On June 24, 2022, in Dobbs v. Jackson Women's Health Organization, the United States Supreme Court effectively overturned Roe v. Wade, which since 1973 has given women in America federal protection over their constitutional right to terminate a pregnancy. The American College of Obstetricians and Gynecologists1 (ACOG), the Society for Maternal Fetal Medicine,2 the American Medical Association,3 the American Academy of Pediatrics,4 and many other medical organizations condemned the decision unequivocally, citing the known safety of abortion, concerns about widening health care disparities, and the violation of the doctor–patient relationship.
Abortion is extremely common, with 1 in 4 women requiring one in their lifetime, worldwide.5 There are 2 methods for pregnancy termination, surgical (or in-office procedures) and medical (or at-home management). Both abortion methods are safe, with the risk of dying from an induced abortion of 0.6 in 100,000 procedures.6–8 Data from the United States show that the risk of dying from a full-term pregnancy and childbirth is 14 times higher than the risk of dying after a legal abortion,6 and maternal mortality is higher among African American women compared with Caucasian ones.9 Estimates indicate that after a total abortion ban in the United States, maternal mortality will increase by 21%, with increases as high as 33% for black women.10
Restrictive abortion laws are detrimental for maternal and infant health in several ways. They undermine the quality of medical advice provided to patients; increase the risk of unsafe abortions and subsequent complications; enhance psychological distress; heighten the risk of postpartum depression; create more emotional and socioeconomic hardship; and restrict the emotional and financial resources to children compared with the situation when a woman is ready to give birth and able to support a child.11–14 After House Bill 2 was enacted in Texas in 2013, abortion facilities fell from 41 to 19, and the limitations placed on women accessing abortion services led to a 25% increase in abortions occurring at ≥12 weeks of gestation during the year following its implementation, compared with the preceding year.15
Approximately 70,000 women die of unsafe abortions annually and an additional 5 million suffer temporary or permanent disability, making unsafe abortions one of the most common causes of maternal mortality.16–18 Countries with the least restrictive abortion laws, such as several European countries, where abortion is legal and the rate of contraceptive use high, have lower abortion rates and fewer adverse outcomes related to abortions. By contrast, countries with more restrictive abortion laws, such as those in Latin America, Africa, and the Caribbean, have higher abortion rates with less safe procedures. Reports from several countries confirm that more restrictive abortion laws do not lead to fewer abortions, but to more unsafe abortions and to more maternal deaths.14,16,17,19–23
In 2018, >92% of the abortions in the US were performed in the first 13 weeks of pregnancy, in part because of access to medical abortion.24 Medication abortion has become increasingly popular in the United States and many other countries, even when surgical abortion is available.25,26 It was used in 31% of abortions in 201427 and in almost 54% of the abortions conducted at ≤9 weeks in 2019.28 Despite its prevalence, mifepristone has been controversial ever since its approval by the US Food and Drug Administration in 2000. For example, a bill in Oklahoma, which was not enacted, would have banned its prescribing, dispensing, and distribution.29 Laws in over 30 states limit mifepristone prescribing to physicians, even though nonphysician practitioners prescribe other medications with similar safety profiles.29 In Texas, a law went into effect in December 2021, limiting the use of mifepristone and misoprostol to the first 7 weeks of a pregnancy, despite FDA approval to 10 weeks. The use of mifepristone is also the most effective regimen recommended by ACOG for treating early pregnancy loss and thus this law creates significant hurdles for women and the health care providers assisting them, in addition to making abortions more challenging.30,31
Mifepristone was also approved by the FDA in 2012 for the treatment of Cushing syndrome in patients that are not candidates for surgery or have not achieved remission after surgery,32 and is currently the only glucocorticoid receptor antagonist approved for this condition.33 The FDA approval for this use for mostly based on the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the treatment of endogenous Cushing Syndrome) clinical trial, which showed that 60% of patients with hyperglycemia reached their glycemic endpoint, 38% of the patients had a decrease in their diastolic blood pressure, and 87% of patients had an improvement in clinical status.33,34 The benefit of mifepristone in Cushing Syndrome is because of its ability to bind the glucocorticoid receptor, by an affinity about 18-times higher than that of cortisol, and block the activity of cortisol.35 This application was first demonstrated in 1985, in a patient with Cushing syndrome as a result of ectopic ACTH secretion.36
AREAS OF UNCERTAINTY
Use of mifepristone and misoprostol for second trimester abortion
Worldwide, about 10%–15% of abortions occur during the second trimester.37,38 In the United States, they can be performed medically or surgically. Although the combination of mifepristone and misoprostol is recommended for medical abortions during the second trimester, the consensus about the ideal combination regimen is unclear. ACOG recommends mifepristone 200 mg orally followed in 24–48 hours by misoprostol, 800 μg vaginally then 400 μg vaginally or sublingually every 3 hours for up to a maximum of 5 doses, or mifepristone 200 mg orally followed in 24–48 hours by misoprostol 400 μg administered buccally every 3 hours for up to a maximum of 5 doses.39
Use of mifepristone and misoprostol in the third trimester.
The Society of Family Planning and ACOG do not have recommendations for medical management of labor induction for termination or fetal demise above 28 weeks as it does for gestations below this cut-off. Further research is needed to arrive at specific recommendations.
Leiomyoma, a frequent steroid hormone-dependent benign tumor of the uterus of unknown etiology that has estrogen and progesterone receptors, occurs in up to 70% of the women of reproductive age. The affected individuals present with pain, menorrhagia, and subfertility because of the distortion of the uterus. This condition is a frequent indication for surgical intervention among those of reproductive age.40–43 Although hysterectomy is the definitive treatment, myomectomy is an alternative for those who desire to preserve their uterus, and medical approaches are also of great interest.41,44 Several pieces of evidence indicate that progesterone may be involved in the pathogenesis of leiomyoma, making antiprogestins, such as mifepristone, an attractive therapeutic option.43 Various dosages of mifepristone have been used in different studies, and 10–20 mg/d seems to provide the most benefit, and higher doses increased the risk of adverse effects, such as hot flushes, elevated aspartate aminotransferase and alanine aminotransferase levels, endometrial hyperplasia, and antiglucocorticoid effects.41–43,45 Although mifepristone reduces fibroid volume and the size of the uterus, the slow regrowth of the tumor has been reported after treatment discontinuation.32,46,47 A prospective placebo-controlled trial of 30 women found that 50 mg mifepristone every other day for 3 months led to a significant decrease in the total leiomyoma volume, significantly decreased bleeding days, and improved serum hemoglobin.44 In an open-label cohort study of adult women presenting with at least moderately severe symptoms from leiomyoma, 2.5 mg (ultra-low dose) oral mifepristone for 6 months led to a 11% decrease in uterine volume and improved symptoms and the quality of life.48 A randomized controlled trial of 100 women who received 5 or 10 mg of oral mifepristone daily for 3 months showed significant reductions in the uterine size and symptomatic improvement after 90 days of treatment. Based on these data, the authors concluded that the 5 mg regimen led to an improvement comparable with the 10 mg regimen.49 In a double blind, randomized clinical trial, 5 mg oral mifepristone daily for 3 months led to a >28% decrease in the fibroid volume along with symptomatic improvement, whereas the placebo group had a 1.8% increase in fibroid volume.45 A meta-analysis of 11 randomized controlled trials, which enrolled 780 premenopausal women with symptomatic uterine leiomyomas, found that 2.5–25 mg/d of mifepristone administered for 3–6 months significantly reduced the uterine volume and alleviated symptoms. Based on these results, the authors recommended 2.5 mg/d mifepristone for 3–6 months.50
Mifepristone in a politicized climate
All aspects of reproductive health, including sex education and contraception, have been extensively politicized in the United States, and this is particularly true for abortion,51–53 for which laws that restrict its availability were referred to as political football.5 In the post-Roe era, state laws that ban or restrict abortion fail to distinguish between medical and surgical abortion and it is anticipated that securing and using abortion medication will carry the same legal risks as performing surgical abortion.54 The magnitude of the challenges that health care providers and patients with medical conditions distinct from pregnancy complications should anticipate, is illustrated by the recent report of a pharmacist in Texas who required speaking directly to a prescriber on the phone before filling a misoprostol prescription for miscarriage management; a pharmacist who refused to fill a methotrexate prescription for a patient with an ectopic pregnancy55; and methotrexate treatment being discontinued in patients with rheumatoid arthritis and lupus.56,57
In September 2020, 21 US senators requested that the FDA remove mifepristone from the market.58 Even more troubling than the politicization aspect is that their letter used inaccurate medical arguments, such as mifepristone is a “deadly pill” and an “imminent hazard to public health,” deplored that mifepristone was “politically rewarded with an accelerated approval process,” and underscored that “pregnancy is not a life-threatening illness”. This, even though between September 2000, when mifepristone was approved, and December 2018, only 0.00003604 women per year have died (24 of 3.7 million women).59 The availability of mifepristone will be particularly challenging for women living in states that ban abortion from the moment of fertilization, such as Oklahoma, where in May 2022 the Governor signed into law a bill that bans abortions from the moment of conception.60
A topic that requires immediate attention is the need to increase education and awareness among politicians on medical topics, particularly with reproductive health. A 2017 study that conducted semistructured interviews with state legislators and their aides about abortion-related decisions reported that they could not find one instance where a legislator formed or changed an opinion based on scientific evidence, but they referred to selected scientific facts to justify their claims. Rather than examining the quality of the research, respondents tended to accept evidence from their own trusted sources.61
The wealth of data that provide details about a person's location, movements, purchase history, and even intentions intensify the politicization of abortion and have become a major consideration in the post-Roe era. In the context of the restrictions to safe and legal abortion, on June 30, 2022, the Health and Human Services Office of Civil Rights issued new guidelines to patients and providers to ensure access to safe reproductive services. These guidelines emphasize that privacy and secure health information are not protected by HIPAA rules when accessed from or stored on a cell phone or tablet. Furthermore, the guidelines stress the need to avoid giving permission to apps about a person's location.62 In this context, it is important to note that Latice Fisher, an African American woman from Mississippi, was prosecuted in 2017 after a stillbirth at approximately 36 weeks, when she admitted to hospital staff that she could not afford taking care of more children. In data obtained from her phone, police found that she had searched for mifepristone and misoprostol and purchased misoprostol after an online search. She was charged with second-degree murder, even though there was no evidence she took the pills and was held in jail for several weeks. The murder charges were eventually dropped, but her ordeal lasted over 3 years.63,64
As part of the politicization of abortion and the dissemination of misinformation, it is important to recognize that since 2015, 9 U.S. states have introduced medically inaccurate legislation that require health care providers to inform women that medical abortions may be stopped or reversed.27 As of 2018, 4 states require abortion providers to inform women about this.65 A law in Arizona, passed in 2015 and repealed in 2016, required women to be counseled about the possibility of reversing a medical abortion.27 Moreover, a 2022 bill introduced in Ohio proposed requiring health care providers to supply patients with information about abortion reversal at least 24 hours before providing mifepristone.66 Lawmakers persist in these endeavors even though a study specifically designed to evaluate these reversal methods showed the methods are dangerous. In a randomized controlled trial, 12 participants were given mifepristone and daily progesterone. Three women experienced bleeding severe enough to require transport to a hospital. The trial was halted before goal recruitment because of these complications and the authors concluded that they could not estimate the efficacy of progesterone for mifepristone antagonization due to safety concerns.67 Bills in various states proposing to advise women about the possibility of reversing a medical abortion were called legislating without evidence.65 ACOG does not support prescribing progesterone to stop a medical abortion and considers such legislative mandates a “dangerous political interference” that “compromise[s] patient care and safety”.68
The restrictions and politicization of abortion, although always disastrous for individual and public health in general, could not have come at a worse time. The maternal mortality ratio in the United States doubled between 2000 and 2014, despite medical advances that were made during this period, even though it decreased in other high-income countries over the same period.69,70 Among high-income countries, the United States has the highest maternal mortality rates and is the only industrialized country in the world where maternal mortality rates continue to increase.71 In 2015, the United States ranked 33rd among the 46 developed countries in the Save the Children report, even though it had the highest health expenditure per capita worldwide.72 The rates are higher among minorities and women living in high-poverty areas.9,73 Similarly, infant mortality rates are higher among infants of single, Black, and low-income mothers than among infants of married, white, and moderate or high-income mothers.74
Abortion restrictions predominantly affect minorities, people affected by poverty, those with mental health diagnoses and lack of health care,75–78 and may worsen their economic outcomes.79 The recent changes in abortion legislation will compound existing racial, ethnic, and socioeconomic inequities,76 and the politicization of mifepristone will overwhelmingly affect those populations, given that in 2014, 75% of abortions occurred in poor or low-income women.80 The current climate of abortion restrictions only promises to worsen an already spiraling challenge and will accentuate and widen disparities and inequities, at a time when preventing them should be a nationwide priority in health care and beyond.
PubMed, Society of Family Planning, ACOG, the World Health Organization (WHO).
The recommended medication abortion regimen uses 2 medications, mifepristone and misoprostol. If mifepristone is unavailable, misoprostol can be used alone to induce abortion but with typically lower efficacy.81 Mifepristone was initially developed and received approval for use in France in 198882,83 and is now approved in the United Kingdom, Sweden, and about 60 other countries.84 Mifepristone received U.S. FDA approval for pregnancy termination up to 49 days in 2000. Because of its safety record and the evidence from its widespread use, the FDA approved the use of mifepristone for up to 70 days of gestation in 201685 and the WHO advocates for medical abortion up to 12 weeks.86
Mifepristone is a selective progesterone receptor modulator that binds to progesterone receptors with a higher affinity than progesterone, but does not activate them.87,88 Mifepristone causes several changes in a gravid uterus: it leads to structural changes in the endothelium of decidual capillaries, decidual necrosis, softening of the cervix, and increases uterine contractility and its sensitivity to prostaglandins.89–93 Misoprostol is a synthetic analog of prostaglandin E1 (PGE1) that is stable at room temperature and readily absorbed through mucous membranes.94 Misoprostol protects the gastrointestinal mucosa from damage caused by alcohol or nonsteroidal anti-inflammatory medications, such as aspirin.95 Initially, misoprostol was introduced and approved by the FDA to treat gastric ulcers in those who are long-term users of nonsteroidal anti-inflammatory medications, and is also approved for use in medical abortion, as part of a regimen that comprises mifepristone followed by misoprostol.85,96
A hurdle in the provision of medical abortion is the Risk Evaluation and Mitigation Strategy (REMS) requirement.97 The REMS stipulates that mifepristone be dispensed only in a clinic, medical office, or hospital, that dispensing clinicians must obtain certification to provide mifepristone, and that patients are required to sign an FDA-approved agreement before receiving the medication and be informed about the potential adverse effects.97 ACOG opposes the REMS requirement as mifepristone is extremely safe and effective and it substantially limits access particularly to communities facing barriers to care.98 During the COVID-19 pandemic, the FDA ruled that abortion pills could be mailed to patients.99 In December 2021, the FDA announced a permanent decision allowing the mailing of pills and the expansion of access to medical abortion pills in pharmacies.100,101
Contraindications to medical abortion include an allergy to one of the two drugs,85 long-term steroid use,102 ectopic pregnancy,102–104 chronic adrenal failure,102,105 pregnancy beyond 70 days (the WHO allows use up to 12 weeks or 84 days with a regimen comprising 200 mg oral mifepristone followed 36–48 hours later by 800 μg vaginal misoprostol, followed by subsequent 400 μg misoprostol doses, vaginally or sublingually, every 3 hours for a maximum of 4 doses),85,106,107 the presence of an IUD,102 inherited porphyria,102 severe asthma,105 coagulopathy or the use of anticoagulants,105,108,109 and severe anemia.108,109 Follow-up after a medical abortion can be performed in-office in 1 to 2 weeks with a transvaginal ultrasound, a serum beta human chorionic gonadotropin (HCG) level obtained the day of mifepristone with a repeat in 1 week, or a telehealth visit in 1 week and an at-home pregnancy test 4 weeks after misoprostol is taken. There is also the option of a “no-touch” (also known as “no-test” or “no-contact”) medical abortion, if a person does not have any significant medical history, does not have known risk factors for ectopic pregnancy, and has a reliable last menstrual period. This form of abortion involves evaluating the patient by phone or via telehealth and monitoring the symptoms by remote follow-up, with the omission of screening lab work and ultrasound.110
Internationally, these drugs have been used to provide safe abortion care to patients for many years without requiring direct contact. Several studies have examined the feasibility of screening patients by history alone and supplying mifepristone and misoprostol by mail.111–113 A prospective case-series study followed 406 patients who underwent medical abortions in the US, Mexico, and Moldova without an ultrasound or pelvic examination. Three patients (1%) experienced a serious adverse event; 2 of them were admitted to the hospital for heavy bleeding and were managed with aspiration; and 1 patient presented a persistent gestational sac 19 days after enrollment. However, most participants (90%) were satisfied with their experience.114 In a systematic review of 13 studies comprising 15 study groups, which examined the provision of medical abortion through telemedicine at ≤10 gestational weeks, the rates of complete abortion, continuing pregnancies, hospitalizations, and blood transfusion were similar to those of in-person abortion. Although the rates of surgical completion were higher than expected, acceptability was high among participants and clinicians.115
During the COVID-19 pandemic, reproductive health providers were faced with the challenges of a public health crisis and a time-sensitive medical issue, pregnancy. When the FDA removed the requirements to dispense mifepristone in-person in 2021, it cited several studies that provided evidence of the safety of no-touch abortion during the pandemic via telemedicine. In a study of 10 sites from 13 states and Washington, DC, comprising 1157 medical abortions performed via telehealth between 2016 and 2020, Chong et al116 reported that >50% of participants did not have a screening ultrasound with only 10 serious adverse events reported, including 5 blood transfusions (0.4%). A retrospective cohort study of 334 patients from Hawaii who underwent telehealth abortion between April and November 2020, 149 (44.6%) women had telemedicine with in-person pickup of mifepristone-misoprostol, 75 (22.5%) had telemedicine visits and received the medications by mail, and 110 (32.9%) had the traditional in-person visits. The success rates of complete medical abortion without surgical intervention were 96.8%, 97.1%, and 93.6%, respectively, for the 3 groups. The authors noted that the no-test protocol is safe with low rates of adverse events.117 A much larger study of 52,142 women in Great Britain examined outcomes before and after the no-test medical abortion protocol was implemented via telemedicine, in the wake of the COVID-19 pandemic, and found that the telemedicine group showed higher effectiveness, and the acceptability of telemedicine was also high.118
Self-managed abortion (SMA) is a termination of pregnancy performed by an individual outside of a formal health care system and has been observed across the world, even when there is access to safe and legal abortion.119–121 In the current environment of worsening abortion access, attention is turning to SMA.122 SMA can include self-sourcing and ingesting mifepristone and misoprostol, misoprostol alone, other medications or pills, herbs, toxic substances, or physical methods (ie, trauma or inserting foreign objects into the uterus).123 Approximately 7% of pregnancy-capable people in the United States have attempted SMA during their lifetime.123 Non-Hispanic Black and Hispanic women and those below 100% of the federal poverty line are more likely to have attempted SMA. Despite its long existence, research on the topic is lacking. A systematic review performed in 2019 analyzed 99 studies and found that those who chose SMA did so because of financial and logistical constraints and concern about their legal, emotional, and social safety.120 A method noted in nearly every study was ingestion of toxic substances, self-harm, or physical trauma, underscoring that people will go to extremes to terminate a pregnancy.120 Of those who used SMA, overall effectiveness and safety was noted across the studies and across various methods. In those who used mifepristone and misoprostol, high effectiveness was noted.120 In a study of 2797 women from the US who used abortion medication that was mailed to them between 2018 and 2019, and 95.5% felt that self-management was the right choice. Underscoring the safety of this method, less than 1% had complications, with 0.6% requiring a blood transfusion, and 0.5% receiving intravenous antibiotics.122
We are entering a new era of restricted access to reproductive health services. What is especially alarming is that the voices of medical experts, pregnancy capable people, and empiric scientific data are being actively ignored by elected officials. The US maternal health crisis, already a lethal embarrassment, will worsen as abortion restrictions are enacted across the country.
Unintended pregnancy and abortion are common, and they occur irrespective of the legality of abortion. Mifepristone and its use in medication abortion has been challenged since its introduction to the United States in 2000, but its safety continues to be confirmed in new ways. In the US, medical abortion has recently undergone a de-medicalization process. Initially, patients were required to have an ultrasound and blood work before medical abortion. During the COVID-19 pandemic, patients had a telehealth visit and may or may not have had an ultrasound. Studies examining those patients' outcomes showed the safety of a no-touch medical abortion process. Because of the overturn of Roe v. Wade, there is an increased focus on SMA and SMA using mifepristone and misoprostol will become more common in the post-Roe landscape. Based on the available data, providers and patients should feel comfortable with its use.
In addition to its utility in medical abortion, mifepristone has other applications. Areas for future study include its use for induction termination and fetal demise in the third trimester, and the management of leiomyoma and abnormal uterine bleeding. Explaining the mechanisms by which mifepristone decreases leiomyoma size and bleeding is a critical area for future studies. The use of mifepristone should not be fettered by arbitrary political interference uninformed by scientific evidence.
The authors acknowledge that not all people who have a uterus identify as female and those who identify as transgender, gender nonbinary, and those on the gender spectrum can experience pregnancy and abortion. The authors use the term woman for brevity's sake throughout the document and request the reader's patience and understanding.
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