Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial
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Ekkehard Schleussner
, Thomas Lehmann
Abstract
Intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with impaired placentation. Patients who are at risk of developing both these disorders can be identified by abnormal uterine artery Doppler at mid-trimester pregnancy. Nitric oxide (NO)-donors like pentaerithrityl-tetranitrate (PETN) reduce the impedance in the uteroplacental vessels and possess protecting effects on the endothelium. We tested the effectiveness of the NO-donor PETN for secondary prevention of IUGR, PE, and preterm birth in pregnancies at risk. Some 111 women who presented with abnormal placental perfusion at 19–24 weeks of gestation (w.o.g.) were included into a prospective, randomized, placebo-controlled, double-blinded study. The primary endpoint was IUGR and/or perinatal death. Secondary endpoints were preterm birth, PE, and placental abruption. Pentaerithrityl-tetranitrate significantly decreased the risk for IUGR and/or perinatal death [adjusted relative risk (RR) 0.410; 95% confidence interval, CI, 0.184–0.914] and for IUGR (adjusted RR 0.436; 95% CI 0.196–0.970). Preterm birth before 32 w.o.g. (adjusted RR 0.204; 95% CI 0.052–0.801) was reduced, but not the risk for PE. No placental abruption occurred in the PETN, but five occurred in the placebo group. These results suggest that secondary prophylaxis of adverse pregnancy outcome might be feasible in pregnancies exhibiting abnormal placentation using PETN.
Institute of origin: Department of Obstetrics, University Hospital Jena, Bachstr. 18, 07743 Jena, Germany. The trial is registered at ClinicalTrials.gov, number: NCT01355822 http://clinicaltrials.gov/ct2/show/NCT01355822.
Acknowledgments
We would like to thank the clinical pharmacist of the University Hospital Jena, Dr. Michael Hartmann, PhD for providing and handling the study medication, the research midwives Andrea Schröter and Ute Koerbs for their excellent assistance in patient care, and Dr. Heike Hoyer, PhD for biometric consulting.
References
[1] Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. 2011;31:66–74.10.1002/pd.2660Suche in Google Scholar
[2] Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369:1791–8.10.1016/S0140-6736(07)60712-0Suche in Google Scholar
[3] Bujold E, Morency AM, Roberge S, Lacasse Y, Forest JC, Giguere Y. Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2009;31:818–26.10.1016/S1701-2163(16)34300-6Suche in Google Scholar
[4] Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116:402–14.10.1097/AOG.0b013e3181e9322aSuche in Google Scholar PubMed
[5] Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, et al. Saving Mothers’ Lives: reviewing maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. Br J Obstet Gynaecol. 2011;118:1–203.Suche in Google Scholar
[6] Chang J, Elam-Evans LD, Berg CJ, Herndon J, Flowers L, Seed KA, et al. Pregnancy-related mortality surveillance–United States, 1991–1999. MMWR Surveill Summ. 2003;52:1–8.Suche in Google Scholar
[7] Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post JA, Coomarasamy A, et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. Can Med Assoc J. 2008;178:701–11.10.1503/cmaj.070430Suche in Google Scholar PubMed PubMed Central
[8] Daiber A, Gori T. Vascular tolerance to nitroglycerin in ascorbate deficiency: results are in favour of an important role of oxidative stress in nitrate tolerance. Cardiovasc Res. 2008;79:722–3.10.1093/cvr/cvn174Suche in Google Scholar PubMed
[9] Daiber A, Wenzel P, Oelze M, Munzel T. New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance. Clin Res Cardiol. 2008;97:12–20.10.1007/s00392-007-0588-7Suche in Google Scholar PubMed
[10] Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction. Cochrane Database Syst Rev. 2010;(6): CD006780. DOI: 10.1002/14651858.CD006780.pub2.10.1002/14651858.CD006780.pub2Suche in Google Scholar PubMed
[11] Dragoni S, Gori T, Lisi M, Di Stolfo G, Pautz A, Kleinert H, et al. Pentaerythrityl tetranitrate and nitroglycerin, but not isosorbide mononitrate, prevent endothelial dysfunction induced by ischemia and reperfusion. Arterioscler Thromb Vasc Biol. 2007;27:1955–9.10.1161/ATVBAHA.107.149278Suche in Google Scholar PubMed
[12] Froen JF, Gardosi JO, Thurmann A, Francis A, Stray-Pedersen B. Restricted fetal growth in sudden intrauterine unexplained death. Acta Obstet Gynecol Scand. 2004;83:801–7.Suche in Google Scholar
[13] Gardosi J, Francis A. Adverse pregnancy outcome and association with small for gestational age birthweight by customized and population-based percentiles. Am J Obstet Gynecol. 2009;201:e21–8.10.1016/j.ajog.2009.04.034Suche in Google Scholar PubMed
[14] Huppertz B, Burton G, Cross JC, Kingdom JC. Placental morphology: from molecule to mother – a dedication to Peter Kaufmann – a review. Placenta. 2006;27:S3–8.10.1016/j.placenta.2006.01.007Suche in Google Scholar
[15] Kahler C, Schleussner E, Moller A, Seewald HJ. Nitric oxide donors: effects on fetoplacental blood flow. Eur J Gynaecol Obstet Reprod Biol. 2004;115:10–4.10.1016/S0301-2115(02)00429-3Suche in Google Scholar
[16] Klemmensen A, Tabor A, Osterdal ML, Knudsen VK, Halldorsson TI, Mikkelsen TB, et al. Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women. Br J Obstet Gynaecol. 2009;116:964–74.10.1111/j.1471-0528.2009.02150.xSuche in Google Scholar
[17] Lees C, Langford E, Brown AS, de Belder A, Pickles A, Martin JF, et al. The effects of S-nitrosoglutathione on platelet activation, hypertension, and uterine and fetal Doppler in severe preeclampsia. Obstet Gynecol. 1996;88:14–19.10.1016/0029-7844(96)00070-1Suche in Google Scholar
[18] Lees C, Valensise H, Black R, Harrington K, Byiers S, Romanini C, et al. The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Ultrasound Obstet Gynecol. 1998;12:334–8.10.1046/j.1469-0705.1998.12050334.xSuche in Google Scholar PubMed
[19] Mandruzzato G, Antsaklis A, Botet F, Chervenak FA, Figueras F, Grunebaum A, et al. Intrauterine restriction (IUGR). J Perinat Med. 2008;36:277–81.10.1515/JPM.2008.050Suche in Google Scholar PubMed
[20] Meher S, Duley L. Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007;(2):CD006490.10.1002/14651858.CD006490Suche in Google Scholar PubMed PubMed Central
[21] Poon LC, Volpe N, Muto B, Yu CK, Syngelaki A, Nicolaides KH. Second-trimester uterine artery Doppler in the prediction of stillbirths. Fetal Diagn Ther. 2013;33:28–35.10.1159/000342109Suche in Google Scholar PubMed
[22] Quinn MJ Jr, Crouse LC, McFarland CA, LaFiandra EM, Johnson MS. Reproductive and developmental effects and physical and chemical properties of pentaerythritol tetranitrate (PETN) in the rat. Birth Defects Res B Dev Reprod Toxicol. 2009;86:65–71.10.1002/bdrb.20184Suche in Google Scholar PubMed
[23] Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost. 2009;7:58–64.10.1111/j.1538-7836.2008.03230.xSuche in Google Scholar PubMed
[24] Richardus JH, Graafmans WC, Verloove-Vanhorick SP, Mackenbach JP. Differences in perinatal mortality and suboptimal care between 10 European regions: results of an international audit. Br J Obstet Gynaecol. 2003;110:97–105.10.1046/j.1471-0528.2003.02053.xSuche in Google Scholar
[25] Roberge S, Nicolaides K, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2013;41:491–9.10.1002/uog.12421Suche in Google Scholar PubMed
[26] Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010;362:1282–91.10.1056/NEJMoa0908056Suche in Google Scholar PubMed PubMed Central
[27] Rodger M, Hague W, Kingdom J, for the TIPPS Investigators. The Thrombophilia in Pregnancy Prophylaxis Study (TIPPS): a multi-national randomized trial of dalteparin versus no dalteparin to prevent pregnancy complications in pregnant thrombophilic women. J Thromb Haemost. 2013;11:78.Suche in Google Scholar
[28] Steiner H, Schneider KTM. Dopplersonographie in Gynäkologie und Geburtshilfe, A4 Referenzkurven. Heidelberg: Springer Medizin Verlag;2008:2. Auflage, 326–7.Suche in Google Scholar
[29] Thangaratinam S, Langenveld J, Mol BW, Khan KS. Prediction and primary prevention of pre-eclampsia. Best Pract Res Clin Obstet Gynaecol. 2011;25:419–33.10.1016/j.bpobgyn.2011.02.008Suche in Google Scholar PubMed
[30] Valensise H, Vasapollo B, Novelli GP, Giorgi G, Verallo P, Galante A, et al. Maternal and fetal hemodynamic effects induced by nitric oxide donors and plasma volume expansion in pregnancies with gestational hypertension complicated by intrauterine growth restriction with absent end-diastolic flow in the umbilical artery. Ultrasound Obstet Gynecol. 2008;31:55–64.10.1002/uog.5234Suche in Google Scholar PubMed
[31] Villar J, Purwar M, Merialdi M, Zavaleta N, Thi Nhu Ngoc N, Anthony J, et al. World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries. Br J Obstet Gynaecol. 2009;116:780–8.10.1111/j.1471-0528.2009.02158.xSuche in Google Scholar PubMed
[32] Voigt M, Schneider KT, Jahrig K. Analysis of a 1992 birth sample in Germany. 1: new percentile values of the body weight of newborn infants. Geburtshilfe Frauenheilkd 1996;56:550–8.10.1055/s-2007-1023283Suche in Google Scholar PubMed
[33] Xu H, Perez-Cuevas R, Xiong X, Reyes H, Roy C, Julien P, et al. An international trial of antioxidants in the prevention of preeclampsia (INTAPP). Am J Obstet Gynecol. 2010;202: e231–9.10.1016/j.ajog.2010.01.050Suche in Google Scholar PubMed
The authors stated that there are no conflicts of interest regarding the publication of this article.
©2014 by Walter de Gruyter Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Review articles
- The relationship between gestational weight gain and fetal growth: time to take stock?
- Risk factors for pregnancy-associated venous thromboembolism: a review
- Academy’s Corner
- Africa is only 14 km away from my country
- Primary prevention of preterm birth
- Original articles – Obstetrics
- Mother knows best? Comparing primiparous parturients’ expectations and predictions with actual birth outcomes
- Silent chorioamnionitis and associated pregnancy outcomes: a review of clinical data gathered over a 16-year period
- Clinical factors associated with failed trials of labor in late preterm and term twin pregnancies
- Relation of placental diagnosis in stillbirth to fetal maceration and gestational age at delivery
- Evaluation of a novel placental alpha microglobulin-1 (PAMG-1) test to predict spontaneous preterm delivery
- The relationship of praise/criticism to learning during obstetrical simulation: a randomized clinical trial
- Sickle cell disease and pregnancy outcomes: population-based study on 8.8 million births
- Differences between external and internal fetal heart rate monitoring during the second stage of labor: a prospective observational study
- Perinatal management of preterm premature ruptured membranes affects neonatal prognosis
- Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial
- Umbilical vein volume flow in monochorionic twin pairs at 11–14 weeks
- Gestational weight gain according to number of fetuses in Japanese women
- Original article – Fetus
- Prenatal diagnosis of sex chromosome aneuploidies and disorders of sex development – a retrospective analysis of 11-year data
- Short communication
- Reference range for amniotic fluid index measurements in a Brazilian population
- Congress Calendar
- Congress Calendar
Artikel in diesem Heft
- Frontmatter
- Review articles
- The relationship between gestational weight gain and fetal growth: time to take stock?
- Risk factors for pregnancy-associated venous thromboembolism: a review
- Academy’s Corner
- Africa is only 14 km away from my country
- Primary prevention of preterm birth
- Original articles – Obstetrics
- Mother knows best? Comparing primiparous parturients’ expectations and predictions with actual birth outcomes
- Silent chorioamnionitis and associated pregnancy outcomes: a review of clinical data gathered over a 16-year period
- Clinical factors associated with failed trials of labor in late preterm and term twin pregnancies
- Relation of placental diagnosis in stillbirth to fetal maceration and gestational age at delivery
- Evaluation of a novel placental alpha microglobulin-1 (PAMG-1) test to predict spontaneous preterm delivery
- The relationship of praise/criticism to learning during obstetrical simulation: a randomized clinical trial
- Sickle cell disease and pregnancy outcomes: population-based study on 8.8 million births
- Differences between external and internal fetal heart rate monitoring during the second stage of labor: a prospective observational study
- Perinatal management of preterm premature ruptured membranes affects neonatal prognosis
- Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial
- Umbilical vein volume flow in monochorionic twin pairs at 11–14 weeks
- Gestational weight gain according to number of fetuses in Japanese women
- Original article – Fetus
- Prenatal diagnosis of sex chromosome aneuploidies and disorders of sex development – a retrospective analysis of 11-year data
- Short communication
- Reference range for amniotic fluid index measurements in a Brazilian population
- Congress Calendar
- Congress Calendar