Few COVID-19 Studies Include Pregnant Women, Prompting Outcry

Heather Boerner

June 10, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

When a pregnant woman walked into his office with COVID-19 symptoms, Jim Thornton, MD, knew he wanted to enroll her in a clinical trial to see what medication could help her.

Thornton, a professor of obstetrics and gynecology at the University of Nottingham in the United Kingdom, has spent his career conducting randomized controlled trials in pregnant women. But when he looked for an appropriate trial, the choices were scant. Of the 2042 COVID-19 clinical trials listed on ClinicalTrials.gov on June 10, just three are looking at therapeutics in pregnant women; most therapeutic trials exclude pregnant women.

It is, he said, "a poor show."

"Obviously, the excuse is that the regulatory people are saying you can't put pregnant women in," said Thornton, who also tracks COVID-19 in pregnant and lactating women and disentangles duplicate data from fresh data online. "But actually, it's my colleagues who aren't even making an effort. They ought to be ringing up the regulatory people saying, 'Look, I've got a pregnant woman. I want to recruit her.' If everyone rang up like that, we would get in."

A growing number of clinicians are working to involve pregnant women in clinical trials. In March, the American College of Obstetricians and Gynecologists (ACOG) joined 18 other medical organizations to call on the National Institutes of Health (NIH) and the US Food and Drug Administration (FDA) "to ensure that pregnant and lactating women are included in all research for the development of vaccines and therapeutics related to COVID-19."

Since then, more commentaries, letters, and viewpoints on the topic have been published. And they appear to have spurred action.

The international SOLIDARITY trial, sponsored by the World Health Organization (WHO), changed its inclusion criteria to allow pregnant women to participate. And a large trial in the United Kingdom — RECOVERY — allows pregnant and lactating women to participate with informed consent.

The NIH National Institute of Allergy and Infectious Diseases (NIAID) is also moving in this direction. We are "currently exploring research opportunities related to COVID-19 treatments in pregnancy," NIAID officials told Medscape Medical News in a statement.

A Changing Tide

Traditionally, pregnant women have been excluded from clinical trials as a matter of course. Early in pregnancy, especially, when a fetus's organs develop, certain drugs can cause malformations, sometimes severe. But in April 2018, the FDA issued draft guidance on how to safely include pregnant women in clinical trials, proposing that pregnant women be included if preclinical studies suggest no ill effect of the drug on the woman and the fetus.

Later that year, the Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC), formed in 2016 and funded by the NIH, issued 15 recommendations for improving access to clinical trials for pregnant and lactating women.

These include integrating pregnant and lactating women more broadly into the research agenda; reducing liability for researchers who conduct studies that include pregnant women; and reforming regulations around the inclusion of pregnant women in studies, such as removing the requirement that both parents consent to participation in clinical trials that only benefit the fetus, which would enable single mothers to participate.

The Opposite of Innovation

Sylvia LaCourse, MD, assistant professor of allergy and infectious diseases and global health at the University of Washington in Seattle, has been following these changes. Early in the pandemic, she looked at which clinical trials underway would enroll participants who were pregnant or breast-feeding. It was almost impossible to figure out without clicking on every single trial in clinical trial registries. So she took a more direct route.

"I just emailed a whole bunch of principal investigators for trials" of COVID-19 therapies, she said. In addition to asking them to clarify their pregnancy exclusion criteria, she said she told them that "this would be really nice information to have very clear. And if pregnant people are excluded, then that should be clear as well. And a reason why should be there."

The response at the time was that almost no one was including pregnant women in trials. None of the trials testing remdesivir for hospitalized, acutely ill patients permitted pregnant women. Compassionate use was the only available option for clinicians looking to use remdesivir in seriously ill pregnant patients.

Even more concerning to LaCourse was that large trials led by organizations like the WHO and the NIH excluded pregnant and lactating women with no explanation. So she and her colleagues called out, in a viewpoint, the SOLIDARITY trial and NIAID Adaptive COVID-19 Treatment Trial for excluding pregnant and breast-feeding women despite designs meant to "remove barriers to implementing a large-scale trial by simplifying procedures and outcomes."

"Continued exclusion of pregnant and lactating women represents exnovation," LaCourse and her colleagues wrote — the opposite of innovation.

One group of researchers did the painstaking work of evaluating every one of the trials underway for pregnancy inclusion or exclusion. Maged Costantine, MD, division director of maternal–fetal medicine at The Ohio State University Wexner Medical Center in Columbus, and colleagues reviewed 18 global clinical trial registries to find out if clinicians could enroll their pregnant patients. They found that less than 2% of all COVID-19 clinical trials allowed pregnant women, or women who could become pregnant, to participate.

Maged was also involved in a similar review of ClinicalTrials.gov, which showed that two-thirds of the trials explicitly excluded pregnant women.

"Even a trial evaluating high doses of anti-inflammatory and antioxidant dietary supplements, such as eicosapentaenoic acid and gamma-linolenic acid, has excluded pregnant women," Costantine and his colleagues wrote.

Not Doing Harm

Early surveillance data suggest that pregnant women are at no more risk for severe outcomes from COVID-19 than nonpregnant women, and that excluding them from receiving investigational therapeutics could cause more harm than the medications themselves, as reported by Medscape Medical News.

There have been early reports of maternal death from COVID-19, as well as multiple reports of preterm birth, LaCourse noted.

And there is an increased risk for long-term negative outcomes in women with COVID-19, including heart disease, which could add to pre-existing pre-eclampsia, Costantine said.

In addition, immunologic changes related to pregnancy might make women more susceptible to viral respiratory infections, according to a recent comment in the Lancet. "Beyond the virus-specific risks, illnesses with high fevers early in pregnancy are associated with specific birth defects, such as neural tube defects," the authors wrote.

There are some drugs being tested for COVID-19 that are contraindicated during pregnancy. The antipsychotic chlorpromazine (Thorazine), for instance, is associated with increases in certain birth defects.

Others, like hydroxychloroquine and remdesivir, have been used to treat malaria and Ebola, respectively, in pregnant women. Enoxaparin (Lovenox), a low-molecular-weight heparin recommended for blood clotting during pregnancy, is being tested for COVID-19, but not all enoxaparin trials include pregnant women.

Still others, including the antiprotozoal nitazoxanide, amoxicillin/clavulanate, and azithromycin, fall into that middle category for pregnancy and risk — preclinical evidence that the drugs are not harmful in pregnancy — but no human trials in pregnant women. Acetaminophen also falls into this category.

This is the type of scenario where you can make the case even more clearly to people that not having data on pregnancy can be a harm.

But the need for these drugs is even more important for pregnant women with COVID-19, said Jodie Dionne-Odom, MD, director of the women's HIV program at the University of Alabama at Birmingham. She was working with colleagues to organize a conference at the NIH on the inclusion of pregnant women in clinical research when the pandemic hit. The conference, scheduled to take place at the end of April, didn't happen.

One of the issues the conference team had planned to address — before the COVID outbreak happened — was, "What do you do in an outbreak, when there's a clear motive to include pregnant women in treatment and vaccine trials and the opportunity is lost?" Dionne-Odom said.

"This is the type of scenario where you can make the case even more clearly to people that not having data on pregnancy can be a harm," she added.

Change on the Horizon

The argument is not to put pregnant women in phase 1 trials of totally untested investigational medicines, Dionne-Odom said. But by phase 3, a drug has been shown to be safe in nonpregnant people.

If animal studies show no signs of negative pregnancy outcomes and no excess of fetal abnormalities, researchers could start a phase 1 trial specifically for pregnant women while phase 2 and 3 studies go on in the general population, she explained.

Alternatively, researchers could add pregnant women to phase 3 trials of agents and vaccines currently under investigation.

"In some fields, only 5% of clinical trials move from phase 1 to phase 2, and only 15% of those make it to phase 3," she reported.

"If we wait until next summer to see the outcomes of current trials and then we enroll pregnant women in the vaccine trials and the treatment trials, you can see that we're already 2 years behind," Dionne-Odom said.

There is a very real possibility that "a vaccine could become available and approved for everybody but pregnant women," she said.

But there is some hope on the horizon. In response to feedback, SOLIDARITY now enrolls pregnant women. And clinicians can invoke expanded access and emergency use to prescribe remdesivir for seriously ill COVID-19 patients who are pregnant.

But simply including pregnant women in a trial design does not compel women to participate, said Costantine. It just gives clinicians the ability to offer their patients more options.

Thornton said he spoke to his pregnant COVID patient about the RECOVERY trial at the University of Oxford, but she declined.

"Importantly, things are changing," said LaCourse. "I am potentially optimistic."

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