eclampsia, or superimposed pre-eclampsia) was not significantly different between the groups (14/50, 28% in ISMN vs. 12/50, 24% in placebo group; p = 0.7). The mean gestational age at diagnosis of hypertensive disease (35.4 vs. 36 weeks, ISMN vs. placebo groups, p = 0.7) or the rate of severe disease (8/50, 16% in ISMN vs. 7/50, 14% in the placebo group; p = 0.9) did not differ significantly between the two groups. Stillbirths (1 vs. 2), NICU admission rates (18 vs. 10%), and neonatal mortality (2 vs. 2) were also similar between the groups.
Conclusion: The results of the randomized controlled trial of nitric oxide in the prevention of pre-eclampsia (NOPE) showed that in high-risk women receiving standard aspirin prophylaxis from less than 16 weeks, there is no significant reduction in the incidence of hypertensive disorders of pregnancy in the ISMN group, to the desired extent. There was no significant effect on the severity of disease, gestational age at diagnosis of disease or maternal-perinatal morbidity due to low-dose isosorbide mononitrate.
Keywords: Aspirin; Isosorbide mononitrate; NOPE; Nitric oxide; Pre-eclampsia; Prevention; Prophylaxis; Randomised controlled trial.
© Federation of Obstetric & Gynecological Societies of India 2018.