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. 2019 Dec;23(70):1–72. doi: 10.3310/hta23700

Glyceryl trinitrate to reduce the need for manual removal of retained placenta following vaginal delivery: the GOT-IT RCT.

Fiona C Denison, Kathryn F Carruthers, Jemma Hudson, Gladys McPherson, Graham Scotland, Sheonagh Brook-Smith, Cynthia Clarkson, Mathilde Peace, Jane Brewin, Gin Nie Chua, Nina Hallowell, Jane E Norman, Julia Lawton, John Norrie
PMCID: PMC6970217  PMID: 31912780

Abstract

BACKGROUND

Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative.

OBJECTIVE

To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management.

DESIGN

A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis.

SETTING

There were 29 obstetric units in the UK involved in the study.

PARTICIPANTS

There were 1107 women (glyceryl trinitrate group, n = 543; placebo group, n = 564) randomised between October 2014 and July 2017.

INTERVENTIONS

Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group.

MAIN OUTCOME MEASURES

Four primary outcomes were defined: (1) clinical - the need for manual removal of placenta, (2) safety - measured blood loss, (3) patient sided - satisfaction with treatment and side effects and (4) economic - cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics.

RESULTS

No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval -£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p < 0.001). The need for a blood transfusion was also more common in the glyceryl trinitrate group than in the control group (odds ratio 1.53, 95% confidence interval 1.04 to 2.25; p = 0.033).

CONCLUSIONS

Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN88609453.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 70. See the NIHR Journals Library website for further project information.

Plain language summary

A retained placenta is diagnosed when, following the birth of a baby, the placenta is not delivered. When this situation occurs, women are at risk of bleeding heavily. The only way to treat a retained placenta is for a trained doctor to remove it by an operation in theatre. This procedure can be painful and upsetting. Furthermore, the timing of the operation can interrupt mother–baby bonding immediately after giving birth. The study tested if the use of glyceryl trinitrate spray, given as two puffs under the woman’s tongue following the diagnosis of retained placenta, may help the placenta to deliver without an operation. The study also tested if glyceryl trinitrate was safe, assessed what women thought about the treatment and compared the costs of glyceryl trinitrate with those of current operative management. This study included 1107 women diagnosed with retained placenta following the birth of their baby. Half of the women were treated with glyceryl trinitrate spray and the other half were treated with a dummy spray, which looked identical but did not contain the active treatment. If the placenta delivered within 15 minutes of the study treatment being taken, this was considered a success. However, if the placenta did not deliver within 15 minutes and the woman had to have her placenta removed by an operation, then this was viewed as unsuccessful. Neither the woman nor the clinical staff knew if the treatment given was the glyceryl trinitrate spray or the dummy spray. The results indicate that, although women were happy to be involved in the trial and the treatment was safe, the use of glyceryl trinitrate spray did not reduce the need for the placenta to be manually removed by an operation in theatre. Furthermore, glyceryl trinitrate spray was not cost-effective.

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References

  1. National Institute for Health and Care Excellence (NICE). NICE Clinical Guideline 190: Intrapartum Care for Healthy Women and Babies. London: NICE; 2014. URL: www.nice.org.uk/guidance/cg190 (accessed 1 February 2018).
  2. Cheung WM, Hawkes A, Ibish S, Weeks AD. The retained placenta: historical and geographical rate variations. J Obstet Gynaecol 2011;31:37–42. URL: https://doi.org/10.3109/01443615.2010.531301 doi: 10.3109/01443615.2010.531301. [DOI] [PubMed]
  3. Stones RW, Paterson CM, Saunders NJ. Risk factors for major obstetric haemorrhage. Eur J Obstet Gynecol Reprod Biol 1993;48:15–18. https://doi.org/10.1016/0028-2243(93)90047-G doi: 10.1016/0028-2243(93)90047-G. [DOI] [PubMed]
  4. Combs CA, Murphy EL, Laros RK. Factors associated with postpartum hemorrhage with vaginal birth. Obstet Gynecol 1991;77:69–76. [PubMed]
  5. Lennox C, Marr J. Scottish Confidential Audit of Severe Maternal Morbidity: Reducing Avoidable Harm. 10th Annual Report. Edinburgh: Healthcare Improvement Scotland; 2014. URL: www.healthcareimprovementscotland.org/our_work/reproductive,_maternal_child/programme_resources/scasmm.aspx (accessed 1 February 2018).
  6. Combs CA, Laros RK. Prolonged third stage of labor: morbidity and risk factors. Obstet Gynecol 1991;77:863–7. [PubMed]
  7. Ely JW, Rijhsinghani A, Bowdler NC, Dawson JD. The association between manual removal of the placenta and postpartum endometritis following vaginal delivery. Obstet Gynecol 1995;86:1002–6. https://doi.org/10.1016/0029-7844(95)00327-N doi: 10.1016/0029-7844(95)00327-N. [DOI] [PubMed]
  8. Abdel-Aleem H, Abdel-Aleem MA, Shaaban OM. Nitroglycerin for management of retained placenta. Cochrane Database Syst Rev 2015;11:CD007708. https://doi.org/10.1002/14651858.CD007708.pub3 doi: 10.1002/14651858.CD007708.pub3. [DOI] [PMC free article] [PubMed]
  9. Barnes F. Hour-glass contraction of the uterus treated with nitrite of amyl. Br Med J 1882;1:377. https://doi.org/10.1136/bmj.1.1107.377 doi: 10.1136/bmj.1.1107.377. [DOI] [PMC free article] [PubMed]
  10. Dufour P, Vinatier D, Puech F. The use of intravenous nitroglycerin for cervico-uterine relaxation: a review of the literature. Arch Gynecol Obstet 1997;261:1–7. https://doi.org/10.1007/s004040050189 doi: 10.1007/s004040050189. [DOI] [PubMed]
  11. Chedraui PA, Insuasti DF. Intravenous nitroglycerin in the management of retained placenta. Gynecol Obstet Invest 2003;56:61–4. https://doi.org/10.1159/000072734 doi: 10.1159/000072734. [DOI] [PubMed]
  12. DeSimone CA, Norris MC, Leighton BL. Intravenous nitroglycerin aids manual extraction of a retained placenta. Anesthesiology 1990;73:787. https://doi.org/10.1097/00000542-199010000-00031 doi: 10.1097/00000542-199010000-00031. [DOI] [PubMed]
  13. Lowenwirt IP, Zauk RM, Handwerker SM. Safety of intravenous glyceryl trinitrate in management of retained placenta. Aust N Z J Obstet Gynaecol 1997;37:20–4. https://doi.org/10.1111/j.1479-828X.1997.tb02212.x doi: 10.1111/j.1479-828X.1997.tb02212.x. [DOI] [PubMed]
  14. 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;71:172–3. https://doi.org/10.1097/00000542-198907000-00039 doi: 10.1097/00000542-198907000-00039. [DOI] [PubMed]
  15. Rolbin SH, Hew EM, Bernstein A. Uterine relaxation can be life saving. Can J Anaesth 1991;38:939–40. https://doi.org/10.1007/BF03036985 doi: 10.1007/BF03036985. [DOI] [PubMed]
  16. Bullarbo M, Tjugum J, Ekerhovd E. Sublingual nitroglycerin for management of retained placenta. Int J Gynaecol Obstet 2005;91:228–32. https://doi.org/10.1016/j.ijgo.2005.08.020 doi: 10.1016/j.ijgo.2005.08.020. [DOI] [PubMed]
  17. Ekerhovd E, Bullarbo M. Sublingual nitroglycerin seems to be effective in the management of retained placenta. Acta Obstet Gynecol Scand 2008;87:222–5. https://doi.org/10.1080/00016340701855654 doi: 10.1080/00016340701855654. [DOI] [PubMed]
  18. Redick LF, Livingston E. A new preparation of nitroglycerin for uterine relaxation. Int J Obstet Anesth 1995;4:14–16. https://doi.org/10.1016/0959-289X(95)82102-G doi: 10.1016/0959-289X(95)82102-G. [DOI] [PubMed]
  19. Laslett LJ, Baker L. Sublingual nitroglycerin administered by spray versus tablet: comparative timing of hemodynamic effects. Cardiology 1990;77:303–10. https://doi.org/10.1159/000174612 doi: 10.1159/000174612. [DOI] [PubMed]
  20. Marmor A. Comparative evaluation of a new formulation of isosorbide dinitrate oral spray and sublingual nitroglycerin tablets. Am J Cardiol 1990;65:43J–45J. https://doi.org/10.1016/0002-9149(90)91311-S doi: 10.1016/0002-9149(90)91311-S. [DOI] [PubMed]
  21. Curry SH, Lopez LM, Lambert CR, Kwon HR, Stack RK. Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization. Biopharm Drug Dispos 1993;14:107–18. https://doi.org/10.1002/bdd.2510140203 doi: 10.1002/bdd.2510140203. [DOI] [PubMed]
  22. Wight LJ, VandenBurg MJ, Potter CE, Freeth CJ. A large scale comparative study in general practice with nitroglycerin spray and tablet formulations in elderly patients with angina pectoris. Eur J Clin Pharmacol 1992;42:341–2. https://doi.org/10.1007/BF00266360 doi: 10.1007/BF00266360. [DOI] [PubMed]
  23. Farley AE, Graham CH, Smith GN. Contractile properties of human placental anchoring villi. Am J Physiol Regul Integr Comp Physiol 2004;287:R680–5. https://doi.org/10.1152/ajpregu.00222.2004 doi: 10.1152/ajpregu.00222.2004. [DOI] [PubMed]
  24. Royal College of Obstetricians and Gynaecologists (RCOG). Obtaining Valid Consent to Participate in Perinatal Research Where Consent is Time Critical (Clinical Governance Advice No. 6a). London: RCOG; 2016.
  25. 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;17:267. https://doi.org/10.1186/s13063-016-1394-1 doi: 10.1186/s13063-016-1394-1. [DOI] [PMC free article] [PubMed]
  26. 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. https://doi.org/10.1186/s13063-016-1323-3 doi: 10.1186/s13063-016-1323-3. [DOI] [PMC free article] [PubMed]
  27. 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;18:36. https://doi.org/10.1186/s12910-017-0196-7 doi: 10.1186/s12910-017-0196-7. [DOI] [PMC free article] [PubMed]
  28. Coviello EM, Grantz KL, Huang CC, Kelly TE, Landy HJ. Risk factors for retained placenta. Am J Obstet Gynecol 2015;213:864.e1–864.e11. https://doi.org/10.1016/j.ajog.2015.07.039 doi: 10.1016/j.ajog.2015.07.039. [DOI] [PMC free article] [PubMed]
  29. Great Britain. Data Protection Act 1998. London: The Stationery Office; 1998. URL: www.legislation.gov.uk/ukpga/1998/29/contents (accessed 1 February 2018).
  30. Aspire Pharma Ltd. Glytrin, 400 Micrograms per Metered Dose, Sublingual Spray. Petersfield: Aspire Pharma Ltd. URL: www.medicines.org.uk/emc/medicine/10739 (accessed 1 February 2018).
  31. Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659–63. https://doi.org/10.2307/2336502 doi: 10.2307/2336502. [DOI]
  32. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549–56. https://doi.org/10.2307/2530245 doi: 10.2307/2530245. [DOI] [PubMed]
  33. Denison F, McPherson G, Scotland G, Brook-Smith S, Clarkson C, Peace M, Brewin J, et al. A pragmatic adaptive sequential placebo controlled randomised trial to determine the effectiveness of Glyceryl trinitrate for retained placenta (Got-it trial). Southampton: National Institute for Health Research. URL: www.fundingawards.nihr.ac.uk/award/12/29/01 (accessed 10 July 2019).
  34. Royal College of Obstetricians and Gynaecologists (RCOG). Obtaining Valid Consent to Participate in Research While in Labour (Clinical Governance Advice No. 6a). London: RCOG; 2010.
  35. Vernon G, Alfirevic Z, Weeks A. Issues of informed consent for intrapartum trials: a suggested consent pathway from the experience of the release trial [ISRCTN13204258]. Trials 2006;7:13. https://doi.org/10.1186/1745-6215-7-13 doi: 10.1186/1745-6215-7-13. [DOI] [PMC free article] [PubMed]
  36. Britten N. Qualitative interviews in medical research. BMJ 1995;311:251–3. https://doi.org/10.1136/bmj.311.6999.251 doi: 10.1136/bmj.311.6999.251. [DOI] [PMC free article] [PubMed]
  37. Pope C, Mays N. Reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health services research. BMJ 1995;311:42–5. https://doi.org/10.1136/bmj.311.6996.42 doi: 10.1136/bmj.311.6996.42. [DOI] [PMC free article] [PubMed]
  38. Glaser BG, Strauss AL. The Discovery of Grounded Theory. New York, NY: Aldine; 1967.
  39. Strauss A, Corbin JM. Basics of Qualitative Research: Grounded Theory Procedures and Techniques. London: Sage Publications, Ltd; 1990.
  40. Curtis L, Burns A. Unit Costs of Health and Social Care 2016. Canterbury: Personal Social Services Research Unit, University of Kent. 2016. URL: www.pssru.ac.uk/project-pages/unit-costs/unit-costs-2016/
  41. Department of Health and Social Care. NHS Reference Costs 2015 to 2016. London: Department of Health and Social Care. URL: www.gov.uk/government/publications/nhs-reference-costs-2015-to-2016
  42. Joint Formulary Committee. British National Formulary. March 2018 update (online). London: BMJ Group and Pharmaceutical Press. URL: www.medicinescomplete.com (accessed 5 April 2019).
  43. Information Services Division Scotland. Scottish Health Service Costs (2016). Edinburgh: Information Services Division Scotland. URL: www.isdscotland.org/Health-Topics/Finance/Costs/File-Listings-2016.asp (accessed 5 April 2019).
  44. National Institute for Health and Care Excellence (NICE). Costing Statement: Blood Transfusion Implementing the NICE Guideline on Blood Transfusion (NG24). London: NICE; 2015. URL: www.nice.org.uk/guidance/ng24/resources/ (accessed 5 April 2019).
  45. NHS. OPCS Classification of Interventions and Procedures. 2019. URL: www.datadictionary.nhs.uk/web_site_content/supporting_information/clinical_coding/opcs_classification_of_interventions_and_procedures.asp (accessed 20 July 2018).

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