Prenatal Elexacaftor/Tezacaftor/Ivacaftor for Fetal Meconium Ileus: First Italian Case and Narrative Overview of the Emerging Evidence

Introduction: Cystic fibrosis (CF) frequently presents prenatally with meconium ileus (MI), a condition associated with significant neonatal morbidity and long-term gastrointestinal complications. The advent of highly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), during pregnancy remains off-label, and their role as in utero therapy for affected fetuses of carrier mothers is still emerging. Methods: We conducted a narrative literature review using PubMed, Embase, and Scopus to identify published reports of in utero CFTR modulator therapy for MI between 2022 and 2026. Seven relevant studies were identified and qualitatively synthesized. Their findings were interpreted in comparison with the present case. Results: We describe the first Italian case of prenatal ETI therapy for fetal CF. At 32 weeks’ gestation, ultrasound (US) findings were suggestive of evolving MI. Both parents were carriers of F508del CFTR and subsequent testing confirmed fetal homozygosity. Following urgent multidisciplinary consultation and ethics committee approval, maternal ETI therapy was initiated at 33 weeks’ gestation. After 21 days of treatment, follow-up fetal US demonstrated improvement in bowel dilatation and hyperchogenity. The infant was delivered at 36 + 2, passed meconium spontaneously, and required no surgical intervention. Pharmacokinetic assessment showed substantial transplacental transfer of all three ETI components, with cord-to-maternal plasma ratios of 0.34 (elexacaftor), 2.48 (tezacaftor), and 0.58 (ivacaftor), and detectable concentrations in amniotic fluid. Postnatally, sweat chloride was elevated, and pancreatic function transitioned from initially preserved to pancreatic insufficiency within the first month of life. Conclusions: This case and literature review suggest that prenatal CFTR modulation may influence the early trajectory of CF, potentially by preventing MI and potentially delaying the progression to pancreatic insufficiency and potentially reducing later gastrointestinal complications. While evidence remains limited, these findings highlight a potential therapeutic window during fetal life and underscore the need for prospective data collection, structured registries, and harmonized clinical guidance in this evolving field.