Prenatal CFTR modulator therapy for fetal cystic fibrosis: Emerging evidence, clinical considerations, and future directions.

BACKGROUND: The consequences of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein dysfunction or absence begin during fetal development, with pancreatic, intestinal, hepatobiliary, and reproductive manifestations evident at birth. The advent of CFTR modulator therapies (CFTR modulator)-most notably elexacaftor/tezacaftor/ivacaftor (ETI), approved for children and adults with CF who carry responsive variants, and the recently approved vanzacaftor/tezacaftor/deutivacaftor (VTD), currently indicated for older pediatric and adult populations-has transformed long-term health outcomes and substantially increased the number of pregnancies among individuals with CF. As maternal use of CFTR modulator during pregnancy has become more common, early observational studies and case series suggest potential fetal benefit for fetuses affected by CF, particularly with respect to inspissated meconium obstructing the terminal ileum, potentially reducing the need for postnatal surgical intervention.

METHODS: To synthesize current evidence regarding maternal, fetal, and neonatal outcomes following prenatal CFTR modulator exposure; describe the rationale and early experience with intentional prenatal therapy for affected fetuses; and outline practical counseling and monitoring strategies. Evidence was drawn from clinical pregnancy cohorts, pharmacokinetic studies, case series treating fetal meconium ileus, mechanistic fetal and animal models, and expert consensus documents, including the PRenatal MOdulator Treatment to PrEvent CF ComplicaTions (PROTECT) Workshop summary. Both maternal- and fetal-indication uses of CFTR modulator were evaluated.

RESULTS: Continuation of ETI during pregnancy has been associated with stabilization of maternal pulmonary function and nutritional status and has not been linked to an increased risk of congenital anomalies, preterm delivery, or miscarriage in available observational cohorts. Both ETI and VTD cross the placenta and achieve fetal drug exposure at concentrations expected to be pharmacologically active. Case series in fetuses with CF describe improvement or resolution of prenatal bowel abnormalities indicative of evolving meconium ileus, with suggestive evidence of preservation of exocrine pancreatic function and the male reproductive tract in limited cases. Cataracts have rarely been reported, are typically small and not visually significant, and have not been consistently observed across cohorts. Prenatal exposure may result in falsely negative newborn screening results. However, the optimal timing and duration of prenatal modulator initiation for fetal benefit, fetal pharmacokinetics and pharmacodynamics, and long-term neurodevelopmental outcomes remain uncertain.

CONCLUSION: Prenatal CFTR modulator therapy shows promise as the first fetal therapy for CF. While continuation for maternal CF is supported by available evidence (although not label-approved), fetal-indication use remains investigational. Robust counseling, interdisciplinary coordination, and structured monitoring are essential, alongside ongoing research to define therapeutic windows, safety, and long-term outcomes.