Policies for the Inclusion of Pregnant Women in Research

Abstract

Leading medical organizations have called for advancement of pregnancy-specific research to reduce harmful evidence gaps. However, meeting this objective poses ethical, legal, and policy dilemmas for investigators, oversight committees, academic institutions, and sponsors. To better understand the extent to which policies may facilitate or hinder the inclusion of pregnant women in research, we conducted two studies: an international study of laws, regulations, and ethical guidelines from a diverse sample of 59 countries and a study of policies from 84 top-funded US research institutions. We found that most policies use risk-based criteria for determining whether pregnant women should be included in research. Among countries with inclusion policies for pregnant women, 76% had risk-based policies (i.e., inclusion is based on risks and benefits to the pregnant woman and/or fetus), 13% had inclusionary policies (i.e., pregnant women should or must be included in research unless there is a valid scientific or ethical reason for exclusion), and 11% had exclusionary policies (i.e., pregnant women should or must be excluded from research unless there is a valid scientific or ethical reason for inclusion). In the US study, 96% of institutions had risk-based policies, 3% had exclusionary policies, and 1% had inclusionary policies. We also found that many policies referred to pregnant women as vulnerable. To promote fair and responsible inclusion of pregnant women in research, academic institutions, sponsors, and oversight agencies should adopt and implement policies with inclusionary language and refrain from referring to pregnant women as vulnerable.

Growing recognition of harmful gaps in evidence for medical care of women during pregnancy has led to nternational calls for advancing pregnancy-specific research.^1-8 Research involving pregnant women poses ethical and legal dilemmas for investigators, oversight committees, academic institutions, and sponsors. On the one hand, including pregnant women in research is vital to promoting the health of this population by ensuring that its members have access to therapies being tested in clinical trials as well as appropriate and safe treatment with medications approved for adult use.^7,8 Studies indicate that most medications are prescribed to pregnant women without sufficient data regarding safety and efficacy for that specific population, due to lack of clinical or epidemiologic research involving pregnant women.⁹ On the other hand, research during pregnancy often raises concerns about the ethics of imposing uncertain risks on the fetus. Thus, it is often considered necessary by oversight bodies to exclude pregnant women from research to protect fetuses (and future children) from potential teratogenic risks, even where risks are unlikely or theoretical.^10-12 Strong concern about such risks can be traced to the thalidomide tragedy, in which over 10,000 children were born with severe birth defects after their mothers were prescribed the drug for morning sickness—an event which cast a “long shadow” over both the use of medications during pregnancy, and the culture of research required to ensure their safety.¹³

Many have observed that in retrospect, the regulatory and legal responses to the thalidomide tragedy were paradoxical. Policies adopted in the wake of the event emphasized maximal protection for fetuses from drug exposure, including the exclusion of pregnant women from research, which left enduring gaps regarding the safety of most drugs used in pregnancy, thereby further entrenching the circumstances that led to the tragedy in the first place.¹³ Concerns about legal liability have also contributed to reluctance to conduct pregnancy research.¹⁴ However, a report from the National Academies of Science, Engineering and Medicine found no evidence of legal liability for harm within clinical studies, situating liability risk in clinical settings.⁶

Even with this emphasis on protecting pregnant women and fetuses from research-related risks, US human research protection (HRP) polices permit enrollment of pregnant women in research.^12,15 Subpart B of the US Department of Health and Human Services (DHHS) regulations governing research with humans (45 CFR 46), for example, holds that an institutional review board (IRB) may approve research involving pregnant women if it determines that “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.”¹⁶ The Council for the International Organizations of Medical Sciences (CIOMS) guidelines also reflect this risk/benefit approach to including pregnant women in research.^17,18 Risk-based policies allow inclusion only when potential risks to the woman or fetus are minimal or offset by direct benefit. However, in practice, they often function as de facto exclusion.

While the US regulations do not explicitly discourage the inclusion of pregnant women in research, they have been identified as a barrier to appropriate inclusion. Before its revision in 2018, the Common Rule categorized pregnant women as “vulnerable,” alongside children, prisoners, and individuals with intellectual disabilities. Due to concerns that this designation inaccurately implied that pregnant women are incapable of providing valid consent or are at excess risk of exploitation, the revisions to the Common Rule removed pregnant women from the list of research participants classified as vulnerable.^12,16 The CIOMS guidelines note that “pregnant women must not be considered vulnerable simply because they are pregnant.”¹⁷ However, the historical linkage between vulnerability and pregnancy may still affect the ethical decision-making of investigators and ethics committee members by leading them to focus on avoiding clinical research risks by excluding pregnant women from research.⁷

HRP policies (including laws, regulations, and institutional rules) can play an important role in helping researchers, oversight committees, academic institutions, and sponsors address the ethical dilemmas concerning the inclusion of pregnant women in research. However, empirical data about the content and scope of such policies is limited. While there have been some insightful analyses of regulations in specific countries, comparative studies of country-specific and institutional-specific policies are lacking.^19,20 In this paper, we report the results of two complementary studies designed to enhance our understanding of the extent to which HRP policies may facilitate or hinder the inclusion of pregnant women in research. The aim of the first study was to characterize the international landscape for pregnancy research by analyzing the laws, regulations, and ethical guidelines concerning the involvement of pregnant women in research adopted by different countries. The aim of the second study was to use parts of the coding framework developed for the first study to analyze policies from the top-funded US research institutions to determine their impact on the inclusion of pregnant women in research.

STUDY MATERIALS AND METHODS

For the international study, we sampled policies concerning research with pregnant women from 59 countries. Our sample included the top 40 countries ranked by total research and development (R&D) funding for the most recent available year, 2021.²¹ To ensure adequate representation from different continents, we also included the top 5 countries, ranked by annual births, from each continent, if they were not already included in the top 40 R&D countries. For each country, we collected data on total R&D funding, R&D funding rank, gross domestic product (GDP), population, fertility rate, and continent (North America, South America, Europe, Asia, Africa, Oceania). R&D data was obtained from the National Science Foundation. Other country data was obtained from the World Bank and Trading Economics.^22,23

We developed our coding framework based on a review of key papers and reports on the ethics of including pregnant women in research, Subpart B of the DHHS regulations, and the US Food and Drug Administration (FDA) draft guidance.^5-8,11,15,16 The coding framework was refined after an initial review of the policies. Two pairs of researchers independently coded the policies and then resolved disagreements. A third researcher answered questions from the coders about how to interpret the policies during the coding process. Inter-rater agreement was assessed statistically prior to reaching agreement on the final coding of the data. Many of the policies were available from the US Office for Human Research Protection’s compilation of international human research ethics standards.²⁴ If we could not find the policy there, we located it by means of an internet search. Collection and coding of data was done from February to April 2025. Policies were coded according to questions 1-4 and 5-7 specified in table 1.

Table 1.

Questions Used to Code Polices Concerning the Inclusion of Pregnant Women in Research

1. Does the country have human research protection laws, regulations, or ethics guidelines? [Y/N]

2. If the answer is yes to 1, what type of guidance does it have?

a. National law

b. Government agency regulation

c. National or agency ethics guideline

d. Defers to another source (such as an international ethics code). Note: if the country defers to another source, this source is used to answer questions 3-7.

3. Do the laws/regulations/guidelines cover pregnancy specifically? [Y/N]

4. Do the laws/regulations/guidelines include statements concerning inclusion/exclusion of pregnant women in research? [Y/N]

5. If the answer is yes to 4, what type of inclusion/exclusion statement does it have?

a. Inclusionary: Pregnant women are included in research unless a valid scientific or ethical reason justifies exclusion.

b. Exclusionary: Pregnant women are excluded from research unless a valid scientific or ethical reason justifies inclusion.

c. Risk-based: Inclusion or exclusion of pregnant women is based on the balance of risks and benefits to the women and fetus.

d. Other.

e. No policy statement.

6. Does the policy describe pregnant women as vulnerable? [Y/N]

7. Does the policy refer to fairness, access, or justice when describing inclusion or exclusion of pregnant women? [Y/N]

8. Does the policy provide guidance on pregnancy testing or contraception? [Y/N]

9. Does the policy provide guidance on what to do if a participant becomes pregnant while enrolled in the study? [Y/N]

10. Does the policy provide guidance for obtaining the father’s consent under some conditions? [Y/N]

Note: The international study used questions 1-4 and 5-7; the US study used questions 5-10.

For the US study, we used questions from the coding framework developed for the international study and included some other questions related to contraception, enrollment of participants who become pregnant during the study, and the nongestational partner’s/father’s consent (see table 1). The policies examined in the US study came from institutions identified by an earlier study conducted by some members of our research team.²⁵ The earlier study analyzed IRB policies from the top 105 US research institutions, ranked by total research funding, and identified 96 institutions with policies on the inclusion of pregnant women in research. Starting with this sample, we excluded policies that were not publicly accessible, which left 84 policies. Two pairs of researchers independently coded these policies and then resolved disagreements. A third researcher answered questions from the coders about how to interpret the policies during the coding process. Inter-rater agreement was assessed statistically prior to reaching agreement on the final coding of the data. Policies that could not be accessed were excluded from coding. We also collected data on the institution’s geographic region, research funding rank, public versus private status, and Association for the Accreditation of Human Research Protection Programs (AAHRPP) accreditation status. Data collection and coding took place from May to July 2025. Inter-rater reliability was fair for most of the policy categories (Cohen’s Kappa ranged from −0.06 to 0.47).

R (version 4.3.2) was used in the data analysis in both studies and a p-value <0.05 was considered as significant. For the international study, the variables R&D funding, GDP, population, GDP per capita, and fertility rate had a skewed distribution; we therefore log-transformed these variables before the analyses. We used Fisher’s Chi-square test to evaluate the association between categorical variables and linear regression to assess the association with continuous variables. We used logistic regression to evaluate the association between IRB policies regarding pregnant women and R&D funding, GDP, population, GDP per capita, and fertility rate while adjusting for geographic region.

For the US study, the variable R&D funding had a skewed distribution; we therefore used log-transformed values in the regression model. We used logistic regression to evaluate the association between IRB policies regarding pregnant women and the characteristics of the institutions. Each IRB policy was used as a response variable in turn and the following variables were included as predictors: R&D funding, public/private status of the institutions, AAHRPP Accreditation, and geographic region.

STUDY RESULTS

For the international study, the distribution of countries was Europe (34%), Africa (17%), Asia (15%), Oceania (12%), South America (12%), and North America (10%). The mean GDP for these countries was $1.6 trillion (S.D. $4.2 trillion). The mean GDP per capita was $28,482 (S.D. $26,489). The mean total R&D funding was $43.8 billion (S.D. $137 billion). The mean population was 103 million (S.D. 259 million).

All the countries in our sample had laws, regulations, or ethics guidelines for protecting human subjects in research. Thirty-one percent had government agency regulations; 20% had national laws; 12% had ethics guidance; and 37% had ethics guidance that deferred to another source (such as CIOMS). In our sample, 85% of countries had laws, regulations, or ethics guidelines that covered pregnancy specifically and 76% had criteria for inclusion of pregnant women in research. Among those with inclusion criteria, 76% had risk-based policies, 13% had inclusionary policies, and 11% had exclusionary policies. Thirty-four percent of the policies had language that referred to pregnant women as vulnerable, and 8% had language that referred to notions of fairness, access, or justice when discussing the enrollment of pregnant women in research. Overall inter-rater reliability was moderate or better for most of the categories (Cohen’s Kappa ranged from 0.37 to 0.87). See table 2 for summary data from the international study and table 3 for examples of policy language.

Table 2.

Policies for Including Pregnant Women in Research from 59 Countries

Type of guidance	count/percent
National law	12 (20%)
Government agency regulation	18 (31%)
Ethics guidance	7 (12%)
Ethics guidance that defers to another source (e.g. CIOMS)	22 (37%)
Does the guidance have inclusion/exclusion criteria?
Yes	45(76%)
No	14 (24%)
Type of inclusion/exclusion statement [N = 45]
Risk-based	34 (76%)
Inclusionary	6 (13%)
Exclusionary	5 (11%)
Does the policy refer to pregnant women as vulnerable?
Yes	20 (34%)
No	39 (66%)
Does the policy refer to fairness, access, or justice when discussing inclusion/exclusion of pregnant women?
Yes	5 (8%)
No	54 (92%)

Table 3.

Examples of Language for Inclusion for Pregnant Women in Research

Inclusionary language
Belgium
“Pregnant women should be presumed to be eligible for participation in biomedical research.”27
Nigeria
“Pregnant women, socially, culturally, economically, politically, educationally, physically and psychologically disadvantaged groups, groups with constrained autonomy and other vulnerable populations should not be excluded from research without explicit reasons for doing so; particularly from studies that can advance their health and wellbeing.”28
University of Washington
“The UW supports the policy of providing pregnant women with the same opportunities as non-pregnant women to participate in research unless the individual meets exclusionary criteria or the study poses more than minimal risk to the fetus.”29
Exclusionary language
Ecuador
“In the event of pregnancy occurring during the development of the clinical trial, the woman will be excluded as a research subject.”30
South Africa
“Pregnant women, women planning to become pregnant, or breastfeeding women are usually excluded from human clinical trials where a new chemical entity (NCE) or medicines with no information on safety in pregnancy/lactation are investigated for treatment of a particular disease/condition or disorder.”31
Stony Brook University
Pregnant women in FDA studies are defined as vulnerable in this policy.32
Risk/benefit language
Uganda
“Data supporting the conduct of a clinical trial involving both children and pregnant/lactating women should demonstrate that the benefit to these populations outweighs the risk … For research interventions or procedures that have the potential to benefit children and pregnant/lactating women, risks must be minimized and outweighed by the prospect of potential individual benefit.”33
Germany
“A clinical trial on pregnant or breastfeeding women may be conducted only where, in addition to the conditions set out in Article 28 [“General rules], the following conditions are met: the clinical trial has the potential to produce a direct benefit for the pregnant or breastfeeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved.”34
Duke University
“Pregnant women or fetuses may be involved in research at DUHS only if the IRB determines that all of the following ten (10) conditions [2-5 below indicate risk/benefit language] are met (45 CFR 46.204):
1. …
2. 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
3. Any risk is the least possible for achieving the objectives of the research
4. If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with 45 CFR 46.116 and 117
5. 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 45 CFR 46.116 and 117, 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. … ”35

Among all the country variables examined (geographic region, total R&D funding, GDP, population, GDP per capita, and fertility rate), only geographic region was significantly associated with types of polices. Of the European countries, 85% (17/20) have policies that defer to other sources (chiefly CIOMS), whereas North American and South American countries have no policies that defer to other sources (p = 0.007). Fifty-five percent (11/20) of European countries have policies that refer to pregnant women as vulnerable but no countries in North America or Oceania have policies that refer to pregnant women as vulnerable (p = 0.024). Forty-three percent (3/7) of South American countries have policies that refer to fairness, access, or justice when discussing enrollment of pregnant women in research but none of the countries in North America, South America, Europe, Asia, or Oceania have policies that use such language (p = 0.0067). Because there were statistically significant differences in R&D funding, GDP, population, GDP per capita, and fertility rate across geographic regions, we adjusted for geographic region in the logistic regression analysis. We did not observe statistically significant associations between R&D funding, GDP, population, GDP per capita, and fertility rate and policies for including pregnant women in research after adjusting for geographic region.

In the US study, we found that 73% of institutions were AAHRPP accredited, 27% were not AAHRPP accredited, 68% were public, and 32% were private. The geographic distribution was West (32%), South (29%), Midwest (24%), and Northeast (15%). Among these institutions, 96% had risk-based inclusion policies, 3% had exclusionary policies, and 1% had inclusionary policies. Fifty-seven percent of the policies referred to women as vulnerable, 81% addressed the father’s consent, 32% provided guidance on what happens if a participant becomes pregnant while enrolled in a study, 24% provided guidance on pregnancy testing or contraception, and 11% mentioned fairness, justice, or access when discussing inclusion of pregnant women in research. See table 4 for summary data for the US study.

Table 4.

Policies for Including Pregnant Women in Research from 84 US Institutions

Type of inclusion/exclusion statement [N = 80]	count/percent
Risk-based (96%)	77
Exclusionary (3%)	2
Inclusionary(1%)	1
Does the policy refer to pregnant women as vulnerable?
Yes (57%)	48
No (43%)	36
Does the policy refer to fairness, access, or justice when discussing inclusion/exclusion of pregnant women?
Yes (11%)	9
No (89%)	75
Does the policy provide guidance on pregnancy testing or contraception? [N = 83]
Yes (24%)	20
No (76%)	63
Does the policy provide guidance on what to do if a participant becomes pregnant while enrolled in the study?
Yes (32%)	27
No (68%)	57
Does the policy provide guidance for obtaining the father’s consent under some conditions?
Yes (81%)	68
No (19%)	16

There was no association between the public/private status of the universities, AAHRPP accreditation, or geographic region and any of the IRB policies regarding pregnant women. Higher R&D funding was negatively associated with having a guidance on pregnancy testing or contraception (P-value = 0.02, OR = 0.67 for each doubling of R&D funding, 95% CI = 0.48, 0.95) and positively associated with requiring father’s consent under some conditions (P-value = 0.01, OR = 1.56 for each doubling of R & D funding, 95% CI = 1.09, 2.23).

DISCUSSION

Our most significant finding is that most of the HRP policies we examined in these two studies did not actively support the inclusion of pregnant women in research, potentially contributing to their harmful underrepresentation in biomedical research. Most of the policies have risk-based inclusion rules like those found in 45 CFR 46, Subpart B. In the US study, 96% of policies were risk-based, and in the international study, 73% were risk-based. We also found that some of the policies were exclusionary (11% for the international samples and 3% for the US sample). While 13% of countries in our study had inclusionary policies, only 1% of US institutions did.

Another key finding is that many policies still refer to pregnant women as vulnerable, a designation that may encourage investigators and ethics committees to take steps to exclude them from research. In the international study, 34% of countries, including 55% of European countries, had policies that refer to pregnant women as vulnerable. In the US study, 57% of institutions had policies that refer to pregnant women as vulnerable, which is a troubling finding given that the vulnerability designation was removed from the Common Rule (subpart A of the DHHS regulations) in 2018. This change was made in response to concerns that vulnerability (1) is a medically inaccurate term (pregnancy itself does not limit a woman’s capacity to provide valid informed consent), and (2) can have a chilling effect on even ethically appropriate and urgently needed research in pregnancy. The persistence of this language may reflect not only a legacy of caution, but also institutional inertia and limited guidance on how to revise policies following the 2018 Common Rule update. It may also reflect a deeper and worrisome misattribution of diminished agency to pregnant women, based solely on their pregnancy status. Many bioethics publications and professional guidelines now use the terms “special” or “complex” to describe pregnant women; CIOMS now discourages classifying any group as inherently vulnerable.¹⁷

Although risk-based policies permit the enrollment of pregnant women in research, they can be interpreted as restrictive, especially in contexts where research in pregnancy has traditionally been considered ethically suspect. For instance, even as 45 CFR 46 at Subpart B is widely permissive of research with pregnant women, research addressing the treatment or prevention of illness in pregnancy remains rare, and the evidence base woefully inadequate. Even in cases where pregnant women are most at risk for a disease or its morbidities (e.g., HIV prevention, tuberculosis, seizure disorders), they are excluded from clinical research studies. Most drugs are approved without human pregnancy data addressing fetal safety, without dosing appropriate to the physiologic changes of pregnancy, and without information about the risks and benefits of drugs for the health of the pregnant woman.²⁶ Another problem with risk-based approaches is that they are often deployed in an institutional environment in which there is a general practice of summarily excluding pregnant women from research without justification—a model of “presumed exclusion.” In other words, the burden of justification is presumed to fall only on investigators who plan to include pregnant women in their research, not on those who plan to exclude pregnant women.

Increasingly, bioethicists have emphasized the importance of fair access to the benefits of research—both for individuals seeing direct benefits of a study and populations whose care might be informed by study findings. Research oversight bodies are well-positioned to facilitate research aligned with principles of justice regarding pregnancy. Rather than focus narrowly on reducing and eliminating risk in biomedical research studies, they can explore and implement approaches that support inclusion. Two immediate opportunities are eliminating the language of vulnerability from pregnancy research guidance and requiring justification for studies that exclude pregnant women. Even the exercise of providing justification for excluding pregnant women from a study—or assessing the strength of that justification—may help reinforce the importance of conducting research in pregnancy and moving toward a research agenda that more robustly supports the health of pregnant women and their children. Because IRBs and investigators do not always follow HRP policies, future research should explore how policy language shapes protocol approval or investigator behavior in practice, including whether exclusion justifications are commonly required.

Laws and policies can play an important role in shaping biomedical research. Despite the global emphasis on the importance of gathering data to inform the care of women who are pregnant, most laws and policies reinforce a pattern and culture of exclusion that have led to harmful evidence gaps. Instead, policies that respect the capacity of pregnant women to make decisions about research participation, support reasonable approaches to (and the inevitability of) risk-benefit trade-offs in pregnancy, and require justification for the exclusion of individuals who are or might become pregnant from studies could make an outside difference in advancing ethically appropriate and urgently needed research.

LIMITATIONS

One limitation of our international study is that the sample may be biased because we surveyed only 59/193 countries in the world (30.6%). However, we do not consider this to be a significant limitation of this study because we included all the countries that are the primary supporters of research involving pregnant women (i.e., the top 40 countries ranked by R&D funding), and we diversified our sample so that it included at least six countries from each geographic region.

Sampling bias is also a potential concern with the US institutional study, because we coded policies from the top 84 research institutions (ranked by funding) and did not code policies from institutions that receive less funding. However, we do not consider this to be a significant limitation of this study because the top-funded institutions are much more likely to have policies pertaining to the inclusion of pregnant women in research than institutions that receive much less funding since they are less likely to conduct research involving pregnant women.

A limitation of both studies was that inter-rater reliability was fair or only slight (Cohen’s Kappa <0.40) for some of the variables the raters coded. However, we do not believe this issue undermines the overall reliability of our data since the raters independently coded the data and were able to resolve their disagreements, with the help of a third party in some cases.

Another limitation of both studies is that we did not assess legal interpretations of the policies, or regulatory or institutional guidance, all of which can impact decisions made by investigators and ethics committees. Additional research is needed to better understand how HRP policies concerning pregnant women are interpreted and applied in different settings.

CONCLUSION

Asignificant percentage of national and institutional HRP policies do not actively support the inclusion of pregnant women in research, perpetuating a culture of exclusion resulting in impactful evidence gaps. To promote fair inclusion of pregnant women in research toward robust data to inform their care, academic institutions, sponsors, and oversight agencies should adopt HRP policies with language that supports the inclusion of pregnant women in research unless a valid scientific or ethical reason justifies exclusion. HRP policies should also refrain from referring to pregnant women as vulnerable. Both are important and immediately actionable steps that can contribute to ensuring that pregnant women receive safe, effective, and optimal medical care—critical to their health and that of the next generation.