With regard to research involving pregnant women and fetuses, the federal regulations governing research with humans (45 CFR 46) say nothing about balancing risks and benefits between the pregnant woman and the fetus. Moreover, an examination of the regulations raises additional issues. Consider the rule in Subpart B of the regulations—the section that provides special protections for pregnant women and fetuses—stating that any risk should be the least possible for achieving the objectives of the research.1 This rule could be interpreted as applying to the pregnant woman as well as to the fetus. However, there might be types of research in which risks to the woman can be reduced by increasing risks to the fetus. For example, x-rays to monitor the woman for a disease condition could increase risks for the fetus. In this type of situation, one can minimize risk for the fetus or minimize it for the woman, but one cannot do both. How, then, should the rule on minimizing risk be interpreted?
This article explores how to apply the regulations to research that holds out a prospect of direct benefit to the pregnant woman or the fetus. Do the regulations provide sufficient protection for pregnant women and fetuses, or should they be supplemented with additional rules? To address these issues, it will help to distinguish between 1) research directed toward a medical condition of the fetus that holds out a prospect of direct benefit to the fetus and 2) research directed toward a medical condition of the pregnant woman that holds out a prospect of direct benefit to the woman.2
Federal Regulations on Risks and Benefits
Subpart A of the regulations contains rules that are general, in the sense that they apply to all human research to which the regulations apply, unless they conflict with more stringent rules in the regulations that apply to special populations. Subpart A contains two rules that are especially relevant to the present discussion: 1) risks to subjects should be minimized, and 2) risks to subjects should be reasonable in relation to any anticipated benefits to subjects and the importance of the knowledge that may reasonably be expected to result.3 The first of these rules is taken to mean that, if there are alternative ways to achieve satisfactorily the research objectives, the least risky alternative should be chosen.
In addition, there are rules that are specific to particular populations of research subjects. One of these populations is pregnant women and fetuses, for whom the following additional protections are stated in Subpart B:
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(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.
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(c)
Any risk is the least possible for achieving the objectives of the research.4
These two rules are the only special protections concerning risks and benefits in the regulations on research involving pregnant women and fetuses. The first of these rules uses the concept “minimal risk,” which is defined in the regulations as follows:
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.5
The second of these rules appears to be an alternative wording of the Subpart A rule that risks should be minimized.6
In considering what protections for fetuses should be in place, comparing the rules for research with fetuses to the rules for research with children may be instructive. Child subjects are another population for whom there are special rules for assessing risks and benefits. These rules are based on the concern that children are vulnerable and need extra protection compared to adults. Two of the rules that apply to pediatric research involving greater than minimal risk but presenting the prospect of direct benefit to child subjects are relevant to the comparison of rules for research with fetuses: 1) the risk is justified by the anticipated benefit to child subjects, and 2) the relation of the anticipated benefit to the risk is at least as favorable to child subjects as that presented by available alternative approaches.7 The first of these two rules for research with children modifies the general rule in Subpart A on balancing risks and benefits. Specifically, the importance of the knowledge to be gained is not included in the assessment of risks and benefits for child research subjects.
Research Aiming to Benefit the Fetus
In research directed toward a medical condition of the fetus and that holds out a prospect of direct benefit to the fetus, one question concerns how risks to the fetus should be balanced against benefits to the fetus. Subpart B does not address this. However, investigators must comply with the applicable rules in Subpart A, as well as the rules in Subpart B.8 A relevant rule in Subpart A is the one requiring that risks to subjects be reasonable in relation to anticipated benefits to subjects and the importance of the knowledge that may reasonably be expected to result. This rule is applicable because no rule in Subpart B replaces it. When applied to research with a prospect of benefiting the fetus, this rule yields the following conclusion: risks to the fetus should be reasonable in relation to anticipated benefits to the fetus and the importance of the knowledge reasonably expected to result. Although this rule provides one approach to balancing risks and benefits for the fetus, we should consider whether this is the most justifiable approach. I would draw attention to the corresponding rules for children, one of which states that the risks should be justified by the anticipated benefits to the subject, without regard to the importance of the knowledge that might reasonably be expected.
Clearly, this protection for children is stronger than that for fetuses; levels of risk that might be allowed for a fetus because they are considered to be offset by the importance of the knowledge to be gained would not be permitted for children. The other relevant rule for children states that the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches. Having such a rule increases protections for children; it prevents child subjects from being enrolled in a study when there is a more favorable alternative. No such rule is in place to protect fetuses involved in research. A question that naturally arises is whether it is justifiable that fetuses lack the special protections that we extend to children.
One could argue that we should have comparable rules for children and for fetuses that can develop into children. In research that aims to benefit the fetus, the well-being of the child into which the fetus potentially can develop is an important consideration. Concern for the well-being of the child requires that protections be in place to prevent unjustifiable research-related injuries to the fetus that will impact the child. This moral requirement does not depend on one's views concerning the moral status of the fetus. Although we might disagree concerning the moral status of fetuses, we can reasonably agree that unjustifiable harm to a future child should be avoided. We should protect fetuses that are subjects of research before they develop into children, just as we protect children who are subjects of research when they are children. Based on these considerations, I suggest that we should have the following rules for research with a prospect of direct benefit to the fetus. First, risks to the fetus should be justified by the anticipated benefits to the fetus. Second, the relation of the anticipated benefit to the risk should be at least as favorable to the fetus as that presented by available alternative approaches.
Subpart B contains a rule stating that any risk should be the least possible for achieving the objectives of the research. Yet this rule does not take into account the problem mentioned at the beginning of this paper: there can be situations in which risks to the fetus or to the woman can be minimized, but not risks to both. In these circumstances, whose risks should be minimized? I suggest that, when there is such a choice, the risk to the fetus should be minimized, based on several considerations. First, fetuses are unable to protect themselves, and there is concern to prevent research-related harm to the children into which they would develop. By contrast, the pregnant woman with decision-making capacity can decide whether to participate in research that does not minimize risk to her because of the need to minimize risk for the fetus. Second, I have argued that there should be parity in protections for children and fetuses that can develop into children. We require that risks to the child be minimized, and we should do the same for fetuses that can develop into children.
This argument also provides a reason to reject another possible view—namely, that what should be minimized is the combined risks to the fetus and the pregnant woman. The problem with this view is that an approach minimizing the combined risks does not necessarily minimize risks to the fetus. The view I am defending takes into account the fact that, like research benefits, research risks to the fetus and the pregnant woman are sometimes interrelated. When risks to the pregnant woman materialize, they can sometimes have adverse effects on the fetus. Judgments about how best to minimize risk to the fetus would need to take such relationships into consideration.
In research directed toward a medical condition of the fetus that has a prospect of direct benefit to the fetus, what protections should we have concerning risks and benefits for the woman? Because Subpart B does not address explicitly
Should we have rules for research with fetuses that can develop into children that are comparable to the rules for research with child subjects?
the balancing of risks and benefits for the woman, the rule in Subpart A again applies. In applying this rule to the woman, on one interpretation, it yields the following: risks to the pregnant woman are reasonable in relation to any anticipated benefits to the fetus and pregnant woman and the importance of the knowledge that may reasonably be expected to result. This interpretation leaves open the possibility that both the fetus and pregnant woman can be benefitted, based on the idea that direct benefit to the fetus can be also beneficial to the pregnant woman. For example, improving the health of the fetus can improve the emotional well-being of the pregnant woman and, in some cases, diminish or prevent the burden to her of caring for a handicapped child.
An alternative view has been put forward by Chervenak and Mc-Cullough, who hold that in the type of research under consideration, protection of pregnant women against risks should include the following criterion:
the mortality risk to the pregnant woman is reliably expected to be low and the risk of disease, injury, or disability to the pregnant woman is reliably expected to be low or manageable for current and future pregnancies.9
There are several problems with the Chervenak and McCullough approach. First, they offer no analysis of what they mean by “low risk.” In the absence of such guidance, it is not clear what would count, in their view, as low risk. Second, their criterion does not provide for balancing risks and benefits, but rather attempts to set a ceiling on risks to the pregnant woman. This approach does not allow the appropriate level of risk to the woman to be judged in relation to the degree of anticipated benefit to the fetus and the pregnant woman. Third, Chervenak and McCullough do not identify any view other than the one they advocate, and thus, they do not offer arguments in support of their criterion over alternatives. An advantage of the Subpart A rule, as interpreted above, is that it permits assessments of risk in relation to the degree of anticipated benefit and the importance of the knowledge to be gained. This provides a degree of flexibility, so that judgments about risks can be based on the facts of the particular situation. Based on these considerations, the Subpart A rule as interpreted seems preferable.
Another risk-related protection for the pregnant woman is provided by the rule on minimizing risk. Again, the issue concerning whose risks are to be minimized is relevant. I argued above that if there is a choice between minimizing risk to the fetus or to the pregnant woman, risks to the fetus should be minimized. If that argument is acceptable, then an appropriate rule for the pregnant woman is that risks to her should be minimized to the extent that doing so is consistent with minimizing risks to the fetus.
Research Aiming to Benefit the Pregnant Woman
For research directed toward a medical condition of the pregnant woman and that holds out a prospect of direct benefit to the woman, one question concerns how risks to the pregnant woman should be balanced against benefits to her. A relevant rule is the Subpart B requirement that any risk be the least possible for achieving the objectives of the research. The previous discussion concerning minimizing risk would seem to apply to this context as well, suggesting that risks to the woman should be minimized to the extent that doing so is consistent with minimizing risks for the fetus.
Also relevant is the rule in Subpart A stating that risks to subjects should be reasonable in relation to anticipated benefits for the subjects and the importance of the knowledge that may reasonably be expected to result. This rule applies to adult subjects generally, and it applies to pregnant women as well because no rules in Subpart B supersede it. In applying this rule to the woman in the type of research under consideration, on one interpretation, it yields the following: risks to the pregnant woman are reasonable in relation to any anticipated benefits to the woman and fetus and the importance of the knowledge that may reasonably be expected to result. This rule seems justifiable on the grounds that similar protection should apply to pregnant women as applies to adults generally.
In this type of research, what risk-related protections should there be for the fetus? In addressing this question, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research offered only that risks to the fetus be minimized.10 As previously argued, this rule is justifiable. However, this rule is not sufficient, as it would permit high levels of risk, as long as they are minimized relative to the objectives of the study. Because fetuses are unable to protect themselves and there is concern to prevent harm to the children into whom they would develop, it is appropriate to have a ceiling on risks to the fetus in research with a prospect of direct benefit to the pregnant woman. There are several alternative risk levels to consider. One is the level found in the current rule for research not holding out a prospect of direct benefit for the pregnant woman or fetus—namely, that the risk be no more than minimal, based on the concept of minimal risk as defined in the regulations. In opposition to this risk level, one can point out an important difference between the type of research under consideration and research holding out no prospect of direct benefit. Specifically, the prospect of benefit to the pregnant woman could provide a reason to permit research that involves more than minimal risk to the fetus.
A second alternative would permit a higher level of risk, drawing upon a concept in the special protections for children: “a minor increase over minimal risk.” This approach has the merit of permitting a somewhat larger risk to the fetus for the sake of the woman, while placing a limit on how much that increase in risk can be. It also is supported by the idea that there should be parity between protection of child subjects and protection of fetal subjects that can develop into children. For child subjects, a minor increase over minimal risk is the risk ceiling for a research intervention that has no prospect of direct benefit to the child, provided that the intervention “is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition.”11 An underlying principle seems to be that this risk ceiling is appropriate when a research intervention offers no direct benefit to the child but offers other important benefits. Similarly, we might say that direct benefit to the pregnant woman is an example of “other important benefits.” Thus, having a fetal risk ceiling corresponding to a minor increase over minimal risk for research holding out a prospect of direct benefit to the pregnant woman would be consistent with the current protections for child subjects.
Conclusion
The questions raised here about balancing risks and benefits need to be addressed, given the various types of research involving fetuses and pregnant women. For instance, maternal-fetal surgery aims to correct a variety of fetal malformations in utero; current interest is focused on surgical closure of meningomyelocele, tracheal occlusion for diaphragmatic hernia, and laser ablation of anastomoses in twin-twin transfusion syndrome, among other areas.12 In addition, there is growing interest in research involving the administration of pharmacologic agents during pregnancy.13 Also worth mentioning is a type of research expected in the future: prenatal gene transfer aimed at correcting certain genetic diseases in the fetus.14
Although this article focuses on research involving pregnant women and fetuses that could directly benefit the pregnant woman or the fetus, a thorough critical examination of Subpart B would address several additional questions, including the following: Should we permit research that does not hold out a prospect of direct benefit for the pregnant woman or fetus and that involves greater-than-minimal risk to the fetus? Is the pregnant woman's informed consent sufficient, or are there situations in which it is justifiable to require the father's informed consent as well? And is it ever permissible for inclusion or exclusion criteria to include the woman's decision for or against abortion?
With regard to research that holds out a prospect of direct benefit for the pregnant woman or the fetus, the following guidelines are proposed for balancing risks and benefits:
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Guidelines pertaining to research directed toward a medical condition of the fetus and that holds out a prospect of direct benefit to the fetus:
Risks to the fetus are justified by the anticipated benefits to the fetus.
The relation of the anticipated benefit to the risk is at least as favorable to the fetus as that presented by available alternative approaches.
Risks to the fetus are minimized.
Risks to the pregnant woman are reasonable in relation to any anticipated benefits to the fetus and pregnant woman and the importance of the knowledge that may reasonably be expected to result.
Risks to the pregnant woman are minimized, to the extent that doing so is consistent with minimizing risks to the fetus.
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Guidelines pertaining to research directed toward a medical condition of the pregnant woman and that holds out a prospect of direct benefit to the woman:
Risks to the pregnant woman are reasonable in relation to any anticipated benefits to the pregnant woman and fetus and the importance of the knowledge that may reasonably be expected to result.
Risks to the pregnant woman are minimized, to the extent that doing so is consistent with minimizing risks to the fetus.
Risks to the fetus are no greater than a minor increase over minimal risk.
Risks to the fetus are minimized.
If these proposed guidelines are reasonable, they suggest a need to initiate discussions on revising the current regulations so that they provide guidance that is thorough and justifiable. Appropriate regulation is needed for ongoing research, including research on maternal-fetal surgery and pharmacologic testing during pregnancy, as well as future research in prenatal gene transfer, among other areas.
Acknowledgments
Research for this paper was supported by grant number R03HG005225 from the National Human Genome Research Institute. The content of this paper is solely the responsibility of the author and does not necessarily represent the official views of the National Human Genome Research Institute or the National Institutes of Health. The author thanks the anonymous reviewers of an earlier draft for their helpful comments.
References
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