Prenatal Use of Sirolimus in Fetal Therapy: Current Evidence, Clinical Applications, and Future Directions

Prenatal imaging, genomic diagnosis, and pathway-directed pharmacology increasingly permit treatment of selected fetal disorders before birth. This narrative review evaluates maternally administered sirolimus as transplacental fetal therapy, emphasizing cardiac rhabdomyomas associated with tuberous sclerosis complex and severe vascular or lymphatic malformations. Sirolimus inhibits mechanistic target of rapamycin complex-1, a pathway central to cell growth, angiogenesis, and lymphangiogenesis. Published fetal case reports and small series describe regression of symptomatic cardiac rhabdomyomas and improvement in outflow obstruction, arrhythmia, cardiac dysfunction, hydrops, or impending fetal compromise. Evidence for prenatal treatment of vascular and lymphatic malformations is earlier. Still, it includes large cervicofacial lymphatic malformations and complex capillary-lymphatic-venous malformations threatening airway obstruction, hemorrhage, hydrops, or perinatal instability. Reported maternal adverse effects include mucositis, hyperlipidemia, cytopenias, infection risk, and impaired wound healing. Transplant pregnancy data have not identified a consistent malformation pattern, but exposures are sparse and confounded, while product labeling warns of embryo-fetal toxicity based on animal studies. Prenatal sirolimus therefore remains an investigational intervention for carefully selected, life-threatening or organ-threatening fetal disease managed by specialized multidisciplinary teams. Prospective registries and multicenter studies are needed to define dosing, fetal pharmacokinetics, stopping rules, delivery planning, and long-term outcomes.