The Cystic Fibrosis Foundation organised a multidisciplinary committee to develop this Position Paper to outline current knowledge and best practices in reproductive health care for individuals with cystic fibrosis. Working groups reviewed the literature and provided relevant guidance on reproductive health services, fertility, contraception, preconception and pregnancy, and cystic fibrosis transmembrane conductance regulator (CFTR) modulator exposure in utero and during lactation. Findings included: (1) reproductive health-care provision should be standardised, and education should begin at cystic fibrosis diagnosis and revisited annually; (2) contraception is safe overall, but underutilised in those with cystic fibrosis compared with the general population; (3) fertility might be improving with CFTR modulators for females with cystic fibrosis, but not for males with cystic fibrosis-assisted reproductive technologies are still required for males to achieve biological parenthood; (4) pregnancy requires close monitoring and unique screening for diabetes; and (5) CFTR modulator exposure in utero has implications for infant monitoring and cystic fibrosis screening results in newborns.

Background The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor–tezacaftor–deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor–tezacaftor–deutivacaftor compared with standard of care elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older. Methods In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor–tezacaftor–ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor–tezacaftor–deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was –3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. Findings In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=202) or vanzacaftor–tezacaftor–deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6–38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor–tezacaftor–ivacaftor (n=289) or vanzacaftor–tezacaftor–deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5–42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor–tezacaftor–deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor–tezacaftor–ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI –0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor–tezacaftor–deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor–tezacaftor–ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI –0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor–tezacaftor–deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor–tezacaftor–ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]). Interpretation Vanzacaftor–tezacaftor–deutivacaftor is non-inferior to elexacaftor–tezacaftor–ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor–tezacaftor–deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators. Funding Vertex Pharmaceuticals.

Background Data from cystic fibrosis (CF) animal models and case studies suggests that in utero administration of CF transmembrane conductance regulator (CFTR) modulators (variant specific therapies, VST) can rescue CFTR-related pathophysiology in the fetus. Use of VST during pregnancy to prevent disease in infants has not been systematically studied. Through stakeholder engagement, we sought to determine if formal research evaluation is warranted. Methods We surveyed CF care center directors to assess their awareness of the potential off-label use of VST for in utero treatment of a fetus with CF. We then conducted a one-day, international multidisciplinary workshop to review available pre-clinical and clinical data, embryology principles and federal drug regulation considerations, identify knowledge gaps, and consider future clinical study designs. Results Sixty-two unique individuals responded to the survey; 92% were aware of use of VST to treat pregnant females who are CF carriers for the prevention of CF complications in the fetus. Expert workshop presentations suggested that use of VST in pregnant females carrying a fetus with CF to mitigate complications of CF is relatively safe and effective in animal models and human case series to date. Further research is needed to understand the optimal timing of VST initiation during pregnancy to improve clinical outcomes, to understand VST pharmacokinetics, and optimize dosing of VST during pregnancy and lactation, and to evaluate the long-term infant safety among those exposed to VST in utero. Conclusions Based on available data and knowledge gaps, stakeholders agreed that formal evaluation of in utero and early life VST therapy in a prospective trial is warranted.

Recent improvements in cell-free DNA technology have enabled non-invasive prenatal testing (NIPT) to screen for fetal single-gene autosomal recessive conditions from maternal blood as early as the first trimester. This technique can determine the fetal risk for cystic fibrosis (CF) with a single blood sample from a pregnant person without the need for a partner sample, which is required for traditional carrier screening.A retrospective review of 100,106 consecutive general-risk pregnant patients who underwent CF carrier screening was completed. All positive CF carriers underwent cell-free DNA testing, which reported a risk of the fetus being affected with CF. Pregnancies with at least a 1 in 4 risk were classified as high risk. Results of confirmatory testing were solicited from all high-risk cases, and a random sample of 50 % of low-risk cases were used to compute test performance analytics.The study cohort included 2,587 CF carriers and 20 cases with high-risk cell-free DNA results where the CF-affected status of the fetus/neonate was known, of which 13 were affected. All cases (n = 8) with a 9 in 10 cell-free DNA estimated risk were affected. The assay correctly identified all known affected fetuses as high risk (sensitivity of 100 %). Of the 13 affected, 12 cases had at least one CFTR variant eligible for CFTR modulator therapy. Additionally, 75 % of all cell-free DNA fetal risk results were returned before 18.5 weeks gestation, providing ample time for diagnostic testing and initiation of in utero treatment if indicated.Carrier screening with reflex to cell-free DNA analysis provides a personalized fetal risk assessment and efficient turnaround times at an early gestational age, without the need for a partner sample for a general risk population. This screening method can precisely guide prenatal diagnostic testing to identify CF-affected fetuses that may benefit from in utero therapy.

Background The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older. Methods In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -30 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. Findings In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 310 years (IQR 226-385), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 331 years (IQR 245-422), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 05 (SE 03) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 03 (03) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 02 percentage points [95% CI -07 to 11]; p<00001), and for Trial VX20-121-103, was 02 (SE 03) percentage points in the vanzacaftor- tezacaftor-deutivacaftor group versus 00 (02) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 02 percentage points [95% CI -05 to 09]; p<00001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor- ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]). Interpretation Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

The use of elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with increased fertility in women with cystic fibrosis (CF) and is increasingly used during pregnancy to support both maternal and fetal health. However, little is known about the pharmacokinetics (PK) of ETI during pregnancy, which is crucial for optimizing its efficacy and safety. This study aimed to predict the PK of ETI during pregnancy and to determine the maternal dose required to achieve therapeutic concentrations in both the maternal and fetus. The pregnancy physiological-based pharmacokinetic (PBPK) model within the Simcyp Simulator was used to predict the maternal and feto-placental exposure of ETI. Placental kinetics were parameterized using permeability parameters determined from the physicochemical properties of these compounds. The model closely predicted the observed data, with the observed ETI maternal plasma concentrations, cord concentrations, and infant plasma concentrations mostly falling within the range of predicted 5th to 95th percentiles. Steady-state simulations up to gestational week 40 predicted a continuous decline in ETI concentrations, with the AUC declining to 32.4-37.5% of baseline levels by week 40. However, the 5th percentile of trough concentrations for ETI consistently remained above the efficacy thresholds, both in mother and fetus. Therefore, it appears reasonable to maintain standard dosing regimen during pregnancy, complemented by careful monitoring. A clinical trial, such as the ongoing Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS) study, is required to further confirm the efficacy and safety of ETI in this population.

Abstract Introduction With therapy advances, people with cystic fibrosis (CF) are living longer, healthier lives, and thus increasingly have general and CF-specific sexual and reproductive health (SRH) questions. The CF Foundation is supporting the Sexual Health, Reproduction, and Gender Research (SHARING) Working Group to identify knowledge gaps, research priorities, and infrastructure needed for CF SRH research. SHARING includes pulmonologists, nurses, research coordinators, registered dieticians, psychiatrists, endocrinologists, reproductive urologists, and community members with CF. Objective In Spring 2023, SHARING developed and distributed a SRH prioritization survey for the CF community. During the annual in-person workshop, the group used these results to establish research priorities and develop studies that would address identified knowledge gaps. Methods SHARING partnered with Community Voice, a virtual platform for people with CF and their caregivers to share their perspectives on ongoing and future CF SRH research, care, and programming. We provided a list of 15 SRH research topics and asked respondents to rank the top five. We analyzed survey results using descriptive statistics. We also summarized discussions and future key directions for CF SRH research. Results A total of 303 respondents (85% people with CF and 15% caregivers) completed the survey. Sixty-five percent of people with CF were women and 37% of the people with CF for whom caregivers responded were women/girls. The majority (95% of adults, 98% of people with CF for whom caregivers responded) identified as White; 5% of adults and 10% of people with CF for whom caregivers responded were Hispanic/Latino. The majority (73%) of people with CF were >30 years old and 68% of those with CF for whom caregivers responded were <18 years old. Table 1 summarizes respondent demographics. The top five SRH topics were: 1) effects of CF modulator therapy (elexacaftor/tezacaftor/ivacaftor, ETI) on sex hormones; 2) effects of sex hormones on CF; 3) fertility; 4) pregnancy; and 5) SRH/mental health (Figure 1). People with CF prioritized pregnancy, sexual functioning, parenthood, and menopause, while caregivers prioritized ETI effects on sex hormones, fertility, mental health, and assisted reproductive technology (ART). SRH priorities differed by gender identity. Men and caregivers of men/boys prioritized fertility, mental health, SRH care provision, sexual functioning, and ART, while women and caregivers of women/girls prioritized the effect of sex hormones in CF, pregnancy, menopause, and contraception. During workshop proceedings, SHARING identified the need for further research on the interplay between sex hormones, CF pathophysiology, ETI, fertility, and ART, and a focus on the impact of infertility on mental health for males with CF. Conclusions SRH is an important and emerging area of research in CF. Research priorities are not uniform among people with CF and their caregivers, particularly across genders. Thoughtful consideration of such perspectives can ensure that future CF SRH research is relevant and responsive to CF community needs. SRH providers should be aware of the concerns in this understudied population from research and patient care perspectives. Disclosure No.

Sexual and reproductive health (SRH) in cystic fibrosis (CF) is an expansive field that has recently gained more attention with the improved fertility and longevity of our CF population in the era of CFTR modulator therapy. People with cystic fibrosis (pwCF) – both men and women - have identified this field as a priority area of interest for clinicians to focus research and educational efforts [ [1] Kazmerski T.M. Moy C. Aliaj E. Hudson J. Wright B. Poranski M. et al. Prioritizing sexual and reproductive health research and care for people with cystic fibrosis: A 2023 workshop report from the Cystic Fibrosis Foundation Sexual Health, Reproduction, and Gender (SHARING) Research Working Group. J Cyst Fibros. 2024; Abstract Full Text Full Text PDF Scopus (0) Google Scholar ]. SRH in CF is a broad topic encompassing not just fertility and sexuality, but also health outcomes associated with SRH events such as pregnancy/parenthood, and health services delivery of SRH needs in the unique context of specialized CF care centers. A recent systematic review neatly summarizes progress toward understanding the impacts CF has on SRH and highlights areas needed for further study [ [2] Iyer A.G. Yu B. Reddy A. Khera M. Optimizing sexual reproductive health of men and women with cystic fibrosis: A systematic review. J Cyst Fibros. 2024; Abstract Full Text Full Text PDF Scopus (0) Google Scholar ]. This issue of the Journal of CF includes five articles that not only further our understanding of SRH in CF, but also demonstrate the tools necessary to deliver high-quality care in this growing field.

BackgroundTo address sexual and reproductive health (SRH) concerns among people with cystic fibrosis(PwCF), the CF Foundation created the Sexual Health, Reproduction, and Gender Research (SHARING) Working Group. This report summarizes CF community SRH research priorities and workshop discussions/future study planning.MethodsPre-workshop, we distributed a community prioritization survey on CF SRH research/care. During the workshop, we used results and reviewed existing research to establish research priorities and design studies to address identified knowledge gaps.ResultsA total of 303 respondents (85 % PwCF, 15 % caregivers) completed the survey. Highly-rated SRH topics were: 1) effects of CF modulator therapy on sex hormones; 2) effects of sex hormones on CF; 3) fertility; 4) pregnancy; and 5) SRH/mental health. Twenty-four workshop participants established the need for further research on sex hormones and CF, optimizing SRH care provision, and fertility/ART.ConclusionSRH is an important and emerging area in CF and thoughtful consideration of community perspectives can ensure that future research is relevant and responsive.

45%) children were more likely to be in the high BMI, low FEV 1 /FVC category (Figure 1).Conclusions: Our preliminary data suggest that most children with CF have normal growth at age 3, regardless of their race and ethnicity.Normal growth was associated with high FEV 1 at age 6 in all groups, and poor growth appeared to affect the lung function of Black non-Hispanic children disproportionately.Our findings support optimizing nutrition in early life to support good lung function.The disparity in the negative effect of poor growth on Black non-Hispanic children raises the possibility that there may be additional race-related factors affecting lung function, but this requires a more-detailed, longer investigation.

Conclusions: Adolescent and young adult NHB people have a higher prevalence of CFRD than adolescent and young adult NHW people, and NHB and Hispanic adolescents have a higher incidence of CFRD.Large multicenter studies performed in a diverse CF population are warranted to determine what factors contribute to earlier development of CFRD in minoritized groups to mitigate racial and ethnic inequities in diabetes outcomes.

BackgroundCystic fibrosis (CF) is an inherited disorder causing impaired mucociliary clearance within the respiratory tract, and is associated with bronchiectasis, chronic respiratory infections, and early death. Airway clearance therapies have long been a cornerstone of management of individuals with CF, although evidence supporting their use is lacking. We designed a randomized controlled trial to quantitatively compare the effects of different forms of airway clearance on mucociliary clearance.MethodsThree different physiotherapy methods to augment cough-clearance were studied in addition to cough-clearance alone: high-frequency chest-wall oscillating vest, oscillatory positive expiratory pressure, and whole-body vibration. We used gamma scintigraphy after inhalation of radiolabeled particles to quantify mucus clearance before, during, and after physiotherapy. As secondary endpoints, we measured concentrations of small molecules in exhaled breath that may impact mucus clearance.ResultsTen subjects were enrolled and completed study procedures. No differences were identified between any method of airway clearance, including cough clearance alone. We did identify changes in certain small molecule concentrations in exhaled breath following airway clearance.ConclusionsDue to the limitations of this study, we do not believe the negative results suggest a change in clinical practice with regard to airway clearance. Findings pertaining to small molecules in exhaled breath may serve as future opportunities for study.

Elexacaftor, tezacaftor, ivacaftor (ETI) have been associated with marked clinical improvements in adults with CF, which appears to be associated with increased fertility. However, maternal and fetal effects of therapy continued during pregnancy are not well understood. We collected maternal blood, infant blood, cord blood, and breast milk from 3 mother-infant pairs from women who elected to remain on ETI therapy while pregnant. Our results demonstrated relatively high levels of ETI in cord blood, suggesting placental transfer of these compounds, as well as low levels of ETI in breast milk and infant blood, suggesting further transfer of these compounds to breast-fed infants in the postnatal period. These data underscore the need for larger studies on the effects of modulator surrounding reproduction.