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

  • G. Ponmozhi
  • Anish Keepanasseril
  • Jayanthi Mathaiyan
  • K. Manikandan
Original Article
  • 20 Downloads

Abstract

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

Pre-eclampsia Prevention Prophylaxis Nitric oxide Isosorbide mononitrate Aspirin Randomised controlled trial NOPE 

Notes

Acknowledgements

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.

Author Contributions

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.

Ethics Approval

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].

Supplementary material

13224_2018_1100_MOESM1_ESM.docx (73 kb)
Supplementary material 1 (DOCX 73 kb)

References

  1. 1.
    Wilkinson H, on behalf of the Trustees and Medical Advisers. Saving mothers’ lives. Reviewing maternal deaths to make motherhood safer: 2006–2008. BJOG. 2011;118(11):1402–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Prakash J, Pandey LK, Singh AK, et al. Hypertension in pregnancy: hospital based study. J Assoc Physicians India. 2006;54:273–8.PubMedGoogle Scholar
  3. 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. 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
  5. 5.
    Roberge S, Villa P, Nicolaides K, et al. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther. 2012;31(3):141–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Anderson UD, Gram M, Åkerström B, et al. First trimester prediction of preeclampsia. Curr Hypertens Rep. 2015;17(9):584.CrossRefPubMedGoogle Scholar
  7. 7.
    Elzbieta Poniedzialek-Czajkowska BM. Nitric Oxide in Normal and Preeclamptic Pregnancy [Internet]. http://www.eurekaselect.com. [cited 2016 Nov 28]. Available from: http://www.eurekaselect.com/73857/article.
  8. 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.
  9. 9.
    Visintin C, Mugglestone MA, Almerie MQ, et al. Management of hypertensive disorders during pregnancy: summary of NICE guidance. BMJ. 2010;25(341):c2207.CrossRefGoogle Scholar
  10. 10.
    Martin AM, Bindra R, Curcio P, et al. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks gestation. Ultrasound Obstet Gynecol. 2001;18(6):583–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Woodman RJ, Kingwell BA, Beilin LJ, et al. Assessment of central and peripheral arterial stiffness: studies indicating the need to use a combination of techniques. Am J Hypertens. 2005;18(2 Pt 1):249–60.CrossRefPubMedGoogle Scholar
  12. 12.
    Naidu MUR, Reddy BM, Yashmaina S, et al. Validity and reproducibility of arterial pulse wave velocity measurement using new device with oscillometric technique: a pilot study. Biomed Eng OnLine. 2005;23(4):49.CrossRefGoogle Scholar
  13. 13.
    Harris RA, Nishiyama SK, Wray DW, et al. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010;55(5):1075–85.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Thijssen DHJ, Black MA, Pyke KE, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300(1):H2–12.CrossRefPubMedGoogle Scholar
  15. 15.
    Report of the National High Blood Pressure Education. Program working group on high blood pressure in pregnancy. Am J Obstet Gynecol. 2000;183(1):S1–22.CrossRefGoogle Scholar
  16. 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.
  17. 17.
    Akolekar R, Syngelaki A, Poon L, et al. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther. 2013;33(1):8–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Abshagen UW. Pharmacokinetics of isosorbide mononitrate. Am J Cardiol. 1992;70(17):61G-66G.CrossRefPubMedGoogle Scholar
  19. 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
  20. 20.
    Kalidindi M, Velauthar L, Khan K, et al. The role of nitrates in the prevention of preeclampsia: an update. Curr Opin Obstet Gynecol. 2012;24(6):361–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Nakatsuka M, Tada K, Kimura Y, et al. Clinical experience of long-term transdermal treatment with nitric oxide donor for women with preeclampsia. Gynecol Obstet Invest. 1999;47(1):13–9.CrossRefPubMedGoogle Scholar
  22. 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

Copyright information

© Federation of Obstetric & Gynecological Societies of India 2018

Authors and Affiliations

  1. 1.Jawaharlal Institute of Postgraduate Medical Education and ResearchPondicherryIndia
  2. 2.Fetal Care Research Foundation and Mediscan Systems, ChennaiMylaporeIndia
  3. 3.The Fetal ClinicPondicherryIndia

Personalised recommendations