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Ethical considerations in research involving pregnant women12
ACOG Committee Opinion Ethical Considerations in Research Involving Pregnant Women The American College of Obstetricians and Gynecologists 409 12th Street, SW PO Box 96920 Washington, DC 20090-6920
This Committee Opinion is designed to provide reasonable guidelines for research that involves pregnant women. In the past, investigators have been reluctant to conduct research on pregnant women because of concerns for the potential to do harm to the fetus. Although attention to the ethical principle of nonmaleficence is admirable, the resulting sense of restraint has limited the growth of knowledge in some areas of normal physiology, pathophysiology, and therapeutic approaches during pregnancy. In this Committee Opinion, the Committee on Ethics affirms both the need for such research and the obligation for researchers, institutional review boards, and others reviewing clinical research to evaluate with extreme care the potential effects of proposed research on the pregnant woman and the developing fetus (1). Pregnant women should be presumed to be eligible for participation in clinical studies even if the research is not primarily related to pregnancy (2). Research should be encouraged to advance the management of 1) underlying medical conditions in women who become pregnant, 2) conditions of pregnancy, 3) complications of pregnancy, and 4) prenatal conditions that might threaten the health of the resulting child. Human experimentation is a necessary part of medical research because certain information can be obtained in no other way. For example, human immunodeficiency virus (HIV) infection research using zidovudine (AZT) for pregnant women resulted in a significant reduction of the incidence of transmission of the virus to offspring (3). Such experimentation may be attended by a certain element of risk. Investigators must therefore use research design methods that employ all available means to maximize safety and to narrow risk. Involvement in research protocols in no way diminishes the physician’s responsibility to provide the most appropriate clinical management. Research objectives should not affect clinical management. 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 her fetus is always the primary concern. Guidelines for protection of research participants are applicable to all pregnant women, regardless of the woman’s intention to complete the pregnancy (4 – 6). Neither physician nor patient should be expected to participate in research that is contrary to personal ethical judgment. 194
WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999
Reprinted with permission from ACOG Committee Opinion, Number 213, November 1998 Requests for authorization to make photocopies should be directed to: Copyright Clearance Center 222 Rosewood Drive Danvers, MA 01923 (978) 750-8400 © 1999 by the Jacobs Institute of Women’s Health Published by Elsevier Science Inc. 1049-3867/99/$20.00 PII S1049-3867(99)00015-8
THE CONTEXT: ETHICS IN RESEARCH To be considered ethically justified, human research 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 subjects, a system for independent monitoring of outcomes and of protection of human subjects, and a fair allocation of the burdens and benefits of research among potential subject groups (7). Although it is important to try to distinguish ethical problems involving patient care from ethical issues related to research, a definite line cannot always be drawn between these two areas. Physicians often assume the dual role of research scientist and clinical practitioner, which may result in serious conflicts of interest. Patients may experience confusion as to whether they are, in fact, research subjects. The function of the investigator is to generate knowledge that has the potential to benefit patients in the future. But clinicians are expected to act in the best interests of their own current patients. Researchers need to recognize these potential problems, strive to resolve them before beginning specific research projects, and inform patients about potential conflicts as they seek consent for research participation.
INFORMED CONSENT Appropriate and adequately informed consent and institutional or agency review, or both, are fundamental to the formulation of any research protocol (8). The researcher has an obligation to disclose and discuss all material risks to the woman and fetus— ones that are likely to affect the patient’s decision to participate or not in the research. Research that consists of observation and recording without clinical intervention is of ethical concern only insofar as it may involve informed consent and the preservation of confidentiality. Informed consent is an intentional and voluntary process that grants a clinician or researcher the authority to perform certain interventions. It implies the possibility of choosing not to participate in a research protocol and the right to withdraw from a study at any time. The participation of a pregnant woman in a research study is based on the expectation that she will consider carefully the best interests of the fetus as well as her own interests.
INVOLVEMENT OF PRIMARY CAREGIVERS IN THE CONSENT PROCESS The decision to participate in a research project that involves pregnant women requires a complex weighing of risk and benefit for mother and fetus. It is generally advantageous for the researcher to include the patient’s attending obstetrician or primary caregiver in the informed consent process prior to the patient’s enrollment in a study. This physician often has general knowledge of a woman’s history, family, values, and lifestyle that may be helpful in the informed consent process. The patient should be encouraged to consult her attending obstetrician independently before deciding to participate (9). When the attending physician is not initially involved in the consent process, the researcher still has an obligation to provide information about the study to the patient’s primary caregiver, unless the patient has a specific objection. This information should include the requirements of the study and its possible outcomes and complications. 195
Both researcher and primary caregiver should avoid inappropriately inflating the patient’s perception of the therapeutic benefit expected from participation in the study. Studies have shown that research subjects tend to believe, despite careful explanation of research protocols, that they will benefit from participation in the study (10). This risk of “therapeutic misconception” may be increased when the patient’s own physician is involved in the consent process and especially when one physician plays both research and clinical management roles.
RESEARCH RELATED TO DIAGNOSIS AND THERAPY Research during pregnancy requires balancing of risk and benefit for two distinct but interrelated entities—the pregnant woman and her fetus. The pregnant woman, the researcher, and the patient’s obstetrician must balance potential benefit to the woman, to the fetus, and to society as a whole against the level of risk that may be incurred as a result of participation in the study. All parties concerned need to strive for clear communication about the following issues:
• Does the research involve therapy or diagnosis that might influence 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 subjects? The prospective subject must be apprised if no explicit benefit is expected as a result of the study. 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 patient has understood this aspect of the study correctly. • Is there more than “minimal” incremental risk generated by the research? The researcher must be able to communicate to the potential subject the incremental risks entailed in the research (beyond the level of background risk) and the probability of occurrence of adverse events. Anything more than minimal incremental risk must be weighed carefully against the potential merit of the study in considering the advisability of participation. 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” (11).
RECOMMENDATIONS OF THE COMMITTEE ON ETHICS The Committee on Ethics makes the following recommendations for research involving pregnant women. In addition, federal regulations govern conduct of all federally funded research involving pregnant women or fetuses and serve as a pattern that should be observed in the design and implementation of all research on pregnant women (5): I. All research on pregnant women should be conducted in a manner consistent with the following ethical principles: A. It should conform to general scientific standards for research. B. Conscientious efforts should be made to avoid any financial or nonfinancial conflicts between appropriate health care and research objectives. C. Researchers should not offer inducements, financial or otherwise, designed to influence participation in research, beyond reasonable compensation for the pregnant woman’s time and expenses. This is especially important because the pregnant woman’s choices affect the fetus as well as herself. D. Health care needs of the individual patient should take precedence over research interests in all situations affecting clinical management.
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WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999
II. Research involving diagnostic and treatment modalities for either the pregnant woman or the fetus should conform to the following: A. Be conducted only with the informed consent of the pregnant woman. (Currently, federal regulations require informed consent of the father, if he is available, except when the research is designed to meet the health needs of the mother [12]. Proposed regulatory revisions would eliminate the requirement for paternal consent for all research described in section D below [13]. A decision on this issue had not been reached at the time of publication.) B. Be evaluated for its potential impact on the fetus, and that evaluation should be communicated as part of the informed consent process. C. Be conducted only when the alternative modalities available within the study are considered to be one of the following: 1. Therapeutic equivalents (clinical equipoise) (14) or 2. Superior to the alternative of not participating in the study. D. Be conducted only when any incremental risk to the fetus from participation in the research is minimal or is incurred because of activities designed to meet the health needs of the woman or the fetus. III. Research that does not have potential therapeutic value to either the pregnant woman or fetus is never appropriate if either might be placed at more than minimal risk.
Throughout the development of this Committee Opinion, there has been an attempt to strike a reasonable balance among protection of human subjects, the eligibility of pregnant women to participate in research, and the benefits that society could derive from advances in research. These potential benefits include reduction in fetal, infant, and maternal mortality and morbidity.
REFERENCES 1. Robertson J. Ethical issues related to the inclusion of pregnant women in clinical trials (I). In: Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 2. Washington, DC: National Academy Press, 1994:18 –22 2. Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 1. Washington, DC: National Academy Press, 1994:188 3. Connor EM, Sperling RS, Geber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173–1180 4. Department of Health, Education, and Welfare. Protection of human subjects: fetuses, pregnant women, and in vitro fertilization. Federal Register 1975;40:33256, 33552 5. Protection of Human Subjects, 45 C.F.R. Sect. 46(b) (1997) 6. Fetal Research, 42 U.S.C. Sect. 289g(b) (1996) 7. Beauchamp TL, Childress JF. Principles of biomedical ethics. 4th ed. New York: Oxford University Press, 1994:441 8. American College of Obstetricians and Gynecologists. Ethical dimensions of informed consent. ACOG Committee Opinion 108. Washington, DC: ACOG, 1992 9. Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 1. Washington, DC: National Academy Press, 1994:196 10. 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;17:20 –24 11. Protection of Human Subjects, 45 C.F.R. Sect. 46.102(i) (1997) 12. Protection of Human Subjects, 45 C.F.R. Sect. 46.207(b) (1997); Sect. 46.208(b) (1997) 13. Department of Health and Human Services. Protection of human subjects. Federal Register 1998;63:27794 –27804
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14. Beauchamp T. The intersection of research and practice. In: Goldworth A, Silverman W, Stevenson DK, Rivers R, Young EW, eds. Ethics and perinatology. New York: Oxford University Press, 1995:231–244
198
WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999
This Committee Opinion is designed to provide reasonable guidelines for research that involves pregnant women. In the past, investigators have been reluctant to conduct research on pregnant women because of concerns for the potential to do harm to the fetus. Although attention to the ethical principle of nonmaleficence is admirable, the resulting sense of restraint has limited the growth of knowledge in some areas of normal physiology, pathophysiology, and therapeutic approaches during pregnancy. In this Committee Opinion, the Committee on Ethics affirms both the need for such research and the obligation for researchers, institutional review boards, and others reviewing clinical research to evaluate with extreme care the potential effects of proposed research on the pregnant woman and the developing fetus (1). Pregnant women should be presumed to be eligible for participation in clinical studies even if the research is not primarily related to pregnancy (2). Research should be encouraged to advance the management of 1) underlying medical conditions in women who become pregnant, 2) conditions of pregnancy, 3) complications of pregnancy, and 4) prenatal conditions that might threaten the health of the resulting child. Human experimentation is a necessary part of medical research because certain information can be obtained in no other way. For example, human immunodeficiency virus (HIV) infection research using zidovudine (AZT) for pregnant women resulted in a significant reduction of the incidence of transmission of the virus to offspring (3). Such experimentation may be attended by a certain element of risk. Investigators must therefore use research design methods that employ all available means to maximize safety and to narrow risk. Involvement in research protocols in no way diminishes the physician’s responsibility to provide the most appropriate clinical management. Research objectives should not affect clinical management. 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 her fetus is always the primary concern. Guidelines for protection of research participants are applicable to all pregnant women, regardless of the woman’s intention to complete the pregnancy (4 – 6). Neither physician nor patient should be expected to participate in research that is contrary to personal ethical judgment. 194
WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999
Reprinted with permission from ACOG Committee Opinion, Number 213, November 1998 Requests for authorization to make photocopies should be directed to: Copyright Clearance Center 222 Rosewood Drive Danvers, MA 01923 (978) 750-8400 © 1999 by the Jacobs Institute of Women’s Health Published by Elsevier Science Inc. 1049-3867/99/$20.00 PII S1049-3867(99)00015-8
THE CONTEXT: ETHICS IN RESEARCH To be considered ethically justified, human research 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 subjects, a system for independent monitoring of outcomes and of protection of human subjects, and a fair allocation of the burdens and benefits of research among potential subject groups (7). Although it is important to try to distinguish ethical problems involving patient care from ethical issues related to research, a definite line cannot always be drawn between these two areas. Physicians often assume the dual role of research scientist and clinical practitioner, which may result in serious conflicts of interest. Patients may experience confusion as to whether they are, in fact, research subjects. The function of the investigator is to generate knowledge that has the potential to benefit patients in the future. But clinicians are expected to act in the best interests of their own current patients. Researchers need to recognize these potential problems, strive to resolve them before beginning specific research projects, and inform patients about potential conflicts as they seek consent for research participation.
INFORMED CONSENT Appropriate and adequately informed consent and institutional or agency review, or both, are fundamental to the formulation of any research protocol (8). The researcher has an obligation to disclose and discuss all material risks to the woman and fetus— ones that are likely to affect the patient’s decision to participate or not in the research. Research that consists of observation and recording without clinical intervention is of ethical concern only insofar as it may involve informed consent and the preservation of confidentiality. Informed consent is an intentional and voluntary process that grants a clinician or researcher the authority to perform certain interventions. It implies the possibility of choosing not to participate in a research protocol and the right to withdraw from a study at any time. The participation of a pregnant woman in a research study is based on the expectation that she will consider carefully the best interests of the fetus as well as her own interests.
INVOLVEMENT OF PRIMARY CAREGIVERS IN THE CONSENT PROCESS The decision to participate in a research project that involves pregnant women requires a complex weighing of risk and benefit for mother and fetus. It is generally advantageous for the researcher to include the patient’s attending obstetrician or primary caregiver in the informed consent process prior to the patient’s enrollment in a study. This physician often has general knowledge of a woman’s history, family, values, and lifestyle that may be helpful in the informed consent process. The patient should be encouraged to consult her attending obstetrician independently before deciding to participate (9). When the attending physician is not initially involved in the consent process, the researcher still has an obligation to provide information about the study to the patient’s primary caregiver, unless the patient has a specific objection. This information should include the requirements of the study and its possible outcomes and complications. 195
Both researcher and primary caregiver should avoid inappropriately inflating the patient’s perception of the therapeutic benefit expected from participation in the study. Studies have shown that research subjects tend to believe, despite careful explanation of research protocols, that they will benefit from participation in the study (10). This risk of “therapeutic misconception” may be increased when the patient’s own physician is involved in the consent process and especially when one physician plays both research and clinical management roles.
RESEARCH RELATED TO DIAGNOSIS AND THERAPY Research during pregnancy requires balancing of risk and benefit for two distinct but interrelated entities—the pregnant woman and her fetus. The pregnant woman, the researcher, and the patient’s obstetrician must balance potential benefit to the woman, to the fetus, and to society as a whole against the level of risk that may be incurred as a result of participation in the study. All parties concerned need to strive for clear communication about the following issues:
• Does the research involve therapy or diagnosis that might influence 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 subjects? The prospective subject must be apprised if no explicit benefit is expected as a result of the study. 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 patient has understood this aspect of the study correctly. • Is there more than “minimal” incremental risk generated by the research? The researcher must be able to communicate to the potential subject the incremental risks entailed in the research (beyond the level of background risk) and the probability of occurrence of adverse events. Anything more than minimal incremental risk must be weighed carefully against the potential merit of the study in considering the advisability of participation. 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” (11).
RECOMMENDATIONS OF THE COMMITTEE ON ETHICS The Committee on Ethics makes the following recommendations for research involving pregnant women. In addition, federal regulations govern conduct of all federally funded research involving pregnant women or fetuses and serve as a pattern that should be observed in the design and implementation of all research on pregnant women (5): I. All research on pregnant women should be conducted in a manner consistent with the following ethical principles: A. It should conform to general scientific standards for research. B. Conscientious efforts should be made to avoid any financial or nonfinancial conflicts between appropriate health care and research objectives. C. Researchers should not offer inducements, financial or otherwise, designed to influence participation in research, beyond reasonable compensation for the pregnant woman’s time and expenses. This is especially important because the pregnant woman’s choices affect the fetus as well as herself. D. Health care needs of the individual patient should take precedence over research interests in all situations affecting clinical management.
196
WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999
II. Research involving diagnostic and treatment modalities for either the pregnant woman or the fetus should conform to the following: A. Be conducted only with the informed consent of the pregnant woman. (Currently, federal regulations require informed consent of the father, if he is available, except when the research is designed to meet the health needs of the mother [12]. Proposed regulatory revisions would eliminate the requirement for paternal consent for all research described in section D below [13]. A decision on this issue had not been reached at the time of publication.) B. Be evaluated for its potential impact on the fetus, and that evaluation should be communicated as part of the informed consent process. C. Be conducted only when the alternative modalities available within the study are considered to be one of the following: 1. Therapeutic equivalents (clinical equipoise) (14) or 2. Superior to the alternative of not participating in the study. D. Be conducted only when any incremental risk to the fetus from participation in the research is minimal or is incurred because of activities designed to meet the health needs of the woman or the fetus. III. Research that does not have potential therapeutic value to either the pregnant woman or fetus is never appropriate if either might be placed at more than minimal risk.
Throughout the development of this Committee Opinion, there has been an attempt to strike a reasonable balance among protection of human subjects, the eligibility of pregnant women to participate in research, and the benefits that society could derive from advances in research. These potential benefits include reduction in fetal, infant, and maternal mortality and morbidity.
REFERENCES 1. Robertson J. Ethical issues related to the inclusion of pregnant women in clinical trials (I). In: Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 2. Washington, DC: National Academy Press, 1994:18 –22 2. Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 1. Washington, DC: National Academy Press, 1994:188 3. Connor EM, Sperling RS, Geber R, Kiselev P, Scott G, O’Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331:1173–1180 4. Department of Health, Education, and Welfare. Protection of human subjects: fetuses, pregnant women, and in vitro fertilization. Federal Register 1975;40:33256, 33552 5. Protection of Human Subjects, 45 C.F.R. Sect. 46(b) (1997) 6. Fetal Research, 42 U.S.C. Sect. 289g(b) (1996) 7. Beauchamp TL, Childress JF. Principles of biomedical ethics. 4th ed. New York: Oxford University Press, 1994:441 8. American College of Obstetricians and Gynecologists. Ethical dimensions of informed consent. ACOG Committee Opinion 108. Washington, DC: ACOG, 1992 9. Mastroianni AC, Faden R, Federman D, eds. Women and health research: ethical and legal issues of including women in clinical studies. Vol 1. Washington, DC: National Academy Press, 1994:196 10. 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;17:20 –24 11. Protection of Human Subjects, 45 C.F.R. Sect. 46.102(i) (1997) 12. Protection of Human Subjects, 45 C.F.R. Sect. 46.207(b) (1997); Sect. 46.208(b) (1997) 13. Department of Health and Human Services. Protection of human subjects. Federal Register 1998;63:27794 –27804
197
14. Beauchamp T. The intersection of research and practice. In: Goldworth A, Silverman W, Stevenson DK, Rivers R, Young EW, eds. Ethics and perinatology. New York: Oxford University Press, 1995:231–244
198
WOMEN’S HEALTH ISSUES VOL. 9, NO. 4 JULY/AUGUST 1999