Managing Pregnancies in Clinical Trials: Regulatory Guidance and Best Practices

Clinical research historically has excluded pregnant women, creating major data gaps. Today, less than 1% of trial participants are pregnant, and most approved drugs lack pregnancy safety data. There are various reasons pregnant women are often excluded from clinical trials: 

• Scientific and medical concerns: potential fetal harm, unknown pharmacokinetics and dosing, Complex mother-fetus risks, and impact on maternal health.
• Religious or cultural considerations: Emphasis on fetal protection, Paternalistic IRB attitudes, Participation and social norms. 
• Liability and legal concerns: Fear of fetal-harm lawsuits, Insurance and compensation, Regulatory ambiguity, Cascading regulatory costs

Regulators such as US FDA now emphasize a balanced approach – gathering information on drug use in pregnancy by allowing inclusion when appropriate, while protecting fetal safetyf FDA guidance and recent legislation stress that trials should broadly reflect real-world populations, with any exclusions (like pregnancy) justified by safety and scientific rationale. In fact, pregnancy is explicitly identified as a historically underrepresented group in FDA diversity initiatives. This shift in thinking – codified by laws like FDARA and FDORA and by draft FDA guidances – is intended to improve evidence on treating pregnant patients.

Regulatory Context and Diversity Guidance

FDA regulations and guidances set the framework for handling pregnancy in trials. The FDA’s 21 CFR Part 50 Subpart B (pregnant women, fetuses, and neonates) and 21 CFR Part 56 (IRB requirements) require heightened protections for pregnant participants. For example, FDA recommends that if a study offers benefit solely to the fetus, both the pregnant woman and her partner must consent (with narrow exceptions). Crucially, FDA guidance mandates that “each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate”. In practice, this means consent forms and discussions must spell out known pregnancy risks (and uncertainties) based on available animal or prior data. IRBs reviewing these trials must include members experienced with maternal-fetal medicine and ensure extra safeguards (per 21 CFR 56.111(a)(2) and (b)).

At a higher level, FDA’s draft guidance on pregnant women (2018) explicitly endorses “judicious inclusion of pregnant women in clinical trials” to inform safe drug use in pregnancy. Similarly, the 2020 FDA guidance on broadening trial diversity urges sponsors to continuously “broaden eligibility criteria” as safety data accrues, narrowing unnecessary exclusions. These documents reinforce that excluding pregnant women should not be automatic: instead, inclusion should be considered whenever the potential benefits outweigh risks. In summary, the regulatory message is clear: plan trials for diversity (as now required by law with Diversity Action Plans) and, where scientifically justified, include or at least carefully manage pregnant participants.

Informed Consent and Pre-Screening Procedures

Before enrollment, trials must address pregnancy risk. Protocols almost universally exclude pregnant or breastfeeding women, and require women of childbearing potential (WOCBP) to use reliable contraception and have negative pregnancy tests at screeningonbiostatistics.blogspot.com. Per longstanding FDA advice, informed consent must cover pregnancy issues explicitly: if nonclinical reproduction studies are lacking, sponsors must “fully inform” women and advise on contraceptive measuresonbiostatistics.blogspot.com. In practice, consent forms and discussions should include pregnancy-specific language and summarize what is (and isn’t) known about fetal risk.

• Contraception and Testing: Investigators should ensure WOCBP agree to use effective birth control (including abstinence) and take a pregnancy test before each dosing period. FDA guidance has long recommended pregnancy tests at screening and counseling on contraceptiononbiostatistics.blogspot.com. Some trials repeat tests periodically to catch early pregnanciesonbiostatistics.blogspot.com.

• Risk Disclosure: Consent discussions must describe potential risks to a fetus. The FDA draft guidance stresses that subjects be informed about “reasonably foreseeable impact” of trial participation on the fetus or neonate. Even if evidence is limited, the consent should transparently explain any known animal or human data, and state unknowns. This empowers participants to make decisions with full awareness of pregnancy-related risks.

Managing Pregnancies Discovered During Trials

Despite precautions, some participants will become pregnant during a study. Best practices focus on timely detection, notification, and safety:

• Detection: Continue pregnancy testing throughout the study (e.g. at regular visits or follow-ups). One biostatistics review notes that trials “usually perform pregnancy tests periodically” so pregnancies can be caught earlyonbiostatistics.blogspot.com.

• Immediate Actions: If a pregnancy is identified, the standard practice is to stop the study drug to avoid further exposureonbiostatistics.blogspot.com. The investigator should promptly notify the sponsor and IRB, and arrange any needed medical follow-up. FDA guidance goes further: it recommends unblinding the subject’s treatment (drug vs placebo) so the woman and her physician can discuss risks based on actual exposure. The patient should then undergo a second informed-consent process that incorporates the new risk-benefit assessment. For example, if the drug may benefit the mother, continuation might be allowed if potential benefits outweigh fetal risks (with the mother’s informed agreement). Otherwise, she should be withdrawn from treatment.

• Data and Follow-Up: Regardless of continuation, sponsors must collect detailed follow-up data. FDA guidance explicitly states that “regardless of whether the woman continues in the trial, it is important to collect and report the pregnancy outcome”. In practice, this means recording gestational age at drug exposure, duration of exposure, and all outcomes (live birth, gestational age at delivery, congenital events, etc.). The pregnant participant should receive standard obstetrical care and fetal monitoring alongside the study’s safety assessments. For example, cord blood or neonatal samples might be collected for drug levels if relevant.

• Discontinuation and Missing Data: If the participant discontinues the study, subsequent efficacy visits are often ceased; statisticians typically handle missing data using predefined methods. Notably, many sponsors maintain a pregnancy registry or report form for study pregnanciesonbiostatistics.blogspot.com. These registers feed into post-market surveillance (and often meet regulatory reporting requirements). Any adverse fetal outcome (miscarriage, birth defect, etc.) must be reported as a serious adverse event per 21 CFR 312.32/64.

• Monitoring: Trials with pregnant subjects or exposures require specialized monitoring. For example, the protocol should specify involvement of obstetric/maternal-fetal experts on the safety monitoring team. Ongoing review of maternal and fetal safety signals is essential – a dedicated data monitoring committee may be warranted. In extreme cases (e.g. clear evidence of harm), the trial’s stopping criteria may trigger halting enrollment.

Reporting and IRB Notification

Pregnancy events are subject to regulatory and ethics oversight. Investigators should report any pregnancy to the IRB as soon as it is identified (often as an “unanticipated problem” in light of initial exclusion criteria). FDA guidance notes that IRBs reviewing such protocols must have the right expertise and must ensure “additional safeguards” are in place for pregnant subjects. For example, IRBs should verify that consent materials address pregnancy, that medical backup (e.g. obstetric care) is arranged, and that procedures (e.g. prohibition of termination inducements) are followed.

Sponsors, in turn, must follow safety-reporting rules. Under FDA IND regulations, any pregnancy with drug exposure is reported to FDA (particularly if it results in a serious fetal or neonatal outcome). The IRB and health authorities should be kept informed according to institutional policies. In practice, many trials use a structured form or registry entry to document trial pregnancies and outcomesonbiostatistics.blogspot.com. This ensures timely communication of safety information to all stakeholders.

Ethical Considerations of Inclusion vs. Exclusion

The exclusion of pregnant women raises ethical issues. Traditionally, fear of fetal harm led to a protective approach, but contemporary ethicists argue that systematic exclusion often causes more harm. As one commentary notes, refusing to study drugs in pregnancy “merely shifts risk to the clinical context” – doctors and patients then must decide on therapies with no evidence, which is “hardly an ethical approach”. High-profile cases (e.g. thalidomide) illustrate the dangers of not studying drugs in pregnancy. In fact, a commissioned analysis found no liability cases from including pregnant women in trials, whereas many lawsuits have arisen from unforeseen drug harms in pregnant patients after approval.

Conversely, including pregnant participants – with proper precautions – yields direct benefits. It allows rigorous collection of safety/efficacy data in a controlled setting, reducing uncertainty. Experts stress it is a humane and scientific responsibility to prioritize pregnant women’s inclusion when possible. Denying them evidence essentially “denies pregnant women—and their healthcare providers—the evidence necessary to make informed decisions”. Modern ethical guidance and FDA policy now urge balancing fetal protection with the pregnant woman’s health needs, rather than default exclusion.

Recommendations and Future Directions

Given this landscape, sponsors and investigators can follow several best practices:

• Education and Consent: Develop clear, patient-friendly consent materials that discuss pregnancy risks and emphasize the importance of contraception for WOCBP. Train staff to discuss these issues openly.

• Safety Monitoring: Include pregnancy in safety monitoring plans. Engage obstetric/maternal-fetal medicine consultants in trial planning and oversight.

• Trial Design: Where feasible, design trials to allow pregnant participants (or planned pregnancy cohorts) for conditions that affect women of childbearing age. FDA’s 2018 draft guidance and recent NIH recommendations encourage such trials for pregnancy-specific or relevant indications.

• Community Engagement: Build partnerships with obstetric care providers and clinics. Embedding trial activities in OB settings can greatly improve recruitment and trust among pregnant patients.

• Regulatory Planning: Anticipate the need for pregnancy considerations in regulatory submissions. Under the Pregnancy and Lactation Labeling Rule (PLLR), FDA expects clear labeling of pregnancy data (or lack thereof). Sponsors should be prepared to update labels as new pregnancy data emerge.

• Continued Advocacy: Engage with regulatory agencies. FDA’s task forces and guidance initiatives (e.g. on diversity action plans) reflect ongoing shifts. Industry input can help shape policies that balance scientific goals with patient safety.

In summary, managing trial pregnancies requires a structured approach: robust informed consent, vigilant monitoring, regulatory reporting, and ethical reflection. With these measures, sponsors can protect participants while generating the much-needed data on drug safety in pregnancy. As one expert put it, including pregnant women in research is no longer a question of if but when and how – given the broad benefits of more equitable, evidence-based care.

References: 

• FDA guidance (2018) "Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials"
• FDA guidance (2020) "Enhancing the Diversity of Clinical Trial Populations-Eligibility Criteria, Enrollment Practices, and Trial Designs". This guidance was subsequently removed, but the talking points are still there. 
• The FDA law blog (2025) "Clinical Research Representation: Pass it On"
• Onbiostatistics.blogspot.com (2017) "Exclusion of pregnant women from clinical trial and pregnancy test for women of childbearing potential (WOCBP)"
• Life Science Leader (2025) "Pregnant Women: An Underrepresented Group In Clinical Trials"
• Applied Clinical Trials (2025) "Pregnant Women: An Underrepresented Group in Clinical Trials"