USE OF CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MODULATORS IN PREGNANCY

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators (CFTRm), including deutivacaftor, elexacaftor, ivacaftor, lumacaftor, tezacaftor and vanzacaftor, are licensed as various single and combination products for the treatment of cystic fibrosis (CF). A combination product containing elexacaftor-tezacaftor-ivacaftor (ETI) is available as Kaftrio^®.

Poorly-controlled CF in pregnancy can result in exacerbation of maternal pulmonary disease and poor nutritional status, increasing the risk of adverse pregnancy outcomes, including premature delivery and impaired fetal growth. Maternal clinical decline has been described following modulator therapy cessation during pregnancy. CF must be well-controlled during pregnancy to prevent complications.

Treatment with elexacaftor-tezacaftor-ivacaftor (ETI) combination therapy forms most of the available safety data on CFTRm use in pregnancy.

CFTRm use in pregnancy does not appear to be associated with increased risks of malformation, miscarriage, intrauterine fetal death or stillbirth, altered fetal growth, or preterm delivery. However, studies with larger sample size and higher quality methodology are required to confirm these findings. Uncontrolled case reports have documented cases of neonatal complications and neurodevelopmental impairments. Again, higher quality studies are required to determine whether these events occur with greater incidence following in utero CFTRm exposure.

Non-congenital lens opacities have been observed in children treated with ivacaftor-containing regimens, and consequently, several uncontrolled studies have reported formal cataract assessments in children exposed to CFTRm in utero. Three cases of small bilateral cataracts have been reported in the literature, all following in utero exposure to ETI combination treatment. Although these data are too limited to establish a causal relationship between CFTRm use in pregnancy and congenital cataract development, formal eye assessment is recommended following in utero CFTRm exposure.

There are a small number of cases of CFTRm exposure in the second and third trimester, where treatment was initiated following fetal CF diagnosis. These data provide some preliminary evidence of the possible benefits of CFTRm use in women who are CFTR carriers and pregnant with a fetus with CF. Treatment of the fetus with CFTRm requires multidisciplinary specialist care from a Fetal Medicine Unit and neonatal services.

CFTRm use in pregnancy can lower the immunoreactive trypsinogen concentration in the offspring, resulting in false-negative newborn blood spot CF screening results. CFTR genetic testing should be considered for all infants born to mothers on CFTR modulators to avoid delayed diagnosis.

Exposure to CFTRm at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors which could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.