In my view, the pharma industry is not yet doing enough to address the lack of prescribing information available for pregnant women – but right now, none of us are. Unfortunately, there are important disincentives. Some of them are economic, but there are regulatory and ethical complexities as well. Caution is often preached when it comes to pregnant women and research, but I think it is important to think about the ways that caution has been distributed – unevenly and unfairly. Of course testing medicines and prescribing them in pregnancy is an area that requires care and caution, given the risks that some of these medications might entail for women and their offspring. But much less attention has been paid to the risks of not testing or prescribing, and those risks can be significant.
The unwillingness to test medications has led to a dearth of data to guide dosing or give providers information about the safety profile of medication, and can make them reticent to use medications important for maternal or fetal health. Often providers making prescribing decisions (and women too) think that by not prescribing (or taking) medicine they are being “better safe than sorry.” But failure to treat illness can have dire consequences: in pregnancy, untreated depression is associated with fetal growth restriction and prematurity, even suicide; untreated asthma is associated with preeclampsia, premature delivery, hemorrhage and low birthweight; in women with diabetes, inadequate glucose control can result in a high chance of severe birth defects; failure to continue treatment for multiple sclerosis in pregnancy can leave women permanently unable to walk. When essential medication is avoided, the risks to women and their children can be huge.
As a physician, I often felt frustrated about not being able to provide the data or reassurance my pregnant patients need and deserve when it comes to the medicines they take – and that frustration has profoundly shaped my career. My medical training is in obstetrics and gynecology, and I was particularly drawn to the field because of the complex social and ethical issues involved in treating pregnant women. As I took care of patients and encountered these myriad issues, I found that there was not much in the literature to help me navigate them. It occurred to me that there was a big gap – and a significant need – for a conversation around these issues that was steeped in both clinical and scientific expertise, as well as robust social and ethical methods and theory. I did a fellowship in bioethics, and from then on my approach has always been at the intersection of ethics and women’s health. And it is an intersection that still requires a tremendous amount of work.
As I identified pressing questions facing women’s health, and worked to address them, my passion only grew. And as a physician caring for women, I found the lack of evidence to guide care not only frustrating but also, to be frank, ethically unacceptable. I would have a patient who needed a medication to stay healthy during pregnancy but could offer only experience and intuition to assure her that the drug I was prescribing was safe and effective in her changing body – but I could not offer her scientific evidence. I could emphasize what we knew about the harms of not taking any medication (which tend to be greater than the risks of taking them), but I knew my patients deserved better.
A question of ethics
As I learned more, I was also concerned about the way that people were construing what ethics required. I have served on several research oversight committees (Institutional Review Boards, or IRBs) over the years. Most studies that we reviewed excluded pregnant women, even studies that didn’t impose any risk, like interview studies. No wonder there was no data on drugs in pregnancy! Nobody on the IRBs talked about whether this was appropriate or fair. When I raised the question of whether it was right to exclude pregnant women, I didn’t get much traction. Some IRB members thought it was outside the scope of the IRBs authority – offering that their primary purpose was to protect people from the harms of research rather than make sure there was fair access to its benefits. Others suggested that it would be too ethically complex – or unethical altogether – to expose pregnant women to the risks of research.
I realized that we needed clarity on the requirements of ethics, and so I partnered with two colleagues in bioethics – Maggie Little at Georgetown, and Ruth Faden at Johns Hopkins. We published a paper that explained the ways in which exclusion of pregnant women was ethically problematic (1). We argued that ethics doesn’t preclude their inclusion in research; rather, ethics requires it! And from there the Second Wave Initiative – a research and advocacy effort to ensure that the health needs of pregnant women are fairly addressed in the biomedical research agenda – was launched.
Bringing pregnant women into the picture
Our initial goal was to make vivid the ways in which the status quo – that pregnant women and their interests were excluded from most research – was ethically unacceptable. We laid out the reasons in our paper and in several other articles in the literature, as well as raising the subject in the media. When issues arose that highlighted the problems of exclusion, we wrote about them too.
For instance, as the H1N1 epidemic hit and disproportionately affected pregnant women in 2009, we wrote in the New York Times about the ways in which the absence of data for anti-influenza medications may have made matters worse (2). Later that year, we wrote a longer piece in the Times about the ways that the lack of evidence harmed women in the context of H1N1, and the importance of gathering the needed evidence (3). We also pointed out opportunities to collect what we called “low hanging fruit”: data that could be gathered without imposing any risk on women or solving any difficult ethical puzzles. One example was a piece we wrote in the American Journal of Public Health about the National Children’s Study, a large US study that planned to collect data on the effects of the environment on 100,000 children – at least 90,000 of which would be enrolled before birth (4). In other words, this was a huge study that enrolled pregnant women. But as designed, maternal health indicators were collected only as predictors of children’s health. In short, the study enrolled pregnant women but studied them as part of a child’s “environment” rather than as ends in themselves.
Clearly, we need to get pregnant women, and their health interests, back into view. It seems like the Second Wave Initiative is taking hold, and a conversation about the evidence gaps around pregnant women and the harms that ensue is developing. For instance, this year we will have a report from PRGLAC, the NIH task force established by the 21st Century Cures Act to advise the secretary of Health and Human Services (HHS) on gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women (see “A Tall Task”). In addition, the FDA recently asked for feedback on draft guidance for research with pregnant women. In that document, they described the need to fill research gaps for drugs and biologics in pregnancy as a “critical public health need” – an important and powerful statement from the FDA. And it is also absolutely true. We simply cannot afford to continue to leave pregnant women out of conversations about public health.
Right now, my research group is working hard on what we call the PHASES Project (www.hivpregnancyethics.org). It is an NIH-funded project that I have been leading addressing ethical challenges to filling research gaps around pregnancy and HIV and it comorbidities. We have done extensive research and stakeholder engagement, including a qualitative study of 140 women in the US and Malawi that explored their views and experiences about HIV research and pregnancy, as well as interviews with a range of individuals who help shape the HIV research landscape, including researchers, scientists, policymakers, IRB members and other experts in the US and Southern Africa, and are in the process of publishing our findings (5). We have convened a Working Group of truly outstanding leaders in HIV and women’s health that is charged with developing ethics guidance for HIV research in pregnancy, which we hope to launch later this year.
Exclusion brings its own risks
As for my advice to pharma: it is important for any entity conducting research to consider pregnant women and their interests in their product development plans. For instance, for drugs likely to be used by pregnant women, reprotoxicity studies should be conducted earlier – ideally before large scale efficacy trials are underway. Pharmacokinetic studies should also be conducted where drugs are likely to be used in pregnant women. Often these studies can be done “opportunistically” meaning the research-specific risks are minimal and limited to the risks of a blood draw.
I would urge the pharma industry to be mindful of the risks of not conducting these trials. You only need look to the recent events around the HIV medication, Dolutegravir. After it was widely distributed, a prospective study suggested an increased risk of neural tube defects among children whose mothers took the drug around the time of conception (these findings are preliminary, and further data are needed to confirm or refute them) (6). Such information is absolutely critical to helping patients make informed decisions about which medications to take, and also about contraception and pregnancy. Some people may worry that findings like this – that may or may not be clinically significant – could interfere with development of potentially beneficial drugs. But as obstetricians and others are very aware, few decisions, including the decision not to take a medication, are risk-free. Clearer data on the risks and benefits of drugs to pregnant women will help us all identify the best ratio of benefit versus risk, allowing us to optimize care for both women and their children.
- AD Lyerly et al., “The second wave: towards responsible inclusion of pregnant women in research”, Int J Fem Approaches Bioeth, 1, 5–22 (2008). DOI: 10.1353/ijf.0.0047.
- The New York Times, “A custom drug”, (2009). Available at: bit.ly/customdrug. Accessed October 2, 2018.
- The New York Times, “Pregnancy is no time to refuse a flu shot”, (2009). Available at: bit.ly/NYTflushot. Accessed October 2, 2018.
- AD Lyerly et al., “The National Children’s Study: a golden opportunity to advance the health of pregnant women”, Am J Public Health, 99, 1742–1745 (2009). DOI: 10.2105/AJPH.2009.165498.
- KA Sullivan et al., “Women’s views about a paternal consent requirement for biomedical research in pregnancy”, J Empir Res Hum Res Ethics, 13, 349–362 (2018). DOI: 10.1177/1556264618783834.
- R Zash et al., “Neural-tube defects with dolutegravir treatment from the time of conception.” New Engl J Med, 379, 979-81 (2018). DOI: 10.1056/nejmc1807653.
Anne Drapkin Lyerly is MD, Professor, Department of Social Medicine; Research Professor, Department of Obstetrics/Gynecology; Associate Director, Center for Bioethics, University of North Carolina at Chapel Hill, USA.
