Rat fetuses don’t appear harmed by giving pregnant mothers Trikafta
Research comes in wake of increases in pregnancies among women with CF
Exposure in utero to the cystic fibrosis (CF) medication Trikafta (elexacaftor/tezacaftor/ivacaftor) didn’t appear to negatively affect organ development in fetal rats whose mothers were given it, but it did change the activity of some genes, a study finds.
While the functional impacts of the changes remain to be understood, researchers are moving forward with human studies to better learn how using Trikafta during pregnancy affects both mother and child.
The so-called highly effective CFTR modulator therapy is approved in the U.S. for CF patients ages 2 and older. Its safety in younger or pregnant patients isn’t established.
“Our end goal would be to change the labeling of Trikafta for pregnant women and children under 2 years of age,” Elena Schneider-Futschik, PhD, a researcher at the University of Melbourne in Australia and the study’s senior author, said in a university news release. “Importantly, this research will also offer women living with cystic fibrosis a sense of normality — a normal pregnancy and all the wonderful experiences that it brings.”
The study, “Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy,” was published in the British Journal of Pharmacology.
While CF doesn’t typically render women infertile, female patients can have a harder time getting pregnant than other women. This may be linked with several factors, including irregular menstrual cycles associated with poor nutrition and thicker cervical mucus that makes fertilization more difficult.
CFTR modulator therapies like Trikafta have changed this outlook. Better overall health and thinner mucus throughout the body could make pregnancy easier. Indeed, there’s been a dramatic increase in pregnancies among women with CF in recent years.
Studying effects of Trikafta on developing fetus
While it may be better for a woman to continue CFTR modulators during pregnancy, their effects on a developing fetus aren’t known. Clinical trials that tested the treatments didn’t involve pregnant women, but a handful of clinical cases in which female patients used Trikafta after becoming pregnant didn’t show any relevant adverse events to their offspring, according to the authors.
In a study published this year, the researchers showed that when pregnant rats were treated for a week with the components of Trikafta, the medication could pass through the placenta, which surrounds a developing fetus in utero, and accumulate in fetal tissues including the blood, brain, and other organs.
Here, the scientists looked at the potential impacts of exposure on fetal development. Pregnant rats were treated with Trikafta for a week — or were left untreated — and gene activity changes in the organs of the developing fetuses were measured.
No obvious structural changes were observed in the organs of the Trikafta-exposed fetuses, including the pancreas, liver, lung, small intestine, the brain’s cortex, or the thymus, an immune organ.
Gene activity analyses identified very few relevant differences in the liver, lungs, and small intestine between the fetuses who were and weren’t exposed to Trikafta. In the thymus, 29 genes had different activity levels with exposure, which were often related to muscle structure and development.
The greatest number of changes were observed in the cortex, where four dozen genes had altered activity in the Trikafta-exposed rats. Several were important for brain and nervous system development.
Overall, “the functional significance of these gene changes is unknown and warrants further longer-term studies to determine the safety of [Trikafta] on brain and thymus development,” wrote the researchers, who noted while there may be some risks to a developing fetus, that must be weighed against the mother’s need for Trikafta. Stopping treatment could have negative consequences on her health.
Infants born with CF might also benefit from early fetal exposure, possibly preventing the onset of some symptoms altogether.
“This could equate to something close to a cure,” Schneider-Futschik said.
Among the ongoing studies aimed at exploring the use of CFTR modulators in pregnancy is the MAYFLOWERS observational study (NCT04828382), which will look at lung function changes in women with CF who are taking highly effective CFTR modulators throughout pregnancy and in the two years thereafter.
In another study, scientists will measure levels of Trikafta in women with CF during pregnancy, along with their developing offspring, in order to learn more about how it moves across the placenta.
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