The fetal fentanyl syndrome: Additional evidence in support of a new human teratogen.

PURPOSE: Prenatal opioid exposure has been inconsistently associated with congenital anomalies. In 2023, fentanyl was proposed as a human teratogen in ten infants with documented exposure and a consistent pattern of abnormalities. Disrupted cholesterol biosynthesis was proposed as the pathogenetic mechanism.

METHODS

We evaluated 56 children aged 0 to 4 years with confirmed prenatal fentanyl exposure. We collected data on intrauterine exposures, dysmorphic features, congenital anomalies, neonatal course, feeding, growth and development, cholesterol precursors, and genetic testing. We analyzed the role of coexposures and specific features in predicting clinical and developmental outcomes. Associations between dysmorphology categories and outcomes were tested. Using diagnostic frameworks from fetal alcohol spectrum disorders, we evaluated criteria for a potential fetal fentanyl syndrome.

RESULTS

Among the enrolled patients, microcephaly, failure to thrive, feeding difficulties, and gastrostomy placement were common. A distinctive pattern of craniofacial dysmorphology was identified. Developmental delays affected 47% of individuals, and autism or a high risk was identified in 50% of those screened. Genetic testing was noncontributory. Elevated cholesterol precursors were seen in some patients when tested in the first weeks of life. Dysmorphology severity was associated with microcephaly, failure to thrive, hypotonia, and gastrostomy use.

CONCLUSION

Prenatal fentanyl exposure was associated with a recognizable pattern of dysmorphology, growth restriction, impaired brain development, and neurodevelopmental deficits. These findings support fentanyl as a human teratogen.