Nitroglycerin for treatment of retained placenta: A randomised, placebo-controlled, multicentre, double-blind trial in the UK

Autoři: Fiona C. Denison aff001;  Kathryn F. Carruthers aff001;  Jemma Hudson aff002;  Gladys McPherson aff002;  Gin Nie Chua aff003;  Mathilde Peace aff001;  Jane Brewin aff004;  Nina Hallowell aff005;  Graham Scotland aff002;  Julia Lawton aff007;  John Norrie aff008;  Jane E. Norman aff001
Působiště autorů: Tommy’s Centre for Maternal and Fetal Health, Medical Research Council Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom aff001;  Centre for Healthcare Randomised Trials, Health Services Research Unit, University of Aberdeen, Aberdeen, United Kingdom aff002;  Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom aff003;  Tommy’s, London, United Kingdom aff004;  Wellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom aff005;  Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom aff006;  Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom aff007;  Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom aff008
Vyšlo v časopise: Nitroglycerin for treatment of retained placenta: A randomised, placebo-controlled, multicentre, double-blind trial in the UK. PLoS Med 16(12): e1003001. doi:10.1371/journal.pmed.1003001
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003001



Retained placenta following vaginal delivery is a major cause of postpartum haemorrhage. Currently, the only effective treatments for a retained placenta are the surgical procedures of manual removal of placenta (MROP) and uterine curettage, which are not universally available, particularly in low- and middle-income countries. The objective of the trial was to determine whether sublingual nitroglycerin spray was clinically effective and cost-effective for medical treatment of retained placenta following vaginal delivery.

Methods and findings

A randomised, placebo-controlled, double-blind trial was undertaken between October 2014 and July 2017 at 29 delivery units in the UK (Edinburgh, Glasgow, Manchester, Newcastle, Preston, Warrington, Chesterfield, Crewe, Durham, West Middlesex, Aylesbury, Furness, Southampton, Bolton, Sunderland, Oxford, Nottingham [2 units], Burnley, Chertsey, Stockton-on-Tees, Middlesborough, Chester, Darlington, York, Reading, Milton Keynes, Telford, Frimley). In total, 1,107 women with retained placenta following vaginal delivery were recruited. The intervention was self-administered 2 puffs of sublingual nitroglycerin (800 μg; intervention, N = 543) or placebo spray (control, N = 564). The primary clinical outcome was the need for MROP, assessed at 15 minutes following administration of the intervention. Analysis was based on the intention-to-treat principle. The primary safety outcome was measured blood loss between study drug administration and transfer to the postnatal ward or other clinical area. The primary patient-sided outcomes were satisfaction with treatment and side-effect profile, assessed by questionnaires pre-discharge and 6 weeks post-delivery. Secondary clinical outcomes were measured at 5 and 15 minutes after study drug administration and prior to hospital discharge. There was no statistically significant or clinically meaningful difference in need for MROP by 15 minutes (primary clinical outcome, 505 [93.3%] for nitroglycerin versus 518 [92.0%] for placebo, odds ratio [OR] 1.01 [95% CI 0.98–1.04], p = 0.393) or blood loss (<500 ml: nitroglycerin, 238 [44.3%], versus placebo, 249 [44.5%]; 500 ml–1,000 ml: nitroglycerin, 180 [33.5%], versus placebo, 224 [40.0%]; >1,000 ml: nitroglycerin, 119 [22.2%], versus placebo, 87 [15.5%]; ordinal OR 1.14 [95% CI 0.88–1.48], p = 0.314) or satisfaction with treatment (nitroglycerin, 288 [75.4%], versus placebo, 303 [78.1%]; OR 0.87 [95% CI 0.62–1.22], p = 0.411) or health service costs (mean difference [£] 55.3 [95% CI −199.20 to 309.79]). Palpitations following drug administration were reported more often in the nitroglycerin group (36 [9.8%] versus 15 [4.0%], OR 2.60 [95% CI 1.40–4.84], p = 0.003). There were 52 serious adverse events during the trial, with no statistically significant difference in likelihood between groups (nitroglycerin, 27 [5.0%], versus placebo, 26 [4.6%]; OR 1.13 [95% CI 0.54–2.38], p = 0.747). The main limitation of our study was the low return rate for the 6-week postnatal questionnaire. There were, however, no differences in questionnaire return rates between study groups or between women who did and did not have MROP, with the patient-reported use of outpatient and primary care services at 6 weeks accounting for only a small proportion (approximately 5%) of overall health service costs.


In this study, we found that nitroglycerin is neither clinically effective nor cost-effective as a medical treatment for retained placenta, and has increased side effects, suggesting it should not be used. Further research is required to identify an effective medical treatment for retained placenta to reduce the morbidity caused by this condition, particularly in low- and middle-income countries where surgical management is not available.

Trial registration ISRCTN88609453 NCT02085213

Klíčová slova:

Adverse events – Blood pressure – Blood transfusion – Drug administration – Heart rate – placenta – Questionnaires – Surgical and invasive medical procedures


1. Cheung WM, Hawkes A, Ibish S, Weeks AD. The retained placenta: historical and geographical rate variations. J Obstet Gynaecol. 2011;31(1):37–42. doi: 10.3109/01443615.2010.531301 21280991

2. MacLeod J, Rhode R. Retrospective follow-up of maternal deaths and their associated risk factors in a rural district of Tanzania. Trop Med Int Health. 1998;3(2):130–7. doi: 10.1046/j.1365-3156.1998.00174.x 9537275

3. World Health Organization. The world health report 2005: make every mother and child count. Geneva: World Health Organization; 2005 [cited 2019 Dec 3]. Available from:

4. Abdel-Aleem H, Abdel-Aleem MA, Shaaban OM. Nitroglycerin for management of retained placenta. Cochrane Database of Systematic Reviews. 2015;(11):CD007708. doi: 10.1002/14651858.CD007708.pub3 26558329

5. Chedraui PA, Insuasti DF. Intravenous nitroglycerin in the management of retained placenta. Gynecol Obstet Invest. 2003;56(2):61–4. doi: 10.1159/000072734 12900527

6. DeSimone CA, Norris MC, Leighton BL. Intravenous nitroglycerin aids manual extraction of a retained placenta. Anesthesiology. 1990;73(4):787.

7. Ekerhovd E, Bullarbo M. Sublingual nitroglycerin seems to be effective in the management of retained placenta. Acta Obstet Gynecol Scand. 2008;87(2):222–5. doi: 10.1080/00016340701855654 18231892

8. Lowenwirt IP, Zauk RM, Handwerker SM. Safety of intravenous glyceryl trinitrate in management of retained placenta. Aust N Z J Obstet Gynaecol. 1997;37(1):20–4. doi: 10.1111/j.1479-828x.1997.tb02212.x 9075542

9. Peng AT, Gorman RS, Shulman SM, DeMarchis E, Nyunt K, Blancato LS. Intravenous nitroglycerin for uterine relaxation in the postpartum patient with retained placenta. Anesthesiology. 1989;71(1):172–3. doi: 10.1097/00000542-198907000-00039 2502047

10. Bullarbo M, Tjugum J, Ekerhovd E. Sublingual nitroglycerin for management of retained placenta. Int J Gynaecol Obstet. 2005;91(3):228–32. doi: 10.1016/j.ijgo.2005.08.020 16226759

11. Visalyaputra S, Prechapanich J, Suwanvichai S, Yimyam S, Permpolprasert L, Suksopee P. Intravenous nitroglycerin for controlled cord traction in the management of retained placenta. Int J Gynaecol Obstet. 2011;112(2):103–6. doi: 10.1016/j.ijgo.2010.08.021 21144515

12. Bullarbo M, Bokstrom H, Lilja H, Almstrom E, Lassenius N, Hansson A, et al. Nitroglycerin for management of retained placenta: a multicenter study. Obstet Gynecol Int. 2012;2012:321207. doi: 10.1155/2012/321207 22685465

13. Farley AE, Graham CH, Smith GN. Contractile properties of human placental anchoring villi. Am J Physiol Regul Integr Comp Physiol. 2004;287(3):R680–5. doi: 10.1152/ajpregu.00222.2004 15142834

14. Barnes F. Hour-glass contraction of the uterus treated with nitrite of amyl. Br Med J. 1882;1(1107):377.

15. Dufour P, Vinatier D, Puech F. The use of intravenous nitroglycerin for cervico-uterine relaxation: a review of the literature. Arch Gynecol Obstet. 1997;261(1):1–7. doi: 10.1007/s004040050189 9451516

16. Redick LF, Livingston E. A new preparation of nitroglycerin for uterine relaxation. Int J Obstet Anesth. 1995;4(1):14–6. doi: 10.1016/0959-289x(95)82102-g 15636964

17. Rolbin SH, Hew EM, Bernstein A. Uterine relaxation can be life saving. Can J Anaesth. 1991;38(7):939–40. doi: 10.1007/BF03036985 1742836

18. Denison FC, Norrie J, Lawton J, Norman JE, Scotland G, McPherson GC, et al. A pragmatic group sequential, placebo-controlled, randomised trial to determine the effectiveness of glyceryl trinitrate for retained placenta (GOT-IT): a study protocol. BMJ Open. 2017;7(9):e017134. doi: 10.1136/bmjopen-2017-017134 28928192

19. National Institute for Health and Care Excellence. Intrapartum care: care of healthy women and their babies during childbirth. NICE clinical guideline CG190. London: National Institute for Health and Care Excellence; 2017.

20. Hallowell N, Snowdon C, Morrow S, Norman JE, Denison FC, Lawton J. The role of therapeutic optimism in recruitment to a clinical trial in a peripartum setting: balancing hope and uncertainty. Trials. 2016;17(1):267. doi: 10.1186/s13063-016-1394-1 27245155

21. Lawton J, Hallowell N, Snowdon C, Norman JE, Carruthers K, Denison FC. Written versus verbal consent: a qualitative study of stakeholder views of consent procedures used at the time of recruitment into a peripartum trial conducted in an emergency setting. BMC Med Ethics. 2017;18(1):36. doi: 10.1186/s12910-017-0196-7 28539111

22. Lawton J, Snowdon C, Morrow S, Norman JE, Denison FC, Hallowell N. Recruiting and consenting into a peripartum trial in an emergency setting: a qualitative study of the experiences and views of women and healthcare professionals. Trials. 2016;17:195. doi: 10.1186/s13063-016-1323-3 27066777

23. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70(3):659–63.

24. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549–56. 497341

25. Cytel. East. Version 6.4.1. Cambridge (MA): Cytel; 2016.

26. StataCorp. Stata statistical software: release 14. College Station (TX): StataCorp; 2015.

27. Department of Health and Social Care. NHS reference costs 2015 to 2016. London: Department of Health and Social Care; 2016 [cited 2019 Jan 5]. Available from:

28. British national formulary. 76th revised edition. London: Pharmaceutical Press; 2018.

29. Information Services Division Scotland. File listings 2016: costs. Available from: Last accessed 1/5/2019.

30. National Institute for Health and Care Excellence. Costing statement: blood transfusion—implementing the NICE guideline on blood transfusion (NG24). London: National Institute for Health and Care Excellence; 2015 [cited 2019 Dec 3]. Available from:

31. StataCorp. Stata user’s guide: release 13. College Station (TX): Stata Press; 2013.

32. Laufen H, Leitold M. Glyceryl-1-nitrate pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 1987;23(3):287–93. doi: 10.1111/j.1365-2125.1987.tb03047.x 3105569

33. Laslett LJ, Baker L. Sublingual nitroglycerin administered by spray versus tablet: comparative timing of hemodynamic effects. Cardiology. 1990;77(4):303–10. doi: 10.1159/000174612 2127377

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PLOS Medicine

2019 Číslo 12

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