Miscarriage occurs in 20% of all pregnancies (Fernlund et al, 2018) and medical management using misoprostol is now a popular treatment option as opposed to surgical intervention. Current research indicates the use of mifepristone in combination with misoprostol due to higher efficacy rates with this combination (Tulandi and Al-Fozan, 2018).
Mifepristone and misoprostol
Mifepristone is a synthetic steroid which acts as a progesterone antagonist (Im and Appleman, 2010). Progesterone is an important endogenous hormone required for ongoing pregnancy (Dunford and Fyfe, 2018). On a cellular level, mifepristone blocks progesterone uptake leading to decreased levels which initiates uterine contraction, cervical softening, dilation, and sensitising the myometrium to prostaglandins; hormones which support uterine contractility (Im and Appleman, 2010; Medsafe, 2013; Dunford and Fyfe, 2018).
Misoprostol is a prostaglandin analogue which binds to prostaglandin receptors and mimics the effect of prostaglandins. The resulting uterine contraction, softening and dilation of the cervix lead to expulsion of products of conception (Medsafe, 2016; Dunford and Fyfe, 2018).
Guidelines for the medical management of first trimester miscarriage in New Zealand recommend misoprostol alone and do not mention mifepristone (Hutt Valley District Health Board, 2014; Canterbury District Health Board, 2015; Auckland District Health Board, 2017). National Institute for Clinical Excellence ([NICE], 2019) guidelines also recommend misoprostol but do not recommend mifepristone for missed or incomplete miscarriage. Mifepristone is recommended in the American College of Obstetricians and Gynecologists ([ACOG], 2018) guidelines and is used internationally as adjuvant treatment for effective management of miscarriage (Tulandi and Al-Fozan, 2018).
Review of the latest evidence
A randomised control trial conducted by Schreiber et al (2018), evaluated the efficacy of mifepristone plus misoprostol, compared to misoprostol alone for first trimester medical management of miscarriage. Participants were randomised into two groups: mifepristone plus misoprostol (n = 148) or misoprostol only (n = 149). Between 0.5-5.5 days of post-treatment, the mifepristone plus misoprostol group found 83.3% of participants had complete gestation sac expulsion compared to the misoprostol only group of 67.1%. This had a relative risk of 1.25 (95% confidence interval [CI]=1.09 − 1.43, p=0.001). This trial demonstrated that mifepristone used in combination with misoprostol was significantly more effective than misoprostol alone in medical management of miscarriage in the first trimester.
Serious adverse effects occurred in 3.4% of participants in the mifepristone plus misoprostol group compared to 2% in the misoprostol only group, the difference was not statistically significant (p=0.47). Although, headaches were reported as a significant adverse effect, occurring in 59.1% of participants in the mifepristone plus misoprostol group, compared to 47.7% in the misoprostol only group. The reported statistical findings had borderline significance (relative risk of 1.24 [95% CI=1.00 − 1.54, p=0.05]). However, vomiting was reported as a significant adverse effect occurring in 26.8% of women in the mifepristone plus misoprostol group, compared to 15.2% of women in the misoprostol only group (relative risk of 1.76 [95% CI = 1.11 − 2.79, p=0.01]) (Schreiber et al, 2018).
Sinha et al (2018) conducted a randomised double-blind placebo-controlled trial, which again compared the use of mifepristone plus misoprostol against placebo plus misoprostol for first trimester miscarriage management. Patients were selected and randomised into two groups: mifepristone plus misoprostol (n=46); and placebo plus misoprostol (n=46). The mifepristone plus misoprostol group had an 86.7% completion rate compared to 57.8% in the placebo plus misoprostol group (p=0.009). In addition, surgical intervention was required for 13.34% of the mifepristone plus misoprostol group compared to 42.2% of the placebo plus misoprostol group (p=0.002). Complete expulsion occurred faster in the mifepristone plus misoprostol group with 65.9% of participants completing the process within four hours of the initial dose, compared to 11.4% achieving completion in the placebo plus misoprostol group (p<0.0001). These results suggest the use of mifepristone in combination with misoprostol is significantly more effective than misoprostol alone. Adverse effects of treatment in this trial found no significant difference in the amount of vaginal blood loss between both groups. The mifepristone plus misoprostol group had a mean value of 6.20 days of vaginal bleeding compared to the placebo plus misoprostol group mean value of 6.22 days (p=0.384). Reduction in haemoglobin levels was not significantly different between the two groups (mean drop of 0.6 grams percent [g%] compared to 0.62 g% [p=0.848]). Nausea and vomiting occurred significantly less in the mifepristone plus misoprostol group (17.8% of women), compared to 42.2% of women in the placebo plus misoprostol group (p=0.009). Overall, client satisfaction levels were reported higher in the mifepristone plus misoprostol group with 84.4%, compared to the placebo plus misoprostol group of 60% (p=0.012) (Sinha et al, 2018).
A retrospective cohort analysis of women experiencing first trimester pregnancy loss between 2011 and 2013, in an acute Australian-based unit, assessed the efficacy of mifepristone in addition to misoprostol (Dunford and Fyfe, 2018). An amount of 281 women had undertaken medical management opting for either mifepristone plus misoprostol (n=179) or misoprostol only (n=102). The mifepristone plus misoprostol group had a success rate of 73% compared to 56% in the misoprostol only (p=0.012). Further intervention was required for 27% of the mifepristone plus misoprostol group compared to 44% the misoprostol only group (p=0.012). These findings agree with current research suggestions that mifepristone plus misoprostol increases the efficacy of medical management of miscarriage.
Furthermore, no significant differences in time to completion were reported. The mifepristone plus misoprostol group had a mean completion time of 6.80 days compared to the misoprostol only group of 6.70 days (95% CI=0.49 − 2.84, p=0.17). Adverse effects were not reported, however no significant difference was reported between the two groups with regards to vaginal bleeding requiring admission, surgical intervention or blood transfusion (2.8% in the mifepristone plus misoprostol group, compared to 1% in the misoprostol only [p=0.3121]). However, the study did report lack of sufficient power to assess differences in blood loss between the two groups (Dunford and Fyfe, 2018).
A systematic review and network meta-analysis of randomised trials was conducted by Al Wattar et al (2019). The authors assessed treatment options for the management of first trimester miscarriage. A selection of electronic databases was searched: CINAHL, AMED, MEDLINE, Embase, and Cochrane Library and 125 studies were reviewed. Of these, 9 trials involving 932 participants in total assessed the efficacy of mifepristone plus misoprostol. Other management options reviewed included misoprostol alone, expectant management, surgical sharp dilation and curettage, electric vacuum aspiration, manual vacuum aspiration, and misoprostol in addition to electric vacuum aspiration.
Results from the meta-analysis reported the use of mifepristone plus misoprostol significantly more effective than misoprostol alone with a relative risk of 1.49 (95% CI=1.09 − 2.03). Mifepristone plus misoprostol had a cumulative rank probability of effectiveness of 89.3%, comparatively misoprostol alone had a cumulative rank probability of effectiveness of 34.8%. These findings indicate mifepristone had higher efficacy rates than misoprostol alone (Al Wattar et al, 2019).
Different dosage regimes and routes of administration of mifepristone plus misoprostol appear to impact on the rate of success, and may lead to inconsistences when comparing research (Colleselli et al, 2016). The randomised control trial conducted by Schreiber et al (2018) had a dosage regime of 200mg of mifepristone orally, followed by 800mcg of misoprostol vaginally. Similarly, the randomised, double-blind, placebo-controlled trial conducted by Sinha et al (2018) had a dosage regime of: mifepristone 200 mg orally, 800 mcg of misoprostol vaginally, followed by 2-4 repeat doses of 400 mcg misoprostol orally until complete expulsion of products of conception.
The retrospective cohort analysis conducted by Dunford and Fyfe (2018) had a dose regime of 200 mg of oral mifepristone, followed by two consecutive doses of 400 mcg oral misoprostol. In addition, the systematic review and network meta-analysis of randomised trials by Al Wattar et al (2019) found a significant range of doses between studies; from 200 mg-600 mg of mifepristone orally, and 400 mcg-1 200 mcg of misoprostol orally or vaginally. Whilst the outcome of the above research articles all agree mifepristone plus misoprostol increases the efficacy of medical management of miscarriage, further research should address the most effective dose.
Conclusion
Current research suggests that the use of mifepristone plus misoprostol significantly increases the efficacy of medical management of miscarriage. Further research is required to ascertain the strength of this claim in regard to dosage regimes including adverse effects. However, evaluation of current management pathways should assess the benefits of implementing mifepristone plus misoprostol. The data obtained from this report should promote greater clinical discussions on current management and potential changes to guidelines. Educating women on all available options, possible risks and benefits is essential in ensuring individuals are fully informed and able to provide informed consent.