Life expectancy has increased for people with cystic fibrosis (CF); consequently, reproductive health concerns have become more important and should be reviewed every year, according to a new position paper issued by the Cystic Fibrosis Foundation, published in The Lancet Respiratory Medicine.

“More and more females with cystic fibrosis are becoming pregnant and want to become pregnant,” said lead author Raksha Jain, MD, MSCI, professor of medicine and medical director of the Adult Cystic Fibrosis Program at the UT Southwestern Medical Center, Dallas. 

The Cystic Fibrosis Foundation has not issued previous guidance on reproductive health in people with the disease, said Jain. A multidisciplinary committee summarized the latest evidence-based knowledge on topics including fertility, contraception, preconception and pregnancy, and the impact of CF transmembrane conductance regulator (CFTR) modulator exposure in utero and postpartum.

Management of CF has been revolutionized by the advent of CFTR modulators that target the underlying defect in the CFTR protein caused by mutations in the CFTR gene, but data on their impact on reproductive health are limited.

CF reduces the chances of pregnancy for women with the disease, but CFTR modulators are facilitating more pregnancies by improving patients’ health, although men with CF must still rely on assisted reproductive technology to become biological parents. 

Standards of Care and Strategic Partnerships

People with CF want to discuss their reproductive concerns with their CF healthcare team rather than other care providers, according to the position paper. To that end, the authors included a detailed sexual and reproductive health timeline checklist for CF care teams that covers the lifespan for both males and females. Topics include sexual orientation and fertility in adolescence and young adulthood, along with issues of contraception, parenthood, and cancer screening in adulthood.

However, given the increasing need for reproductive health care for individuals with CF, the CF care teams should proactively find partners in these areas who are familiar with CF and to whom patients can be referred for specific reproductive health care, the authors emphasized.

Contraception Concerns

Persistent misconceptions about fertility and the safety of available contraception likely contribute to an unplanned pregnancy rate of nearly 50% in women with CF, as shown in a recent survey. In fact, “Most CFTR modulators, including ivacaftor, elexacaftor-tezacaftor-ivacaftor, and vanzacaftor-tezacaftor-deutivacaftor, do not exhibit drug-drug interactions with hormonal contraception,” the authors of the position paper wrote. 

Research also debunks the concern that all antibiotics reduce the effectiveness of hormonal contraception, but this is only true of the rifamycins, nirmatrelvir, and ritonavir, but not ciprofloxacin, the authors noted. 

As in the general population, the effectiveness of contraception depends on whether it is used reliably, and many individuals with CF opt for intrauterine devices and implants. However, those with estrogen should be used with caution in women at risk for venous thromboembolism, according to the position paper. 

Pregnancy Preparation and Monitoring

An expert review published in Obstetrics & Gynecology sounded similar themes about the expanded reproductive options for individuals with CF and the need for a team approach to support successful pregnancies. 

“Pulmonologists have watched this change happen in their clinics; obstetricians largely have not,” said Beth L. Pineles, MD, PhD, assistant professor of obstetrics and gynecology in the Division of Maternal-Fetal Medicine at the University of Pennsylvania Perelman School of Medicine, Philadelphia, and lead author of the report. 

Many of today’s obstetricians trained when CF was considered a reason to counsel against pregnancy, but that framing is now incorrect for most patients, Pineles emphasized. Two notable developments are worth flagging for CF clinicians, she said. 

First, carrier screening has changed. The American College of Medical Genetics and Genomics expanded its panel to 100 variants in 2023, and single-gene noninvasive prenatal screening for fetal CF is now commercially available, although it is not yet endorsed by US medical societies, said Pineles. “Separately, case reports of maternal modulator therapy treating an affected fetus, resolving meconium ileus, preserving exocrine pancreatic function, and, in one infant, preserving the vas deferens, are promising,” she said.

Historically, up to 35% of people with CF experienced infertility, with causes including thick acidic cervical mucus, low BMI, CF-related diabetes, and diminished ovarian reserve, Pineles said. “Modulators appear to improve several of these factors, cervical mucus most directly,” she said. Managing the other fertility concerns involves the work already done by an individual’s care team, with attention to nutrition, glycemic control, and pulmonary status done deliberately before conception rather than after a positive pregnancy test, she emphasized. “The most useful step is preconception consultation with maternal fetal medicine and with genetics, alongside a discussion with the patient’s CF team,” she added.

Pregnancies in women with CF have roughly doubled since the advent of CFTR modulators, with the sharpest rise in 2020, but clinicians should not assume that the medications alone are responsible, said Pineles. Better health and a real desire for pregnancy are part of the equation, and no currently available data separate planned from unplanned pregnancies, she added.

Notably, the evidence on safety regarding CFTR modulators and pregnancy is reassuring but thin, Pineles said. “Pregnant people were excluded from the modulator trials, so use in pregnancy is off-label and rests on animal data, small case series, and retrospective cohorts,” she said. Although the available evidence suggests that modulators are likely safe during pregnancy, they do cross the placenta in meaningful amounts, she said. “Neonatal cataracts and transaminitis have been reported in small series, but neither has been clearly attributed to exposure, and nothing more serious has been documented,” Pineles noted. 

Based on available evidence, patients with CF are generally counseled to stay on modulators through pregnancy, since the maternal benefit of preserved lung function is concrete, and the fetal risk appears low, Pineles said. “Stopping a drug that is keeping someone well is its own risk,” she said. “One practical caveat is that an exposed newborn can have a false-negative newborn screen, so genetic testing is needed to diagnose CF in that infant,” she added.

Implications for Infants

Evidence is limited, but available studies show no significant association between CFTR use and pregnancy outcomes. A 2020 international survey of 64 pregnancies in 61 women showed that the medications were well tolerated overall. The two reported adverse events deemed related to CFTR use were a pulmonary exacerbation during pregnancy, which may have been related to underlying CF lung disease rather than the medication, and a postpartum diagnosis of acute myeloid leukemia. 

Exposure to CFTR modulators in utero also has implications for infant monitoring and CF screening results in newborns. CFTR modulators cross the placenta and could affect the effectiveness of standard newborn screening for CF. Chorionic villus sampling or amniocentesis are alternative screening options; although not risk-free, the risks are documented and below 1%, according to the position paper.

Individuals with CF need to know that pregnancy is possible and that hormonal contraception has no known negative side effects beyond what is known in the general population and outlined in the position paper, said Jain. In addition, more data are needed on the impact on babies of mothers with CF taking CFTR modulators and other medications, she said. 

Looking ahead, more contemporary estimates of complications are needed to inform patient discussions, as most of the pregnancy complication data precede the modulator era, Pineles said. Two studies in progress, MAYFLOWERS and HOPeCF, should help, she said. “We also need prospective studies of fetal transplacental therapy and validation of single gene noninvasive prenatal screening for CF,” Pineles noted.

Both the position paper and the review by Pineles and colleagues were supported by the Cystic Fibrosis Foundation. Pineles reported having no financial conflicts to disclose. Disclosure information for the other authors is available in each of the original study publications.