Mixed messaging between leading advisory groups such as the World Health Organization and the Centers for Disease Control and Prevention is a direct result of the lack of evidence among pregnant women due to their exclusion from pre-market clinical trials. This neglect is not without precedent or public health cost. In light of women’s history month, the historical lessons on pregnant woman’s involvement in vaccine research warrants reflection in the context of the COVID-19 pandemic and going forward.
Katharine McCarthy, PhD, MPH
The eligibility, and even prioritization, of pregnant women to receive the coronavirus vaccine is at stark odds with their exclusion from coronavirus vaccine pre-market clinical trials. The main reason for this exclusion is concerns over liability of potential fetal harm. Rather than affording protection, however, avoiding knowledge generation among an at-risk population forces women to make health decisions using insufficient evidence. Both Pfizer-BioNTech and Moderna coronavirus vaccines use a mRNA platform which is immunogenic, but non-infectious, meaning there is no risk of infection from the vaccine. While evidence is limited, there are also no documented risks to the fetus nor has there been demonstrated risk in animal studies.
The eligibility of pregnant women in vaccine rollout raises questions regarding the timeliness of animal and toxicity studies. Why, for example, were such tests not carried out earlier, such as when a candidate vaccine was identified? Further, when it became clear that vaccines’ benefits outweighed potential harm, why was an amendment to include pregnant women not created?
Instead, conducting a clinical trial to assess safety and efficacy among pregnant women post initial eligibility will have the very real challenge of identifying participants that agree to be potentially assigned to a control arm, and risk forgoing a possibly life-saving intervention. Without a control arm, it could take years for a sufficient amount of data documenting adverse side effects to emerge for valid comparison.
The public health cost of delay in timely and appropriate inclusion of pregnant women in clinical research has alarming historic lessons.
During the 2018 Ebola epidemic in the Democratic Republic of Congo, for example, vaccination policies at first excluded pregnant and lactating women. Although the policy was reversed 10 months later, the delay led to a case fatality rate of more than 90 percent among pregnant women in some outbreak areas.
Other historic examples of delayed public health benefit include administration of yellow fever and rubella vaccines. These examples not only delayed epidemic control at the cost of the health of women and their infants, but also resulted in elective termination of pregnancies which were otherwise intended.
The persistent caution due to theoretical risks in conducting pregnancy-related research perhaps most notably stems from two events during the 1950-1960s. The first followed the prioritization of pregnant women and children in the 1955 campaign to administer the new inactivated poliovirus vaccine. One company (Cutter Laboratories) ineffectively inactivated the virus such that up to 200,000 recipients mistakenly received an unattenuated strain of polio, resulting in 200 cases of varying paralysis and 10 deaths. Soon after, the use of thalidomide, a drug widely prescribed in Europe for nausea during pregnancy in the early 1960s, was recognized as a teratogen following widespread birth defects after its use.
The long-lasting influence of these tragedies has precluded the participation of pregnant women in clinical trials of non-obstetric related therapeutics to this day. Indeed, a global review of clinical trial registries identified less than 2 percent of all COVID-19 registered trials, including the use of a medication/supplement, included pregnant women.
Balanced against the theoretical risk of fetal harm, however, is the cost of excessive caution. Excluding pregnant women from pre-market trials not only causes some women to forgo access to a potentially lifesaving intervention, but vaccine policy based on limited or poor-quality data also has inherent health risks.
Vague guidance which advises women to discuss vaccination during pregnancy in consultation with their clinician may reinforce disparities among poor women who are more likely to be uninsured or have inadequate access to care. The resulting uncertainty undermines confidence in essential public health services needed to achieve epidemic control.
Rather than a misguided attempt of protection through exclusion, the needs of pregnant women must be represented in research. Instead of pregnancy constituting a sufficient reason for exclusion, the complex biological and ethical tradeoffs between maternal and fetal risks and benefits must be weighed using information on potential for harm extrapolated from animal studies, whether the risks of inclusion can be minimized, and the importance of the evidence to be gained for maternal and fetal health.
Ultimately, we must not underestimate the capacity of women to make informed decisions about whether or not it is appropriate to participate in research trials which have implications for their benefit. Otherwise, we risk repeating missteps of the past which ultimately block women from receiving the same evidence-based care available to men.
Katharine McCarthy, PhD, MPH, is a perinatal epidemiologist and a postdoctoral research fellow with The Blavatnik Family Women’s Health Institute at the Icahn School of Medicine at Mount Sinai. Her research focuses on disparities in maternal and newborn health, the measurement of essential maternal and newborn interventions and promoting reproductive autonomy, particularly among adolescents.