In Utero Treatment of Fetal Cystic Fibrosis

The role of elexacaftor/tezacaftor/ivacaftor in preventing meconium ileus

By Clement L. Ren, MD, MBA, ATSF

Patient background 

The patient is a now 2-week-old girl with cystic fibrosis (CF) whose mother was evaluated at the CF Center at CHOP when the patient was 20 weeks gestational age (GA). Prenatal testing revealed that the patient had 2 copies of F508del, and a fetal ultrasound showed echogenic bowel. The parents were referred to CHOP for prenatal counseling about CF. Based on case reports of women with and without CF taking elexacaftor/tezacaftor/ivacaftor (ETI) while pregnant to prevent meconium ileus (MI), and after discussion of the potential, but unknown, benefits and risks of in utero ETI therapy, the parents elected to pursue this therapy for the patient. 

Diagnostic findings

• Amniocentesis showed the patient was F508del homozygous.
• A fetal ultrasound at 20 weeks GA showed echogenic bowel and breech position.

Clinical course/treatment

Maternal ETI therapy was initiated at 24 weeks GA. A follow-up ultrasound showed dilated bowel, which remained dilated throughout the pregnancy but did not increase in size. An elective Cesarian section was planned at 39 weeks GA, but the mother’s water broke the day before, so the infant was delivered 1 day prior to the planned surgery. The patient was delivered uneventfully, and an abdominal radiograph on the day of birth showed dilated loops of bowel without air-fluid levels. (See Figure 1.) Barium enema showed micro-colon and the terminal ileum could not be visualized. Repeat enema failed to fill the terminal ileum, and on day of life 2, surgical intervention was planned. However, the infant began to stool spontaneously, and surgery was deferred.

Figure 1: Abdominal radiograph on DOL 1 showing dilated loops of bowel. Figure 2: Abdominal radiograph on DOL 7 showing a normal bowel gas pattern.

Over the course of the next 10 days, the infant continued to pass meconium and received N-acetyl cysteine via nasogastric tube and enema. Repeated X-ray on day of life 7 showed the dilated loops had resolved. (See Figure 2.) Oral feeds were gradually advanced, and she was discharged on day of life 16 on full feeds of maternal breast milk and pancreatic enzyme replacement therapy after having gained 60 grams per day in the preceding 4 days. A fecal elastase (FE) obtained on DOL 12 was 216 micrograms/gram (normal >200). An eye exam was normal, as were liver function tests.

Outcomes

The patient was seen for follow-up at the CF Center at CHOP at 21 days of age. Her weight gain was 50 grams per day. A fecal elastase obtained on the day of visit was 129 microgram/gram and her sweat chloride was 86 mmol/L on one arm and 76 mmol/L on the other arm. The mother is continuing to take ETI and is breast feeding the infant.

Discussion 

• There has only been one published case report of in utero ETI therapy to prevent MI in a fetus diagnosed prenatally with CF. In that case, the infant was born without any intestinal obstruction. In this case the infant was not completely asymptomatic, but did not require surgical intervention for MI.
• The infant’s fecal elastase levels suggest that she have preserved pancreatic function.
• Her sweat chloride levels suggest that she is still receiving a pharmacologic effect from ETI. Whether this represents residual effect from in utero ETI or from ETI in breast milk remains to be determined.

Key points

• In utero ETI therapy can prevent gastrointestinal complications of fetal CF.
• In utero ETI may also result in preserved pancreatic function.
• The sweat test can be used as a biomarker to assess CFTR function in infants receiving ETI in breast milk.