(258) Impact of Temporal Changes in CFTR Activity on Fertility, Conception, Pregnancy, and Lactation in CF Ferrets

Background: In the highly effective modulator therapy era more CF women are considering parenthood. A better understanding of the impact of pancreatic sufficiency and other CFTR-dependent processes on reproductive health is critical. We recently reported that CFTR modulator administration in utero fully protected male CF ferrets from developmental reproductive pathologies. Here, using CFTR modulator responsive CFTR^G551D ferrets we studied the effects of temporal changes in CFTR activity, on conception, pregnancy, and lactation.

Methods: Ferrets on lifelong CFTR modulator therapy were compared to ferrets that had discontinued treatment for at least one month before reinitiating modulator dosing coincident with breeding. We evaluated the reproductive health by conception rate (productive pregnancy/breedings), fertility (kits/breedings), and litter size (kits/productive pregnancies). Longitudinal modulator pharmacokinetic (PK) studies comparing the blood to breastmilk levels were performed in 3 jills. Kits received modulator exclusively through breastmilk for the first 23 days of life, afterwards, the modulator was orally dosed with formula. The fecal elastase-1 levels of the kits were measured at 3 weeks and 9 weeks.

Results: The lack of modulator dosing in the mom did not decrease the conception rate compared to lifelong therapy in this cohort (66% vs. 54%, P >0.05). However, their fertility was significantly reduced (3.8 vs. 6.8, p< 0.05), and their litter size was smaller (1.5 vs. 6.9, p< 0.05). This decrease in litter size is partially explained by a higher prevalence of premature birth, miscarriage and even terminal morbidity of the jill with larger litter sizes ( >6 fetuses) requiring euthanasia. We observed acute fatty liver of pregnancy (AFLP) in four CF mothers requiring euthanasia in the third trimester (1 week prior to delivery). AFLP diagnosis was supported by highly elevated alanine aminotransferase (ALT) (2000 U/L versus normal 100 U/L), and hepatic steatosis. Extensive inflammatory cells infiltration around the bile ducts was also observed in one of the cases. In the CF ferrets that had discontinued modulator, AFLP was observed 42.9% (3/7) of cases, compared to only 8.3% rate (1 of 12) in the lifelong modulator cohort. For the >90% of lifelong modulator dosed jills with normal pregnancy and lactation, CFTR modulator was present in the breastmilk at a concentration 30.5%~46.8% of blood levels. This modulator level in the breastmilk led to blood levels in the kits that were nearly equivalent to those of the nursing jill (70% in kit versus mom blood levels). Kits fed with breastmilk maintained pancreatic sufficiency (PS) in 71.5% CF kits at 3 weeks. Direct oral dosing of the kits increased the modulator levels in the blood to equivalent with the nursing mom, but did not change the proportion of PS kits, indicating the importance of early prevention of pancreas activity loss in CF kits.

Conclusions: The temporal changes in CFTR activity caused by removal and reinitiation of modulator therapy in the CF ferret model had long-term impact on critical organs such as the pancreas, which under the metabolic stress of pregnancy can lead to complications such as AFLP. Breastmilk delivery of CFTR modulator was sufficient to maintain pancreas function in most neonatal kits.

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