Pregnant women are routinely excluded from clinical trials for drugs and vaccines.
With no effective cure and limited treatment options, the development of safe and effective vaccines for COVID-19 is a high priority. Vaccines both protect individuals against infection and reduce community spread of the virus by interrupting transmission pathways.
Once safe and effective vaccines for COVID-19 are available, the challenge will be to ensure their fair distribution across and within countries. In addition to global equitable access, fair priorities will need to be set within jurisdictions. Immediate priority groups will likely include health-care workers, personal care attendants, first responders, adults over age 65 and other high-risk adults with existing health conditions. But after that, groups that need consideration include pregnant women.
COVID-19 in pregnancy
While there is limited data on the prevalence and severity of COVID-19 among pregnant women, it is thought that they could be at risk of serious complications from COVID-19. One study in the United States found that infected pregnant women were 1.5 times more likely to be admitted to the intensive care unit and 1.7 times more likely to receive mechanical ventilation than infected non-pregnant women.
A systemic review and meta-analysis that included 17 studies (2,567 pregnancies) found that admission to the intensive care unit was required in seven per cent of cases, whereas the rate of admission for infected non-pregnant women was 4.2 per cent. This review also confirmed an increased risk of preterm birth and delivery by caesarean section.
These facts, as well as the likelihood that pregnant women’s access to drug therapies for COVID-19 may be restricted (as is the case for most drug therapies during pregnancy), suggest that pregnant women should be a target population for COVID-19 vaccine research. And yet, the default position for both drug and vaccine research is to exclude pregnant women from research participation because of risks to the pregnant women and their offspring.
Two major tragedies — thalidomide prescribed for morning sickness during the 1950s and diethylstilbestrol (DES) prescribed to prevent miscarriage from the 1940s to the 1970s — cemented the view that pregnant women and their offspring were vulnerable and should be protected from research risk. Ironically, while both these cases involved harm arising in the clinical setting due to a lack of adequate prior clinical research, the result has been to systematically exclude pregnant women from clinical trials.
The risks of exclusion
The lack of evidence that a vaccine is safe and can provoke an immune response in pregnant women undermines effective decision-making for both clinicians and pregnant women, possibly resulting in the use of unsafe vaccines. Without research, pregnant women and their offspring are exposed to the avoidable risks of off-label and compassionate use of non-evidence-based vaccinations.
Exclusion from research does not dodge the risk of unproven vaccinations; it simply shifts this risk from a carefully monitored clinical trial to the privacy of a doctor’s office. Excluding pregnant women from vaccine research is both unjust and imprudent from a public health perspective.
Last year, the Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) Working Group issued a Guidance on Pregnant Women and Vaccines Against Emerging Epidemic Threats: Ethics Guidance for Preparedness, Research and Response. This guidance is grounded in the belief that “pregnant women cannot be ignored as the scientific and biomedical communities continue to innovate and develop new medicines and tools to improve health.” It provides a generic “road map for the ethically responsible, socially just and respectful inclusion of the interests of pregnant women in the development and deployment of vaccines against emerging pathogens.”
COVID-19 vaccine trials
Forty-four candidate vaccines for COVID-19 are currently in human clinical trials: 29 in Phase 1, 14 in Phase 2 and 11 in Phase 3 trials. Phase 1 trials focus on safety and dosage and typically recruit a small number of research participants. Phase 2 trials continue to gather information about adverse events and immune response and usually involve hundreds of people.
Phase 3 randomized controlled trials involve tens of thousands of healthy volunteers where some are immunized with the candidate vaccine and others receive a placebo. The goal is to determine if persons who are vaccinated are protected from infection. If the candidate vaccine proves safe and effective, then it can be licensed for use in the general population.
It is reported that, to date, Johnson & Johnson, Moderna and Pfizer, all of whom have started Phase 3 clinical trials, have indicated an interest in future vaccine trials involving pregnant women, possibly in early 2021. A problem with including pregnant women in the Moderna or Pfizer trials is that their vaccines use an unproven gene-based technology.
To minimize the risk of harm to pregnant women and their offspring, the vaccines tested in this population should be ones that use a more established technology. The Johnson & Johnson COVID-19 vaccine uses the same technology as their Ebola vaccine, which has been given to pregnant women.
Including pregnant women in trials
Moving from the general to the specific, there are at least two scientifically valid options for the inclusion of pregnant women in vaccine trials. One option involves standalone Phase 1 trials for pregnant women that would be initiated following the successful completion of Phase 1 and 2 studies in the general population and the start of Phase 3 studies in this population.
This approach allows for greater clarity in trial design and ease in safety monitoring during the clinical trial because only pregnant women are included and end points can be specifically defined for pregnant women and their offspring. A pregnancy-specific trial could increase the likelihood of effective pregnancy-related risk counselling and informed consent processes, involvement of investigators with relevant expertise and effective follow-up.
Alternatively, Phase 1 vaccine trials for pregnant women could be embedded into Phase 3 trials in the general population. This approach entails reduced startup costs compared to initiating a separate trial, given the main trial protocols, infrastructure, staff, monitoring arrangement and regulatory approval will already have been established.
Pregnant women and their offspring must not be left behind in the race to develop safe and effective vaccines for COVID-19.