Mifepristone in emergency contraception

A recent meta-analysis evaluates the efficacy of low-dose mifepristone as an emergency contraceptive compared to other interventions. Beyond its effectiveness in reducing pregnancy rates, its mechanism of action and ability to interfere with endometrial receptivity has reignited the debate surrounding its bioethical implications and the information women receive about its possible effects.

A recent article analyzes the efficacy of low-dose mifepristone as an emergency (postcoital) contraceptive.

The paper, authored by Shaalini Ramanadhan et al. from Oregon Health and Science University (USA), was published in the Cochrane Database of Systematic Reviews, 2026 (Issue 9. Art. No.: CD016275).

It examines 87 clinical trials conducted over the last three decades, with data from approximately 36,000 women of reproductive age.

The study evaluates the effectiveness, safety, side effects, and acceptability of mifepristone compared to other emergency contraceptive measures—specifically oral regimens (levonorgestrel, the Yuzpe method, and ulipristal acetate) and copper or levonorgestrel intrauterine devices (IUDs)—in reproductive-age women within 5 days of unprotected intercourse.

This was a meta-analysis of 87 randomized clinical trials (RCTs) with cumulative data from approximately 36,000 women. The majority of trials (79 studies) were conducted in China, in addition to studies in the UK, Cuba, and multinational settings.

The critical outcome was the number of pregnancies averted. Secondary outcomes included the presence of adverse effects, altered menses, and acceptability (assessed as degree of treatment satisfaction).

Efficacy analysis

Credit: Robin Marty – flickr

Compared to levonorgestrel, low-dose mifepristone (<25 mg) demonstrated a 27% relative reduction in pregnancy rates, a finding supported by high-certainty evidence. In absolute terms, the risk of pregnancy is reduced from approximately 20 per 1,000 women with levonorgestrel to between 12 and 15 per 1,000 women with mifepristone; both low and medium doses (25–50 mg) showed superior efficacy.

Compared with the Yuzpe regimen—a combined estrogen (ethinylestradiol) and levonorgestrel (progestin) regimen that is largely obsolete outside certain developing countries—mifepristone reduced the risk of pregnancy to a tiny fraction of that observed with this traditional combined regimen.

Compared with the copper IUD, the evidence is still insufficient to draw definitive conclusions, as only two clinical trials are available.

Tolerability, mechanism, and side effects

Mifepristone, like ulipristal acetate, acts by selectively blocking progesterone receptors, thereby preventing progesterone from exerting its protective role in maintaining pregnancy.

Some studies claim that, administered in the late follicular phase, before the luteinizing hormone (LH) peak, it can inhibit or delay ovulation. However, its ability to block the effect of progesterone enables it to disrupt the implantation process or, at doses greater than 200 mg, induce abortion of the implanted embryo, with the result that it is authorized as a chemical abortifacient in many countries.

The Cochrane review reports that low-dose mifepristone has a lower incidence of nausea, vomiting, and general malaise, in addition to reducing spotting or bleeding after treatment.

The main adverse effect identified was an increased likelihood of delayed menstruation. This effect is common with other emergency contraceptives.

Mechanism of action

As stated, mifepristone belongs to the antiprogestogen (antiprogestin) family and acts by directly blocking the receptors for progesterone, the hormone required to sustain pregnancy. Levonorgestrel, the most widely used emergency contraceptive, acts as a potent synthetic progestogen.

Selective progesterone receptor blockers such as mifepristone and ulipristal acetate can act both by inhibiting or delaying ovulation and by interfering with the embryo’s implantation process, depending on the time of administration.

When administered in the early stages of the fertile window of the menstrual cycle—between 5 and 3 days before ovulation—its primary mechanism seems to be to inhibit or delay ovulation, thus preventing fertilization and subsequent embryo formation.

However, if administered in the late phase of the fertile window—between 2 and 3 days before ovulation and the day of ovulation itself—this capacity largely disappears; nevertheless, due to its anti-implantation effect, it maintains its efficacy in reducing pregnancy rates.

Accordingly, when administered just after the LH surge or after ovulation, oocyte release occurs; the contraceptive effect of inhibiting ovulation therefore fails to explain the method’s sustained efficacy.

On the other hand, mifepristone has been shown to have effects on the endometrium through binding to progesterone receptors in the endometrial tissue, thereby inhibiting the action of this hormone. This impairs the normal secretory transformation of the endometrium required for the “implantation window”.

Furthermore, it disrupts endometrial receptivity due to asynchronous development between the endometrial glands and stroma, altering the expression of cellular receptivity markers (such as integrins and pinopodes). As a result, the uterine cavity becomes hostile to blastocyst adhesion.

At high doses (such as those used in chemical abortion), massive blockade of progesterone receptors causes breakdown of the uterine decidua, rupture of the endometrial blood vessels, and shedding of the mucosal lining. At this dose level, this action severely impairs implantation or interrupts post-implantation embryo development by detaching the gestational tissue, causing death of the embryo.

Bioethical assessment

The drugs and devices used in emergency contraception are controversial because of the mechanism of action by which they prevent pregnancy. However, regulatory bodies such as the European Medicines Agency and the US Food and Drug Administration, based on the information provided by the manufacturing laboratories, have adopted the approach that the only mechanism of action of these drugs is to prevent or delay ovulation, thus preventing fertilization and pregnancy.

As we have previously reported though, there are studies that refute this claim. While it is true that they have a certain ability to inhibit or delay ovulation, the mechanism of action that contributes most significantly to their effectiveness in preventing pregnancy is their ability to interfere with the implantation of the embryo in the endometrial decidua.

This interceptive activity, which ultimately ends the life of the early embryo, is exerted mainly if the drug is administered from 2-3 days prior to ovulation, at which point the ovarian follicle has reached a size where the drug can no longer stop its progression to rupture and oocyte release.

This phenomenon is shared by both formulations containing levonorgestrel (progestogen) and those containing ulipristal acetate and mifepristone (anti-progestogens), with the added concern that the latter continue to exert their anti-implantation activity if administered after ovulation. Their ability to block progesterone receptors prevents this hormone from performing its supportive role during early pregnancy, leading to loss of the embryo.

These early abortions—defining abortion as termination of the embryo’s biological development at any stage of its progression—can be confused in many cases with delayed menses, which can be accompanied by bleeding and other symptoms.

The inclusion of mifepristone within the battery of drugs used in emergency contraception, should it be authorized, will further intensify the ethical debate regarding ending the life of the unborn child in its early stages of development, especially when this information is systematically withheld from users, both in patient information leaflets and by the regulatory bodies that are reluctant to include the anti-implantation effect in the information provided.

Mifepristone has a greater capacity than ulipristal acetate to induce early abortion. Its molecular structure, which differs slightly from that of ulipristal acetate, has been observed in vivo to upregulate expression of epithelial estrogen receptor-β and progesterone receptor-B, while downregulating stromal vascular endothelial growth factor and surface molecules MUC1 and integrin αVβ3.

Its high affinity for glucocorticoid receptors seems to be behind its potent abortifacient effect, which exceeds that of ulipristal acetate. In vitro studies in three-dimensional models of cultured endometrial cells have shown that mifepristone, if administered immediately after ovulation, is highly effective in preventing embryo implantation. These findings support several studies previously conducted by Gemzell-Danielsson et al., which confirm its effects on the molecular architecture of the endometrium and the embryo.

It should be noted that mifepristone is not authorized as an emergency contraceptive in most countries, except for some such as Armenia, China, Cuba, Taiwan, Russia, and Vietnam, due precisely to its proven abortifacient activity.

The lack of legal protection afforded to the preimplantation embryo—leaving it vulnerable to practices such as elective abortion, embryo selection and disposal associated with assisted reproduction techniques, and research using surplus embryos from these techniques that entails their destruction—constitutes an attack on human life and dignity.

The mechanisms of action of contraceptives, particularly emergency contraceptives, seem to matter less and less to regulatory agencies when what is at stake is the life of the human embryo in its early stages of development.

To deny the ability of mifepristone, even at low doses, to interfere with implantation of the embryo in the endometrium is to ignore the available evidence regarding the mechanism of action of a drug with proven abortifacient efficacy.

Its anticipated approval as an emergency contraceptive will further increase the enormous plight of human embryos whose development is terminated when these drugs prevent their natural progression in the uterine endometrium.

Furthermore, failure to inform users of this mechanism also constitutes an attack on their freedom and right to know how these drugs act in preventing pregnancy and their ethical implications.