Is APR therapy safe for women?

Mifepristone is a progesterone antagonist. It binds more aggressively to uterine progesterone receptors than progesterone but does not activate the receptor. The action of mifepristone is an example of competitive inhibition which is the ability of one chemical substance (e.g., mifepristone) to inhibit the effect of another (e.g., progesterone) by competing with it for binding (e.g., uterine progesterone receptor binding). The primary effect of mifepristone in medication abortion is to cause a separation of the decidua basalis from the trophoblast, which results in the death of the embryo.3 

Abortion Pill Reversal increases the mother’s progesterone concentration levels. Increasing progesterone concentration improves the likelihood of progesterone and uterine progesterone receptor (PR) binding thus reversing the effects of mifepristone. Progesterone activates uterine progesterone receptors, promotes placental development, prepares the uterus for embryo implantation,1 and inhibits uterine contractions.2 

Progesterone Safety

Physicians have safely used progesterone in reproductive medicine since the late 1970’s.3 Progesterone is a critical regulator of normal human female reproduction4 and has been shown to reduce the risk of premature birth.5 The American Society for Reproductive Medicine reports no increased risk from using progesterone in early pregnancy.6 The UK National Institute for Health and Care Excellence states that progesterone use during pregnancy is safe.7

Abortion Pill Reversal Safety

The 2023 Progesterone-After-Mifepristone—pilot for efficacy and reproducibility clinical trial by Turner et al. found that “there was no major hemorrhage or other clinically significant adverse events.”8 The 2018 Abortion Pill Reversal case series by Delgado et al. found that there was no increase in birth defects after receiving progesterone treatment (2.7 percent) as compared to the birth defect rate in the general population (3 percent).9

Creinin Study – Safety

The American College of Obstetricians and Gynecologists (AGOG) warns that “limited available evidence suggests that use of mifepristone alone without subsequent administration of misoprostol may be associated with an increased risk of hemorrhage.”10 The only evidence cited by ACOG is a 2019 placebo-controlled, randomized APR trial for women who were seeking an abortion. Mitchell Creinin, M.D., a critic of APR therapy and compensated advisor to Danco, a distributor of mifepristone, led the study.

The study enrolled twelve women seeking an abortion. Ten completed the study. Five women ingested 200 mg mifepristone followed by 200 mg oral progesterone. Five women consumed 200 mg of mifepristone, followed by a placebo. None of the women received misoprostol. The study scheduled a two-week follow-up where the women received an ultrasound. If the ultrasound indicated they had an ongoing pregnancy, then a clinician completed their abortion surgically.

In the published journal article for this study Dr. Creinin states that the side effects of APR treatment and placebo are no different. 

“First, patients who receive high dose oral progesterone treatment do not experience side effects that are noticeably different than placebo.”11 Mitchell Creinin, M.D.

The researchers stopped the study early because three of the ten women experienced heavy vaginal bleeding. However, it is essential to understand which women experienced complications. One woman in the progesterone group visited the emergency room but was found to be completing her abortion. She did not require any medical treatment. Two women in the placebo group visited the emergency room and required emergency surgeries to complete their abortion. One of these women in the placebo group also needed a transfusion due to the severity of her hemorrhage (see figure).

The authors claim that they had to stop the study due to complications of the abortion reversal process. However, the women who received progesterone did not require any medical treatment. Only the women who did not receive APR therapy needed medical intervention. Thus, the ACOG warning of hemorrhage risk is misleading because it implies that APR therapy is unsafe when, in fact, women who used only mifepristone needed emergency intervention. Doctor Creinin’s conclusion underscores this observation:

“Patients in early pregnancy who use only mifepristone may be at high risk of significant hemorrhage” Mitchell Creinin, M.D.

Creinin Study – Efficacy

The Creinin study also showed that APR treatment is effective. Only two out of five women (40 percent) had ongoing viable pregnancies in the placebo group. However, four of five patients (80 percent) receiving progesterone had an ongoing viable pregnancy. Thus, the Creinin study provides evidence that APR is effective. Refer to “What is the continuing pregnancy rate after APR?” for additional information.

NEXT: What are the three outcomes after mifepristone ingestion?

  1. Coomarasamy, A., H. Williams, E. Truchanowicz, P. T. Seed, R. Small, S. Quenby, P. Gupta, et al. 2015. “A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.” New England Journal of Medicine 373 (22): 2141‐2148. https://doi. org/10.1056/NEJMoa1504927. ↩︎
  2. Scarpin, Katherine M., J. Dinny Graham, Patricia A. Mote, and Christine L. Clarke. 2009. “Progesterone Action in Human Tissues: Regulation by Progesterone Receptor (Pr) Isoform Expression, Nuclear Positioning and Coregulator Expression.” Nuclear Receptor Signaling 7 (December): e009. https://doi.org/10.1621/nrs.07009. ↩︎
  3. Di Renzo Gian Carlo, Tosto Valentina, Tsibizova Valentina. 2020. “Progesterone: History, Facts, and Artifacts.” Best Practice & Research Clinical Obstetrics & Gynaecology, Progesterone In Obstetrics And Gynaecology 69 (November): 2‐12. https://doi.org/10.1016/j.bpobgyn.2020.07.012 ↩︎
  4. Scarpin Katherine M., Graham J. Dinny, Mote Patricia A., Clarke Christine L. 2009. “Progesterone Action in Human Tissues: Regulation by Progesterone Receptor (Pr) Isoform Expression, Nuclear Positioning and Coregulator Expression.” Nuclear Receptor Signaling 7 (December): e009. https://doi.org/10.1621/nrs.07009 ↩︎
  5. Di Renzo Gian Carlo, Tosto Valentina, Tsibizova Valentina, Fonseca Eduardo. 2021. “Prevention of Preterm Birth with Progesterone.” Journal of Clinical Medicine 10 (19): 4511. https://doi.org/10.3390/jcm10194511 ↩︎
  6. ASRM. 2008. “Progesterone Supplementation during the Luteal Phase and in Early Pregnancy in the Treatment of Infertility: An Educational Bulletin.” Fertility and Sterility 89 (4): 789-792. https://doi.org/10.1016/j.fertnstert.2008.02.012 ↩︎
  7. NICE. 2021. “Ectopic Pregnancy and Miscarriage: Diagnosis and Initial Management, [C] Progestogens for preventing miscarriage.” https://www.nice.org.uk/guidance/ng126/evidence/evidence-review-c-pdf-10889099534. ↩︎
  8. Turner, Joseph V., Deborah Garratt, Lucas A. McLindon, Anna Barwick, and M. Joy Spark. 2023. Progesterone after Mifepristone: A Pilot Prospective Single Arm Clinical Trial for Women Who Have Changed Their Mind after Commencing Medical Abortion. Journal of Obstetrics and Gynaecology Research, November, jog.15826. https://doi.org/10.1111/jog.15826. ↩︎
  9. Delgado, George, et al. “A Case Series Detailing the Successful Reversal of the Effects of Mifepristone Using Progesterone.” Issues in Law & Medicine, vol. 33, no. 1, 2018, pp. 21–31. https://pubmed.ncbi.nlm.nih.gov/30831017/. ↩︎
  10. Medication Abortion Up to 70 Days of Gestation. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/10/medication-abortion-up-to-70-days-of-gestation. ↩︎
  11. Creinin, Mitchell D., et al. “Mifepristone Antagonization With Progesterone to Prevent Medical Abortion: A Randomized Controlled Trial.” Obstetrics & Gynecology, vol. 135, no. 1, Jan. 2020, p. 158. journals.lww.com, https://doi.org/10.1097/AOG.0000000000003620. ↩︎