Though the World Health Organization has lifted the emergency alert on the Zika virus, scientists continue their push to develop a vaccine. Late last year, the virus reached Asia, where outbreaks are ongoing. It will remain a global threat to pregnant women as long as humans travel and mosquitoes stow away with them.
The pursuit of a truly effective Zika virus vaccine, however, is handicapped by a long-standing clinical practice: the exclusion of pregnant women from drug development and vaccine trials. The main reason for this is ethical: Why expose a growing fetus, or a mother-to-be, to unknown risks in an experimental setting? Both fetus and mother are classified as “vulnerable” and regarded as members of a protected population. None of the current Phase 1 trials for a Zika vaccine include pregnant women.
Regrettably, the potential risks associated with excluding pregnant women from drug-development trials in general are routinely unexamined. From 2000 to 2010, about 98 percent of the 172 drugs approved by the U.S. Food and Drug Administration were not evaluated for the risks they may pose to pregnant women, according to a study conducted by researchers from the University of Washington in Seattle. This despite the fact that about 90 percent of the 4 million women annually pregnant in the U.S. take at least one medication because of pregnancy-associated health issues, such as morning sickness, diabetes and high blood pressure. In other words, a supposedly safe FDA-approved drug may expose a mom-to-be and her fetus to potentially harmful side effects.
The practice has contributed to a gap in our knowledge of pregnancy. Numerous studies over several decades have shown that pregnancy entails more than just a nine-month body transformation. For example, the body changes affect the immune systems of mothers-to-be, all under the direction of a biological network in communication with the fetus.
Our ignorance of the precise ways in which a woman’s changing body and immune system interact in the course of pregnancy causes physicians to be hesitant about choosing newer treatment options. This hesitancy can lead to medical mishaps, with pregnant women left helplessly awaiting the outcome of complications.
Unexpected, potentially avoidable complications should serve as distress calls to both physicians and researchers to better collaborate to fill the gap in our knowledge about pregnancy. To that end, the Global Forum on Bioethics in Research took an important step, meeting late last year in Buenos Aires, when it urged the inclusion of pregnant women in clinical trials. Short of a change in practice, ignorance will continue to play an outsized role in the rationale for excluding pregnant women from most clinical trials. In the case of the Zika virus, the status quo produces a medical dilemma.
The virus’ known dire consequences — microcephaly and other congenital birth defects — stem from infection during pregnancy and are the main reasons fueling the urgency of the vaccine search. But the responses of only non-pregnant subjects are being studied in the clinical trials. When contagions like Zika disproportionately affect pregnant women, excluding moms-to-be may end up harming them and their babies more than it helps.
Indeed, our research highlights the risks of this practice in Zika vaccine trials, as well as in drug-development trials in general.
It is well established that pregnancy naturally suppresses a woman’s immune system so her body doesn’t reject the fetus, essentially viewed as a foreign object. To determine how a Zika virus behaves in this environment, we infected the blood of healthy men, non-pregnant women and pregnant women ages 18 to 39 with both the African and Asian strains, and studied the samples 40 hours later.
We found that the Zika virus opportunistically builds on a woman’s natural bodily response to pregnancy by targeting specific white blood cells to further weaken her immune system, which enables the virus to spread and increases the chances that the fetus will be harmed. This behavior almost resembles that of HIV, but the Asian strain is especially effective at “tricking” these cells into believing that no biological threat is present during the first and second trimester.
The implication of this finding is as startling as it is clear. To decide the most effective Zika virus vaccine based on tests among non-pregnant women with different body chemistry may produce a vaccine not potent enough for expectant mothers. It should be noted that women also undergo anatomical and physiological changes during pregnancy, including increased blood volume and cardiac output, changes that can dramatically affect drug metabolism.
The rationale for excluding mother to protect fetus in vaccine or drug clinical trials is more a product of hope than knowledge. More likely, classifying pregnant women as members of a vulnerable population, and simply leaving it at that, puts them on psychological tenterhooks when taking appropriate vaccinations or drugs treatment, even when necessary.
By contrast, the addition of expectant mothers as subjects in vaccine and drug-development trials holds out an intriguing and desirable possibility: a tailored therapy for different trimesters of pregnancy that caters specifically to the health and well-being of both mother and child.
Jae Jung is an international authority on viral infections and a professor and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC. Suan-Sin Foo is an expert in mosquito-born viruses and is a postdoctoral scholar and research associate in the Department of Molecular Microbiology and Immunology at the Keck School of Medicine.