Assessing the Risk of Fetal Fentanyl Syndrome Amid the Ongoing Fentanyl Epidemic: A Comprehensive Approach Using Diverse Data and Methods

About This Grant

PROJECT SUMMARY Fentanyl is a potent synthetic opioid used for the treatment of severe pain. It is also responsible for a large proportion of illicit opioid use and overdose deaths in the United States. The fentanyl epidemic affects young women and spills into pregnancy such that opioid-related overdoses are now a leading cause of maternal mortality. Moreover, in 2023, a report of ten cases suggested that maternal abuse of fentanyl during pregnancy causes a pattern of structural abnormalities referred to as “Fetal Fentanyl Syndrome (FFS)” characterized by distinctive facial features and congenital anomalies of hands and feet. In response, NIDA issued a Notice of Special Interest (NOT-DA-26-003: Consequences of Prenatal Fentanyl Exposure) to promote research on the potential teratogenic effects of prenatal fentanyl exposure in humans. We propose to assess the effect of maternal fentanyl use during pregnancy on the risk of specific congenital malformations in general, and the risk of FFS in particular. The project will use four coordinated and complementary approaches that allow evaluation of both illicit and prescription fentanyl use. Aim 1 will use proxies for illicit fentanyl uptake obtained from national databases (e.g., fentanyl overdose deaths) to create a temporo-spatial instrumental variable and evaluate its association with FFS rates in the population. This innovative ecological approach avoids confounding at the individual level (e.g., by alcohol exposure). Aim 2 will use a unique linkage between birth defects and neonatal abstinence syndrome surveillance programs in several US states to evaluate the association between maternal and infant toxicology screens positive for fentanyl and FFS. Aim 3 will use data from the FDA Adverse Events Reporting System to assess whether FFS was disproportionally reported for prescription fentanyl relative to other opioids in the time period prior to the medical community having been alerted to the syndrome. Aim 4 will use data obtained from nationwide healthcare utilization databases of publicly and commercially insured pregnancies linked to newborns to compare the risk of FFS for prescription fentanyl during pregnancy relative to other prescription opioids. This study will be designed as a target trial emulation and will use advanced analytic methods to minimize biases. For all aims, FFS cases (reports, clinical records or claims profiles) will be adjudicated by dysmorphologists. The interpretation will consider timing of exposure during pregnancy, potential dose-response and the potential role of adulterants in illicit fentanyl. Each approach provides a unique lens through which to examine the question, and together, they will strengthen our confidence in the conclusions drawn. Our proposal benefits from the collective experience and established track record of a multidisciplinary team, and our prior work and preliminary assessments attest to the project's feasibility. Ultimately, completion of this research will contribute information to our understanding of fentanyl’s teratogenic risk in humans and inform clinical guidelines and pregnancy safety narratives in drug labels.