Why Drug Safety in Pregnancy Remains a Critical Topic

Written by:
Anne Broe Lambourne, MD PhD, Engagement Manager at Epidemiology & Scientific Strategy, Real World Evidence, IQVIA
Emily W. Bratton, MSPH, PhD, Senior Director of Applied AI Science at IQVIA

The effects of prescription drug exposure during pregnancy remain a significant unknown and evidence gap for many important treatments. For individuals managing chronic illnesses, such as autoimmune disease, diabetes, or mental health conditions, treatment cannot simply be paused for the duration of pregnancy. Medications are often essential to maintaining maternal health, preventing disease progression, and reducing the risk of pregnancy complications, and the discontinuation or modification of therapies may pose substantial risk(s) to maternal health. Under ideal circumstances, women would have informed discussions with their clinicians regarding their treatment prior to pregnancy. Yet, despite common medication-use during pregnancy, the scientific foundation guiding these discussions and decisions is frequently delayed, incomplete, or absent.

At the heart of this challenge lies a structural limitation in how evidence is generated. Traditional clinical trials have historically excluded pregnant women, largely due to ethical concerns surrounding fetal risk and maternal vulnerability.

While well-intentioned, such exclusion has resulted in a long-standing evidence deficit. Health care providers are often forced to make treatment decisions without robust data, instead balancing known maternal benefits against uncertain fetal risks. In many cases, clinicians must rely on theoretical mechanisms, animal data, or post-market signals, rather than clear, pregnancy-specific evidence. The roll-out of vaccinations during the Covid-19 pandemic is a good example of the impact of the lack of evidence during pregnancy¹.

Over the past decade, advances in real-world data sources, improved methodologies for pregnancy study design, and increasingly detailed regulatory guidance on drug labeling have also addressed the growing need for data^2,3,4,5. However, persistent challenges remain. Evidence generation is slow, fragmented, and often inconclusive, leaving both patients and providers navigating uncertainty during one of the most critical periods of care.

Both U.S. and European regulatory bodies have increasingly turned to existing data sources to support evidence generation in pregnancy. The European Medicines Agency (EMA) has a longstanding tradition of using secondary data, and this approach is now gaining momentum in the United States. The U.S. Food and Drug Administration (FDA) is shifting from a historical reliance on primary data collection alone towards a more balanced model that incorporates both primary data collection studies, and analyses of existing data sources.

Regardless of the data source, however, timelines remain a fundamental challenge.

It often takes ten years or more to gather sufficient evidence on drug safety in pregnancy. Even after a decade of data collection, conclusions are often cautious, frequently ending with the assessment that additional data remains necessary.

For patients and clinicians making decisions today, this lag means that uncertainty persists long after a drug has entered widespread use.

To provide more comprehensive information for clinicians and patients, the FDA replaced their five categories of safety for use during pregnancy in 2014 with specific information about safety during pregnancy, lactation, and general population of reproductive age⁶. The EMA has also taken action to enable faster evidence generation for drug safety during pregnancy and lactation, including initiatives in both the preclinical and post-authorization phase⁷. This reality underscores the need to examine not only what evidence is generated, but how it is generated – and whether current approaches are sufficient to meet the needs of pregnant individuals.

Current regulatory guidance in both the U.S. and the EU provides detailed direction on how pregnancy safety data should be generated, evaluated, and communicated. Guidance documents outline expectations for pregnancy exposure study design, the establishment and operation of exposure registries, and the integration of findings into drug labeling. These frameworks are intended to promote consistency, transparency, and scientific rigor across studies.

Pregnancy exposure studies play a vital role within this framework. They serve as a key mechanism for collecting post-market data when clinical trials have excluded pregnant individuals. Through registries and observational analyses, regulators seek to better understand real-world medication use and outcomes during pregnancy.

While the regulatory structure is robust on paper, implementation remains complex. Translating guidance into actionable, timely evidence generation continues to be a challenge, particularly given the ethical, operational, and methodological considerations unique to pregnancy research.

A range of study methodologies is used to evaluate drug safety in pregnancy, each with distinct strengths, limitations, and design considerations. The choice of methodology depends heavily on study objectives, feasibility, and the existing evidence base.

At a high level, the objectives of clinical research during pregnancy fall into two categories. First, studies may aim to support the development of therapeutics intended specifically for pregnancy-related conditions. Second, they may aim to support the development and safe use of therapeutics for medical conditions that coexist with pregnancy.

Although regulatory guidances continue to evolve, and collaboration among regulatory agencies is increasing, several challenges continue to decelerate progress.

1. Ethical considerations remain central. Determining when, and under what conditions, it is appropriate to include pregnant individuals in research requires careful assessment of potential risks and benefits. Data privacy concerns further complicate study design, particularly when enhancing existing data with prospective data collection and linking maternal and infant health records across systems.
2. There is also an ongoing need for standardized protocols. Variability in study design, outcome definitions, and data collection methods limits the ability to compare results across studies or aggregate data effectively.
3. Operational challenges present another barrier. Supporting women and infants throughout a study requires additional infrastructure and often technological solutions to offer participant-centric designs and ease burden of data collection. Pregnancy and the postpartum period represent life-changing transitions, and successful study participation may depend on providing lactation support, flexible follow-up options, and other accommodations to minimize burden.

Addressing these challenges will require a fundamental shift in how pregnancy research is approached. One key lesson is the importance of creating a culture that supports the inclusion of pregnant individuals in clinical trials when there is no strong theoretical basis for harm. Exclusion should not be the default as per the ICH guidance.

Risk assessment must consider biological plausibility. The COVID-19 pandemic provides a clear example when pregnant individuals were forced to weigh the potential risks of vaccination against the known risks of infection. In this case, infection posed a far greater threat to both maternal and fetal health than vaccination, highlighting the consequences of delayed or absent evidence.

Moving forward, stakeholders should be encouraged to develop clear criteria, such as frequency of use and seriousness of unmet medical need, for identifying priority medications for study in pregnancy. This prioritization can help focus limited resources on therapies with the greatest potential impact.

Greater use of existing data sources, including electronic health records and registry data, offers another path forward. Enhancing the ability to link these data sources as well as enhancing existing data with prospective data collection through pragmatic trials can unlock more comprehensive insights while minimizing additional burden on pregnant individuals. Missing variables can be layered onto existing datasets, enabling robust evidence generation without exposing mothers or fetuses to unnecessary risk.

Together, these approaches represent an opportunity to close long-standing evidence gaps and support safer, more informed treatment decisions for pregnant individuals.

1. Limb, Matthew. “Covid-19: Confusion around vaccination during pregnancy likely to have contributed to deaths of 27 women in the UK.” BMJ, 13 Oct. 2023, https://doi.org/10.1136/bmj.p2388.
2. The European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP). “Annex 2 to the Guide on Methodological Standards in Pharmacoepidemiology”. Available at http://www.encepp.eu/standards_and_guidances
3.   Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). “Postapproval Pregnancy Safety Studies Guidance for Industry.” Available at https://www.fda.gov/media/124746/download
4. NICE real-world evidence framework. “NICE real-world evidence framework.” Available at https://www.nice.org.uk/corporate/ecd9/chapter/introduction-to-real-world-evidence-in-nice-decision-making. 23 June 2022.
5. Huybrechts, Krista F., et al. “Use of real‐world evidence from healthcare utilization data to evaluate drug safety during pregnancy.” Pharmacoepidemiology and Drug Safety, vol. 28, no. 7, 10 May 2019, pp. 906–922, https://doi.org/10.1002/pds.4789.
6. NICE real-world evidence framework. “NICE real-world evidence framework.” Available at https://www.nice.org.uk/corporate/ecd9/chapter/introduction-to-real-world-evidence-in-nice-decision-making. 23 June 2023
7. Medicines during Pregnancy and Breastfeeding.” European Medicines Agency (EMA), 4 June 2025, www.ema.europa.eu/en/human-regulatory-overview/research-development/medicines-during-pregnancy-breastfeeding.
8. Dey, Teesta, et al. “Advancing maternal and perinatal health through clinical trials: Key insights from a WHO global consultation.” The Lancet Global Health, vol. 13, no. 4, Apr. 2025, https://doi.org/10.1016/s2214-109x(24)00512-6.
9. “ICH E21 Guideline on Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials – Scientific Guideline.” European Medicines Agency (EMA), 13 Nov. 2025, www.ema.europa.eu/en/ich-e21-guideline-inclusion-pregnant-breastfeeding-individuals-clinical-trials-scientific-guideline.