Type of publication:
Randomised controlled trial

Author(s):
Devall A.; Chu J.; Beeson L.; Hardy P.; Cheed V.; Sun Y.; Roberts T.; Ogwulu C.O.; Williams E.; Jones L.; Papadopoulos J.F.; Bender-Atik R.; Brewin J.; Hinshaw K.; Choudhary M.; Ahmed A.; Naftalin J.; Nunes N.; Oliver A.; Izzat F.; Bhatia K.; Hassan I.; Jeve Y.; Hamilton J.; Deb S.; Bottomley C.; Ross J.; Watkins L.; *Underwood M.; Cheong Y.; Kumar C.; Gupta P.; Small R.; Pringle S.; Hodge F.; Shahid A.; Gallos I.; Horne A.; Quenby S.; Coomarasamy A.

Citation:

Health Technology Assessment, November 2021, 25(68) (pp 1-114)

Abstract:
TRIAL DESIGN: A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. METHOD(S): Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1:1 ratio) to receive 200mg of oral mifepristone or matched placebo, followed by 800mug of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. RESULT(S): A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p=0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p=0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of 182 (95% confidence interval 26 to 338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. LIMITATIONS: The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. FUTURE WORK: Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. CONCLUSION(S): Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone.

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Type of publication:
Randomised controlled trial

Author(s):
Chu, Justin J; Devall, Adam J; Beeson, Leanne E; Hardy, Pollyanna; Cheed, Versha; Sun, Yongzhong; Roberts, Tracy E; Ogwulu, C Okeke; Williams, Eleanor; Jones, Laura L; La Fontaine Papadopoulos, Jenny H; Bender-Atik, Ruth; Brewin, Jane; Hinshaw, Kim; Choudhary, Meenakshi; Ahmed, Amna; Naftalin, Joel; Nunes, Natalie; Oliver, Abigail; Izzat, Feras; Bhatia, Kalsang; Hassan, Ismail; Jeve, Yadava; Hamilton, Judith; Deb, Shilpa; Bottomley, Cecilia; Ross, Jackie; Watkins, Linda; *Underwood, Martyn; Cheong, Ying; Kumar, Chitra S; Gupta, Pratima; Small, Rachel; Pringle, Stewart; Hodge, Frances; Shahid, Anupama; Gallos, Ioannis D; Horne, Andrew W; Quenby, Siobhan; Coomarasamy, Arri

Citation:
Lancet; Sep 2020; vol. 396 (no. 10253); p. 770-778

Abstract:
BACKGROUND The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. METHODS MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. FINDINGS Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. INTERPRETATION Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. FUNDING UK National Institute for Health Research Health Technology Assessment Programme.

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Type of publication:
Journal article

Author(s):
CB Okeke Ogwulu, I Goranitis, AJ Devall, V Cheed, ID Gallos, LJ Middleton, HM Harb, HM Williams, A Eapen, JP Daniels, A Ahmed, R Bender‐Atik, K Bhatia, C Bottomley, J Brewin, M Choudhary, S Deb, WC Duncan, AK Ewer, K Hinshaw, T Holland, F Izzat, J Johns, M Lumsden, P Manda, JE Norman, N Nunes, CE Overton, K Kriedt, S Quenby, S Rao, J Ross, A Shahid, *M Underwood , N Vaithilingham, L Watkins, C Wykes, AW Horne, D Jurkovic, A Coomarasamy, TE Roberts

Citation:
BJOG: An International Journal of Obstetrics and Gynaecology; May 2020; Vol 127 (no. 6); p. 757-767

Abstract:
Objectives: To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding.
Design: Economic evaluation alongside a large multi‐centre randomised placebo‐controlled trial.
Setting: Forty‐eight UK NHS early pregnancy units.
Population: Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac.
Methods: An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages.
Main outcome measures: Cost per additional live birth at ≥34 weeks of gestation.
Results: Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673).
Conclusions: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s).

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