December 14, 2018

Pregnant women are considered a “vulnerable” population in the eyes of clinical researchers.

In clinical research, pregnant women are considered a “vulnerable” population, due to the presence of a fetus who cannot consent to participation.¹ To obtain ethical committee approval, clinical study interventions must “[either] directly benefit [or] pose minimal risk to the mother and fetus.” In addition, consent often must be obtained from both parents.

These stringent inclusion criteria for pregnant women frequently preclude clinical trial participation. For this reason, more than 80% of pregnant patients are prescribed therapies that have not been studied in pregnancy.² In a Viewpoint piece published in JAMA,³ Drs Katrina Heyrana, Heather M Byers, and Pamela Stratton from the National Institutes of Health (NIH) in Bethesda, Maryland, advocated for the increased inclusion of pregnant women in clinical trials so that pregnant patients may have equitable access to evidence-based medicine.

In the 1960s and 1970s, clinical trials assessing the efficacy of pharmaceuticals in pregnant women led to unintended consequences for exposed fetuses. Specifically, birth defects following in utero exposure to thalidomide and diethylstilbestrol compelled the US Food and Drug Administration (FDA) to develop policies protecting “female research participants of reproductive age from [teratogens exposure].”¹ However, the investigators wrote, these guidelines initiated a legacy of excluding pregnant women from clinical trials altogether. In the 1990s, the US Food and Drug Administration (FDA) and NIH expanded on existing guidelines, stipulating that research must include female participants in the absence of any “convincing reason for…exclusion.” The Centers for Disease Control and Prevention and the NIH later released recommendations for the inclusion of pregnant women specifically, but these recommendations have lagged, the investigators wrote.⁴ Of the 213 new pharmaceuticals receiving FDA approval from 2003 to 2012, only 5% included any data from pregnant women.¹

Modern concerns regarding the Zika virus have reignited conversations surrounding the inclusion of pregnant women in clinical trials. Despite the disproportionate burden of Zika virus in pregnant women and fetuses, none of the trials of Zika virus vaccine candidates have included pregnant women.⁵ Investigating means of intervention in pregnant populations is essential to curbing Zika incidence, the researchers wrote. If provided “adequate counseling about…conditions and treatment options,” thus, pregnant women should have full capacity to make decisions regarding trial participation.

The investigators emphasized the necessity of “clear, actionable guidelines” for the inclusion of pregnant women in clinical research and addressed 3 subsequent barriers to this achievement. First, they dismissed the characterization of pregnant women as a “vulnerable” population. The researchers instead suggested reclassifying pregnant women as “scientifically complex,” in an effort to acknowledge the autonomy and decision-making capacity of their population.⁵

Second, federal regulations do not define “acceptable risk” to a woman or fetus; per the Common Rule, risk must not exceed that which may be “encountered in daily life or during…medical examinations.”¹ However, these parameters are imprecise: acceptable risk levels may be mediated by the patient’s perceptions and opinions, as well as the urgency of the clinical scenario. Acceptable risk levels must be standardized to facilitate trial participation, the investigators wrote.

Finally, the perceived legal risk following a maternal or fetal adverse outcome has an impact on the willingness of practitioners to perform research in pregnant women. Per a 2015 survey, nearly 73.6% of 4295 obstetricians reported being implicated in a malpractice lawsuit.⁶ This barrier could be mitigated by standardizing informed consent procedures. The researchers further suggested “partnerships with community leaders and ethical and legal experts” so that enrollees receive culturally competent and accessible information regarding study risks. Beyond all other considerations, they emphasized the autonomy of pregnant women and their capacity to make informed decisions when provided adequate counsel and opportunity. The need for adequately researched interventions in this population necessitates their inclusion to allow them to make informed medical decisions, a right afforded to all other patient populations.

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References

1. US Department of Health and Human Services. Protection of human subjects. www.hhs.gov/ohrp/sites/default/files/ohrp/humansubjects/regbook2013.pdf. 2009. Accessed December 3, 2018.
2. Ayad M, Costantine MM. Epidemiology of medications use in pregnancy. Semin Perinatol. 2015;39(7):508-511. doi:10.1053/j.semperi.2015.08.002
3. Heyrana K, Byers HM, Stratton P. Increasing the participation of pregnant women in clinical trials [published online November 7, 2018]. JAMA. doi:10.1001/jama.2018.17716
4. Foulkes MA, Grady C, Spong CY, Bates A, Clayton JA. Clinical research enrolling pregnant women: a workshop summary. J Womens Health (Larchmt). 2011;20(10):1429-1432.
5. Ethics Working Group on ZIKV Research and Pregnancy. Pregnant women and the Zika virus vaccine research agenda: ethics guidance on priorities, inclusion, and evidence generation. http://guidance.zikapregnancyethics.org/wpcontent/uploads/2017/08/Full+Guidance-Pregnant-Women-the-Zika-Virus-Vaccine-Research-Agenda_optimized.pdf. Accessed December 3, 2018.
6. Carpentieri AM, Lumalcuri JL, Shaw J, Joseph GF. Overview of the 2015 American Congress of Obstetricians and Gynecologists’ survey on professional liability. https://www.acog.org/-/media/Departments/Professional-Liability/2015PL SurveyNationalSummary11315.pdf. Published November 3, 2015. Accessed December 3, 2018.