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Background
In the 1980s, the term ‘contragestion’ was coined by French scientists investigating progesterone receptor modulators (PRMs). Contragestion refers to a method that works after ovulation and throughout luteal phase and beyond.1 A contragestive could prevent or disrupt implantation, which may be politically controversial. On the other hand, a strategy to avoid abortion has been the concept of ‘menstrual regulation’ which is widely practised in some parts of the world. Thus, the mechanism of action may be less important than how we name the method to get through political and regulatory constraints and psychosocial barriers.
In the 21st century, the status quo of existing contraceptive choice is not sufficient. Despite a range of contraceptive methods, hormonal and non-hormonal, and various delivery systems and durations of action, we still have high rates of unintended pregnancy. No method of contraception is 100% effective. Also, not all women will want to use a method that constantly releases hormones or have a device present in the body even if it is highly effective and reversible. Uptake of existing methods of contraception is also limited due to experienced or feared side effects. Some women may want an occasional-use method only. While emergency contraception (EC) pills can be used as an occasional method or pericoital method, they are only of limited effectiveness.2 Also, based on the calculations of expected and observed rates of pregnancy in the clinical trials that compared levonorgestrel to ulipristal acetate, it is estimated that EC prevents at best around one-half to two-thirds of pregnancies that might otherwise have occurred.3 4 The only confirmed mechanism of action of EC is through preventing or delaying ovulation.5–7 It is clear therefore that we need a method that remains effective after ovulation and fertilisation, that is, contragestion.
Would women use a contragestive?
Surveys suggest that at least in theory, a substantial proportion of women from various populations would favour methods that prevented pregnancy through postovulatory effects. It is one mechanism of action of the intrauterine device (IUD) which is a highly popular method of contraception. In a survey of over 1000 women in Hong Kong attending for contraception, abortion or postnatal care, 43% and 30% were in favour of using a method that would prevent or disrupt implantation respectively.8 However, in a survey from Scotland of over 400 women seeking insertion of IUDs, abortion and EC, a much higher proportion of respondents were accepting in theory contraceptive methods that worked by preventing implantation (83%) or disrupting implantation (75%).9 Interestingly, 71% of respondents in Hong Kong and 64% in Scotland expressed acceptability towards using a pill to be taken if menses were missed but before pregnancy confirmation.8 9 In addition, in a US survey of women attending contraceptive clinics, 42% stated a theoretical acceptance of a ‘missed menses pill’.10
Prevention of implantation
PRMs such as mifepristone have the potential to be developed as contragestives by preventing or disrupting implantation, depending on the dose, frequency and timing of administration in the menstrual cycle. Mifepristone given in a single dose of 200 mg immediately after ovulation has been shown to disturb secretory development of the endometrium and hence prevent implantation.11 Indeed, a clinical trial conducted in the 1990s using mifepristone as a monthly mid-cycle contraceptive demonstrated effectiveness with just one pregnancy out of 124 cycles, a failure rate comparable with a daily oral contraceptives.12 Existing evidence also shows that when used for EC, mifepristone in a dose of at least 50 mg is more effective than other oral EC, probably because in addition to preventing ovulation it exerts endometrial effects.13
Disruption of implantation
Studies conducted in the 1990s also showed that mifepristone can disrupt implantation when given in the late luteal phase just before the expected menses. However, the rates of continuing pregnancy in the cycles where there was evidence of pregnancy (based on pretreatment serum human chorionic gonadotrophin) was 18%, which was considered not sufficiently effective to be used clinically.14 Efficacy was shown to improve when mifepristone was followed with misoprostol. Two studies that examined mifepristone (150–200 mg) taken the day before expected menses followed by misoprostol (400 mcg oral or vaginal) showed a continuing pregnancy rate of 4%–5% which was still higher than the 1%–2% expected when used for medical abortion in the first 9 weeks of pregnancy.15 16 However, in a recent study from China of 138 cycles where women who had unprotected sex received 50 mg mifepristone followed 24 hours later with 200 mcg misoprostol, the continuing pregnancy rates were only 1.5%.17 Furthermore, retrospective observational studies from Sweden, Austria and Scotland have confirmed the effectiveness of very early medical abortion (VEMA) before an intrauterine pregnancy is observed on ultrasound,18–20 which provides further support for the effectiveness of a contragestive. A large multicountry randomised trial of VEMA is underway that should provide further evidence.
Conclusion
Contragestion could be a highly effective and acceptable form of fertility control in populations around the world. It could be taken only when sex occurred or if menses were missed, or in a regular weekly or monthly regimen. There could be no need to take daily hormones or have a device fitted or removed, which may imply a lower side effect profile overall although it needs to be confirmed in further studies.
In spite of evidence of effectiveness of mifepristone for contragestion and survey evidence for acceptability of postovulatory methods, the development of contragestion has undoubtedly been halted by opposition to the mode of action as a potential disrupter of implantation. Sadly, the world fails to learn that restricting access to medications or procedures that may end pregnancy does not prevent abortion. Ultimately, it is by expanding options of highly effective fertility control that we can prevent more unintended pregnancies and benefit women and the society as a whole. Views from different stakeholders would impact the pathway to get the research and development of contragestion through regulatory approvals. It is therefore the duty of governments, funders, researchers, pharmaceutical industry and women’s health advocates around the world to support the development of contragestion—now.
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References
Footnotes
Contributors SC wrote the first draft of this editorial. HWRL and KG-D contributed to subsequent drafts. All the authors approved the final draft.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SC is editor in chief of BMJ SRH and HWRL is an associate editor of BMJ SRH .
Provenance and peer review Not commissioned; externally peer reviewed.