The Problem with Excluding Menstruating, Pregnant, and Breastfeeding Women from Research Trials
The lack of clinical drug testing on pregnant women has gotten more press than usual lately, due to the recent COVID-19 vaccine trials. But did you know that all women of reproductive age have been historically under-sampled in clinical trials? The inclusion/exclusion criteria for the recent Pfizer and Moderna COVID-19 vaccine clinical trials had specific exclusions for women of reproductive age: they neither tested on pregnant or breastfeeding women (going so far as to require proof of a negative pregnancy test), and required a commitment from all premenopausal women to use birth control.
But the exclusion of fertile and pregnant women from participating in drug trials should concern us. The vast majority of women will be pregnant someday and, a woman’s other health conditions do not simply vanish because she becomes pregnant, and neither (in most cases) does her need for treatment. Yet, while it is estimated that over half of pregnant women take prescription drugs, and that 64–90 percent of pregnant women take some sort of pharmaceutical drugs during pregnancy (both over-the-the-counter and prescription), there is a dearth of clinical evidence to prove the safety of using most of these drugs during pregnancy.
The birth control commitment is a common requirement of women in experimental drug and vaccine trials, and was not unique to the COVID vaccine trials. As in most other trials, the requirement was likely instituted for two reasons, one of which might be less obvious than the other.
The reasons behind the exclusion of fertile women in drug trials
The first, more obvious reason for requiring birth control use in study participants is in order to prevent pregnancy. Due to concerns for drugs affecting an unborn child, testing on pregnant women is ethically fraught (with good reason), although not impossible (more on this later).
The second, less obvious reason, is because hormonal birth control overrides a woman’s natural cycle, replacing her natural, monthly hormonal fluctuations of progesterone and estrogen with a constant, low-dose of synthetic hormones. Now why, you might wonder, would researchers want to do that?
The reason for the under-representation of women in clinical trials for drugs and vaccines largely stems from women’s procreative potential. Women’s menstrual cycles—and the hormonal fluctuations responsible for them—make women far more complicated than men, in terms of how experimental pharmaceuticals will react with women’s monthly changing body chemistry. The “leveling out” effect of birth control prevents a woman’s body from experiencing her monthly cycle, stopping her from ovulating and menstruating (that’s right, even if you have a monthly bleed on hormonal birth control, it’s not menstruation). And, without the monthly rise and fall of estrogen and progesterone, women (and their immune systems) become “easier” to study because there are fewer changing variables. They become more like men, in a sense.
Women’s menstrual cycles and immune systems are more intimately intertwined than many people realize. In fact, this interconnection of menstrual cycles and immune systems is borne out very clearly in things like the greater prevalence of autoimmune disorders in women. Researchers have long known that women’s cycles tend to “interfere” with trials neatly designed around bodies and immune systems that are not subject to monthly hormonal fluctuations (like men’s).
The bodies of women on hormonal birth control are not subject to the cyclical phases of the natural cycle of fertility, nor the ebb and flow of estrogen and progesterone across that cycle. To thoughtfully study women—acknowledging that their cycles can impact results, and designing studies accordingly—is logistically and financially more difficult than testing on men or women on birth control.
For the two reasons described above, women have historically not been studied en masse in clinical trials. This even includes drugs intended to treat diseases that disproportionately affect women. It’s also the reason why so many health issues that disproportionately affect women (like autoimmune diseases), or only affect women (like obstetric and gynecological conditions), or affect women in different ways than men (like heart attacks) are either “orphans” in the drug research landscape, or go unrecognized and undiagnosed by many doctors. Disturbingly, the lack of significant testing on women in clinical trials is also why an estimated 80 percent of drugs that are eventually taken off the market are removed because of adverse side effects in women.
Only very recently have things begun to change meaningfully in this regard—that is, only in the last few decades. And yet, even though inclusion of women in clinical trials is slowly becoming more equitable, the inclusion of fertile, pregnant, or breastfeeding women continues to lag far behind. And because this includes a fair proportion of what women currently are or will someday be, the exclusion of such women from clinical research continues to prove extremely problematic.
Ethical issues with testing on pregnant and breastfeeding women
That isn’t to say that there aren’t legitimate concerns with how experimental pharmaceuticals will impact a pregnancy, should one occur, as well as whether experimental compounds can pass through breast milk, and how they would affect a nursing child. It is right and good that we should exercise caution when considering how experimenting on mothers could impact the health and well being of their babies, in the womb or outside it.
The legacy of thalidomide, a sleep aid that caused limb abnormalities for babies born in the 1960s, has left its mark, and has made drug and vaccine testing on pregnant women all but a nonstarter. And while drugs taken while pregnant pose birth defect risks and are not a small issue, swinging the pendulum toward the opposite extreme of complete exclusion of pregnant women is also highly problematic. Now researchers are fearful of the ethical and legal implications of testing not only on known pregnant women, but on fertile women who could potentially become pregnant, to the point of requiring hormonal disruption (via prescribed contraceptives) from study participants.
Also problematic is how many pregnant and breastfeeding women require treatment through pharmaceuticals for various conditions, but must make these health-care choices without the benefit of clinical data.
The dawn of the COVID-19 pandemic brought this issue to the fore. A study published in the American Journal of Obstetrics and Gynecology found that pregnant women were “70 percent more likely to have been infected with the Covid-19 coronavirus,” and the CDC states that pregnant women are at increased risk for severe COVID-19 illness and death compared to non-pregnant women of reproductive age. These women also experience increased risk of preterm delivery and pregnancy loss.
Given these sobering facts, you might be wondering, what is the CDC’s recommendation for COVID vaccination in pregnancy? “People who are pregnant and part of a group recommended to receive the COVID-19 vaccine may choose to be vaccinated,” says the CDC. The World Health Organization (WHO) first stated it does not recommend the vaccine for pregnant women, before reversing its course to say it may be beneficial and is up to the woman and her doctor. On the WHO webpage for the Pfizer-BioNTech vaccine, it states that “WHO does not recommend the vaccination of pregnant women at this time,” while on its webpage discussing the similar Moderna vaccine, the WHO states, “Nevertheless, based on what we know about this kind of vaccine, we don’t have any specific reason to believe there will be specific risks that would outweigh the benefits of vaccination for pregnant women.”
So what is a pregnant mom who desires safety from COVID-19 to do when faced with this lack of definitive, evidence-based recommendations on available vaccines from the most influential public health authorities in the world? Interestingly, many pregnant healthcare workers, in particular, have chosen to get the vaccine, despite the lack of testing on pregnant women. They have shared their stories on social media and the news, and some have faced backlash for getting vaccinated while pregnant. According to Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, about 20,000 pregnant women have been vaccinated for COVID-19 with no “red flags” so far. And in early March, the CDC released information from its V-Safe vaccine-user survey, noting that 250 pregnant doctors and teachers who received the vaccine have given birth since, with no demonstrated risks of miscarriage, pregnancy complications such as preeclampsia, or birth defects. Still, American College of Obstetricians and Gynecologists (ACOG), the Society of Maternal-Fetal Medicine, and the CDC remind women that given the limited information available, pregnant women may in good conscience choose to receive the vaccine and, women in good conscience may choose not to—it is up to each woman.
What this all means is that pregnant women are still being tested on, in a sense. It is just not within a controlled, clinical research environment, where these women and their babies can be closely monitored (and quickly treated) for any potentially dangerous effects. Women all over the world are losing out on vital information, and making decisions based on inferences, rather than on data specific to them. That is why Pfizer-BioNTech recently started enrolling pregnant women in COVID vaccine clinical trials, an announcement that was met with applause by members of ACOG and other professional health-care organizations.
The situation surrounding COVID-19 and its vaccines exemplifies the need for greater inclusion of women who are pregnant or breastfeeding in drug and vaccine testing done in an ethical manner, taking into consideration that two patients are being studied in such instances. Animal studies can offer imperfect, but important insight into the effects of experimental vaccines and drugs on reproduction. Where animal studies have limitations, testing on donated human tissues and lab-grown cell cultures may help complete the picture, but it is crucial that these tissues and the origins of cell cultures also be ethically obtained.
And as with any new drug or vaccine, the potential benefits must outweigh the risks; the benefits of testing an experimental drug or vaccine on pregnant women must be carefully weighed against any of the potential risks to both women and their unborn children, with the realization that not every drug or vaccine will necessarily pose a benefit proportionate to the risk to justify experimentation in this complex patient group. Yet another consideration is compensation for participation in clinical trials, which can be justified under some circumstances, but must not be so substantial as to be coercive of struggling mothers looking to make ends meet any way they can.
The additional requirements and nuanced ethical considerations needed to test upon pregnant women are no doubt more costly and take more time than choosing to ignore this complex group entirely—but they must be considered.
Women on birth control represent many women—but not all women
Most would agree that asking women to avoid pregnancy during drug or vaccine trials has some grounding in ethical concerns over the effects of an experimental drug on an unborn child (although researchers should be informed that hormonal contraceptives are by no means the only effective way for women to avoid pregnancy). However, requiring hormonal birth control for the purpose of eliminating the variable of women’s cycles—while it may make trials/studies cheaper and less logistically complicated—is almost entirely without ethical merit. In fact, the justification for leaving out fertile, naturally cycling women, simply because they make things more “complicated,” suggests ovulating, menstruating women are not people deserving of equal health information.
For women, our fertility and our immune systems are uniquely interconnected; after all, in order for the human race to continue, female bodies have to accommodate a select group of foreign materials. From sperm to embryos to fully formed babies, female immune systems have to be able to selectively “ignore” certain foreign items, rather than going on the attack. While this is a crucial feature of female immune system, it is often treated as a bug. And because of this perception of our cycles (linked as they are to our immune systems) as overly complicated variables that pharmaceutical companies have long ignored, women are too often left without good information on how drugs and vaccines will impact women who experience natural cycles of menstruation and ovulation.
The lack of inclusion of women who menstruate and ovulate naturally, who breastfeed, and are pregnant represents a wide gap in representation for numerous women. In particular, the required contraception commitment in the COVID-19 trials is another glaring example of how birth control is used to make women more like society’s normative body—which is to say, the male body. The unspoken message here is that women’s natural bodies are not invited to experience the same benefits of science as others. Bodies that do not have a monthly cycle and cannot become impregnated are easier for science to study, easier to rely upon in the workplace, and so on, with the result being that bodies that menstruate, ovulate, and carry life are often left by the wayside, left to fend for themselves.
