Amanda, a nurse in Sacramento, and her husband have been trying to have a baby for more than two years. For the majority of that time, they've been attempting in-vitro fertilization. Last March, the pandemic shuttered most fertility clinics across the U.S., including hers, but treatment resumed in May, and, by December, Amanda, who is forty-one, was ready to transfer one of three frozen embryos into her uterus in the hopes of finally getting pregnant.
In the weeks leading up to the transfer, Amanda and her husband followed the news of promising vaccine-trial results and debated whether they should postpone the procedure so that she could get vaccinated. The large hospital system where Amanda works received an influx of covid-19 cases in the weeks around Thanksgiving. At one point, she estimated, more than a hundred of its three hundred and fifty beds were taken up by coronavirus patients. Like the rest of the nurses in her hospital system, she has been trained and is on call to work in dedicated COVID-19 units and in the intensive-care unit, potentially putting her at heightened risk of exposure. In the end, Amanda and her husband decided they couldn't wait any longer to become parents, and went ahead with the transfer.
A few days before the procedure, Amanda received an e-mail from hospital administrators saying that the vaccine would be distributed that week. She felt she had been forced to make an impossible choice: taking a vaccine that has not been tested on pregnant women and risking harm to a potential pregnancy, or forgoing the vaccine and the protection it offers. "What if I should have waited? What if I do get pregnant and I get COVID?" she recalled wondering. "There are just so many unknowns."
As the F.D.A.-approved vaccine candidates make their way from production lines to frontline workers in nursing homes, hospitals, and in other essential professions, people who are pregnant, breast-feeding, or trying to conceive must contend with the lack of data on how these vaccines will affect them, a developing fetus, or a breast-feeding infant. Although women of reproductive age make up a substantial share of the health-care workforce and the majority of nursing assistants and home health aides, protocols for the coronavirus-vaccine trials specifically exclude pregnant and lactating women, and often contain language requiring that participating women use contraception.
The American College of Obstetricians and Gynecologists published an advisory note last December, which said currently available vaccines "should not be withheld from pregnant individuals" and "should be offered to lactating individuals." The group based its guidance on the theoretical risks posed by the vaccines versus the known risks that COVID-19 poses to pregnant people, who have been designated an increased-risk population by the C.D.C. The statement stops short of encouraging uptake of the vaccine in the pregnant population, instead encouraging pregnant individuals to be "free to make their own decision regarding COVID-19 vaccination."
"Is that even helpful?" Amanda recalled wondering after she read the statement. "There were no pregnant people or lactating women in the studies. From an ethical standpoint, they cannot recommend it." (In January, the American Society for Reproductive Medicine recommended the vaccine for pregnant women or those contemplating pregnancy, but the World Health Organization recommended against vaccination for pregnant women unless they are at high risk of exposure or have comorbidities; W.H.O. did recommend the vaccine for lactating women.)
Public-health experts have been near-unanimous in recommending that frontline and essential workers—health aides, grocery clerks, day-care workers, nurses—should be among the first to receive a COVID-19 vaccine. Well over half of retail workers, nearly three-quarters of teachers, and roughly seventy-nine per cent of the health-care workforce is female; approximately three-quarters of those women are of reproductive age. Since at least the mid-nineteen-nineties, representatives of numerous medical societies and leading research institutions—the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, the National Institutes of Health, and the National Academy of Medicine—have advocated for the inclusion of pregnant and lactating women in vaccine trials, including those for the coronavirus. "If we don't have vaccines that are proven to be safe and effective in pregnant women, we don't have a vaccine for health-care workers," Emily Erbelding, the director of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, said at a September, 2020, workshop by the F.D.A. and N.I.C.H.D. on pregnant women and COVID-19.
In recent months, tens of thousands of people in the U.S. and around the world have participated in trials for vaccine candidates: small-scale Phase I safety trials; Phase II trials, usually of a few hundred people, to see whether the vaccine generates the desired response (such as inducing the body to produce antibodies); and much larger Phase III trials, in which the vaccine and a placebo are administered to determine whether the vaccine provides meaningful protection against the pathogen. In December, vaccines from Pfizer and Moderna were authorized for emergency use by the F.D.A., and other formulations have subsequently been approved in the U.K., India, and elsewhere. Several pharmaceutical companies, including Pfizer and AstraZeneca, have conducted toxicity studies in animals to establish how their vaccine formulations behave in pregnant mammals. But, given the length of human gestation and the additional time needed to observe the infants as they grow, it could be months or years before a vaccine that is considered safe during pregnancy hits the market.
The historical exclusion of pregnant women from clinical research was intended to protect them, and the developing fetus, from the potential harms of novel procedures and pharmaceuticals. But, as the lack of data on the COVID-19 vaccine illustrates, this approach also excludes women from the benefits of new vaccines and medicines. Nine out of ten women will take medication during pregnancy, and seven out of ten will take a prescription drug, yet one study found that, for more than ninety per cent of drugs approved between 1980 and 2000, their risk of causing birth defects was labelled as "undetermined." Until January of 2019, regulations governing medical research on human subjects explicitly mentioned pregnant women as a "vulnerable population," alongside children, incarcerated individuals, and developmentally disabled people. The "vulnerable" label for pregnant women was removed (the others remain) upon the recommendation of a task force established by the 21st Century Cures Act, which was signed into law by President Barack Obama during the last days of his Administration.
The move reflected a shift from "protection from research" to "protection through research," in the language of ethicists and activists who have fought for greater inclusion of pregnant women in clinical trials. The downsides of exclusion are clear. In the case of the COVID-19 vaccine, for example, pregnant women may be given the wrong dosage or denied access, or they may get sick from the disease while they await reliable data. But inclusion has its downsides, too. "Worries about adverse effects on fetuses really are worrisome to people, but people react, oftentimes, out of proportion to the absolute risk," Anne Drapkin Lyerly, a professor of social medicine, obstetrics, and gynecology at the University of North Carolina, Chapel Hill, said. "We're pressing against a lot of deeply human intuitions."
The removal of the "vulnerable" label has not, so far, created the presumption of inclusion that the federal Task Force on Research Specific to Pregnant Women and Lactating Women, known as prglac, recommends. For pharmaceutical companies, researching the effect of drugs or vaccines on the pregnant population presents a lot of risk for little reward. It requires extra expertise and cost and poses potential liability problems; moreover, although roughly half of the population can get pregnant, these individuals likely will spend only a few years of their lifetime in a pregnant or breast-feeding state. But the reluctance to include pregnant women in clinical-research trials points to a deeper conflict about how the medical community addresses the unique relationship between a woman and the fetus, and how one weighs the risks and benefits to both in the course of scientific discovery.
Today's conservative approach to research on human subjects is a correction to the unregulated approaches to past medical experimentation, which placed some people outside the category of "human." "There have been shifting attitudes in terms of who qualifies as a woman," Michele Bratcher Goodwin, a bioethicist and law professor at the University of California, Irvine, said. "Early experimentation on a variety of things, including in the gynecological space, was done on Black women." J. Marion Sims, who is sometimes called the father of modern gynecology, developed his surgical technique for repairing obstetric fistulas—which result in incontinence among postpartum women—on enslaved women, at least one of whom he had purchased expressly for his experiments. "Men like Marion Sims were lauded for the expertise that they were able to develop, and the science that they were able to move forward," Goodwin said.
The horrors of the Second World War yielded the Nuremberg Code and the Declaration of Helsinki, which elucidated the principles of bioethics such as informed consent and balancing risks and benefits. In the aftermath of the Tuskegee experiment, in which Black men with syphilis were left untreated so that scientists could research the course of the disease, the American government and medical establishment began codifying regulations on human research. This effort culminated in the Belmont Report, a statement of ethical principles and guidelines for research on human subjects. Published in 1979, the report was informed by studies of specific subgroups, including prisoners, children, "the institutionalized mentally infirm," and fetuses. In the regulations that eventually resulted, the first three groups were cited as "vulnerable populations," but not fetuses; instead, pregnant women were added to the list. (At the turn of the nineteen-sixties, the catastrophe of thalidomide, the sedative that was prescribed off-label to pregnant women in Europe, Australia, and Canada to treat morning sickness and which caused severe birth defects in tens of thousands of children, had put further distance between pregnant women and clinical research.)
Lori Andrews, a professor at the Chicago-Kent College of Law and the director of Illinois Tech's Institute for Science, Law, and Technology, told me that the abortion politics of the nineteen-seventies, following Roe v. Wade, also informed the drafting of the Belmont Report. Abortion opponents knew that valuable medical knowledge was emerging as a function of legal abortion. Doctors conducted small trials of the rubella vaccine on pregnant women who had scheduled abortions and found that the vaccine virus crossed the placenta and infected the fetus. Another study, of the mumps vaccine, found that although the virus did infect the placenta, it did not infect the fetus. In the early nineteen-seventies, three Boston doctors gave antibiotics to women who were scheduled for therapeutic abortions to see whether the dosage reached the fetus in high-enough concentrations to prevent congenital syphilis.
As Andrews pointed out, abortion opponents pushed states to pass laws barring research on fetuses, rather than let abortion become associated with medical breakthroughs such as vaccines and prenatal diagnostic techniques. In the late nineteen-seventies and throughout the eighties, states including Florida, Missouri, and Oklahoma passed laws to regulate research involving in-utero fetuses that were intended to be aborted. In a 1976 Villanova Law Review article, David G. Nathan, now the president emeritus of the Dana-Farber Cancer Institute, wrote that, following Roe, "Research on the about-to-be aborted fetus became a prime target of abortion opponents."
At the time, Nathan was a professor at Harvard Medical School who had been working on a fetoscopy technique to detect sickle-cell anemia and thalassemia in utero. A 1976 Massachusetts law prohibiting research on fetuses, backed by the Catholic Church and other abortion opponents (including professors at Boston College, a coterie of Orthodox Jews, and some Muslims), forced him to pursue this research in Connecticut, with colleagues at Yale University. Although Nathan successfully lobbied to have the law amended to allow for diagnostic procedures, the law still prohibits research on a fetus that is the subject of a planned abortion. Nathan's experience led him to believe that the labelling of pregnant women as "vulnerable" was intended to protect the fetus. (Abortion politics and vaccines also intersect in the use of fetal stem cells in vaccine research and manufacture. In April, 2020, the U.S. Conference of Catholic Bishops urged the F.D.A. commissioner at the time, Stephen Hahn, to ensure that Catholics could have access to vaccines produced without using "ethically problematic cell lines"; Pope Francis later said that such vaccines were "morally acceptable.")
Even setting ethical concerns aside, the breathtaking interdependence between a woman and the fetus—at times symbiotic, at times somewhat antagonistic—and the sheer dynamism of the maternal-fetal relationship makes researching the effects of drugs and vaccines difficult. Pregnancy depresses the immune system and, in later stages, can diminish lung capacity. (These factors may help explain why pregnant women who contract COVID-19 are at an increased risk of severe illness and death.) Morning sickness can be debilitating for the woman but is also associated with a lower risk of miscarriage. Pregnancy changes the hormonal system, the gastrointestinal tract, the cardiovascular system, and key organs such as the kidneys and the liver—all these fluctuations affect how the body will process drugs and other substances. Furthermore, what may be beneficial to one or both entities in the thirtieth week of pregnancy could be harmful in the third.
In a 2008 paper, Lyerly and two colleagues, the bioethicists Margaret Olivia Little and Ruth Faden, published "The Second Wave: Toward Responsible Inclusion of Pregnant Women in Research," which is widely seen as shifting the paradigm from "protection from" toward "protection through." "The intermingled physiologies distinctly present in pregnancy, and the implications for what are potentially two rather than one person," they wrote, required the thoughtful analysis of risks and benefits to both the fetus and the woman. To capture this spectrum of biological states, instead of "vulnerable," Little proposed in 2010 using the term "scientifically complex." "The alternative to responsible research in pregnancy," they conclude, "is relegating pregnant women to second-class medical citizens—something, it turns out, that is not good for pregnant women nor the fetuses they carry."
In the years since their paper was published, there have been some notable steps toward greater inclusion of pregnant women in trials, including a proliferation of research on the Tdap vaccine in pregnant women; this has resulted in a better understanding of optimal timing for administering the vaccine. There have also been failures, such as the delay in giving pregnant women the Ebola vaccine, despite near-certain fetal death.
In most cases, cost is an obvious deterrent. A responsibly designed trial with pregnant women will require specialists in neonatal medicine, obstetrics, and maternal-fetal health, along with preclinical developmental and reproductive toxicology studies, known as dart studies, carried out on animals. These costs can significantly increase the price tag of a trial that may already cost tens of millions of dollars, George Saade, the chief of obstetrics and director of the Maternal-Fetal Medicine Division at the University of Texas Medical Branch at Galveston, said. Insurance companies may even refuse coverage for a trial with pregnant participants, out of liability concerns. As it stands, the F.D.A. can encourage drug companies to include pregnant women in research trials, but cannot compel them to do so.
Including pregnant women in trials is additionally challenging because the physiology of pregnancy in other animals—even nonhuman primates—doesn't neatly correspond to that of a human pregnancy, Saade told me. Pregnant women's bodies metabolize chemical compounds differently at different points in the pregnancy; a developing fetus is more susceptible to harm in the first trimester than in the third. It may take years before babies or children show the effects of in-utero exposure; that they will volunteer for a lifetime of follow-up is hardly guaranteed. Furthermore, Saade said, drug companies would rather develop new medicines for chronic conditions—medicines that a patient would take over a lifetime—than pour money into additional research on an existing drug, just so someone can take it during a few months of their life.
Only eighteen out of the nine hundred and twenty-seven COVID-related clinical trials under way included pregnant women, a May, 2020, analysis found. In March and again in July, Senators Elizabeth Warren and Patty Murray called for pregnant people to be included in COVID-19 clinical trials, and Warren has introduced legislation, the Maternal Health Pandemic Response Act, to that effect. Murray said that she was "hearing from pregnant and lactating women across Washington State who want more clarity on whether the vaccine is safe and effective for them and their babies," and that prioritizing pregnant and lactating women in study protocols is "absolutely critical."
Moderna, Johnson & Johnson, and Pfizer have all expressed interest in eventually testing their candidates on pregnant women. Even though Pfizer and Moderna's Phase III protocols specifically excluded pregnant and lactating women, twenty-three women in the Pfizer trial and thirteen in Moderna's nonetheless became pregnant. Bill Gruber, Pfizer's senior vice president of vaccine clinical research and development, said that, because the trial began in July last year, there have been no live births yet, but that Pfizer plans to follow up with these women and their infants. The company has finalized the results of its DART studies, conducted on rats, and submitted it to the F.D.A., and hopes to begin enrolling pregnant women in clinical trials in the first half of 2021. A spokesperson from Johnson & Johnson said, "This is a critical population; we are in discussions with regulators and partners regarding their inclusion in our development plan. However, we do not plan to have pregnant women involved in the clinical studies until we have demonstrated efficacy and completed a reproductive toxicity study from a benefit risk perspective." Spokespeople for the Oxford-AstraZeneca vaccine said they hope to include pregnant women in trials and are carrying out preclinical trials to this end. Moderna did not respond to multiple requests for comment.
In this absence of firm data, Kimberly, a thirty-nine-year-old nurse practitioner who is breast-feeding her youngest daughter, born in February, agonized over whether to get vaccinated. Kimberly works in primary care at a small New Jersey clinic that's part of the Inspira Health Network. She is close to her colleagues, who threw her a big baby shower just before her daughter was born (she is still making her way through the vast trove of diapers she received at the shower). When we spoke in mid-December, her colleagues were getting vaccinated that week.
"Do I just do it? Would I be the one that put myself into the trial without the data?" she said. "This isn't about me anymore. This is about another human who is vulnerable to me, so, I think, that's what makes it hard to make that decision." She e-mailed me four days after we spoke. She had been turning the conversation over in her head, and connected fears about the vaccine to different points in history when those in charge had failed to protect public health: Agent Orange, asbestos, thalidomide. "It is hard to make a choice when our trust is broken and we feel like we don't have all of the facts," she wrote. But she planned to get the vaccine, having decided, after careful thought, that the benefits outweighed the risk. "This may be sooner than I anticipated and may alter the course of my breastfeeding journey with my daughter," she said. But she felt compelled to stand by one of her core principles, that she would not ask her patients to do something—get vaccinated—that she wouldn't do herself.
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