Is APR therapy safe for women?

Physicians have safely used progesterone in reproductive medicine since the late 1970’s.1 Progesterone is a critical regulator of normal human female reproduction2 and has been shown to reduce the risk of premature birth.3 The American Society for Reproductive Medicine reports no increased risk from using progesterone in early pregnancy.4

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.”5 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.”6 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.

The 2023 Progesterone-After-Mifepristone—pilot for efficacy and reproducibility (PAMper) clinical trial by Turner et al. found that “there was no major hemorrhage or other clinically significant adverse events.”7 The 2018 case series study 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).8 The ACOG practice bulletin 225 states that “No evidence exists to date of a teratogenic effect of mifepristone.”9

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. 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 ↩︎
  2. 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 ↩︎
  3. 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 ↩︎
  4. 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 ↩︎
  5. 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. ↩︎
  6. 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. ↩︎
  7. 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. ↩︎
  8. Delgado, George, Steven J. Condly, Mary Davenport, Thidarat Tinnakornsrisuphap, Jonathan Mack, Veronica Khauv, and Paul S. Zhou. 2018. “A Case Series Detailing the Successful Reversal of the Effects of Mifepristone Using Progesterone.” Issues in Law & Medicine 33 (1): 21–31. https://pubmed.ncbi.nlm.nih.gov/30831017/ ↩︎
  9. “Medication Abortion Up to 70 Days of Gestation.” 2023. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/10/medication-abortion-up-to-70-days-of-gestation ↩︎