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): e32767. 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


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PLOS Medicine

2019 Číslo 12

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