Children's Hospital Colorado

Providing ETI for Pregnant Carriers of Babies with Cystic Fibrosis

7/25/2024 8 min. read

A pregnant woman laying in a hospital bed receives an ultrasound.

Can off-label use of CFTR modulator prevent cystic fibrosis complications before birth?


The lives of people with cystic fibrosis (CF) have improved dramatically since the groundbreaking CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI, or Trikafta) was FDA-approved in 2019.

In the span of his 23-year career as a pediatric pulmonologist, Scott Sagel, MD, PhD, director of the University of Colorado Cystic Fibrosis Center, has seen CF change from a fatal disease to one in which adult women with CF are healthy and experiencing increased chances of fertility.

“It's one of our great success stories in pediatrics and modern medicine to transition a fatal disease into a chronic adult disorder where people can live near-normal lifespans with an overall improved quality of life,” says Dr. Sagel.

Now, some pregnant women who have just one copy of the mutated cystic fibrosis transmembrane conductance regulator (CFTR) gene and are therefore carriers of CF are taking the modulator for their fetus diagnosed with the genetic disorder. Results have been promising, including for families at Children's Hospital Colorado's Mike Morris Cystic Fibrosis Research and Care Center — one of the largest CF centers in the nation.

“The more data we get, the more we can advocate for cost-effective drugs and insurance coverage as a standard of care.”

- MICHAEL ZARETSKY, MD

Four pregnant carrier mothers being cared for at the Colorado Fetal Care Center whose fetuses were diagnosed with CF were offered Trikafta. Three of them chose to take the medication, with the most promising results from the mother who started the medication earliest in her pregnancy. The mothers and babies were all treated by the multidisciplinary care team at the Colorado Fetal Care Center in coordination with the expertise from the cystic fibrosis team. "We help each other coordinate their care. The pulmonologists work hard to get the drug approved. Then, during the pregnancy, we see the patients weekly to monitor for any potential adverse reactions to ETI,” says Michael Zaretsky, MD, a fetal surgeon and maternal-fetal medicine specialist.

The fortuitous discovery that ETI modulator may help in utero

Physicians first learned that ETI modulator therapy might also help fetuses with CF when women with CF being treated with the therapy were becoming pregnant more easily. This was an unexpected consequence and benefit of the drug since physicians were accustomed to CF decreasing fertility due to general illness and thick cervical mucus that makes it harder to conceive.

In this baby boom among mothers with CF, each was counseled on balancing the unknown risks of taking the CFTR modulator therapy with the mothers’ worsening health from discontinuing ETI during pregnancy. A 2021 case report published in the Journal of Cystic Fibrosis showcased a baby born with CF to a mother who also had CF and was taking Trikafta during pregnancy who did not exhibit signs of the disease at birth. During pregnancy, the 20-week ultrasound showed possible echogenic bowel that raised suspicion for CF, but a repeat ultrasound at 32 weeks was normal. The infant was born without intestinal blockage from meconium ileus (MI), and the newborn screen for CF was actually negative, presumably due to the preservation of digestive pancreatic function by Trikafta crossing the placenta into the fetus.

The increased number of pregnancies among women with CF on Trikafta therapy prompted the much larger Mayflowers real-world, prospective observational study to evaluate maternal and fetal outcomes with CFTR modulators. There are known side effects physicians are monitoring for, such as effects on the liver and eye development in the fetus. So far, it appears to be generally safe.

“Out of this large population, there were a small number of women who have babies with CF, and what we found was that those babies could be missed on the newborn screening because they weren't showing typical signs of having CF after exposure to this drug,” says Edith Zemanick, MD, associate director of the Cystic Fibrosis Research and Care Center.

Cases of CF carrier women taking ETI for a diagnosed fetus

Babies born with CF who do not have meconium ileus at birth tend to have a significantly better clinical course and prognosis compared to those who do. MI is among the earliest and most severe manifestations of CF, occurring in up to 20% of babies born with the disease. It leads to a life-threatening bowel obstruction that often requires surgical intervention, a lengthy NICU stay, long-term risk of digestive complications and poor growth. The possibility of preventing or even reversing this complication is enough motivation for some CF carrier women to take ETI during pregnancy if their babies are identified as having signs of MI on prenatal ultrasonography and are diagnosed with CF during pregnancy. This is despite the fact that there is no published clinical trial data of ETI therapy during pregnancy.

“Physicians have felt increasingly comfortable treating women who have CF through pregnancy with Trikafta because we haven't seen a lot of evidence of problems, and people with CF who stop ETI often get sicker. But treating carriers is different because there’s no benefit to the mother,” says Dr. Zemanick.

Over the past year, physicians at Children’s Colorado discussed the possible benefits and risks of taking Trikafta with four pregnant carriers. “We had very frank conversations with the parents about the risks of taking an off-label drug when we don't know for sure that it's safe or that it will work,” says Dr. Zemanick.

One couple opted not to take the medication due to the lack of data on the risks and effectiveness. The baby was born with intestinal blockage from meconium ileus, which may have still occurred with ETI treatment. Another couple agreed to maternal ETI therapy, but it was not started until 35 weeks gestation due to timing of genetic testing and delays in obtaining insurance coverage. The baby was born at 38 weeks and needed surgery for MI. “It needs to be started earlier. I don't know exactly when, but it probably needs to be started between 30 to 32 weeks gestation or earlier,” says Dr. Sagel.

One couple whose baby was diagnosed in utero with CF was able to get insurance coverage for Trikafta and begin the medication earlier. Their baby was born with signs of MI but did not require surgical intervention. The meconium cleared with enemas.

The fourth pregnant carrier’s fetus showed signs of MI in utero. In-vitro genetic testing results were positive for CF. The parents elected to start Trikafta treatment and even paid out of pocket when their insurance denied coverage.

Once the mom began taking the CFTR modulator therapy, there were clear signs of MI resolution on the ultrasound. The mother and fetus were closely monitored, especially for liver dysfunction and cataracts. There were no side effects of complications of Trikafta therapy.

The baby appeared healthy at birth, with no intestinal obstruction and was discharged home from the nursery with mom. The baby needed to start pancreatic enzymes a few weeks later, and now she is 6 months old, thriving and gaining weight like any other baby. “We don't know for sure what would have happened without Trikafta, but it seemed like she got better once mom started the Trikafta, and we could see the intestinal obstruction on the ultrasound getting better,” says Dr. Zemanick.

Some families have opted to continue taking ETI while breastfeeding.

What’s next for modulator therapy and people with CF

Dr. Zaretsky and Dr. Sagel have developed an observational trial to track outcomes of carrier pregnant mothers who have babies diagnosed in utero with CF and signs of MI, including those who are prescribed off-label use of Trikafta.

Researchers at Children’s Colorado are part of ongoing research and clinical trials to find even better CFTR modulator therapies. Another modulator therapy may be approved by the FDA in winter 2024 for people with cystic fibrosis 6 years of age and older. It is a slightly different formulation given once a day, rather than the twice-daily dosage. “The goal is to develop therapies that restore even more function,” says Dr. Sagel. “We think we could eliminate much disease if we can get to a higher level of restoration of protein function. We're not far from that right now.”

While ETI has become the standard of care for most people with CF, approximately 10% of the United States CF population does not benefit from this therapy. Researchers are focused on developing genetic-based therapies for people who do not qualify for or cannot tolerate CFTR modulators. “That’s the big research push right now and will be the next breakthrough in CF,” says Dr. Zemanick.

All CF patients may benefit from the results of the STOP PEDS study, now enrolling kids from multiple centers, including Children’s Colorado. The goal of the randomized control study is to compare treatments for exacerbation periods with early antibiotics (increased airway clearance plus initiation of oral antibiotics for 14 days) versus tailored therapy (increased airway clearance alone, with the addition of antibiotics for worsening symptoms or failure to improve by day seven). Pilot study results show it may be possible to reduce antibiotic use.

Studies of Trikafta continue, as well. An expanded panel of rare mutations has been found to respond to this CFTR modulator therapy in the laboratory, and that list continues to grow with more research.

While Trikafta is currently FDA-approved for children as young as 2, researchers in Europe are currently studying its safety in children under 2.

There are no current studies on the use of Trikafta for non-carrier moms whose fetuses have been diagnosed with CF. These will come as more people seek access, says Dr. Zaretsky. “The more data we get, the more we can advocate for cost-effective drugs and insurance coverage as a standard of care.”

Researchers are hoping to start a trial, but so far, the drug manufacturer has declined. Instead, physicians at Children’s Colorado are following their patients carefully and collaborating with other researchers to better understand the safety and outcomes of treatment of fetal CF. “Whether there’s a trial or not, there’s going to be compelling examples from case studies,” says Dr. Zaretsky.