Modulator therapy in pregnancy may reduce risk for babies with CF
Babies born without CF complication meconium ileus in small real-world study
Treating expectant mothers with CFTR modulators may help to reduce the risk of intestinal complications for babies with cystic fibrosis (CF), according to a small real-world study from France.
“We hope that such a study, merged with other international programmes, will also provide support for the European Medicines Agency to consider the potential benefit of modulators for CF fetuses,” researchers wrote.
The study, “First real-world study of fetal therapy with CFTR modulators in cystic fibrosis: Report from the MODUL-CF study,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the gene that provides instructions to make the CFTR protein. CFTR modulators are a recently developed class of therapies that are able to boost the functionality of the mutated CFTR protein in people with specific disease-causing mutations.
In newborns, one of the most common symptoms of CF is meconium ileus, a complication where a baby’s first feces gets stuck in the intestines. This can often be visualized before birth using ultrasound.
CFTR modulators can cross placenta to reach fetus
Available CFTR modulators are able to cross the placenta to reach a fetus during pregnancy. This has led some scientists to wonder if it might be possible to prevent complications like meconium ileus by giving the therapies to pregnant women who are carrying babies with CF. Apart from a few case reports, however, there’s not much data on the safety or efficacy of this approach.
In the new study, part of the MODUL-CF trial (NCT04301856) conducted in France, CFTR modulator treatment during pregnancy was explored in 12 women. This group included a mother with CF, others who had children with CF, and some with no family history of CF but showed signs indicative of the disease on ultrasound during pregnancy.
In all cases, prenatal genetic testing was performed to confirm that the fetus definitely had CF and carried at least one copy of F508del, the most common CF-causing mutation that responds to modulator treatment. CFTR modulator treatment was started during the third trimester of pregnancy in all cases.
In eight of the cases, ultrasound showed signs of probable meconium ileus. All of these women were given the modulator therapy Trikafta (elexacaftor/tezacaftor/ivacaftor).
In one case, the woman gave birth just days after starting modulator therapy. In another case, the baby was found to have a severe intestinal malformation soon after starting modulator treatment, and the pregnancy was ultimately terminated. In the remaining six cases where Trikafta was administered for several weeks in the last part of pregnancy, all six babies were born without meconium ileus, implying that modulator therapy during pregnancy can effectively treat this CF complication.
“Resolution of bowel obstruction was observed as soon as 3 days of [Trikafta] treatment,” the researchers noted. However, they also said the small number of participants make it impossible to assess whether meconium ileus would have resolved without treatment.
The other four cases in this study included fetuses with no obvious signs of meconium ileus on ultrasound, but the mothers were nonetheless given modulator treatment as a precaution. Three of these women received Trikafta, and the fourth was given Kalydeco (ivacaftor). In all four cases, the baby did not have meconium ileus at birth.
No reports of major safety issues related to CF modulators during pregnancy
No major safety issues related to modulator treatment during pregnancy were reported in any of the patients, though the researchers stressed that further follow-up is ongoing.
“While no serious safety concerns for neither mothers nor fetuses have been reported, we still need to accumulate data on long-term safety,” they wrote.
Apart from meconium ileus, other symptoms of CF that may be present at birth include low levels of pancreatic enzymes in the stool and in males, absence of the vas deferens (the tube that normally carries sperm out of the testes).
Although none of the children in the study had meconium ileus, pancreatic enzyme levels were generally low, and tests indicated the male babies lacked the vas deferens. The researchers speculated it might be necessary to start modulator treatment earlier, in the first or second trimester, to preempt these complications, though they stressed that more studies will be needed to say for sure.
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