Nitric Oxide in the Prevention of Pre-eclampsia (NOPE): A Double-Blind Randomized Placebo-Controlled Trial Assessing the Efficacy of Isosorbide Mononitrate in the Prevention of Pre-eclampsia in High-Risk Women
- 52 Downloads
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.
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.
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.
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.
KeywordsPre-eclampsia Prevention Prophylaxis Nitric oxide Isosorbide mononitrate Aspirin Randomised controlled trial NOPE
We thank Dr Diwakar Mohan, MD DrPH, Johns Hopkins School of Public Health, Baltimore, USA, for his contribution in designing the study and sample size calculation.
MK and GP conceived and designed the study, while AK and MJ contributed to the design. MK, GP, and AK performed the experiments; MK and GP performed the data analysis, and AK reviewed the results; MJ provided randomization and allocation masking; all authors contributed to the writing of the manuscript final version. MK is the guarantor of the paper.
Compliance with Ethical Standards
Conflict of interest
The authors declare no conflicts of interest.
The study protocol and informed consent forms were approved by the JIPMER Scientific Advisory Committee (for postgraduate dissertations) and JIPMER Institute Ethics Committee for Human Studies, No IEC/SC/2012/4/148; Federal Wide Assurance registration number of the ethics committee is FWA00019293. The Drug Controller General of India approved the use of isosorbide mononitrate for the purpose of this study in the proposed dose and route [CT Drugs/178/2012].
- 3.CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet Lond Engl. 1994;343(8898):619–29.Google Scholar
- 4.Duley L, Henderson-Smart DJ, Knight M, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2004;(1):CD004659.Google Scholar
- 8.Meher S, Duley L. Nitric oxide for preventing pre-eclampsia and its complications. In: Cochrane database of systematic reviews [Internet]. Wiley, 2007 [cited 2016 Nov 28]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006490/abstract.
- 16.Hypertension in Pregnancy—ACOG [Internet]. [cited 2016 Nov 28]. Available from: http://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy.
- 19.Kelly AJ, Munson C, Minden L. Nitric oxide donors for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2011;(6):CD006901.Google Scholar
- 22.Cacciatore B, Halmesmäki E, Kaaja R, et al. Effects of transdermal nitroglycerin on impedance to flow in the uterine, umbilical, and fetal middle cerebral arteries in pregnancies complicated by preeclampsia and intrauterine growth retardation. Am J Obstet Gynecol. 1998;179(1):140–5.CrossRefPubMedGoogle Scholar