ABSTRACT: All women should be presumed to be eligible for participation in clinical studies. The potential for pregnancy should not automatically exclude a woman from participating in a clinical study, although the use of contraception may be required for participation. Research objectives should not interfere with appropriate clinical management. If a conflict arises between medically appropriate patient care and research objectives, patient care should prevail. Consent of the pregnant woman alone is sufficient for most research. Pregnant women considering participation in a research study should determine the extent to which the father is to be involved in the process of informed consent and the decision.
* Update of “Research Involving Women,” in Ethics in Obstetrics and Gynecology, Second Edition, 2004.
Attitudes concerning inclusion of women in research trials have changed dramatically over the past four decades. In the 1970s and 1980s, women were systematically excluded from participating in research trials either because of the fear that unrecognized pregnancy might place an embryo at risk or because a uniform all-male sample would simplify analysis of data. In addition, pregnant women were excluded from most research trials because they were viewed as a vulnerable population requiring special protection, and there was concern that trial participation would result in harm to the fetus. Another fear was that participation of pregnant women in research trials would result in increased liability risk for researchers. In the 1990s, there was a dramatic policy shift toward wide-scale inclusion of women in research trials. This policy shift is a direct result of a conscious effort by government agencies to expand participation of women in research in order to obtain valid, evidence-based information about health and disease in this population (1).
This Committee Opinion is designed to provide reasonable guidelines for research involving women. The American College of Obstetricians and Gynecologists' Committee on Ethics affirms both the need for women to serve as participants in research and the obligation for researchers, institutional review boards (IRBs), and others reviewing clinical research to evaluate the potential effect of proposed research on women of childbearing potential, pregnant women, and the developing fetus.
Rationale for Including Women in Research
All women should be presumed to be eligible for participation in clinical studies. The potential for pregnancy should not automatically exclude a woman from participating in a clinical study, although the use of contraception may be required for participation. Inclusion of women in clinical studies is necessary for valid inferences about health and disease in women. The generalization to women of results from trials conducted in men may yield erroneous conclusions that fail to account for the biologic differences between men and women.
The rationale for conducting research in women is to advance knowledge in the following areas:
- Medical conditions in women (eg, cardiovascular disease)
- Physiology of women
- Sex differences in responses to drugs (eg, antiretroviral agents)
- Sex differences in drug toxicities
- Sex differences in responses to disease (eg, mental disorders)
- Effects of hormonal contraceptives on response to other therapies (eg, seizure medication)
- Variations in response to therapy at different stages of the menstrual cycle and the life cycle
The rationale for conducting research in pregnant and postpartum women is to advance knowledge in the following areas:
- Medical conditions (eg, human immunodeficiency virus [HIV]) in women who become pregnant
- Medical conditions unique to pregnancy (eg, preeclampsia)
- Conditions that threaten the successful course of pregnancy (eg, preterm labor)
- Prenatal conditions that might threaten the health of the fetus (eg, diaphragmatic hernia)
- Physiologic changes that accompany pregnancy and lactation
- Medical conditions related to pregnancy that might affect the future health of women (eg, gestational diabetes)
- Safety of medication during pregnancy and breastfeeding
Human experimentation is a necessary and important part of biomedical research because certain information can be obtained in no other way. Guidelines for protection of research participants have been established and are applicable to women of childbearing potential as well as to pregnant women (2–4). Additional protections have been established for pregnant women (5, 6). Participants in research should expect full disclosure of the known burdens and benefits of the research study and should understand the potential risks as well as benefits. Investigators must use research design methods that aim to maximize safety and minimize risk. A fully informed consent process and review of study protocols by IRBs help to ensure that efforts to increase access to and participation of women in clinical trials will not result in procedural shortcuts that violate basic ethical standards.
Involvement in research protocols should not diminish a woman's expectation that she will receive appropriate medical care during the study and in the future. Health care professionals have a responsibility to provide the most appropriate clinical management, whether or not a woman is a participant in research. Research objectives should not affect clinical management. If a conflict arises between medically appropriate patient care and research objectives, patient care should prevail. For example, it is inappropriate to attempt to delay a medically indicated induction of labor solely to meet gestational age criteria for participation in a research project. The welfare of the patient and, in the case of pregnancy, the patient and her fetus is always the primary concern.
The Ethical Context
Ethical Requirements for Research
To be considered ethically justified, research on human participants must satisfy several conditions. These include a reasonable prospect that the investigation will produce the knowledge that is being sought, a favorable balance of benefits over risks, a proven necessity to use human participants, a system for independent monitoring of outcomes and protection of human participants, and a fair allocation of the burdens and benefits of the research among potential groups of participants (7). These principles should not be weakened by attempts to increase participation of women in research trials.
Although it is important to try to distinguish ethical problems involving patient care from ethical issues related to research, a definitive line cannot always be drawn between the two areas. The dual role that physicians often assume as research scientists and clinical practitioners may result in conflict of interest because each role has different goals and priorities. For example, the primary goal of the investigator is to generate knowledge that has the potential to benefit patients in the future, whereas clinicians are expected to act in the best interests of their current patients. Researchers need to recognize potential conflicts, strive to resolve them before beginning specific research projects, and inform patients about potential conflicts as they seek consent for research participation.
The potential for role conflict becomes readily apparent when innovative therapies are introduced (8). In the context of maternal–fetal surgery, for example, innovative surgical procedures have been conducted, but the long-term impact on both the woman and the fetus is unclear. In this context, it is important to conduct rigorous scientific evaluation of maternal–fetal surgery before these innovative therapies are offered as routine care.
Ethical Principles Supporting the Inclusion of Women
The recent movement to enroll more women in clinical research can be justified by ethical principles: beneficence, nonmaleficence, respect for autonomy, and justice. Because disease processes may have different characteristics in women and men and because women and men may respond differently to treatments and interventions, women need to be included as participants in clinical research. For women to benefit from the results of research (beneficence), the research must be designed to provide a valid analysis as to whether women are affected differently than men (1). Such differential analysis is necessary not only to benefit women, but also to prevent harm; if data from studies with men are inappropriately extrapolated to women, women may actually suffer harm (nonmaleficence).
Arguments previously advanced to defend the exclusion of women from research often cited the possibility of harm to women of reproductive potential or to pregnant women and their fetuses, harm that did not apply to men. However, the risk of such harm can be minimized and, in itself, does not justify the exclusion of women from research that is needed to make valid inferences about the medical treatment of women.
Women have frequently been regarded as a vulnerable population that needs to be protected. Today, however, both civil society and medical ethics recognize the right and the capacity of women to make decisions regarding their own lives and their medical care (respect for autonomy). Similarly, women have the right and the capacity to weigh the risks and potential benefits of participation in research and to decide for themselves whether to consent to participate. This autonomy right is limited, however, by the responsibility of investigators and IRBs to take precautions to limit the risk for research participants, including pregnant women and their fetuses.
Systematic exclusion of women from research violates the ethical principle of justice, which first requires that persons be given what is due them. If the medical treatment of women is invalidly based on studies that excluded women, then women are not receiving fair treatment. Justice requires that women be included in clinical studies in sufficient numbers to determine whether their responses are different from those of men.
In the research setting, justice requires that the benefits of scientific advancement be shared fairly between men and women. Both women and men should be encouraged to participate in research. Researchers should specifically address those obstacles to participation that are experienced disproportionately by women—for example, problems obtaining and paying for adequate child care during time spent as a research participant.
Because of a history of systematic exclusion of women from research, in 1993 Congress directed that women were to be included in all federally funded research projects (9). Consequently, the National Institutes of Health (NIH) now require that women be included in all NIH-funded clinical research, unless a clear and compelling rationale establishes that such involvement would be inappropriate or unsafe (1). Particular focus on the health needs of women is justifiable at this time in view of a history of neglect of such studies.
Appropriate and adequately informed consent by the potential participant or another authorized person and an independent review of the risks and benefits of research by appropriate institutions or agencies (or both) are fundamental to the formulation of any research protocol (10). The informed consent process should not be weakened to benefit the researcher. The consent document should be understandable and written in simple language. In situations in which English is not the primary language of the potential study participant, an interpreter should be used for the consent process to verify the participant's level of understanding of the issues related to risk and benefit. The statement of informed consent may need to be translated into the participant's native language. Researchers should be familiar with federal and state laws and regulations for informed consent in settings where pregnant minors and adolescents may be recruited as participants (11).
The researcher has an obligation to disclose to the woman and discuss with her all material risks affecting her; in the case of a pregnant woman, this includes all material risks to the woman and her fetus (12). Disclosure should include risks that are likely to affect the patient's decision to participate or not to participate in the research. Because the process of informed consent cannot anticipate all conceivable risks, women who develop unanticipated complications should be instructed to contact the researcher or a representative of the IRB immediately. Pregnant women who enroll in a research trial and experience a research-related injury should be informed about their therapeutic options, including those related to the pregnancy.
The potential participant should be encouraged to consult her physician independently before deciding to participate in a research study (13). At the woman's request, the researcher should provide information about the study to her physician. If relevant, this information may include the requirements of the study and its possible outcomes and complications.
Both the researcher and the primary caregiver should guard against inflating the patient's perception of the therapeutic benefit expected from participating in the study. Studies have shown that research participants tend to believe, despite careful explanation of research protocols, that they will always benefit from participation or that the level of actual benefit will be greater than stated in the consent process (14). This risk of “therapeutic misconception” may be increased when the patient's own physician is involved in the consent process, especially when one physician serves as both researcher and clinician.
Consent of the pregnant woman alone is sufficient for most research. When research has the prospect of direct benefit to the fetus alone, paternal consent also may be required (see Table 1). Federal regulations that call for involvement of the father in the consent process for research intended to benefit the fetus are controversial and have generated vigorous debate. Proponents of paternal consent endorse this requirement because they believe that the requirement is consistent with recognition of and respect for the rights of the father in protecting the welfare of his unborn child. They believe that this represents a reasonable compromise between acknowledging paternal rights and reducing barriers to participationin research by pregnant women.
|Table 1. Selected Federal Regulations on Informed Consent for Participants in Human Research*
||45 C.F.R. §46.204(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 of subpart A†
of this part;
||45 C.F.R. §46.204(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
|*Federal regulations on protection of human research participants are found in the Code of Federal Regulations in Title 45, Part 46. Selected sections of the regulations dealing with informed consent are reprinted here; the complete, current version may be found at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.
†Basic HHS policy for protection of human research subjects. 45 C.F.R. §46.101–124 Subpart A (2006).
The Committee on Ethics, however, does not support recognition of distinct paternal rights before the birth of a child. Recognition of paternal rights during pregnancy may infringe on and weaken maternal autonomy—the right of a woman, when pregnant, to independent action in decisions that affect her body and her health. As in clinical situations, the pregnant woman's consent should be sufficient for research interventions that affect her or her fetus. To further complicate matters, the interpretation as to whether research is intended for the benefit of the pregnant woman, the fetus, or both may be subjective. Two researchers conducting identical studies may reach different conclusions as to whether benefits of the research apply to the pregnant woman, the fetus, or both (eg, maternal–fetal surgery for spina bifida).
Informed consent means that women have the right to choose not to participate in a research protocol and the right to withdraw from a study at any time. The participation of a woman in a research study is based on the expectation that she will consider carefully her own interests. The participation of a pregnant woman in a research study is based on the expectation that she will consider carefully her own interests as well as those of her fetus. Typically, pregnant women are quite willing to take personal risks for the benefit of their fetuses; combined with society's expectation that they will do so, women may find themselves under pressure to participate in research that carries risk to them. Such pressure actually may interfere with the ability of the pregnant woman to give fully free consent. In these situations, special care should be taken to ensure that a woman's consent is truly voluntary.
Research Related to Diagnosis and Therapy
Research that consists of observation and recording without clinical intervention (descriptive research) is of ethical concern primarily to the extent that it requires informed consent and the preservation of confidentiality. In research trials where clinical intervention is a component, the benefits and burdens of the trial must be clearly articulated to the participant by the researcher (12). In research studies conducted in pregnant women, both the potential benefit to the woman, the fetus, and society as a whole and the level of risk that may be incurred as a result of participation in the study should be considered. The involvement of the participant's obstetrician ordinarily is appropriate. All parties concerned need to strive for clear communication with regard to the following questions:
- Does the research involve intervention or diagnosis that might affect the woman's or the fetus's well-being, or is the goal of the study to produce scientific results that will be likely to be useful to future patients but offer no demonstrable benefit to current participants?
- Can the prospective participant expect any explicit benefit as a result of participating in the study? If not, she must be apprised of this fact. Those studies that search for general information and are not associated with diagnostic or treatment modalities would be less likely to create the impression that the research will result in direct benefit to the participant. The researcher is still obligated to verify that the participant has understood this aspect of the study correctly.
- Is there more than “minimal risk” to the fetus generated by the research?
According to applicable federal regulations, “minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” (15). It has been questioned whether the “daily life” used for comparison should be that of the general population or that of the participant. Using the participant's daily life as the standard might make a higher level of risk acceptable; therefore, the general population standard is advised (10). Anything beyond minimal risk must be weighed carefully against the potential benefits to the woman and the fetus when the advisability of participation is considered. When a pregnancy has been exposed to risk in the conduct of research, the woman should be strongly encouraged to participate in follow-up evaluations to assess the impact on her and her fetus or child.
It is appropriate for investigators and sponsors, with the approval of the IRB, to require a negative pregnancy test result as a criterion for participation in research when the research may pose more than minimal risk to the fetus. For an adolescent, the process of informed consent should include a discussion about pregnancy testing and the management of pregnancy test results, including whether the results will be shared with her parents or guardian.
Similarly, it is reasonable for investigators and research sponsors, with the IRB's approval, to require the use of effective birth control measures for women of reproductive capacity as an inclusion criterion for participation in research that may entail more than minimal risk to the fetus. Consultation with an obstetrician–gynecologist or other knowledgeable professional is encouraged if questions arise about efficacy and risk of contraceptive measures.
Some study protocols mandate use of a specific contraceptive method, such as oral contraceptives or an intrauterine device. These mandates are inappropriate based on the principles of respect for autonomy, beneficence, and justice. A woman should be allowed to choose a birth control method, including abstinence, according to her needs and values (16). Requiring birth control use by women who are not sexually active violates a commitment to respect them as persons. Hormonal contraceptive methods that could interfere with study results may be excluded on scientific grounds, but additional restrictions are inappropriate.
After informed discussion about the research trial, some women will decline to participate. Researchers should respect this decision and not allow patient refusal to affect subsequent clinical care. Reasonable compensation for a woman's time, effort, and expense as a participant in a research study is both acceptable and desired, but researchers should not offer inducements, financial or otherwise, to influence participation in research beyond reasonable compensation for the woman's time, effort, and expense.
Recommendations of the Committee on Ethics
Federal and state laws and regulations governing research involving women should be observed (2, 5, 11). In addition, the Committee on Ethics makes the following recommendations for research involving women:
- Women should be presumed to be eligible for participation in all clinical studies except for those addressing health concerns solely relevant to men.
- Women should be included in research in sufficient numbers to ensure that inferences from a clinical trial apply validly to both sexes.
- All research on women should be conducted in a manner consistent with the following ethical principles:
- Research should conform to general scientific standards for valid research.
- Research may be conducted only with the informed consent of the woman.
- Researchers should not offer inducements, financial or otherwise, to influence participation in research beyond reasonable compensation for the woman's time, effort, and expense.
- Conscientious efforts should be made to avoid any conflicts between appropriate health care and research objectives. Health care needs of the individual woman should take precedence over research interests in all situations affecting clinical management.
- Research involving pregnant women should conform to the following recommendations:
- Research may be conducted only with the informed consent of the woman. Pregnant women considering participation in a research study should determine the extent to which the father is to be involved in the process of informed consent and the decision.
- Informed consent of the father must be obtained when federal regulations require it for research that has the prospect of direct benefit to the fetus alone.
- Research protocols should be evaluated for their potential impact on both the woman and the fetus, and that evaluation should be made as part of the process of informed consent.
In this Committee Opinion, an attempt has been made to take into account protection of human participants, the eligibility of women to participate in research, and the benefits that society could derive from participation of women in research. These potential benefits include reduction in morbidity and mortality from sex-specific disease processes, as well as reduction in fetal, infant, and maternal morbidity and mortality.
- National Institutes of Health. NIH policy and guidelines on the inclusion of women and minorities as subjects in clinical research – Amended, October, 2001. Bethesda (MD): NIH; 2001. Available at http://grants.nih.gov/grants/ funding/women_min/guidelines_amended_10_2001.htm. Retrieved May 1, 2007.
- Protection of human subjects. 45 C.F.R. §46 (2006).
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (US). The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Washington, DC: U.S. Government Printing Office; 1979. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm. Retrieved May 1, 2007.
- World Medical Association. Declaration of Helsinki: Ethical principles for medical research involving human subjects. Ferney-Voltaire (France): WMA; 2004. Available at: http:// www.wma.net/e/policy/pdf/17c.pdf. Retrieved May 1, 2007.
- Additional protections for pregnant women, human fetuses and neonates involved in research. 45 C.F.R. §§46.201-207 Subpart B (2006).
- Research on transplantation of fetal tissue. Informed consent of donor. 42 U.S.C. §289g-1(b) (2000).
- Beauchamp TL. The intersection of research and practice. In: Goldworth A, Silverman W, Stevenson DK, Young EW, Rivers R. Ethics and perinatology. New York (NY): Oxford University Press; 1995. p. 231–44.
- Innovative practice: ethical guidelines. ACOG Committee Opinion No. 352. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006;108:1589–95.
- NIH Revitalization Act of 1993, Pub. L. No. 103-43 (1993).
- National Bioethics Advisory Commission. Ethical and policy issues in research involving human participants. Bethesda (MD): NBAC; 2001. Available at: http://www.georgetown.edu/research/nrcbl/nbac/human/overvol1.pdf. Retrieved May 1, 2007.
- Additional protections for children involved as subjects in research. 45 C.F.R. §§46.401–409 Subpart D (2006).
- General requirements for informed consent. 45 CFR §46.116 (2006).
- Institute of Medicine (US). Women and health research: ethical and legal issues of including women in clinical studies. Vol. 1. Washington, DC: National Academy Press; 1994.
- Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cent Rep 1987;17(2): 20–4.
- Definitions. 45 C.F.R. §46.102 (2006).
- Anderson JR, Schonfeld TL, Kelso TK, Prentice ED. Women in early phase trials: an IRB's deliberations. IRB 2003;25 (4):7–11.