Research with Pregnant Women: New Insights on Legal Decision-Making.

BackgroundThere is ambiguity with regard to what counts as an acceptable level of risk in clinical research in pregnant women and there is no input from stakeholders relative to such research risks. The aim of our paper was to explore what stakeholders who are actively involved in the conduct of clinical research in pregnant women deem an acceptable level of risk for pregnant women in clinical research. Accordingly, we used the APOSTEL VI study, a low-risk obstetrical randomised controlled trial, as a case-study.MethodsWe conducted a prospective qualitative study using 35 in-depth semi-structured interviews and one focus group. We interviewed healthcare professionals, Research Ethics Committee members (RECs) and regulators who are actively involved in the conduct of clinical research in pregnant women, in addition to pregnant women recruited for the APOSTEL VI case-study in the Netherlands.ResultsThree themes characterise the way stakeholders view risks in clinical research in pregnant women in general. Additionally, one theme characterises the way healthcare professionals and pregnant women view risks with respect to the case-study specifically. First, ideas on what constitutes an acceptable level of risk in general ranged from a preference for zero risk for the foetus up to minimal risk. Second, the desirability of clinical research in pregnant women in general was questioned altogether. Third, stakeholders proposed to establish an upper limit of risk in potentially beneficial clinical research in pregnant women in order to protect the foetus and the pregnant woman from harm. Fourth and finally, the case-study illustrates that healthcare professionals’ individual perception of risk may influence recruitment.ConclusionsHealthcare professionals, RECs, regulators and pregnant women are all risk adverse in practice, possibly explaining the continuing underrepresentation of pregnant women in clinical research. Determining the acceptable levels of risk on a universal level alone is insufficient, because the individual perception of risk also influences behaviour towards pregnant women in clinical research. Therefore, bioethicists and researchers might be interested in changing the perception of risk, which could be achieved by education and awareness about the actual benefits and harms of inclusion and exclusion of pregnant women.

The lack of human data available to inform evidence-based treatment for illness during pregnancy has led to calls for greater inclusion of pregnant women in research, but the extent of their current representation is poorly characterized. Our objective was to measure the current exclusion of pregnant women from industry-sponsored clinical trials as a baseline for future comparison. We compiled data from studies enrolling women of childbearing potential posted on www.ClinicalTrials.gov between 1 October 2011 and 31 January 2012. The review was limited to open United States-based phase IV interventional studies sponsored by the pharmaceutical industry evaluating treatment of conditions that may be experienced by but are not limited to pregnant women and did not involve a medication classified as potentially teratogenic. If there was no mention of pregnancy in the inclusion or exclusion criteria, we contacted a study representative to confirm that pregnant women could be enrolled. Of 558 qualifying industry-sponsored studies, five (1%) were designed specifically for pregnant women. Of 367 phase IV clinical trials with verified inclusion and exclusion criteria, 348 (95%) excluded pregnant women and 19 (5%) did not. We found the exclusion of pregnant women from industry-sponsored clinical trials to be common practice. Moving beyond reflexive exclusion and developing thoughtful criteria for inclusion of pregnant women in clinical research would likely advance the evidence base to inform treatment decisions during pregnancy and lead to better health outcomes for women and children.

NAEPP Expert Panel Report: Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—2004 Update

Accelerating the paradigm shift toward inclusion of pregnant women in drug research: Ethical and regulatory considerations

Position Statement on Tobacco Exposures in Children and Families

Scanty evidence exists about the safety and effectiveness of drugs-and of their efficacious dosing-that women may need to treat acute and chronic health issues during their pregnancies. This lack of evidence puts pregnant women and their fetuses at risk of harm from the use or avoidance of drugs during pregnancy. In light of the protectionist approach in regulations governing research with pregnant women and fetuses, trial sponsors, researchers, clinicians, and institutional review boards (IRBs) have been reluctant to include pregnant women in clinical drug trials, applying ethical reasoning for exclusions that reflects a default exclusionary approach. Yet in recent years, many clinicians, researchers, bioethicists, and professional societies have called for a reexamination of the routine practice of excluding pregnant women from clinical research. This paper proposes a practical approach to an ethical framework for IRBs that supports fair inclusion, rather than routine exclusion, of pregnant women in clinical research. This guidance will aid IRBs in ethically including and appropriately protecting pregnant women in research.

Though much progress has been made on inclusion of non-pregnant women in research, thoughtful discussion about including pregnant women has lagged behind. We outline resulting knowledge gaps and their costs and then highlight four reasons why ethically we are obliged to confront the challenges of including pregnant women in clinical research. These are: the need for effective treatment for women during pregnancy, fetal safety, harm from the reticence to prescribe potentially beneficial medication, and the broader issues of justice and access to benefits of research participation. Going forward requires shifting the burden of justification from inclusion to exclusion and developing an adequate ethical framework that specifies suitable justifications for excluding pregnant women from research.

Topics

Safety of influenza vaccines in pregnant women

Less Hazardous Cigarettes and Diseases of the Lung

Substance use disorders in pregnancy: clinical, ethical, and research imperatives of the opioid epidemic: a report of a joint workshop of the Society for Maternal-Fetal Medicine, American College of Obstetricians and Gynecologists, and American Society of Addiction Medicine

Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Leading medical organizations have called for advancement of pregnancy-specific research to reduce harmful evidence gaps. However, meeting this objective poses ethical, legal, and policy dilemmas for investigators, oversight committees, academic institutions, and sponsors. To better understand the extent to which policies may facilitate or hinder the inclusion of pregnant women in research, we conducted two studies: an international study of laws, regulations, and ethical guidelines from a diverse sample of 59 countries and a study of policies from 84 top-funded US research institutions. We found that most policies use risk-based criteria for determining whether pregnant women should be included in research. Among countries with inclusion policies for pregnant women, 76% had risk-based policies (i.e., inclusion is based on risks and benefits to the pregnant woman and/or fetus), 13% had inclusionary policies (i.e., pregnant women should or must be included in research unless there is a valid scientific or ethical reason for exclusion), and 11% had exclusionary policies (i.e., pregnant women should or must be excluded from research unless there is a valid scientific or ethical reason for inclusion). In the US study, 96% of institutions had risk-based policies, 3% had exclusionary policies, and 1% had inclusionary policies. We also found that many policies referred to pregnant women as vulnerable. To promote fair and responsible inclusion of pregnant women in research, academic institutions, sponsors, and oversight agencies should adopt and implement policies with inclusionary language and refrain from referring to pregnant women as vulnerable.

Facilitating inclusion of pregnant women in clinical research could help answer important questions about the effects of medication use during pregnancy and the ways in which pregnancy alters pharmacokinetics and drug effects.

The Call for Health Care Reform and the Pediatric Nursing Shortage