Prenatal Fentanyl Exposure Association With Characteristic Neonatal Anomalies

Objectives: To investigate if previously described anomalies associated with fentanyl could be identified in our cohort of individuals with active fentanyl use in pregnancy. Methods: Potential cases of a novel syndrome were identified from a prospectively collected database of obstetric patients with substance use disorder enrolled in a multispecialty treatment program from 2014 to 2024 in this case series study. Suspected Fetal Fentanyl Syndrome (FFS) was defined as small head circumference (<10%ile) and at least one other sign: cleft palate, clubfoot, rocker bottom feet, toe syndactyly, single palmar crease, hypoplastic corpus callosum, and hypospadias. The database was screened for findings consistent with this syndrome resembling Smith-Lemli-Opitz Syndrome. Results: From 2014 to 2024, 639 patients were enrolled in the cohort. Of the 103 patients found to have neonates with a small head circumference, 51 individuals self-reported fentanyl use within the last year. Six of these individuals had confirmatory toxicology testing for fentanyl upon program enrollment. Of these individuals’ neonates, 4 displayed characteristic anomalies consistent with FFS. All cases shared lagging head growth, while additional anomalies identified included cleft palate (n=3), short nasal tip (n=1), thin upper lip (n=1), micrognathia (n=1), and hypospadias (n=1). Genetic screening/diagnostic testing varied but an assessment of cholesterol metabolism was not performed. Conclusions: In this cohort, 7.8% of individuals with self-reported fentanyl use had neonates with signs of the previously described FFS. FFS is a proposed syndrome and results should be interpreted with caution. Similar data is needed to confirm and delineate this association and determine long-term developmental effects.