A 17-year-old person with cystic fibrosis (pwCF), homozygous for the F508del variant, experienced an unplanned but desired pregnancy while using elexacaftor/tezacaftor/ivacaftor (ETI) to manage her own CF. The young couple revealed their pregnancy news at 19 weeks gestation, and the father learned he was a carrier for F508del after testing was prompted by the fetus's echogenic bowel on a second trimester ultrasound. Echogenic bowel resolved by 25 weeks gestation, and the family opted not to pursue amniocentesis. The mother used ETI without interruption through a pregnancy complicated by mild polyhydramnios, diet-controlled gestational diabetes in the third trimester, and maternal chorioamnionitis. A male infant was born at 36w6d gestation via spontaneous vaginal delivery, with birth weight in the 89th percentile and length in the 53rd percentile. Due to the risk of a false negative newborn screen from ETI exposure, second-tier testing with CFTR variant analysis was requested. The patient's immunoreactive trypsinogen (IRT) level was 53.6 ng/mL, below the 96th percentile, but DNA testing revealed two copies of the F508del variant. The infant passed meconium within the first day of life, and maternal breastmilk was supplemented by formula due to low supply. Sweat chloride analysis at 3 weeks of age was elevated to 100 mmol/L (left arm) and 97 mmol/L (right). Despite the early introduction of pancreatic enzyme replacement therapy (PERT), he gained weight slowly. He averaged 21 g/day of weight gain in the first month of life, 17 g/day in months 2–4, and 9.6 g/day in months 5–11. Fecal elastase at 1 month of age was 476 mcg/g, which was attributed to maternal ETI use, and PERT was continued due to insufficient weight gain. Additional nutritional interventions included formula fortification up to 28 calories/oz, acid suppression, and supplementation with salt and a multivitamin containing B vitamins, zinc, and fat-soluble vitamins. Though breastfeeding was attempted to continue infant exposure to ETI, the mother produced only about eight ounces of breastmilk per day throughout the first 2 months of the infant's life. This led to maternal distress, and the infant transitioned to formula exclusively by 8 weeks of age. Fat soluble vitamin levels drawn at 7 months of age were within normal limits. At 1 year of age, a fecal elastase value measured 461 mcg/g suggestive of pancreatic sufficiency. 72-h fecal fat analysis also reflected 99% absorption of dietary fat while off PERT. A scrotal ultrasound was performed at 13 months of age, with both the right and left epididymis appearing normal. Two parallel echogenic lines were visualized along the left spermatic cord, suggesting a preserved left vas deferens. The right vas deferens was not definitively seen (Figure 1). Prenatal exposure to highly effective modulator therapy (HEMT) for CF is increasingly common as more pwCF are conceiving and using HEMT throughout their pregnancies. Much of our knowledge about outcomes in these infants is based on case reports and retrospective cohort studies, suggesting relatively positive outcomes for infants, without increased risk for birth defects 1 Here we present the case of a mother with CF who used ETI during conception, gestation, and breastfeeding, and the subsequent effects on her male infant with CF, including resolution of echogenic bowel, preservation of pancreatic function and structural presence of the vas deferens. First, echogenic bowel, which frequently raises concern for the presence of meconium ileus (MI), prompted evaluation of the father for carrier status. In this scenario of a fetus exposed to HEMT throughout gestation, the echogenic bowel resolved prior to delivery, and the infant passed meconium normally after birth. Indeed, treatment of potential MI is the leading reason for carrier parents to consider prenatal treatment with ETI. However, the outcomes of such treatments have been variable in their success in resolving MI 2, and the underlying rate of spontaneous resolution of echogenic bowel in fetuses with CF is unknown. A key feature of this case is that the infant sustained pancreatic-sufficient status throughout the first year of life, despite cessation of breastfeeding, and thus, ETI exposure, by 2 months of age. This finding was confounded by presumptions regarding his genetic variants, his limited time on ETI postnatally, and a weight/height ratio that was consistently less than the 10th percentile. Despite a normal fecal elastase value early in life and no symptoms of pancreatic insufficiency, the persistently poor weight gain led to continuation on PERT for the first year of life. We did not retest pancreatic function until the infant was 12 months of age and due to begin lumacaftor/ivacaftor, and we were surprised to confirm pancreatic sufficiency with both fecal elastase and 72-h fecal fat analysis conducted after withdrawing PERT. The maternal grandmother shared that the infant's mother similarly struggled with weight gain and remained below the 10th percentile for weight/length until a gastrostomy tube was placed as a toddler. Despite the gastrostomy tube, the mother's weight had never exceeded the 20th percentile, though she was healthy in all other aspects of her disease. This case demonstrates the value in not making assumptions regarding pancreatic status in infants who have been exposed to ETI in utero. It is critical to note that human data is lacking regarding the deterioration potential of pancreatic function in the context of abrupt withdrawal of HEMT, though a 3 ferret model suggests that modulator cessation will lead to quick return of a pancreatic insufficient status. Therefore, this case provides evidence of prolonged preservation of pancreatic function even after modulator therapy is stopped in an infant with prenatal exposure. Finally, male infertility is a near-universal feature in CF, due to the abundance of CFTR in the head of the epididymis. Early obstruction of the Wolffian Ducts by dehydrated secretions from the head of the epididymis is postulated to cause non-development of the downstream structures 4. Animal studies demonstrating preservation of the vas deferens in male CF ferrets prenatally exposed to ivacaftor 3 prompted further investigation in this infant. While we are unable to determine if the anatomic presence of a vas deferens translates to preserved fertility, it is a promising finding that early exposure to ETI can positively impact male fertility, and semen analysis is planned after the child achieves puberty. One other case report 5, to our knowledge, has been published showing a preserved vas deferens in an infant exposed to prenatal ETI. The potential of preserving male fertility in infants with CF may drive more pregnant people to undergo testing and opt for prenatal therapy with ETI for male infants with CF. This case demonstrates several unique aspects of an infant with CF exposed to prenatal HEMT from the time of conception, providing additional evidence for the use of HEMT as early as possible in an affected pregnancy. Emma Comadoll: conceptualization, investigation, writing - original draft, Writing - review and editing. Alannah Mascarella: conceptualization, writing - original draft, writing - review and editing, investigation. Marcelo Straus-Takahashi: investigation, visualization, writing - review and editing. Jennifer L. Goralski: conceptualization, investigation, writing - original draft, writing - review and editing, supervision. The authors received no specific funding for this work. Dr. Goralski reports clinical trial funding (paid to the institution) as well as speaker honoraria from Vertex Pharmaceuticals Inc. The other authors declare no conflicts of interest. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.
Comadoll et al. (Sun,) studied this question.