Translating Emerging Data for Fetal Treatment of Cystic Fibrosis

We reviewed the contemporary use of cystic fibrosis transmembrane conductance regulator modulator therapy (CFTRm) during pregnancy, including animal data and published human cases involving unaffected pregnant CF (heterozygote) carriers with a prenatal diagnosis of fetal cystic fibrosis (CF). In pregnant individuals with CF, continuation of CFTRm is associated with preserved maternal pulmonary function comparable to nonpregnant peers and favorable obstetrical outcomes. CFTRm crosses the placenta readily, appears at low levels in breastmilk, and concerns for cataracts from animal models have not been translated clinically. Among 20 reported fetal cases treated prenatally with CFTRm in unaffected carrier individuals, ultrasound findings of meconium ileus (MI) resolved in approximately two-thirds of cases. Several reports describe preserved or borderline exocrine pancreatic function and lower-than-expected sweat chloride levels. Nonresolution of MI was more common when therapy began later in gestation or in the presence of complications such as meconium peritonitis. MI was diagnosed at a mean gestational age of 24 weeks, while treatment began at 31 weeks, reflecting delays in both diagnosis and insurance coverage. The CF Foundation PROTECT Workshop identified key knowledge gaps, including optimal timing of prenatal diagnosis and therapy, fetal pharmacokinetics, neurodevelopmental safety, minimal effective dosing, and prevention of postnatal withdrawal.