CFTR modulator therapy via carrier mother to treat meconium ileus in a F508del homozygous fetus: Insights from an unsuccessful case

Abstract

We present a case of a carrier mother treated with elexacaftor/tezacaftor/ivacaftor (ETI) for in-utero management of meconium ileus in a fetus diagnosed with cystic fibrosis (CF), homozygous for the F508del variant. Following multidisciplinary discussion and shared decision-making involving the parents, ETI was initiated at 27 weeks of gestation. At 38+4 weeks, the infant was delivered. Despite the treatment, the newborn developed meconium ileus, necessitating emergency surgery after birth. We explore potential factors contributing to the lack of success in our case compared to previously reported successful cases in USA and Spain. Drug levels measured in neonatal blood and in maternal breast milk indicated minimal drug exposure, raising questions about whether variability in placental transfer and excretion in breast milk or suboptimal ETI dosing in the overweight mother impacted the outcome. Additionally, the natural variability in meconium ileus outcome, which can range from spontaneous resolution to severe complications must be considered. In our case, ETI may have mitigated the severity of the condition, preventing serious complications like bowel perforation or peritonitis. However, given that about 20 % of all fetal bowel dilation resolves spontaneously, it remains uncertain whether the positive outcomes in prior cases were attributable to ETI or the natural course of the disease. We emphasize the need for more evidence on in utero ETI exposure by advocating for the collection of cases involving ETI treatment for fetal meconium ileus, regardless of outcomes. Developing guidelines will be essential to optimize benefits for both mother and fetus while minimizing risks.