(17) Fetal Impact of CFTR Modulator use during Assisted and Natural Reproduction and Partner Pregnancy in Men with CF

Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator modulator therapy (HEMT, CFTR) has improved the quality of life and long-term prognosis for many people with CF (CF). Thus, more people with CF are considering parenthood. Almost all males with CF (mwCF) are infertile due to congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible by HEMT. However, assisted reproductive techniques (ART) can enable mwCF to father children utilizing the sperm present in their testes. Animal reproductive models suggest no HEMT teratogenicity. Further, the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible. However, to ensure zero sperm exposure to HEMT, the life span of sperm would require mwCF to discontinue CFTR modulators for approximately 3 months prior to ART. Because abrupt discontinuation of CFTR modulators may result in health decline, mwCF and their providers must consider all potential risks. There is no published data in mwCF regarding the use of HEMT during conception and partner pregnancy.

Methods: Beginning in August 2021, CF Center staff in the United States, United Kingdom and Australia completed a 2-page anonymous questionnaire regarding mwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) and/or natural conception with subsequent partner pregnancy.

Results: To date, providers have submitted n=34 surveys for mwCF on CFTR modulators whose partner became pregnant following use of ART (n=32) or natural conception (n=2). The median age of the sample was 32 years (min 24, max 43); 15/34 were homozygous for F508del and the median percent predicted forced expiratory volume in 1 second, and body mass index were 76% (min 22, max 111) and 24 kg/m² (min 18.5, max 32.1) respectively. The majority of mwCF (n=23/34) were using elexacaftor/tezacaftor/ivacaftor. The median time mwCF were on CFTR modulators prior to partner conception was 18 months (min 0, max 82). One newly diagnosed man initiated HEMT following sperm retrieval. Four mwCF stopped CFTR modulators prior to sperm retrieval, one of whom experienced pulmonary decline. Of n=19 mwCF whose condom use during pregnancy was known, none used condoms. Fetal complications among partners of mWCF included: n=3 1^st trimester miscarriage, n=2* COVID, n=2 breech, n=2* vaginal bleeding, n=1 vasa previa. None of the complications was deemed definitively related to use of CFTR modulators. One mwCF experienced testicular infection post-sperm retrieval#. Post-partum complications included n=3# infants with hypoxemia requiring neonatal intensive care unit stay, n=3 maternal blood loss, n=1 forceps delivery, n=1 Cesarean section. No congenital anomalies were reported for any infant. */# overlap

Conclusions: The use of CFTR modulator therapy during partner conception and pregnancy in n=34 mwCF has not resulted in a higher-than-expected miscarriage rate or in congenital anomalies. Providers should consider the risk to the health of mwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators prior to ART or natural partner conception. Survey collection is on going; results will be updated for presentation if the abstract is accepted.

Acknowledgements:

Funding: Asher Family Fund

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