Excerpts from Democrats for Life of Colorado's President, Thomas Perille MD, to the Colorado Medical, Nursing and Pharmacy Boards which walks through the evidence in support of abortion pill reversal:
Members of the Colorado Medical Board, Board of Nursing and Board of Pharmacy,
With the signature of SB23-190 into law by Governor Polis, you have been asked to evaluate a specific medical intervention to determine if it is a “generally accepted standard of practice”. As someone who has reviewed several cases for the Medical Board to determine if a provider deviated from accepted community standards, I would like to provide my perspective based on a careful review of the evidence.
So called “abortion pill reversal” (APR) protocols were developed in response to the rare situation in which a woman pursuing a medication abortion regrets her choice after taking the first pill, mifepristone, but before taking the second drug, misoprostol, in the two-drug regimen. The purpose of APR is to mitigate the abortifacient effects of mifepristone and increase the odds of a continuing pregnancy.
It should be no surprise that some women harbor significant ambivalence about their abortion decision. The Turnaway Study (page 126) reported that within one week of being denied an abortion, 35% of women no longer wished to have an abortion. In 2022, 31 Colorado women (approximately 0.4% of medication abortion patients) sought to pursue APR through the most prominent organization dedicated to APR – Heartbeat International .
As a matter of principle, clinicians routinely honor a patient’s right to withdraw consent from any medical or surgical intervention. Therefore, addressing the needs of women who change their mind about their medication abortion should not be controversial.
Mifepristone was developed in the 1980s as a progesterone antagonist. It is one drug in a whole class of Selective Progesterone Receptor Modulators (SPRMs). The drug binds progesterone receptors twice as avidly as progesterone. In the early 1990s it was studied primarily as a means to terminate early pregnancy .
APR is based on the premise that mifepristone competition for the progesterone receptors is a dynamic process. By flooding the receptors with natural progesterone, one could theoretically overcome the binding of mifepristone to progesterone receptors and reduce its abortifacient effects.
Some abortion researchers have questioned the potential for high dose progesterone to significantly impact mifepristone’s binding to progesterone receptors. They cite the observation that women treated with mifepristone for abortion have high progesterone levels and therefore it would seem implausible that more progesterone would make any difference. They also point to a study of the very potent progestin contraceptive implant, etonogestrel. When it was administered immediately after the ingestion of mifepristone, it did not reduce the percentage of successful medication abortions.
There are animal and human data to counter these arguments. Early in the research on mifepristone it was recognized that its binding to the progesterone receptor could be reduced by increasing progesterone levels. In a study in pregnant rats, those that received mifepristone only had 33% of pups survive. In contrast, those that were given progesterone with mifepristone, 100% of pups survived. A second study in rats demonstrated a clear progesterone mediated reversal of mifepristone induced pregnancy termination in a rat model. As early as 1991, a medical review of mifepristone use in medication abortions recognized that the mifepristone binding to the progesterone receptor could be reversed by adding progesterone. Collectively, these provide proof of principle for APR.
The fact that progestin can interfere with the action of a SPRM in humans is a documented concern outside of mifepristone use for medication abortion. The FDA recommends that progesterone containing hormonal contraceptives not be administered within 5 days of taking the SPRM, ulipristal, so as not to reduce its effectiveness as a form of emergency contraception.
Compelling evidence that a progestin can specifically interfere with a mifepristone (and misoprostol) in a medication abortion was found during a large, randomized, multinational study of depot medroxyprogesterone acetate use as a post-abortive contraceptive. In this study, the administration of medroxyprogesterone in conjunction with the ingestion of mifepristone (Quickstart) was associated with a 400% increase in the odds of a continuing pregnancy compared to delaying the administration of medroxyprogesterone after a mifepristone/misoprostol abortion (Afterstart). While the absolute difference was small (0.9% to 3.6%), the results were statistically significant. Some researchers speculated that depot medroxyprogesterone acetate differs from other progestins, such as etonogestrel, because of its potency and rapid achievement of peak levels.
The first known use of high dose progesterone to mitigate the effects of mifepristone during the course of a medication abortion was in 2006 by Dr. Matthew Harrison. A desperate woman who immediately regretted her medication abortion decision sought his help. Based on the known mechanism of action and the record of safety using progesterone to treat miscarriages, he initiated a course of high dose parenteral progesterone. This resulted in the delivery of a healthy baby girl.
I would argue that even this early adoption of the APR concept met the criteria for a “generally accepted standard of practice” as defined by the Colorado Medical Board. The strategy was plausible based on the known mechanism of action of mifepristone – competitive inhibition of the progesterone receptor. Animal research supported the approach. The intervention was deemed safe in analogous OB indications (miscarriage prevention) at the time. And most importantly, the potential benefit - a life saved- justified an unproven intervention. The only alternative course of action was expectant management which would be anticipated to result in only a 20-40% chance of embryonic survival based on WHO data from 1997.
In 2012, the first case series utilizing progesterone to block the abortifacient effects of mifepristone was published. Four of six (66%) women who were administered parenteral progesterone after taking mifepristone carried their pregnancies to term. A second small case series in 2017 also demonstrated a 66% continuing pregnancy rate after administration of progesterone following mifepristone.
This compares to a historical rate of </= 25% for continuing pregnancy following the administration of mifepristone as a single agent abortifacient. This figure reflects a careful review of the literature in which documentation of ongoing pregnancy was required rather than the less specific term “incomplete abortion”. In other words, many early studies did not distinguish between residual pregnancy tissue which entailed the need for additional procedural intervention from a continuing pregnancy with a living embryo. More mifepristone abortions required surgical evacuation but many of these did not involve the persistence of a living embryo.
The largest case series was a retrospective compilation of patients treated with differing parenteral and oral high dose progesterone regimens within 72 hours of taking mifepristone. The study was reviewed and approved by an institutional review board. There were 547 women with analyzable outcomes and the overall rate of “reversal’ of mifepristone was 48%. Two regimens had the highest rate of reversal – those who received intramuscular progesterone (64%) and those that received the high dose oral regimen consisting of 400 mg bid for three days, followed by 400 mg qd for the first trimester (68%). The success of reversal was dependent on the gestational age – with the highest success rates at the longer gestational ages. The rate of birth defects in the women who received the APR regimen was 2.7% which was commensurate with the rate reported in the general birth population. The preterm delivery rate was only 2.7% which compares favorably with US average of 10%.
The series was criticized because all complications were not reported. This is a fair criticism but needs to be placed in perspective. The administration of progesterone to avert a threatened miscarriage had been employed for decades and found to be safe . For both women and babies, there is “no increase in risk of stillbirth, ectopic pregnancy, congenital abnormalities or adverse drug reactions” utilizing progesterone in a fashion analogous to APR. It has been proven effective in those women with threatened miscarriage and a history of one or more previous miscarriages.
During testimony on SB23-190 in the Colorado House on March 28 two experts in support of APR shared data relevant to the concerns regarding APR safety. Dr. George Delgado (recording at 5:46PM) reported that there were 150 women per month who contacted the Abortion Pill Rescue Network in 2022. All the reported complications were minor (dizziness, nausea, heartburn, injection site discomfort) and represented 0.5% of the 1800 patients. He also reported that there have been over 4000 live births to women who pursued the APR protocol. Dr. Brent Boles (recording at 9:45PM) who leads the Abortion Pill Reversal Services at Heartbeat International corroborated Dr. Delgado’s observations. He added that over 1000 physicians participate in the Abortion Pill Reversal Network including clinicians in Colorado.
One attempt was made to obtain randomized, placebo-controlled data regarding the efficacy of APR by Dr. Mitchell Creinin. The study randomized women seeking an abortion to mifepristone followed by progesterone vs. mifepristone followed by placebo. The study was terminated early because of severe hemorrhagic complications. Although the small sample size precluded drawing statistically significant conclusions, the results tracked with the previously reported case series. 80% of the women who received the progesterone had continuing pregnancies and only 40% of those who received placebo had ongoing pregnancies.
Abortion rights researchers have used the fact that the study was stopped early to cast aspersions on the safety of APR. However, a closer look at the results of the study might lead one to conclude the opposite – that for women changing their mind after taking mifepristone, utilizing progesterone per the APR protocol might be far safer than expectant management. Of the three women who had hemorrhage in the study, only the two women in the placebo group required surgical intervention and one of these also received a blood transfusion. One woman in the progesterone group was seen in the ED but did not require intervention for her completed abortion.
The fact that one woman who received progesterone per the APR protocol sought emergency department care should be unremarkable. Emergency Room utilization in the US following a medication abortion is significantly undercounted. Registry-based studies from other countries are more reliable sources for estimating the complication rates for medication abortion . A Finish study demonstrated a 15.6% hemorrhage rate following medication abortion. And a Canadian study revealed that 10.3% of women undergoing a medication abortion in the first trimester had an emergency department visit.
I recently attended a national meeting of the American College of Physicians in San Diego in which Dr. Eleanor Schwarz, Professor of Medicine and Chief, Division of General Internal Medicine at the University of San Francisco, stated that mifepristone is “safer than Tylenol”. This has been echoed by abortion rights researchers and mainstream media throughout the country. These same researchers implausibly claim that mifepristone followed by progesterone per APR is “dangerous”. There is no plausible scientific reason that mifepristone is safe, but when followed by progesterone, it becomes dangerous. The published and unpublished data coming from the Abortion Pill Reversal Network belies this characterization.
We are left with three observations:
1) There is moderate level (B) evidence that a progestin can mitigate the effects of mifepristone in humans.
2) There is low level (C), but multifaceted, evidence supporting the APR protocol to approximately double the odds of a continuing pregnancy following the administration of mifepristone.
3) There is moderate level (B) evidence that progesterone use is safe to use in a multitude of obstetric indications, including for threatened miscarriages.
Despite these observations, Dr. Mitchell Creinin (recording at 7:40PM), the principal medical expert who testified in favor of SB23-190 and against APR, called APR “medical fraud”. He ignored or dismissed the evidence which I have summarized for you. What he failed to disclose is that he is a paid consultant for Danco Laboratories, which is the distributor of mifepristone. Danco Laboratories has a vested interest in preserving the fiction that mifepristone is entirely irreversible.
Most of the others who testified in support of SB23-190 cited the fact that the AMA and ACOG oppose APR. However, neither the AMA nor ACOG are neutral arbiters of the evidence. Through AMA’s and ACOG’s position statements and the editorial content of the journals they sponsor, they make it clear that they are abortion rights advocates. ACOG’s “advocacy” statement regarding APR is outdated and incomplete. It more accurately reflects the abortion industry’s talking points and not the science behind APR.
What Dr. Creinin and other critics of APR also fail to acknowledge is that clinical recommendations and guidelines are often based on low level evidence. As much as we would like everything we do in medicine to based on double-blinded, placebo-controlled trials, the reality is that only a fraction of what is recommended, and what we do in practice reflects this level (A) of evidence. Cardiology is one of the most evidence-based specialties in medicine. Nonetheless, a recent analysis of their clinical guidelines demonstrated that 41.5% of their recommendations were based on low level (C) evidence.
Using a common recommendation/level of evidence framework , APR would be a Class 2a (Moderate) recommendation utilizing Level C-LD evidence. A 2a recommendation would be one that would support the wide adoption of the practice pending further trial data. There is virtually no other specialty area of medicine – not embroiled by abortion politics - in which a medical intervention, demonstrated to be safe, that resulted in a 50% or greater reduction in mortality based on low level evidence, would be outlawed by a legislative body.
The Handbook for BME Consultants (circa early 2000s) which I utilized to evaluate cases for the Medical Board indicated “the only question you will be asked to answer is whether the licensee’s action or lack of action was or was not below the prevailing standard of care. The standard of care is defined as “…that degree of care, skill, and diligence that is used by ordinarily careful physicians and surgeons in the same or similar circumstances in the community.” It goes on to say, you should “determine how a prudent practitioner might have treated the patient differently”.
I would argue that any clinician who is faced with a woman who has begun, but not completed, the two-drug medication abortion regimen and who regrets her decision and wants to save her baby, should be obliged to offer progesterone per the APR protocol. The potential benefit (a life saved) far outweighs the miniscule risk of administering progesterone (benefit>>>risk). The only alternative – expectant management – is associated with a much poorer outcomes and potentially worse safety - twice the embryo/fetus mortality and a possible greater risk of hemorrhage for the woman.
Thank you for your consideration.
Thomas J. Perille MD FACP FHM
President, Democrats for Life of Colorado