Use of Kaftrio (elexacaftor, tezacaftor, and ivacaftor), sold in the U.S. as Trikafta, helped a woman with cystic fibrosis (CF) more easily become pregnant and maintain her health throughout the pregnancy and child’s birth, according to a case report from France.
The woman had struggled in a previous pregnancy, due to poor fertility and repeat CF exacerbations, before starting on the triple combination treatment developed and marketed by Vertex Pharmaceuticals. Both children and the woman were discharged and went home within a month of her giving birth.
“Our case shows a real benefit for the mother without detection of any adverse foetal outcomes,” the researchers wrote.
The report “Comparison of two pregnancies with and without elexacaftor-tezacaftor-ivacaftor in a woman with cystic fibrosis” was published as a letter in the journal Respiratory Medicine and Research.
Pregnancy rates among women with CF have risen in recent years with improvements in therapeutic options. The report noted that 50 pregnancies among this patient group, resulting in 33 live births, were identified in France in 2019.
Kaftrio started eight months after first difficult pregnancy
Kaftrio, a modulator therapy, is among these options. It helps the defective CFTR (cystic fibrosis transmembrane conductance regulator) protein, the disease’s cause, work more effectively. Kaftrio was approved in France in 2020, and it was available under compassionate use to patients there with advanced CF since 2019.
Little data, however, “are currently available on the use of CFTR modulators in pregnant women, and the real impact on maternal and [fetal prognosis] during pregnancy is still unclear,” the researchers wrote.
A team at Hôpital Foch, near Paris, described two pregnancies, one before and one after starting on Kaftrio, in a woman with CF who was 32 years old at the time of the second pregnancy. The woman had two copies of the F508del mutation (the most common CF-causing CFTR gene mutation), respiratory impairment, chronic airway infection with Pseudomonas aeruginosa and methicillin-resistant S. aureus, exocrine pancreatic insufficiency, and CFTR-related diabetes.
Exact dates of care given were not included in the report.
Her first pregnancy came after seven years of infertility treatment and several in vitro fertilization cycles. During the first trimester, her treatments included pancreatin, montelukast, azithromycin, L-thyroxine, insulin therapy, daily respiratory physiotherapy, and enteral nutrition.
She gained a total of 3 kg (about 6.6 pounds) during the pregnancy. Her diabetes, with blood-sugar levels measured using the glycated hemoglobin A level test, was 6.6% before conception, consistent with a diabetes diagnosis, and 5.7% shortly before her delivery, consistent with pre-diabetes.
Her percent predicted forced expiratory volume in one second (ppFEV1), a measure of lung heath, was 50% before conception. She had three pulmonary exacerbations, a sudden worsening in respiratory symptoms, at 11, 20, and 25 weeks of gestation that were treated with antibiotics, including one intravenous treatment regimen, the scientists reported.
A fourth exacerbation seven months into her pregnancy (28 weeks gestation) required hospitalization and treatment with intravenous antibiotics, which continued until delivery, and nocturnal oxygen.
The baby was born after 33 weeks of gestation by caesarian section, necessitated by the woman’s ppFEV1 having dropped to 31%. Born weighing 2.37 kg (about 5.2 pounds) and with transitory respiratory distress syndrome, the baby was treated with continuous positive airway pressure for 27 hours. The mother and child were released to home care 22 days after delivery.
‘Positive impact’ on woman’s fertility, overall health
Eight months later, the woman started using Kaftrio — elexacaftor at 200 mg and tezacaftor at 100 mg, both taken once daily, and ivacaftor at 150 mg every 12 hours. She naturally became pregnant 20 days after starting the therapy.
This ease of pregnancy and the fertility it implied “appears as a major difference” with the first pregnancy, the scientists wrote.
“After ethical discussion about the patient health and impact of correctors [elexacaftor and tezacaftor], we agreed that the benefits of CFTR modulators outweighed any potential unknown risk to the baby,” they added.
Other treatments remained similar to those used in the initial pregnancy, except for her no longer needing respiratory physiotherapy and enteral nutrition.
Her ppFEV1 had risen to 53% one month after starting on Kaftrio, increasing to 60% pre-delivery, and she gained 10 kg during this pregnancy. Her glycated hemoglobin A levels were a normal 5.5% in tests given before conception and delivery, indicating no diabetes.
She had one pulmonary exacerbation treated at the home with oral antibiotics, and she reported respiratory discomfort in her eighth month of pregnancy (33 weeks of gestation).
Her baby, a boy, was delivered by C-section early, at 34.5 weeks of gestation, due to ruptured membranes in the mother and an abnormal fetal heart rate. He weighed 2.86 kg and also had transitory respiratory distress syndrome that was treated for seven hours with continuous positive airway pressure. Mother and child returned home 11 days after the birth.
“Our case shows a positive impact of [Kaftrio] on fertility. It resulted in a spontaneous pregnancy shortly after beginning the treatment that may have been due to improvements in cervical mucus consistency and pH,” the researchers wrote.
Abnormal CFTR function is associated with poor fertility due to a viscous PH imbalance in cervical mucous. “The current hypothesis still to be proven is that CFTR modulators decrease viscosity and increase pH in cervical mucous secretions,” the researchers added.
They also noted the ease of fertility evident in this pregnancy may be due to the woman’s better nutritional status after starting on Kaftrio.
Kaftrio’s use here was also associated with ppFEV1 improvements and fewer and less severe pulmonary exacerbations. “The patient had never had such good results before,” the researchers wrote.
The first child is still healthy at age 18 months, the team noted, and the other is continuing to be monitored though he was “born without evidence of congenital malformation.”
In the U.S., 45 pregnancies and 29 live births were reported in 2020 among CF patients using Trikafta.
An observational study called the Maternal and Fetal Outcomes in the Era of Modulators (MAYFLOWERS, NCT04828382), which started in 2021, is evaluating the use of CFTR modulator therapy on lung function during pregnancy and lactation. The study is enrolling eligible women with CF at sites across the U.S., and it is estimated to finish in 2025.