Pregnancy Testing of Adolescents During Clinical Research: Managing the Process

Pregnancy testing is often required for participation in clinical research, but little published literature addresses the special issues that arise when adolescents who are not legal adults (minor adolescents) are eligible to participate in such research. Below, we set forth a framework for how such testing should be managed, drawing on considerations of ethics, law, and adolescents’ developmental cognitive capacity to make decisions about research participation and medical care.

Three key bioethical principles underpin research ethics discourse in the United States: respect for persons, beneficence, and justice. Respect for persons is described as follows: “first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.”¹ The principle of respect for persons requires particular attention in the context of unemancipated minor adolescents (referred to simply as “adolescents” for the remainder of this article). A position paper from the Society for Adolescent Medicine states, “With adolescents, respect for persons means balancing respect for the emerging capacity of an adolescent for independent decision-making with the need for continued special protections, where necessary.”² The principle of beneficence requires that we contribute to the welfare of our patients. This principle informs the best-interest standard, which dominates ethical discussions in pediatric care. The principle of justice requires that special populations, such as adolescents, not be excluded from the benefits of medical research.

Organizations of health care providers are generally united in supporting the adolescent’s right to access to confidential reproductive health care.³ All 50 states and the District of Columbia have laws protecting the confidentiality of adolescents seeking sexual and reproductive health care.⁴ Commitments to keep adolescents’ sensitive health information confidential respect the emerging autonomy of adolescents and increase the likelihood that they will access appropriate health care services.⁵ The Society for Adolescent Medicine calls confidentiality an “essential component” of health care for adolescents “because it is consistent with their development of maturity and autonomy and without it, some adolescents will forgo care.”⁶ Our health care system nevertheless reflects the recognition that adolescents do not have fully developed autonomy and are still entitled to protection. Finding the appropriate balance between autonomy and protection (respect for persons and beneficence) can be challenging when conducting pregnancy testing in adolescents involved in clinical research.

The many challenges that arise when conducting adolescent sexual health research have been discussed elsewhere and are not a focus of this article.⁷ We focus instead on the challenges that arise when pregnancy testing is conducted in the course of research unrelated to sexual or reproductive health. In the context of clinical research, the extent to which information about pregnancy testing can be kept confidential will depend on whether and how pregnancy affects study eligibility and whether and how pregnancy affects therapeutic interventions delivered in the context of a clinical trial.

The implications of pregnancy testing in this context fall into one of three categories: 1) the research poses no additional risk to a pregnant participant or her fetus, and pregnancy will not affect study participation; 2) enrollment or continued participation in the research is contingent on a negative pregnancy test, but the research does not pose any risk to the fetus, and the pregnancy does not increase the risk posed by the research to the adolescent; and 3) pregnancy in the context of the research introduces additional risk to the participant or to her fetus. We discuss each in turn below.

Pregnancy Testing Does Not Affect Study Participation, and Study Risks Are Not Affected by Pregnancy:

In some research studies, pregnancy testing is conducted as part of data collection, but the research poses no additional risk to a pregnant participant or her fetus, and pregnancy will not affect study participation. In most, but not necessarily all, cases, these will be minimal risk studies, for which the primary risk will be inadvertent release of sensitive information. For example, longitudinal studies of community health may include data about pregnancy rates and outcomes. When pregnancy does not affect study participation and study procedures do not adversely affect a pregnancy, all pregnancy test results should be provided directly and confidentially to the adolescent. During the consent process, this practice of confidential disclosure should be made clear to the participants and their parents. Investigators should also be prepared to provide information about where the adolescent can seek reproductive health care. The testing process itself also poses the risk of a breach of confidentiality; therefore, such testing should be conducted only when the value of the information gained is sufficient to justify the risk of inadvertent disclosure.

Pregnancy Affects Study Eligibility:

For many studies, pregnancy testing is required to determine initial or continued study eligibility. If a parent and adolescent agree to research participation but the adolescent is then excluded because of a positive pregnancy test, there is a high chance that a parent will deduce the reason for the exclusion. The optimal approach to managing pregnancy testing for these studies depends on the risk level and the potential for direct benefit to the participant.

Pregnancy testing may be required to determine study eligibility for minimal risk studies if the research question is limited to a particular population. For example, investigators examining correlations between environmental exposures and serum hormone levels may exclude individuals who are or who become pregnant. In studies like this, the most significant risk posed to the adolescent participant may be a breach of confidentiality.

The National Commission for the Protection of Human Subjects recommends, “[W]henever parental permission is not a reasonable requirement to protect the well-being of the child, alternatives should be required by the IRB [institutional review board],” and goes on to explain that the recommendation arises from “the general moral principle to avoid harm as well as to respect the autonomy of older children.”⁸ Following the National Commission’s recommendations, federal regulations allow IRBs to waive the requirement for parental permission for some minimal risk research studies when IRBs determine that it is not a reasonable requirement to protect the adolescent research participants.⁹

Whether parental permission should be necessary depends upon an IRB’s interpretation of “a reasonable requirement to protect the well-being of the child.” This provision is most often used to justify a waiver of parental permission for participation in minimal risk sexual and reproductive health research. A requirement for parental permission in these cases may discourage adolescent participation, and it risks inadvertent disclosure of sensitive information.¹⁰ We propose that if the most significant risk posed to an adolescent research participant is the inadvertent disclosure of sensitive information, parental permission is no longer a reasonable requirement to protect his or her well-being. In fact, a requirement for parental permission may paradoxically decrease the adolescent’s well-being. Particularly if a minimal risk study includes an adolescent population that is at especially high risk for pregnancy, investigators and IRBs should consider whether it is appropriate to waive the requirement for parental permission entirely in order to facilitate confidential handling of pregnancy testing.

For greater than minimal risk studies, it will rarely be appropriate to waive parental permission to avoid a breach of confidentiality. In these cases, the risk to confidentiality can be mitigated by discussing the research privately with the adolescent before assent or parental permission is requested. For example, pregnancy testing is routinely required prior to radiographic imaging. An adolescent should understand that if she chooses to participate in research involving such imaging and later becomes pregnant, it may be difficult to avoid revealing the information to her parents. Potentially eligible participants should be reminded that they can choose not to participate in the research for any reason, including concern about managing a positive pregnancy test, and that their reasons for opting out will not be shared with their parents. Caveats to this paradigm may arise when the research study offers the potential for direct benefit to the participant.

Pregnancy Affects Participation in a Direct-Benefit Clinical Trial:

The optimal approach to pregnancy testing is very different if the research is a clinical trial evaluating interventions for a serious medical condition. Unemancipated minor adolescents generally have a right to confidential reproductive and sexual health care, but they do not have full authority over their medical care outside of this arena. Conflicting duties arise when the results of pregnancy testing will directly affect medical care that is otherwise unrelated to sexual or reproductive health. Parents are entrusted with the responsibility to make informed decisions in the best interest of their adolescent child, but they may be unable to make these decisions without knowledge of an adolescent’s pregnancy. The legal and ethical complexity of this issue has been discussed (but not resolved) in the context of pregnancy testing of adolescents undergoing surgery or radiographic imaging.¹¹

In the United States, research regulations require assent of older children and adolescents eligible to participate in clinical research. However, the regulations recognize the primacy of parental authority when research participation is in the best interest of the child. Specifically, the regulations state that “[if] the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research.”¹² For example, a promising experimental cancer treatment medication may be available only through a research protocol, and the protocol may require monthly pregnancy testing of all postmenarcheal females. In this case, the requirement to support the best interests of the adolescent overshadows the requirement to protect her right to confidential results of pregnancy testing. In cases where results of pregnancy testing will not be withheld from parents, the adolescents and their parents should be informed before the trial begins that pregnancy testing is required for study participation and that the results will be shared with both the adolescents and their parents.

Additional Practical Considerations:

It has been suggested that pregnancy testing in clinical research should not be routinely performed in girls under thirteen.¹³ If research interventions have the potential to harm a pregnant research subject or a developing fetus, we believe it is simpler and safer to require pregnancy testing in all females who have begun menstruation. This straightforward approach eliminates the need for researchers to gauge the likelihood that an adolescent is sexually active and minimizes the chances of enrolling a pregnant individual.

It also has been argued that adolescent consent for pregnancy testing should be obtained separately from assent to enrollment.¹⁴ This suggestion warrants cautious consideration. On the one hand, use of a separate consent form that delineates the ramifications of pregnancy testing may help ensure that relevant information is discussed during the consent conversation. On the other hand, every additional document adds to the already substantial research documentation burden. On balance, we believe that a separate pregnancy test consent form should not be routinely required.

The opportunity for an adolescent to speak privately with the person seeking consent is fundamental to maximizing adolescent autonomy. All adolescents should routinely speak with a member of the study team without their parents, early in the consent-assent process. This should be a standard nonoptional practice such that parents and adolescents do not feel singled out. We believe that the simplest effective way to ensure that adolescents have an opportunity for private discussions is to include a sentence in the parental permission template and in the assent template stating that the researcher will speak privately with all adolescents before they are asked to decide about participation. This statement will remind the person seeking consent that a private discussion should take place and will help to normalize the process, decreasing the likelihood that parents will interpret a private conversation as suggesting concern.

Adolescence covers a broad developmental period; a pregnant thirteen-year-old may need to be treated differently from a pregnant seventeen-year-old. Investigators and IRBs should rely on individuals with expertise in adolescent development when issues arise that are not fully addressed by the paradigm above. Investigators should be aware of local resources for adolescents who want to seek confidential reproductive or sexual health care. Referral materials should be immediately available for all adolescents who may have concerns about pregnancy testing or other sexual health issues. Lastly, investigators must be familiar with relevant state laws, including those defining when sexual activity with a minor is a reportable offense.