Note: This is the seventy-fifth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

Even during prior epidemics, pregnant women have been historically excluded from nonobstetric clinical trials, creating a knowledge gap regarding performance of these treatments during pregnancy.

The objective of this review was to summarize the current state of research for pregnant women during the COVID-19 pandemic.

Study Synopsis and Perspective

COVID-19 drug trials to determine the human safety and efficacy of treatments are rapidly proliferating, yet often exclude pregnant and lactating mothers.^[1]

Of 927 such trials across Asia, Europe, and North America published online in May, more than 50% explicitly excluded pregnant women, less than 2% were pregnancy-specific, and others failed to mention the eligibility of pregnant women, creating a knowledge gap regarding treatment use during pregnancy.^[2]

For decades, expectant mothers and their offspring have been considered vulnerable and needing to be shielded from potential research harms, partly because of limb malformations linked to thalidomide and cancer risk from diethylstilbestrol.

However, the resulting regulations and limited clinical trial data could "widely expose" pregnant women to drugs untested in pregnancy, said bioethicist and obstetrician-gynecologist Anne Lyerly, MD, from the University of North Carolina, Chapel Hill. Excluding pregnant women from clinical trials does not eliminate risk, but simply shifts it from research studies to clinical practice.

A previous study published in Obstetrics and Gynecology in 2002 showed that more than 90% of drugs approved by the US Food and Drug Administration from 1980 to 2000 had "undetermined" potential for fetal malformations. "Inadequate information" precluded weighing benefits against risks.^[3]

Recent changes made by federal agencies should theoretically increase inclusion of pregnant women in clinical trials, provided there is a shift in risk conceptualization.

"[T]he focus is so often on fetal risk that we've failed to recognize the benefits of including pregnant women," said University of North Carolina bioethicist and obstetrician-gynecologist Amina White, MD. "Pregnant women should have access to drugs that have been vetted for safety. It's an issue of justice."

Today's clinical research is guided by principles established in 1979 by a federal commission created in 1974 to bolster the ethical underpinnings of human research. These include beneficence, or obligation to maximize benefits and minimize risks, and justice, which ensures equitable distribution of research benefits and burdens to all populations.

Drugs taken early in pregnancy, such as thalidomide for morning sickness, have greater odds of organ and limb malformations, whereas those taken later in pregnancy may affect brain development and birth weight.

"The concern that you may disrupt something in these early stages," with potentially lifelong consequences, "carries a huge weight," said pediatrics researcher Christina Chambers, PhD, MPH, from the University of California, San Diego.

In 1977, US Food and Drug Administration guidelines excluded pregnant women and women "with childbearing potential" from phase I and II clinical trials. The National Institutes of Health Revitalization Act of 1993, intended to increase sex and racial diversity in clinical trials, allowed inclusion in some studies.

Federal regulations currently require any study involving pregnant women to meet 10 criteria. Where "scientifically appropriate," risk must first be tested in pregnant animals and nonpregnant humans, with "least possible" risk to mother or fetus for achieving research objectives.

Bioethicist Maggie Little, PhD, from Georgetown University in Washington, DC, calls for a "cultural shift... Instead of thinking it's unethical to do research with pregnant women, researchers should consider that it's unethical not to include them."

Institutional review boards make the final call for inclusion and still tend toward caution, said University of Pennsylvania obstetrician-gynecologist Michal Elovitz, MD. When Dr Elovitz and colleagues launched a COVID-19 trial of convalescent plasma, they had to submit extensive support for including pregnant and lactating mothers despite widespread use of plasma transfusions for pregnancy complications.

Regulators should reconsider what safety evidence suffices for a trial to be conducted, Dr Elovitz said. "We have to be careful about where benevolence crosses over to patriarchy."

Trials including pregnant women are often costlier, larger, and take longer, given their additional safety and monitoring requirements. Drug makers worry about insurance for liability if harm occurs, Dr Lyerly said.

With little incentive for inclusion, most drugs marketed today are approved without human pregnancy data, which is usually obtained through postmarketing registries. This creates biases, as women likely report only severe reactions thought to be from use of a drug while pregnant. Milder reactions such as headaches or fatigue may go unnoticed. Registries rarely record cases in which neither mother nor offspring experienced negative adverse effects, limiting generalizability.

Fetal drug risk must be balanced against risk for untreated maternal disease. Untreated diabetes increases risk for congenital abnormalities by from 3% to 25%. Untreated hypertension can cause several weeks' prematurity. Until recently, data were insufficient to know which existing medications could best reduce these risks with minimal adverse events. The National Institutes of Health therefore began funding studies of drug metabolism in pregnancy.

Surveys suggest that many pregnant women are keen to participate in clinical research. Participants in a 2013 trial of a common antihypertensive said they preferred the risk for potential adverse effects to delivering at 34 weeks, which was the likely outcome of foregoing treatment. Other patients may be unable to access needed treatments outside of trials.

"There's been a slight movement of the needle," said infectious disease researcher Sylvia LaCourse, MD, MPH, from the University of Washington, Seattle. One large UK-based study of COVID-19 drugs, the Recovery trial, includes pregnant and lactating women. In response to feedback, the World Health Organization amended the COVID-19 trial that it is sponsoring to permit inclusion of pregnant and lactating women.

"Whenever there's a successful large-scale trial that includes pregnant women, it sets a precedent," said Dr LaCourse. Even a small number of pregnant study participants can illuminate whether a drug acts differently during pregnancy.

Greater inclusion does not eliminate risk but may detect potentially harmful drugs before thousands are affected. Clinical research minimizes the potential for harm, Dr Lyerly said. "There's no way to take the risk away entirely. But if you don't look, it doesn't mean it goes away."

Jyoti Madhusoodanan is a science writer based in Portland, Oregon.

Clinical Implications

• More than half of all COVID-19 trials worldwide excluded pregnancy; only 1.7% were pregnancy-specific.
• Knowledge gaps concerning the safety and efficacy of COVID-19 interventions created by the exclusion of pregnant women may ultimately harm them.
• Implications for the Healthcare Team: The investigators urge team members to encourage their professional organizations to advocate for timely inclusion of pregnant women in appropriate trials.

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