A randomized controlled trial comparing isosorbide dinitrate-oxytocin versus misoprostol-oxytocin at management of foetal intrauterine death

Autoři: Gabriel Arteaga-Troncoso aff001;  Aide E. Chacon-Calderon aff002;  Francisco J. Martinez-Herrera aff002;  Sylvia G. Cruz-Nuñez aff003;  Marcela Lopez-Hurtado aff004;  Aurora Belmont-Gomez aff005;  Alberto M. Guzman-Grenfell aff006;  Blanca E. Farfan-Labonne aff007;  Carlos J. Neri-Méndez aff003;  Francisco Zea-Prado aff003;  Fernando M. Guerra-Infante aff004
Působiště autorů: Department of Cellular Biology and Development, National Institute of Perinatology, Mexico City, Mexico aff001;  Department of Obstetrics and Gynecology, Women’s Clinic and Neonatology, Secretariat for National Defense, Mexico City, Mexico aff002;  Department of Obstetric and Gynecology, National Institute of Perinatology, Mexico City, Mexico aff003;  Department of Infectology and Immunology, National Institute of Perinatology, Mexico City, Mexico aff004;  Department of Clinical Pharmacology, National Institute of Perinatology, Mexico City, Mexico aff005;  Department of Immunobiochemistry, National Institute of Perinatology, Mexico City, Mexico aff006;  Department of Neurosciences, National Institute of Perinatology, Mexico City, Mexico aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0215718



The metabolic activity of endogenous nitric oxide (NO) and the medical use of nitrovasodilatory drugs like isosorbide dinitrate have been shown to be potential inducers inducers of cervical ripening prior to surgical evacuation of the uterus.


To assess the therapeutic efficacy and safety of combined isosorbide dinitrate-oxytocin in the management of intrauterine foetal death (IUFD).


Sixty women with IUFD after 20 weeks of gestation requesting uterine evacuation were randomly selected to receive isosorbide dinitrate gel solution (80 mg/1.5 mL; n = 30) or misoprostol gel solution (100 mcg/1.5 mL; n = 30) every 3 h with a maximum of four doses or until a Bishop score >7 was reached. Subsequently, patients received a high dose of intravenous oxytocin until complete uterus evacuation was achieved. Therapeutic efficacy was evaluated by mean the relative risk of the foetal expulsion based on comparison of event rates, and the proportion of women induced to labor at 7, 10 and 15 h after the administration of isosorbide dinitrate or misoprostol. Safety was assessed on the basis of woman´s vital signs and evaluation of adverse effects, including headache, abdominal pain, pelvic pain, lower back pain, nausea, dizziness and vomiting.


The foetal expulsion rate using the isosorbide dinitrate-oxytocin combination was approximately 4.4 times, and at least 2.1 times, the foetal expulsion rate with the misoprostol-oxytocin regimen at any given point in time. The proportion of women achieved vaginal delivery at 15 hours was 100% for the isosorbide dinitrate-oxytocin group and 86.7% for the misoprostol-oxytocin group. The average delivery induction interval was significantly lower when isosorbide dinitrate-oxytocin was used (8.7 ± 3.1 h) than when misoprostol-oxytocin (11.9 ± 3.1 h) was used. A total of 20% of patients in the isosorbide dinitrate-oxytocin group recorded headache, and no cases of uterine tachysystole, haemorrhage or coagulopathy were recorded.


This study indicates that intravaginal isosorbide dinitrate followed by intravenous oxytocin was more effective than the conventional method used to induce labour in the medical management of foetal death in pregnancies after 20 weeks of gestation.

Trial registration

Clinicaltrials.gov NCT02488642.

Klíčová slova:

Abdominal pain – Blood pressure – Fetal death – Headaches – Heart rate – Nitric oxide – Oxytocin – Pregnancy


1. Koopmans L, Wilson T, Cacciatore J, Flenady V. Support for mothers, fathers and families after perinatal death. Cochrane Database Syst Rev 2013;6:CD000452. doi: 10.1002/14651858.CD000452.pub3 23784865

2. Rådestad I, Steineck G, Nordin C, Sjögren B. Psychological complications after stillbirth—influence of memories and immediate management: population based study. BMJ 1996;312:1505–1508. doi: 10.1136/bmj.312.7045.1505 8646141

3. Silver RM, Heuser CC. Stillbirth workup and delivery management. Clin Obstet Gynecol 2010;53:681–690. doi: 10.1097/GRF.0b013e3181eb3297 20661052

4. World Health Organization. Induction and augmentation of labour. In: WHO, UNFPA, UNICEF, World Bank, editor. Managing Complications in Pregnancy and Childbirth: A Guide for Midwives and Doctors. Geneva: WHO; 2000. pp. 17–25.

5. Hughes EG, Kelly AJ, Kavanagh J. Dinoprostone vaginal insert for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol 2001;97:847–855. doi: 10.1016/s0029-7844(00)01216-3 11336776

6. Neiger R, Greaves PC. Comparison between vaginal misoprostol and cervical dinoprostone for cervical ripening and labor induction. Tenn Med 2001;94:25–27. 11194687

7. Bolnick JM, Velazquez MD, Gonzalez JL, Rappaport VJ, McIlwain-Dunivan G, Rayburn WF. Randomized trial between two active labor management protocols in the presence of an unfavorable cervix. Am J Obstet Gynecol 2004;190:124–128. doi: 10.1016/s0002-9378(03)00952-9 14749647

8. Khan RU, El-Refaey H, Sharma S, Sooranna D, Stafford M. Oral, rectal, and vaginal pharmacokinetics of misoprostol. Obstet Gynecol 2004;103:866–870. doi: 10.1097/01.AOG.0000124783.38974.53 15121558

9. Arteaga-Troncoso G, Villegas-Alvarado A, Belmont-Gomez A, Martinez-Herrera FJ, Villagrana-Zesati R, Guerra-Infante F. Intracervical application of the nitric oxide donor isosorbide dinitrate for induction of cervical ripening: a randomised controlled trial to determine clinical efficacy and safety prior to first trimester surgical evacuation of retained products of conception. BJOG 2005;112:1615–1619. doi: 10.1111/j.1471-0528.2005.00760.x 16305563

10. Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, et al. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739–749. 6115052

11. Ignarro LJ. Heme-dependent activation of soluble guanylate cyclase by nitric oxide: regulation of enzyme activity by porphyrins and metalloporphyrins. Semin Hematol 1989;26:63–76. 2564216

12. Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta 1993;1178:153–175. doi: 10.1016/0167-4889(93)90006-b 7688574

13. Murad F. Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic GMP signal transduction system. Adv Pharmacol 1994;26:19–33. doi: 10.1016/s1054-3589(08)60049-6 7913616

14. Chung SJ, Fung HL. Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells. J Pharmacol Exp Ther 1990;253:614–619. 2110975

15. Feelisch M, Kelm M. Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun 1991;180:286–293. doi: 10.1016/s0006-291x(05)81290-2 1656970

16. Michel T, Smith TW. Nitric oxide synthases and cardiovascular signaling. Am J Cardiol 1993;72:33C–38C. doi: 10.1016/0002-9149(93)90253-9 7690516

17. Hsieh FY, Lavori PW. Sample-size calculations for the cox proportional hazards regression model with nonbinary covariates. Control Clin Trials 2000;21:552–560. doi: 10.1016/s0197-2456(00)00104-5 11146149

18. Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2010;10:CD000941. doi: 10.1002/14651858.CD000941

19. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007;99(suppl 2):S160–167.

20. Mariani Neto C, Leão EJ, Barreto EM, Kenj G, de Aquino MM, Tuffi VH. Use of misoprostol for labor induction in stillbirth. Rev Paul Med 1987;105:325–328. 3144030

21. Bartha JL, Comino-Delgado R, Garcia-Benasach F, Martinez-Del-Fresno P, Moreno-Corral LJ. Oral misoprostol and intracervical dinoprostone for cervical ripening and labor induction: a randomized comparison. Obstet Gynecol 2000;96:465–469. doi: 10.1016/s0029-7844(00)00954-6 10960643

22. Titiz H, Wallace A, Voaklander DC. Manual removal of the placenta: a case control study. Aust NZ J Obstet Gynaecol 2001;41:41–44.

23. Gómez Ponce de León R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynecol Obstet 2007;99(Suppl 2):S190–193.

24. Wagaarachchi PT, Ashok PW, Narvekar NN, Smith NC, Templeton A. Medical management of late intrauterine death using a combination of mifepristone and misoprostol. BJOG 2002;109:443–447. doi: 10.1111/j.1471-0528.2002.01238.x 12013166

25. Haghighi L, Moukhah S, Goshtasbi A. Comparing the effect of oral and vaginal isosorbide dinitrate in pre-induction cervical ripening in term pregnancy: a controlled clinical trial. Adv Biomed Res 2015;4:129–134. doi: 10.4103/2277-9175.158259 26284225

26. Espey MG, Miranda KM, Feelisch M, Fukuto J, Grisham MB, Vitek MP, et al. Mechanisms of cell death governed by the balance between nitrosative and oxidative stress. Ann N Y Acad Sci 2000;899:209–221. doi: 10.1111/j.1749-6632.2000.tb06188.x 10863541

27. Rapaport RM, Draznin MB, Murad F. Endothelium-dependent vasodilator- and nitrovasodilator-induced relaxation may be mediated through cyclic GMP formation and cyclic GMP-dependent protein phosphorylation. Trans Ass Am Physicians 1983;96:19–30.

28. Nicoll AE, Mackenzie F, Greer IA, Norman JE. Vaginal application of the nitric oxide donor isosorbide mononitrate for preinduction cervical ripening: a randomized controlled trial to determine effects on maternal and fetal hemodynamics. Am J Obstet Gynecol 2001;184:958–964. doi: 10.1067/mob.2001.111797 11303205

29. Cox DR. Regression models and life-tables (with discussion). J R Stat Soc Series B Stat Methodol 1972;34:187–220.

Článek vyšel v časopise


2019 Číslo 11