Sylvia Baedorf Kassis, MPH
Instructor, Master of Science in Clinical Investigation (MSCI) Program, Boston University School of Medicine, Division of Graduate Medical Sciences, Boston, MA, USA
According to the 2010 National Survey on Drug Use and Health, an estimated 4.4% of pregnant women reported illicit drug use in the past 30 days, including heroin and the harmful use of prescription opioid analgesic medications.1,2 Given the prevalence of substance use in this population, as well as the potential benefits and unknown consequences of intervention for both the pregnant mother and fetus, clinicians require a solid evidence base for how best to treat pregnant women with unhealthy substance use.
The Belmont Principle of Justice dictates that the burdens and benefits of research be distributed fairly and equally,3 yet the current regulatory framework and a pervasive fear of legal liability discourage the inclusion of pregnant women in clinical trials testing pharmacologic treatments because of the potential risk to the fetus. In recent years, research ethics thought leaders have begun calling for medical researchers and pharmaceutical manufacturers to reconsider the exclusion of pregnant women from clinical research and challenging Institutional Review Boards (IRBs) to approve their responsible inclusion.4 For researchers interested in studying treatments for addiction in pregnancy, understanding the regulations and developing a thoughtful, well-justified study protocol are essential.
Current regulations regarding the inclusion of pregnant women in research studies have been influenced by several factors. According to Levine, the US Supreme Court’s 1973 decision in Roe v. Wade to legalize abortion led to an ongoing ethical controversy surrounding a woman’s right to choose as balanced against the potential rights of a fetus.3 Further, the devastating consequences of treating pregnant women with thalidomide, diethylstilbestrol, and the Dalkon Shield adversely affected research among this population, in spite of the fact that none of those consequences were the result of pregnant women’s participation in research.4 In fact, these tragedies were largely the unfortunate result of too little available research data to inform the use of medications in pregnancy. Nevertheless, the effect of these events was a move to categorize pregnant women as a vulnerable population requiring special protections. While the resulting research regulations provide important safeguards to women and fetuses, they also place serious restrictions on the systematic collection of data, thus limiting the evidence-based practice of medicine in this group.
The inclusion of pregnant women and fetuses in clinical research is covered under 45 CFR 46.204 of Subpart B of the Code of Federal Regulations,5 which states that pregnant women and their fetuses can be included only if the study meets 10 criteria concerning preclinical study data availability, the risk profile, potential benefits, informed consent provisions, pregnant minors, and pregnancy termination (see Table). However, ambiguity in the wording of some of these criteria can present significant challenges to IRBs and impede approval of the research, particularly in evaluating whether the research risk to the fetus is greater than minimal when there is little to no benefit to either woman or fetus. IRBs are left to grapple with just how much risk is acceptable. Even in cases of potential benefit to the fetus and/or pregnant woman, as in addiction treatment studies, the frequently narrow interpretation of the regulations either encourages the removal of pregnant women from the study design or altogether discourages research aimed at studying this population. Despite general agreement that pregnant women should have access to sound information and advice upon which to base medical decisions for themselves and their fetuses, due largely to concern over legal liability IRBs tend to be highly conservative regarding the review and approval of research involving women who are, or could become, pregnant.4
Table: 45 CFR 46.204, Subpart B: Pregnant women or fetuses may be involved in research if ALL of the following conditions are met:
|a. Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
b. The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means;
c. Any risk is the least possible for achieving the objectives of the research;
d. If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with the informed consent provisions;
e. If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of subpart A of this part, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest;
f. Each individual providing consent under paragraph (d) or (e) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
g. For children as defined in Sec. 46.402(a) who are pregnant, assent and permission are obtained in accord with the provisions of the Protections for Children Involved as Subjects (Subpart D);
h. No inducements, monetary or otherwise, will be offered to terminate a pregnancy;
i. Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; AND
j. Individuals engaged in the research will have no part in determining the viability of a neonate.
More Recent Considerations
A general increase in the understanding of the complex physiologic changes of pregnancy—including metabolism, body weight, plasma volume, and hormone levels—has exposed the clear limitations of applying data from other populations to pregnant women. As such, this population needs safe and effective treatment with adequate pharmacokinetic details to identify the appropriate therapeutic dose of medications across each of the trimesters of pregnancy and to quantify the risks of exposure of the fetus.6 In addition, reticence to treat pregnant women because of concern over limited fetal safety data has its own risks, as is often seen in under- or untreated asthma, depression, diabetes, and cancer.6
Consequently, in recent years there has been a backlash against conservative regulatory interpretations and a call for pregnant women to be thought of as complex rather than vulnerable research subjects so that issues relevant to all aspects of women’s health can be appropriately studied. “Complex” means that there are special considerations to take into account in studying them; not that they should be protected from inclusion in research.4 The ethical imperative is that the responsible inclusion of pregnant women in research is to the benefit of the subjects. But given the highly protectionist regulatory environment, how can researchers move forward with gathering evidence that could benefit this population?
Toward the Responsible Inclusion of Pregnant Women in Addiction Research
While there are clearly agents that should not be studied in pregnancy because of their known toxic or teratogenic effects, substance use disorders pose such a high risk to pregnancy outcomes that research on addiction treatments can often be readily justified. For example, the Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study, is a randomized controlled trial of the impact of methadone versus buprenorphine treatment during pregnancy on maternal outcomes and on the occurrence of neonatal abstinence syndrome.7 In a discussion of the study at an NIH workshop on the inclusion of pregnant women in clinical research, Jones noted that that the ethics approval process had not been particularly challenging, and credited her IRB’s experience with two similar protocols for the favorable review.4 Despite the reported ease of the MOTHER study’s approval, however, if a researcher is interested in pursuing such an area of investigation, it is often in the best interest of the study to start a conversation with the local IRB early in the protocol development process. Such proactive behavior enables the IRB to pre-emptively review the relevant regulations and guidance documents and allows researchers to feel out the regulatory climate at their institution so that potential issues can be addressed in advance. Since the decision to enroll pregnant women in a specific trial must be based on a careful risk/benefit assessment, consideration of the following aspects, in collaboration with local IRB professionals, can support researchers’ efforts to include pregnant women in their studies:
- Prior studies:
- Have any similar studies been approved by the local IRB? If so, how did investigators address any ethical concerns in order to allow the study to proceed?
- What are the current standards of care and limits of knowledge for the condition under study in pregnant women? Justify the inclusion of pregnant women:
- Why must this population be studied?
- How does the topic under investigation affect pregnant women?
- What are the risks to the pregnant woman and the fetus, and how will they be minimized?
- Argue why it would be unethical to exclude pregnant women from the research study.
- Develop a thoughtful recruitment strategy:
- Is it possible to include a pre-screen of medical records to approach only those who have a high probability of being eligible in order to minimize distress due to exclusion?4
- Address issues of informed consent:
- What information do pregnant women need about the known and unknown risks, as well as the potential benefits, of the agent under investigation in order to give truly informed consent?
- For multi-center studies, consider the comprehensive care environment and culture at each of the sites:
- What is the experience of the sites with pregnant women who have opioid dependence?
- What outcome measures will be monitored throughout the pregnancy?
- Will there be any long-term follow-up of the child?
- Should a pharmacokinetic component be added to the study?
Greater detail on the aforementioned considerations can be found in the report of the United States Office of Research on Women’s Health 2010 scientific forum: “Issues in Clinical Research: Enrolling Pregnant Women,”4 and Health Canada’s 2012 “Draft Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Data by Sex.”8
While current federal research regulations and the fear of legal liability can impede the enrollment of pregnant women in clinical trials, there has been a recent movement encouraging the responsible inclusion of this population. Researchers interested in studying pregnant women in trials of treatments for substance use disorders should consider the regulatory environment at their institution and craft a thoughtful justification for why this population must be studied.
1. The American College of Obstetricians and Gynecologists: Committee on Health Care for Underserved Women and the American Society of Addiction Medicine. Committee Opinion on Opioid Abuse, Dependence, and Addiction in Pregnancy. Number 524, May 2012. Available at: http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Health_Care_for_Underserved_Women/Opioid_Abuse_Dependence_and_Addiction_in_Pregnancy
2. Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-41, HHS Publication No. (SMA) 11-4658. Rockville, MD: SAHMSA; 2011. Available at: http://www.oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.pdf.
3. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Bethesda, MD: OHSR; 1979. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html.
4. US Department of Health and Human Services, Public Health Service, National Institutes of Health, Office of Research on Women’s Health. Enrolling Pregnant Women: Issues in Clinical Research. Bethesda, MD: National Institutes of Health; 2011. Available at:
5. US Department of Health and Human Services: Code of Federal Regulations no. 45 CFR 46, Subpart B. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb.
6. Foulkes MA, Grady C, Spong CY, et al. Clinical research enrolling pregnant women: a workshop summary. J Womens Health. 2011;20(10):1429–1432.
7. Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363(24):2320–2331.
8. Health Canada. Draft Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Data by Sex. 9 January 2012. Available at: http://www.hc-sc.gc.ca/dhp-mps/consultation/biolog/draft_iwct_ebauche_ifec/lett-eng.php#a25.