Ethical considerations

The role of ethics in advancing research with pregnant persons 

There is growing recognition of the need to gather evidence to guide the use of medications in pregnancy, especially for infectious diseases such as HIV, hepatitis and syphilis. Largely due to ethical concerns about imposing uncertain risk on the fetus (or sometimes the pregnant person), most studies leading to authorization of drugs and vaccines have excluded individuals who are, and sometimes individuals who may become, pregnant – leading to a dearth of evidence to inform their care. Given the ethical complexities that pregnancy introduces to biomedical research, ethics has historically been viewed as a barrier to the conduct of research with this population (PHASES, 2020).   

But ethics is not only a barrier to research with people who are pregnant; rather, it is a powerful reason to pursue such research, and offers strong justifications for advancing research despite the ethical, regulatory and other challenges of doing so. As such, many organizations and groups have called for advancing research in people who are pregnant as both a critical public health need and an ethical imperative.   

The resources gathered here reflect a growing literature on and guidance for conducting research with pregnant populations, foregrounding the role of ethics in advancing research as well as addressing the ethical complexities that still call for careful consideration of research with this population. In both ways, these resources can be used to support the ethical inclusion of pregnant persons and their interests in the biomedical research agenda.   

Conceptual shifts that support inclusion 

The increasing consensus on the ethical imperative to conduct research with pregnant people reflects a trio of conceptual shifts in how we think about research with this population. These include a shift from understanding pregnant people as a vulnerable population to understanding them as a complex population; from the idea that pregnant persons and fetuses should be protected from research to the recognition that they are best protected through research; and from the general practice of summarily excluding pregnant persons from research, without justification (presumed exclusion) to a model in which they have equitable access to both the direct benefits of research and the benefits of a robust evidence base that would result from their fair inclusion in the biomedical research agenda. Further discussion of each conceptual shift can be found below.

Vulnerable populations data-sf-ec-immutable=

Until recently, pregnant persons were categorized alongside children, prisoners, and individuals with intellectual disabilities as a vulnerable population. Yet unlike these populations there is nothing about pregnancy per se that constrains a person’s ability to provide valid consent or makes them particularly susceptible to exploitation. This designation is therefore inaccurate, and had a chilling effect on research in pregnancy. Ethical and regulatory guidance no longer uses the term vulnerable to describe pregnant people; some instead designate them as a complex population to capture the scientific and ethical complexities that research in pregnancy can bring up. 

Protection from research data-sf-ec-immutable=

Past approaches to research have focused on protecting pregnant persons and fetuses from research risks by excluding them from research or requiring contraception in non-pregnant participants. However, such exclusionary practices have not eliminated risk, but rather shifted it to clinical contexts where more individuals are affected. It is increasingly recognized that the best way to ensure the safety of pregnant persons is to responsibly conduct research that will generate data to inform pregnancy-specific care. 

Presumptive exclusion data-sf-ec-immutable=

Pregnant persons have generally been presumed ineligible to participate in biomedical research. For instance, when pregnant persons are excluded from studies, often no justification is required; it is only their inclusion that requires justification. This default of exclusion has contributed to the dearth of pregnancy specific data. It has also prevented access to studies that provide benefits, including lifesaving treatments. As a matter of justice, pregnant persons deserve a fair share of the benefits of research. This can be facilitated by considering whether it is appropriate to exclude pregnant persons from a particular study and whether broader investments in biomedical research equitably address the health interests of pregnant persons and their children.

Ethical frameworks that support inclusion 

While the exclusion of pregnant persons from biomedical research has reduced pregnancy-specific risk in research contexts, it has not eliminated risk. Rather, it has “shifted the burden of potential risk around drug safety from the clinical trial setting, where safety outcomes are carefully monitored, to the real-world clinical care setting, where safety outcomes are not systemically captured” – with the effect of expanding the scope of harms experienced by this population (WHO/IMPAACT/IAS Call to Action). Harms include potential exposures to risks that are unacceptable for pregnant persons or fetuses, incorrect dosing of drugs leading to either underdosing or toxicity, or limited access to indicated, preferred, or optimal treatments and preventives.  

Ethical frameworks that attend to these harms support inclusion of pregnant persons in biomedical research, primarily as a matter of justice. The PHASES Working Group (2021) identified 3 ethical foundations of the responsibility to address inequities in the evidence base for the use of medication in pregnancy: 

Protect icon

Protection

Pregnant persons and the children they will have deserve equitable protection from drug related risks.  Research is essential to ensuring that the drugs taken by people – e.g. to prevent or treat infections that co-occur with pregnancy, including HIV, hepatitis and syphilis – meet an acceptable safety standard.  

Access icon

Access

Pregnant persons deserve timely access to the most effective medications to protect their health and that of their future children. Pregnancy-specific evidence is needed to avoid delays in access to next-generation treatment and prevention modalities. 

Respect icon

Respect

Pregnant persons deserve equitable respect for their own health. While important research has been done to improve fetal and child outcomes, it is crucial to generate data that allows for consideration of the impact of treatment decisions on maternal health. 

Additional considerations for supporting inclusion

Paternal consent

Whether and how intended fathers (or non-gestational partners, NGPs) should be involved in the informed consent process for research in pregnancy has long been debated. Given his interests in the outcome of pregnancy, some have suggested that he should have a say in whether a pregnant woman may participate in research. On the other hand, a competent person’s informed consent is presumed sufficient to authorize their participation in research in other circumstances which do not differ in a relevant way from pregnancy.

There is broad agreement that a pregnant person’s consent is necessary for her participation: pregnancy does not change an adult person’s right to consent or refuse to consent in either medical care or research. There is some debate about when a pregnant woman’s consent is sufficient for her participation. International guidance (CIOMS) indicates that the pregnant woman is the sole “decision-maker” about research participation; consent of the intended father/NGP is not required, but he may be involved according to the wishes of the pregnant woman:

“Some research involving pregnant women may be directed at the health of the fetus. In such cases, the role of the woman remains the same: she is the decision-maker for any interventions that affect her. This does not exclude the possibility of the woman consulting with the father of the fetus, if she wishes.”

The US Code of Federal Regulations agrees, noting:

“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, [the pregnant woman’s] consent is obtained in accord with [standard] informed consent provisions.”

There is one exception to this rule, in the rare case that the study holds the prospect of direct benefit to the fetus only:

“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 [standard] informed consent provisions … 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.”

Concerns have been raised about the requirement for paternal consent for research that holds the prospect of benefit to the fetus only in Subpart B, as it exceeds what is required in pediatric research and fails to respect the pregnant woman’s autonomy and protect her safety and privacy.

Several organizations have urged removal this narrow paternal consent requirement from US regulations, as follows:

PRGLAC Task Force (2018, Recommendation 4)

Recommends removal of regulatory barriers to research in pregnant women, as follows:

Modify subpart B of the Common Rule

  • Change 46.204(e) in subpart B to maternal consent alone
  • Given the recognized autonomy of a pregnant woman, the evolution of family structure, that for a child only one parental signature is required for research to benefit the child and to align with parental consent for pediatrics


The American College of Obstetricians and Gynecologists (ACOG, 2024):

In summary recommendations and conclusions of Ethics Committee Statement 9, Ethical Considerations for Increasing Participation in Research, ACOG states:

“In general, requiring participation consent from an intimate partner or nongestational intended parent is not warranted, ethically justified, or legally required in research studies exclusively intended to benefit fetuses.”

ACOG allows for paternal consent when the health interests of the father/NGP are directly affected, as in:

“Such consent is appropriate only if there is a risk of the partner's exposure to an investigational agent and exposure to that agent carries more than minimal risk; if data will be collected regarding an intimate partner's impression of the investigational agent; or if the inclusion or exclusion criteria directly relate to an intimate partner, such as if testing of a partner is required for enrollment in the trial (i.e., semen analysis or testing for a sexually transmitted infection). If it is determined that none of the aforementioned conditions apply, intimate partner or nongestational intended parent consent is unwarranted and unethical. Requiring intimate partner consent imposes unnecessary barriers to participation, violates confidentiality and privacy, interferes with choices regarding reproductive options, interferes with a person's right to make independent decisions about their health, and may put an individual at risk in the setting of intimate partner violence.”

Even with the potential problematic implications of requiring paternal consent, many women have identified advantages of paternal/NGP involvement. Guidance documents that raise caution about a paternal/NGP requirement have advanced an alternative model that robustly supports paternal involvement where the pregnant woman deems it helpful or appropriate (see, e.g., CIOMS, above).

PHASES (2020: Ending the Evidence Gap for Pregnant Women Around HIV and Co-Infections)

Recommendation 11: Respect and support decisional authority

“When a pregnant woman of legal standing is eligible to participate in research, her voluntary and informed consent should be sufficient to authorize her participation. Accommodations should be made to facilitate a woman’s ability to engage the father, her family, or other personal supports, and to promote their understanding of the benefits and risks of research participation.”

See also

Ethical considerations for increasing inclusivity in research participants. Committee Statement No. 9. American College of Obstetricians and Gynecologists. Obstet Gynecol 2024;143:e155–63.

Lyerly, AD. Research, pregnancy and the ethics of parental consent. The Lancet Rheumatology 2024, Volume 6, Issue 8, e500 - e501.

Sullivan KA, Little M, Rosenberg NE, Mtande T, Zimba C, Jaffe E, Anderson J, Coleman JS, Gilbert S, Gross Wolf MS, Hoffman I, Rahangdale L, Faden R, Lyerly AD. Women's Views About a Paternal Consent Requirement for Biomedical Research in Pregnancy. J Empir Res Hum Res Ethics 2018 Oct;13(4):349-362.

Close Read more about this discussion and access relevant guidance documents and regulations.

 

Resources

Ethical guidelines for research in pregnancy

Entities that advise or govern the conduct of research have issued guidance on the conduct of research in pregnancy.  These include nongovernmental organizations (e.g., the Council for International Organizations of Medical Science (CIOMS)) and governmental entities. While these guidance documents permit and sometimes explicitly support a wide range of research to be conducted in pregnancy, there is some debate about how they should be interpreted or applied. Some key documents are linked below, with selected commentaries. 

Note that this is an incomplete (and in process) list, and those conducting research in countries not represented here will need to consider local guidance, as available.

WHO and the Council for International Organizations of Medical Sciences (CIOMS) 

Starting in the late 1970s, CIOMS in cooperation with WHO has issued guidelines to provide “internationally vetted ethical principles and detailed commentary on how universal ethical principles should be applied, with particular attention to low-resource settings.” The document was revised most recently in 2016 and includes a Guideline on Pregnant and Lactating Women as Research Participants (Guideline 19, p. 71). The Guideline states that, “Research designed to obtain knowledge relevant to the health needs of the pregnant and breastfeeding woman must be promoted” and addresses several areas of controversy:   

More information about ethical standards and procedures for research with human beings, WHO Department of health ethics and governance

World Medical Association

The World Medical Association recently issued a set of revisions to its international ethical principles to guide medical research involving human participants, otherwise known as the Declaration of Helsinki. Notable revisions include those describing protections for vulnerable individuals and groups (paragraphs 19 and 20).

The accompanying commentary explains that “the new text recognizes that vulnerability may be contextual and dynamic and experienced at varying levels” and that “the default of exclusion for all those in positions of vulnerability had resulted in enormous gaps in medical knowledge about certain populations (especially women, children, and racial and ethnic minoritized groups) and exacerbated disparities. The revision maintains language about a greater risk for those experiencing vulnerability being wronged or incurring harm and demands for specially considered protections, but calls for fair and responsible inclusion after weighing the harms of both inclusion and exclusion and providing adequate support."

United States of America 

US Code of Federal Regulations (45 CFR part 46) 

Research that is conducted or supported by U.S. government funds is required to comply with Human Subjects Protections known as 45 CFR part 46. Where pregnancy is concerned, these include standard protections for all people, known as Subpart A – 2018 Common Rule: Basic HHS Policy for Protection of Human Research Subjects, , as well as additional requirements for pregnancy, specified in Subpart B: Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research. The Common Rule was revised in 2018 and no longer includes pregnant person in the list of individuals considered vulnerable. Subpart B was last revised in 2001. 

Commentary:  Subpart B:  Additional Protections for Pregnant Women, Human Fetuses and Neonates. Little M, Lyerly AD. In: Bankert E, Gordon BG, Hurley EA, Shriver SP, eds. IRB Management and Function. Jones and Bartlett, 2021; 495-502.  

US Food and Drug Administration (US FDA)  

In 2018, the US FDA issued draft guidance addressing scientific and ethical considerations for including pregnant persons in clinical trials. The document states that “Filling the knowledge gaps regarding safe and effective use of drugs in pregnant women is a 118 critical public health need, but one that raises complex issues,” and provides both general and specific guidelines for including pregnant women in clinical trials:  

Australia  

The National Statement on Ethical Conduct of Human Research provides guidelines that must be followed for research funded by Australia’s National Health and Medical Research Council.  Section 4.1 (page 61) provides ethical considerations specific to Women who are Pregnant and the Human Fetus: 

Canada 

On January 11, 2023, the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Social Sciences and Humanities Research Council of Canada (SSHRC) announced the release of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans – TCPS 2 (2022), which replaces TCPS 2 (2018) as the official human research ethics policy of the three federal research funding agencies.  The revised document states that “Women shall not be inappropriately excluded from research solely on the basis of their reproductive capacity, or because they are pregnant or breastfeeding (Article 4.3): 

South Africa

The Department of Health issued general guidance for the ethical conduct of research provides some parameters for when pregnant adults may participate in research. These guidelines note that persons must not be excluded “unreasonably or unfairly on the baise of any of the prohibited grounds for discrimination,” including pregnancy: 

New Zealand 

These national ethical standards, updated in 2019, underscore the importance of research designed to build knowledge relevant to the health need of pregnant and breastfeeding women, and state that “All participants (including pregnant women) are eligible to participate in studies unless there is a clear scientific reason to exclude them”:  

 

 

 Affirming statements, guidance and reports

Leading researchers and organizations now also affirm the need for pregnancy-specific research and have issued statements and reports supporting such research as well as guidance for how to do so ethically and responsibly. Some reports are disease (e.g., HIV) specific, while others offer more general support and guidance:   

 

HIV-SPECIFIC

WHO/IMPAACT/IAS Call to Action

WHO, the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and the International AIDS Society launched a call to action “so women’s voices, interests and concerns are at the centre of new investigational drug trials, and so that no woman is left without informed access to innovative drugs to treat and prevent HIV.”  The ethical framing described above are foundational to the call to action and are further discussed in the JIAS supplement: The ethics of exclusion: why pregnant and lactating women must be front and centre of HIV research, Singh JA, Moodley D, Little M, et al., JIAS, 19 July 2022. 

PHASES (Pregnancy and HIV/AIDS: Seeking Equitable Study) Ethics Guidance 

The PHASES Working Group, an NIH-funded, 26-member interdisciplinary and international group of experts, developed 12 concrete, immediately actionable recommendations for advancing ethical inclusion of pregnant persons in HIV and coinfections research:  

AVAC/PHASES Think Tank and Action Plan 

AVAC, as part of the Coalition to Accelerate and Support Prevention Research (CASPR), in collaboration with the PHASES Project, convened a highly diverse, multi-stakeholder think tank to identify priority advocacy objectives informed by consensus recommendations, and to develop an action plan to help advance the responsible study of HIV prevention in PLP to provide urgently needed evidence.  

 

 

GENERAL, OR OTHER DISEASES (in alphabetical order)

American College of Obstetricians and Gynecologists (ACOG) Ethics Committee Opinion 

Provides a broad overview of the history and ethics of research with pregnant women and addresses issues including informed consent, contraception requirements, and partner consent, highlighting harms of exclusion and cite the “ethical imperative to increase the inclusion of people who can become pregnant, who are pregnant, and who are lactating in research”: 

Global Forum on Bioethics in Research (GFBR) 

Report of 2016 meeting focused on the ethics of research in pregnancy, published in Reproductive Health, including several articles on advancing research in pregnancy: 

Health Policy Partnership 

Policy report on “achieving optimal care for women of childbearing age living with a chronic disease”; identified four pillars of action required to improve care. 

National Academies of Science, Engineering and Medicine (NASEM)

An ad hoc committee of NASEM Clinical Research issued a report (2024) that finds limited evidence of legal liability for inclusion of pregnant and lactating women in clinical research, contradicting perceptions of heightened liability, and makes recommendations to improve the evidence base for the safety and efficacy of medications for pregnant and lactating women while mitigating liability.

Medicines for Malaria Venture

Medicines for Malaria Venture has developed a “Malaria in Mothers and Babies” strategy that aims to “raise the standard of care for pregnant women and their newborns, “including through advancing pregnancy-specific research:

NICHD, Society for Maternal-Fetal Medicine (SMFM) and the American College of Obstetricians and Gynecologists (ACOG) 2015 Workshop   

Report reviews the current state of clinical care and science regarding medication use during the perinatal period, highlighting priority research gaps and key policy-related considerations: 

NIH Report from 2010 Workshop on Enrollment of Pregnant Women 

Report summarizes recommendations around enrolling pregnant women in research: 

NIH Report from 2010 Workshop on Microbicides/PrEP in Pregnancy  

Report summarizes recommendations for advancing inclusion of pregnant and lactating persons in HIV prevention research:  

PREVENT (Pregnancy Research Ethics for Vaccines, Epidemics, and New Technologies)  

Two guidance documents from Wellcome Trust funded projects offer recommendations for advancing ethical inclusion of pregnant women in vaccine research and during epidemics and infectious disease outbreaks: 

PRGLAC Report and Implementation Plan 

Recommendations made to the US Secretary of Health and Human Services regarding research and development of safe and effective therapies specific to pregnant and lactating women (2018) and implementation of such recommendations (2020):   

UK Commission on Human Medicines (CHM)   

An Expert Working Group of the UK’s Commission on Human Medicines (CHM) developed a report on the use of hormone pregnancy tests (HPTs) and adverse effects relating to pregnancy. Conclusions and recommendations (Chapters 7 and 8) broadly call for advancing research in pregnancy. 

UNAIDS/WHO Guidance for HIV Prevention Trials 

Updated guidance on ethical considerations in HIV prevention trials, discussing ethical importance of inclusion of pregnant persons in prevention trials and data to inform use of preventives in pregnancy: 

 

 

Tools for research design and evaluation 

One challenge of advancing research in pregnancy has been a lack of tools for designing and evaluating studies to ensure they meet ethical standards. Several organizations and groups have developed tools. Some are generally applicable to research, while others are country-specific (see also Ethical Guidelines for Research in Pregnancy, above). 

 COUNTRY/REGION-SPECIFIC GUIDANCE

 Canada  

Canada’s Drug and Health Technology Agency (CADTH) - Standing Senate Committee on Social Affairs, Science and Technology.

Off-label Use of Drugs. This position contrasts FDA’s position on off-label use, in which approval for use in adults is inclusive of pregnant adults.

 Commentary: 

European Medicines Agency  

US Food and Drug Administration (FDA) 

Advocacy and training resources

Many individuals in a position to fund, design, or evaluate research may lack understanding of the importance of conducting such research, or expertise relevant to the ethical and scientific challenges that pregnancy entails.

AVAC - Advocate’s Guide to Research in Pregnant and Lactating Populations 

AVAC has developed a resource that provides background on the need for research in pregnant and lactating populations and how advocates can advance inclusion. 

Canadian Mother-Child Collaborative Training Platform 

  • CAMCCO-L - a transdisciplinary and cross-sectoral training platform to better identify the risks and benefits of prescription drug use during pregnancy.     

Coalition to Advance Maternal Therapeutics (CAMT) – Society for Maternal-Fetal Medicine 

ConcepTION 

  • ConcepTION is being created to build a trusted ecosystem for healthcare providers and patients to find evidence-based information on the safety of medications during pregnancy and breastfeeding in a systematic, responsible and ethical way.  

Kigali Dolutegravir Stakeholder Meeting of African Women Living with HIV 

The Global Coalition on Women and AIDS (GCWA)

International Community of Women Living with HIV 

MotherToBaby 

  • MotherToBaby provides information from researchers in the Organization of Teratology Information Specialists (OTIS), a non-profit that evaluates medication risk in pregnancy and breastfeeding.    

US National Institutes of Health Outreach Toolkit

SisterLove, Inc.

  • SisterLove works to eradicate the adverse impact of HIV/AIDS and reproductive health challenges for women and their families in the United States and around the world through education, prevention, support and human rights advocacy.

On the horizon

BRIDGE Commission Report  

BRIDGE (Better Research, Information and Data Generation for Empowerment) is an independent, multidisciplinary group committed to the advancement of practical and action-oriented solutions to overcome information gaps that affect women’s health before, during and after pregnancy. 

International Council for Harmonisation Guideline on the Inclusion of Pregnant and Breastfeeding Individuals in Clinical Studies  

The International Council for Harmonisation held a hybrid meeting in Athens, Greece in May 2022 that engaged seven Working Groups, the ICH Management Committee, the MEDDRA Management Committee and the ICH Assembly. The ICH Assembly endorsed the development of a new ICH Efficacy Guideline on the “Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials” to work towards a framework and best practices to be accepted globally. The Press Release also mentions the effects that the COVID-19 pandemic has had on highlighting the importance of developing harmonized global guidelines that will benefit pregnant and breastfeeding individuals, and assist regulators, healthcare providers, and the pharmaceutical industry in ethically including this population in clinical trials.   

UK Safer Medications in Pregnancy and Breastfeeding Consortium 

The Safer Medicines in Pregnancy and Breastfeeding Consortium is a partnership of 16 leading organisations who are working together to improve the health information available to women who are thinking about becoming pregnant, are pregnant, or are breastfeeding. The partnership spans the NHS, regulators, and leading third sector and charitable organisations. 

 

Additional resources 

Books/Chapters

  • Baylis F and Ballantyne A (eds). Clinical Research Involving Pregnant Women (edited book). Cham, Switzerland: Springer, 2016. 
  • Bankert EA, Gordon B, Hurley EA, Shriver SP (eds.). Institutional Review Board: Management and Function, 3rd Edition. Jones and Bartlett, 2021. 
  • Little M, Wikremsinhe M, Lyerly AD. Research with pregnant women: Frameworks for addressing a neglected & complex population.  In: Iltis A and MacKay D, editors. Oxford Handbook of Research Ethics. New York (NY): Oxford University Press, 2024. 
  • Little MO, Wikremsinhe M, Jaffe E, Lyerly AD.  Research with Pregnant Women: A Feminist Challenge.  In: D’Agincourt-Canning L and Ells C (eds).  Reproduction and Beyond:  Ethical Issues in Women’s Health Care.  New York (NY): Oxford University Press; 2019, p 279-98. 

Articles 

Media/Blogs

 

Disclaimer

The provision of study materials and links from the toolkit to other websites is provided for your convenience and does not indicate endorsement of those materials or sites by WHO. WHO accepts no responsibility for the validity or accuracy of their content. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.