Pregnancy Drug Safety Studies Show Wide Outcome Variation, Review Finds

When regulators approve a new medicine or vaccine, they often require the manufacturer to run a follow-up safety study in pregnant women, because expectant mothers are almost never included in the clinical trials that precede approval. These post-approval studies are meant to answer a deceptively simple question: does exposure to the product during pregnancy harm the mother or the baby? A new analysis suggests the answer is being sought with remarkably inconsistent tools. Researchers examining regulator-mandated, non-interventional pregnancy safety studies registered in the European catalogue of real-world data studies found that the outcomes being measured vary widely from study to study, and that no single outcome was evaluated in every study reviewed.

The analysis, published in Frontiers in Drug Safety and Regulation, was conducted by researchers in Safety Surveillance Research at Pfizer and led by Stacy Chen and Sarah C. MacDonald. The team queried the Heads of Medicines Agency and European Medicines Agency Catalogue of Real-world Data Studies on 12 June 2025, filtering for non-interventional post-approval safety studies in pregnant people that were required by a regulator, covered a human medicinal product, and had a publicly available protocol with prespecified safety outcomes. Of roughly 3,100 studies in the catalogue at the time of the query, only 30 met all of the eligibility criteria, a reminder of how narrow this slice of the pharmacovigilance landscape really is.

Across those 30 studies, the most frequently evaluated outcomes were stillbirth, appearing in 25 studies; congenital malformations, major or minor, in 24 studies; spontaneous abortion in 22; small for gestational age or fetal growth restriction in 21; and preterm birth or labor in 21. Elective termination appeared in 15 studies and preeclampsia in 13. Yet despite this apparent overlap, the researchers found no outcome that was measured in all of the studies, and none of the studies evaluated every outcome recommended by either the United States Food and Drug Administration or the European Medicines Agency. In other words, even the most commonly tracked pregnancy outcomes are not tracked universally.

The authors attribute much of this inconsistency to the guidance documents themselves. The FDA’s 2019 draft guidance on postapproval pregnancy safety studies provides a list of recommended data collection elements, covering the outcome of pregnancy, gestational complications, and infant and neonatal outcomes, but it does not explicitly state which outcomes a study must assess. The EMA’s guidance similarly asks sponsors to justify their chosen pregnancy and infant outcomes without supplying a comprehensive required list. Sponsors are therefore left to propose outcome sets on their own, often receiving feedback only when a post-marketing requirement letter is issued or during protocol review, a process the authors describe as inefficient and one that limits comparability across studies.

Study characteristics clearly shaped which outcomes were measured. Among the 14 studies committed to the FDA, stillbirth was the most studied outcome, appearing in 13 of 14 studies, and the average number of evaluated outcomes was approximately 12 per study, with a range of 5 to 25. Among the 16 EMA-committed studies, stillbirth and congenital malformations tied as the most common outcomes, each in 14 of 16 studies, but the average number of outcomes per study was only about seven, with a range of 2 to 11. Eclampsia, notably, was not evaluated in any EMA-committed study, while it appeared in half of the FDA-committed studies. Preeclampsia and small for gestational age or fetal growth restriction were also more frequently captured in FDA-committed studies.

Product type mattered as well. All six vaccine studies evaluated stillbirth, and five of six measured small for gestational age or fetal growth restriction and preterm birth or labor. Medication studies, of which there were 24, more often evaluated outcomes that require early pregnancy exposure: congenital malformations appeared in 21 of 24 medicinal studies compared with half of the vaccine studies, and elective termination appeared in 62.5 percent of medicinal studies and none of the vaccine studies. The authors suggest this pattern likely reflects when the vaccines under study, such as the RSVpreF vaccine, are recommended for administration during pregnancy, mostly late in pregnancy, which reduces the relevance of early-exposure outcomes. They also note that some outcomes, such as Guillain-Barré syndrome, anaphylaxis, and myocarditis, may be more relevant to vaccine products, yet existing guidance does not differentiate recommended outcomes by vaccine versus medicinal exposure.

Data collection method produced another split. Fourteen studies used primary data collection, typically pregnancy registries, while 16 relied on secondary data sources such as claims databases and medical records. Spontaneous abortion was the most frequent outcome in primary data studies, appearing in 12 of 14, while stillbirth dominated secondary data studies, appearing in 15 of 16. Two outcomes stood out as much harder to capture in secondary data: infant growth and development, measured in 79 percent of primary studies and none of the secondary ones, and elective termination, measured in 71 percent of primary studies versus 31 percent of secondary ones. The authors point out that growth metrics like weight, height, and head circumference are rarely included in secondary databases, and that elective terminations may not appear in claims data if insurance does not cover them or if women pay out of pocket. The FDA guidance itself acknowledges that direct access to mothers allows specialized physical examinations and developmental follow-up of offspring.

Perhaps the most sobering finding concerns statistical power. Finalized studies had a median of only 110 exposed participants, well below what is needed to detect meaningful risks. To detect a risk ratio of at least 2.0 for major congenital malformations, assuming 80 percent power and a 4 percent prevalence rate in the United States, an exposed cohort of approximately 600 is required; only 6 of 13 finalized studies examining that outcome met this threshold. For stillbirth, detecting a risk ratio of at least 3.0 requires roughly 1,700 exposed individuals, and only 4 of 11 finalized studies met that bar, with none of the planned or ongoing studies doing so. These figures echo earlier systematic reviews, which found the median enrollment in pregnancy registries to be just 36 pregnancies and that no registries were designed with sufficient power to assess specific malformations.

There were also signs of movement over time. Of the protocols dated after the FDA guidance was implemented in May 2019, nine outcomes saw an increase in the percentage of studies evaluating them, including preeclampsia, which jumped from zero percent in pre-2019 FDA-committed studies to 90 percent afterward, and eclampsia, which rose from zero to 70 percent. Meanwhile, some outcomes declined in frequency, including congenital malformations, spontaneous abortion, and elective termination, though the authors caution that only four FDA-committed studies predated the guidance, making these comparisons fragile.

The authors argue that harmonized regulatory guidance specifying a required set of outcomes, and ideally target effect sizes, would allow sponsors to generate protocols more efficiently, join existing disease-specific registries rather than building product-specific ones, and permit meaningful comparison of findings across studies. They acknowledge limitations, including the small number of studies analyzed, the reliance on publicly available protocols, the exclusion of studies relying only on spontaneous case reports, and the fact that the FDA does not require its post-approval studies to be registered in the European catalogue, meaning some FDA-committed studies may be missing. Still, the core message stands: without a common outcome framework, the pregnancy safety data that regulators, clinicians, and patients depend on remain fragmented, and the opportunity to pool scarce evidence is being lost study by study.

Subject of Research: Post-approval non-interventional safety studies in pregnancy and the standardization of evaluated outcomes

Article Title: Outcomes of post-approval non-interventional safety studies in pregnancy: wide variation demonstrates need for further standardization

Article References: Chen, S., & MacDonald, S. C. (2026). Outcomes of post-approval non-interventional safety studies in pregnancy: wide variation demonstrates need for further standardization. Frontiers in Drug Safety and Regulation, 6, Article 1805759. https://doi.org/10.3389/fdsfr.2026.1805759

Image Credits: AI Generated

DOI: 10.3389/fdsfr.2026.1805759

Keywords: pregnancy safety studies, post-approval studies, pharmacovigilance, FDA, EMA, congenital malformations, stillbirth, pregnancy registries, real-world data, regulatory guidance, sample size, vaccine safety