Progesterone treatment for women who have changed their minds after taking mifepristone

We are responding to the recent statements released by the Royal New Zealand College of General Practitioners and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists regarding “abortion reversal.”^1,2

We are concerned that the advice given is solely focussed on the provision of abortion and is consequently overly restrictive and heavy-handed if we consider the woman who seeks help after taking mifepristone and regrets her choice. She no longer wants abortion care but seeks help to maintain her pregnancy. Natural progesterone offers her hope and there is little to suggest harm. Considering this treatment and encouraging further research are justifiable based on current evidence and are not unethical.

Since Medsafe approved the use of mifepristone and misoprostol for medical abortion in New Zealand in 2001, we have seen a steady rise to 6,764 medical abortions in 2022.³

Abortion regret and post-abortion distress are recognised psychological phenomena, which will inevitably occur in some women after taking mifepristone and could lead them to seek help to halt the abortion process.^4,5 As a profession we need to listen to the concern of our patient in this situation and be clear about what actions, if any, can be taken to help them.

Mifepristone is a selective progesterone receptor modulator that acts as an antiprogestogen, binding with greater affinity but without activating the progesterone receptor.⁶ In effect, it deprives the growing embryo or foetus of the progesterone needed to sustain placental growth and development. Despite this, mifepristone has never been associated with a significant risk of teratogenicity, so should it fail to induce abortion, the baby born carries the same or very close to the same risk of congenital abnormality as the general population.^6,7

It has been demonstrated in an animal model that administration of natural (micronised) progesterone 15 minutes after mifepristone (a human equivalent of approximately 6–9 hours) can reverse the adverse effects on pregnancy, leading to 81% of the model cohort progressing to live birth.⁸ Furthermore, depot medroxyprogesterone acetate has been shown to reduce the efficacy of the chemical abortion (even using both mifepristone and misoprostol) based on a randomised control trial showing fourfold increase in the chance of embryonic and foetal survival (0.9% vs 3.6%).⁹

There have been two published trials and three case reports/case series of progesterone use to reverse the effects of mifepristone in women.^5,10–13 The largest report, a retrospective cohort study of 547 subjects by Delgado et al., showed encouragingly high rates of pregnancy progression with no evidence of elevated harm to the baby.⁵

So, it appears that progesterone has biological plausibility as a treatment option, with support from an animal model and clinical evidence from a retrospective cohort study. Importantly, the treatment is not known to be harmful in pregnancy and has been used to treat recurrent miscarriage.¹⁴

Creinin et al. attempted to conduct a randomised controlled study in 2020 but this was halted after only 12 enrolled cases due to an unusually high proportion developing serious haemorrhage.¹² This is a recognised adverse effect of mifepristone, but the high rate seen in this study seems unusual and differs from the rate seen elsewhere.¹³ Despite its limitations as a study, it is interesting to note that a higher proportion of those who had progesterone had detectable foetal cardiac activity at 2 weeks, while the numbers of serious haemorrhages seen was greater in the placebo group.¹²

A more recent pilot clinical trial was conducted in Australia by Turner et al. This prospective study was also small, with only six women enrolled, but the positive findings encourage further investigation with a larger trial. There were no clinically significant haemorrhages reported.¹³

A systematic review of the use of micronised progesterone to antagonise the effects of mifepristone was undertaken by Stifani et al. and published in October 2023. They commented on the poor-quality data in most trials but reported encouraging rates of ongoing pregnancy for those treated with progesterone of almost twice that of placebo in those under 7 weeks gestation, and 12% higher in those treated between 7–8 weeks.¹⁵

As clinicians it is important that the treatment we recommend is evidence based. There is a need for further well-designed prospective observational studies to clarify the safety and efficacy of this treatment in the New Zealand context. A larger single-arm trial, similar in design to the pilot study conducted by Turner et.al., is an attractive initial option to clarify the safety of progesterone after taking mifepristone while avoiding the ethical difficulties posed by offering placebo.¹⁴

For the woman who regrets taking mifepristone and no longer seeks abortion, the focus has now become pregnancy care. Based on currently available evidence and the principle of patient-centred care, further research on the option of progesterone therapy is warranted. With careful monitoring, it is highly unlikely to do harm and may do some good for her now wanted pregnancy.