By Sue Coons, MA

On Feb. 18, Pfizer and BioNTech announced they would dose about 4,000 healthy pregnant women with the COVID-19 vaccine to evaluate its safety, tolerability, and immunogenicity. In media statements, the companies said that since the vaccine campaigns initially had been successful, it was time to extend the clinical program to other vulnerable populations, such as pregnant women.1

Women’s health advocates and researchers disagree with the timing of the study. “From my perspective, it’s too late. Pregnant women are not being studied soon enough. We need to devote more of our public and scientific attention to this group,” says Kristina Adams Waldorf, MD, researcher and professor of obstetrics and gynecology at the University of Washington. “The drug companies should have studied the vaccine in pregnant women from the very beginning. We now have more than 30,000 pregnant people in the United States who were vaccinated for COVID-19. As we expected, we have not seen any significant outcomes on the pregnancy or the neonate, which is in line with what we know about the biology. Why couldn’t we offer pregnant women the same reassurance that we did other adults regarding safety and efficacy?”

Although pregnant people were excluded initially from the COVD-19 trials, research has shown they are at higher risk for more severe disease. A study of pregnant patients with SARS-CoV-2 infections in Washington state between March 1, 2020, and June 30, 2020, revealed a fourteenfold increase in case-fatality rates than that of similarly aged people with COVID-19. In fact, pregnant women represented “nearly 10% of SARS-CoV-2 deaths among 20- to 39-year-olds in Washington state.”2 Most patients with SARS-CoV-2 in pregnancy experienced mild disease and recovered, the researchers said. However, one in 11 developed severe or critical disease, one in 10 were hospitalized specifically for a COVID-19 concern, one in 30 were admitted to the ICU for respiratory concerns, one in 60 were mechanically ventilated, and one in 80 died.

The research team also published results showing the SARS-CoV-2 infection rate in pregnant patients was 70% higher than similarly aged adults in Washington state.3 There also was a twofold to fourfold higher prevalence of pregnant patients with COVID-19 infections from communities of color than expected based on the race-ethnicity distribution of pregnant women in Washington in 2018.

“Even when we removed all of the pregnant women that we identified at the time of labor and delivery who were asymptomatic, we still had a 30% higher infection rate in pregnant people,” says Adams Waldorf, the senior author of the study. “We don’t know if that’s because they have larger households, if they have children in day care, or if they themselves are essential workers. Lots of my pregnant patients are working to help support their families in healthcare, teaching, and in elder care facilities.”

Fear of Risks

A week before the Pfizer/BioNTech announcement, National Institutes of Health (NIH) officials published an article stating pregnant and lactating people should have been included in the original COVID-19 vaccine trials. “Long-standing obstacles” to the inclusion of these people exist in clinical research, wrote Diana W. Bianchi, MD, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and colleagues.4

According to information provided by the manufacturers in the emergency use authorizations, pregnant people were excluded in the trials for both the Pfizer and Moderna vaccines. In addition, the data from women who did become pregnant during the trial have provided “limited data to inform evidence of safety and effectiveness in this population.” Some preclinical rodent data were included from the Moderna trial, the authors noted, but did not take place early enough to support the inclusion of pregnant patients in the trial.

“Efforts by the Centers for Disease Control and Prevention through its V-Safe registry as well as industry and the Food and Drug Administration will yield postmarket vaccine surveillance information from pregnant people, including evidence on the effects of the vaccine on pregnancy and infant outcomes,” they wrote. “These data will be useful, but in the meantime, pregnant people and their clinicians must make real-time decisions based on little or no scientific evidence.”

The Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) made recommendations on how to improve the inclusion of pregnant and lactating people in clinical research. Even so, ethical and liability concerns remain barriers to this type of research, the authors wrote. The PRGLAC authors proposed additional protections for these people through rulemaking and government initiatives that can reduce liability.

A pregnant person should have the same evidence about a vaccine that is provided to other individuals, the authors noted. “The information that pregnant and lactating people need to make this decision should be tailored to their individual risks based on potential exposures in their home and work environments, their medical comorbidities, and their demographic characteristics, combined with the evidence on the safety and effectiveness of the vaccine and its potential effects on a fetus. Pregnant and lactating persons should not be protected from participating in research, but rather should be protected through research.”

Pamela Payne, BSN, MSN, NP, a maternal-infant nursing instructor at the Patricia A. Chin School of Nursing at California State University in Los Angeles, says the Pfizer/BioNTech clinical vaccine trial with pregnant women is important — and she wishes that it had been part of the initial clinical trials.

“Pharmaceutical companies are very reluctant to include pregnant women in clinical trials because they worry about the financial and public relations risks should the vaccine or medication prove deleterious to the fetus or the newborn,” she says. “IRBs are tasked with protection of research participants, so they, too, have been reluctant to include pregnant women in clinical trials. Yet this pandemic is of such grave proportions, and the risk of coronavirus infection to pregnant women is so significant, a carefully designed trial should have been earlier on the company’s radar.”

Safety measures can be put into place for this type of trial, she says. “Requiring closer monitoring of pregnant participants in the trial by the safety review board is a way to ensure that any potential adverse effect is being recognized early and evaluated for the possibility of an early end to the trial, should an adverse effect be serious enough to warrant it.”

Adams Waldorf believes there has been a reckoning in science, medicine, and in society to recognize vulnerable and marginalized groups better than in the past, including pregnant people and underrepresented minorities. NIH has put rules in place to ensure women and children are studied more, instead of just the default of white men. “Pregnant women are now being recognized as an important group based on their vulnerability to COVID-19. But, scientifically, when they were not studied in the early vaccine trials, they were essentially marginalized,” she explains. “We have enough preclinical data and data from animal models to have very solid scientific evidence that we don’t think that there will be complications. Excluding pregnant people from the vaccine trials was a mistake.”

The American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and others have been pushing for inclusion of pregnant people. “Fortunately, they were not excluded from receiving the vaccine, but it’s not enough. We need to do more,” Adams Waldorf states.

Evaluating the Trial

Pfizer/BioNTech’s Phase II/III trial is a randomized, placebo-controlled, observer-blind study. It will include women age 18 years and older and between 24 to 34 weeks of gestation. According to the study details, each woman will participate for approximately seven to 10 months, depending on whether she receives the vaccine or placebo. The infants will be monitored through approximately six months of age. The researchers will study safety in infants of vaccinated pregnant women and if the infants received antibodies from the mothers. After a participant’s child is born, participants will be unblinded, and those who were in the placebo group will receive the vaccine.1

“We should be studying women who are getting the vaccine in all trimesters, and following up the infant as well. That’s standard practice,” says Adams Waldorf. “The gold standard is to study all trimesters and to follow the infant up typically for a few years.”

Studying women in the 24-34 week gestation window and following up with newborns certainly is a reasonable accommodation to the risk/benefit profile, Payne says. “Given the critical development of organ systems in the first trimester, it is reasonable to wait until later second trimester to avoid impact on those critical stages. Ideally, should the vaccine prove safe and efficacious in the gestational period under study, results could be carefully reviewed for likelihood of safety and efficacy in earlier gestational periods.”

The trial authors also did not mention an effort to recruit minority participants, even though people of color often experience more severe COVID-19 infection. Payne says she is disappointed to hear that no specific mention of participant diversity was given. “It may be that the company is attempting to have a diverse group and it is important to have that data, given the greater impact that the disease is having in minority populations,” she says. “However, trying to recruit minority participants faces a barrier of suspicion due to historically egregious medical research protocols conducted in these communities, as well as the general societal reluctance to risk the health of a pregnant woman and her fetus. I would hope to see a diverse population, but the knowledge gleaned from the trial is still of such critical need that I would hesitate to criticize the trial solely for a lack of diversity. If minority communities are not currently included, I would hope that the company would design a diverse trial as soon as possible.”

Informing Future Trials

Even with its late start date, the Pfizer/BioNTech vaccine trial in pregnant woman will contribute important data, the researchers say. Every clinical trial with pregnant women, undertaken with careful evaluation of the potential for risks, and with close monitoring of participants throughout the trial, is valuable to reassuring researchers that it is possible to include pregnant women in trials more routinely.

“I am not advocating for future testing of any and every new medication on pregnant women,” Payne says. “However, vaccines or medications that could potentially ameliorate known significant, serious health risks to pregnant women and their fetuses must be studied during pregnancy to provide women and their clinicians the knowledge with which to answer questions of safety and efficacy. I would hope that this vaccine trial will help this goal.”

The studies now will help to inform the next generation of COVID-19 vaccines that might be a little better at covering all the variants, says Adams Waldorf. “All of this research will continue to inform our scientific and medical approach to vaccination in pregnancy.”

REFERENCES

  1. Pfizer News. Pfizer and BioNTech commence global clinical trial to evaluate COVID-19 vaccine in pregnant women. Feb. 18, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-commence-global-clinical-trial-evaluate
  2. Lokken EM, Huebner EM, Taylor GG, et al. Disease severity, pregnancy outcomes, and maternal deaths among pregnant patients with severe acute respiratory syndrome coronavirus 2 infection in Washington State. Am J Obstet Gynecol 2021;S0002-9378(21)00033-8. [Online ahead of print].
  3. Lokken EM, Taylor GG, Huebner EM, et al. Higher SARS-CoV-2 infection rate in pregnant patients. Am J Obstet Gynecol 2021;S0002-9378(21)00098-3. [Online ahead of print].
  4. Bianchi DW, Kaeser L, Cernich AN. Involving pregnant individuals in clinical research on COVID-19 vaccines. JAMA 2021;325:1041-1042.