The overall rate at which women with cystic fibrosis are becoming pregnant dropped slightly in recent years — coinciding with the introduction of CFTR modulators and the clinical trials that led to their approval as CF therapies — but appears to be rising again to pre-trial levels, a study reports.
The study, “Pregnancy among cystic fibrosis women in the era of CFTR modulators,” appeared in the Journal of Cystic Fibrosis. It calls for more research into the impact of these treatments on maternal and fetal health, and on the effectiveness of contraceptives women of childbearing age, noting a “paucity of data” on these topics.
Newer therapies include Kalydeco (ivacaftor) and Orkambi (lumacaftor/ivacaftor) — modulators of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is defective in CF. Both are helping patients live longer and healthier lives. With adults now comprising more than half of all CF patients in the United States, conversations about family planning, contraception and pregnancy have become commonplace.
Researchers at Seattle’s University of Washington School of Medicine, using 2005-14 data from the Cystic Fibrosis Foundation Patient Registry, assessed the overall annual pregnancy rate by genotype (mutation type) of patients to determine if specific characteristics defined those who became pregnant.
In particular, researchers wanted to compare pregnancy rates and outcomes before and after CFTR modulator clinical trials. Such trials of Kaledyco in patients heteroygous for G551D — and of Orkambi for those homozygous for F508del mutations — took place between 2005 and 2014. Results showed a downward trend in annual pregnancy rates among CF women aged 15 to 44 during those years.
Specifically, in women with mutations responding to Kalydeco, pregnancy rates during the Phase 3 clinical trials (NCT01614457 and NCT01614470) of that therapy were 14.4 per 1,000 women-years, compared to 34.0 per 1,000 women-years before the trial period. Statistically, patients in the clinical trial were 35 percent less likely to get pregnant than before the trial.
This, researchers wrote, suggests that contraceptive use may have been affected by patient involvement in trials, all of which strictly enforce birth control in order to prevent pregnancy. In addition, interest in the trials may also have influenced the reproductive choices of women who did not take part, as interest was high in them.
“It cannot be determined if this is a reflection of the overall U.S. trend in pregnancy or some other factor specific to the CF community,” the study says. “Enthusiasm for the studies was extremely high and anticipation of possible inclusion may have influenced the reproductive life goals of women with CF.”
Interestingly, when the U.S. Food and Drug Administration approved Kalydeco in June 2012, the pregnancy rate rose to 38.4 per 1,000 women-years. Statistical analysis showed that there was a 52 percent higher risk of pregnancy after drug approval compared to during the trial period.
Likewise, pregancy rates dropped to 23.2 per 1,000 women-years from 25.1 per 1,000 during the Orkambi trial years (2013-14; NCT01807923 and NCT01807949), although post-trial data on these rates is not yet available.
These results, they said, underscore the need to better understand CFTR modulators and their potential impact on the health of both the mother and her child.
“This investigation found that pregnancy rates were reduced … during controlled trials but have returned to pre-2009 trial levels,” researchers wrote. “That, taken in combination with our finding that the majority of G551D women of childbearing age report ivacaftor use within the same year of becoming pregnant, underscores the need to better understand CFTR modulators given their unknown risk to pregnancy and fetal outcomes.”
Data also showed that pregnancy outcomes did not significantly change between this time period for any genotype, although information was limited.
“With the recent approval of lumacaftor/ivacaftor for F508del homozygous patients, CFTR modulators are reaching a larger patient population, and thus the consequences for contraception and pregnancy may be profound,” researchers concluded, adding that future studies should help determine how CFTR modulators affect hormonal contraceptive method effectiveness and pregnancy outcomes in CF patients of all genotypes.