Sirolimus Treatment for Complex Fetal and Neonatal Vascular Anomalies: Emerging Evidence and Safety Considerations

Background: Vascular abnormalities (VAs) are a broad category of disorders that include vascular malformations (inadequate embryologic blood vessel development) and vascular tumors (characterized by vascular cell hyperplasia). This sometimes-complicated pathology is increasingly being treated with mTOR inhibitors, particularly sirolimus (rapamycin). Only a limited number of neonates treated with sirolimus have been reported in the literature to date, and there is no consensus regarding the optimal treatment regimen for vascular anomalies in this population. The objective of our narrative review is to summarize the most recent information from the specialized literature regarding the efficacy and safety of sirolimus in newborns. Methods: A methodological search was performed through the available data concerning the indications and safety when using sirolimus to treat VAs in newborns. We evaluated articles from the Embase and PubMed academic search engines using the following search terms: (vascular anomalies OR vascular tumors OR venous malformations OR lymphatic malformations OR capillary malformations) AND (neonate) AND (sirolimus OR rapamycin). Results: We identified a lack of consensus regarding indications for treatment initiation, optimal dosing regimens, and duration of therapy. In most published studies, neonates were analyzed within broader pediatric cohorts that included patients up to 18 years of age, rather than as a distinct population. Moreover, only a limited number of investigations have specifically focused on neonates treated with sirolimus and evaluated outcomes from a neonatal subgroup perspective. The available evidence largely consists of isolated case series and reports describing sirolimus use in fetuses and neonates, most commonly for lymphatic malformations or kaposiform hemangioendothelioma; in some instances, sirolimus was administered in combination with propranolol, corticosteroids, or other therapeutic modalities. Nevertheless, across studies and case reports involving fetuses or neonates, sirolimus is generally reported to be effective and well tolerated, with adverse effects that are minimal and reversible. Conclusions: For neonates and even fetuses with large, complex VAs, sirolimus appears to be an effective treatment with no serious adverse events reported to date. Decisions regarding off-label sirolimus initiation should be made by a multidisciplinary team, and parents must be thoroughly informed about potential adverse events. Well-designed randomized controlled trials or high-quality observational studies are needed to further evaluate the efficacy and safety of sirolimus in the neonatal population.