Sins of Omission: Model-Based Estimates of the Health Effects of Excluding Pregnant Participants From Randomized...

More than 90 million women in the United States have given birth. Randomized controlled trials (RCTs) of medications almost always exclude pregnant participants.

To quantify the health effects of excluding pregnant participants from RCTs.

Decision analytic framework applied to case studies of thalidomide, COVID-19 vaccines, and dolutegravir.

Varied.

Pregnant people and their children.

The authors modeled the ex post facto health effects of RCTs, comparing projected health effects of medication uptake had an RCT been conducted versus historically observed outcomes. They also modeled the a priori health effects that could have been anticipated in trial planning. They converted health effect estimates to monetary value using standard benchmarks.

Across case studies, health benefits from conducting RCTs during pregnancy were projected to far exceed expected adverse effects (AEs) from RCTs. For example, had thalidomide been tested in a completed RCT with 200 treated participants, about 33 children would have experienced severe AEs, whereas knowledge from the RCT would have prevented 8000 thalidomide-related birth defects, 99.6% of all thalidomide-related birth defects from 1956 to 1962. Likewise, if RCTs for COVID-19 vaccines had included pregnant participants and if posttrial pregnant uptake were conservatively assumed to mirror that of age- and state-matched nonpregnant women, a projected 20% of COVID-19-related maternal deaths and stillbirths (8% of all maternal deaths and 1% of all stillbirths) in the United States would have been prevented from March to November 2021. Across case studies, the a priori value of RCT data would have exceeded the approximately $100 million cost of phase 1 to 3 RCTs.

Parameter uncertainty.

Systematic inclusion in RCTs could benefit both pregnant people and their children by both speeding AE detection and increasing uptake of beneficial medications.

None.