Fetal Fentanyl Syndrome: An Opportunity to Quantify the Risk in Prospective Cohorts of Patients With Substance Use...

The increased availability of fentanyl in the United States over the past decade extends to women of reproductive age, raising concern about maternal and fetal risks when used in pregnancy. A 2023 case series of 10 infants exposed to fentanyl in utero proposed a "fetal fentanyl syndrome" (FFS), characterized by distinctive craniofacial features, limb anomalies, and genitourinary defects. However, as with any case series, concerns about selective case ascertainment, uncontrolled confounding, imprecise timing of exposure, phenotype heterogeneity, and lack of a denominator preclude causal inference or risk quantification. Two new studies in this issue-Mirsky et al and Dorsey et al-had the opportunity to quantify the risk in prospective cohorts of patients with substance use disorder. However, they leave key questions unresolved. Mirsky et al identify 4 additional infants with craniofacial anomalies and prenatal fentanyl exposure, but their analysis remains effectively a case series. Dorsey et al use a case-control analysis and report a modestly elevated odds of FFS-compatible anomalies with fentanyl exposure, but broad exposure windows, limited phenotype specificity, and lack of adjustment for confounding limit interpretability. Further studies are needed to clarify to what extent prenatal fentanyl exposure contributes to specific patterns of congenital structural anomalies.