Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) has improved the quality of life and long-term prognosis for many people with CF. Thus, more people with CF are considering parenthood. Almost all menwith CF (MwCF) are infertile because of congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible using HEMT, but assisted reproductive techniques (ARTs) can enable MwCF to father children using the sperm in their testes. Animal reproductive models suggest no HEMT teratogenicity, and the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible, although to ensure no sperm exposure to HEMT, the life span of sperm would require MwCF to discontinue CFTR modulators for approximately 3 months before ART. Because abrupt discontinuation of CFTR modulators may result in health decline, MwCF and their providers must consider all potential risks. There are no published data in MwCF regarding use of HEMT during conception and partner pregnancy. Method(s): Beginning in August 2021, CF center staff in the United States, United Kingdom, and Australia completed a two-page anonymous questionnaire regarding MwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) or natural conception with subsequent partner pregnancy. Result(s): Providers have submitted 34 surveys for MwCF on CFTR modulators whose partner became pregnant after use of ART (n = 32) or natural conception (n = 2). The median age of the samplewas 32 (range 24- 43). Fifteen were homozygous for F508del, median percentage predicted forced expiratory volume in 1 second was 76% (range (22-111%), and median body mass index was 24 kg/m2 (range 18.5-32.1). Twenty-three were taking elexacaftor/tezacaftor/ivacaftor. The median time that MwCF were taking CFTR modulators before partner conception was 18 months (range 0-82). One newly diagnosed man initiated HEMT after sperm retrieval. Four MwCF stopped CFTR modulators before sperm retrieval, one of whom experienced pulmonary decline. None of the 19 MwCF whose condom use during pregnancy was known used condoms. Fetal complications in partners of MwCF included three first-trimester miscarriages, two* COVID, two breech presentation, two* vaginal bleeding, and one vasa previa. None of the complications were deemed definitively related to use of CFTR modulators. One MwCF experienced testicular infection after sperm retrieval#. Postpartum complications included three# infants with hypoxemia requiring neonatal intensive care unit stay, three maternal blood loss, one forceps delivery, and one caesarean section. No congenital anomalies were reported for any infant. (*/# overlap). Conclusion(s): Use of CFTR modulator therapy during partner conception and pregnancy in 34 MwCF has not resulted in higher-than-expected miscarriage rates or congenital anomalies. Providers should consider the risk to the health of MwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators before ART or natural partner conception. Survey collection is ongoing;results will be updated for presentationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

A novel cystic fibrosis-pregnancy service: Two-year review after introduction of elexacaftor/tezacaftor/ivacaftor

Background: As a quality service improvement response since elexacaftor/ tezacaftor/ivacaftor (ELX/TEZ/IVA) became available and the yearly average number of cystic fibrosis (CF) pregnancies (n = 7 pre-2020, n = 33 in 2021) increased significantly at an adult CF center (~600 people with CF), a monthly multidisciplinary CF-maternal health virtual clinic was established with antenatal virtual CF exercise classes dedicated to providing adaptive, specialist support to this cohort, aswell as outreach guidance and education to local obstetric teams. Method(s): This was a single-center retrospective reviewof Royal Brompton Hospital CF-Maternal Health multidisciplinary team clinic records and a patient survey from March 2020 to March 2022. Result(s): Of 47 pregnancies in 41 women (median age 30;) eligible for ELX/ TEZ/IVA at start of pregnancy, 40% (n = 19) were unplanned, and 19% (n = 9) used assisted conception. Three women with a history of infertility conceived naturally, having required assisted conception for previous pregnancies, and five women had multiple pregnancies during the study period. ELX/TEZ/IVA was continued in 60% (n = 28), delayed in 28% (n = 13), and stopped in 13% (n = 6) of pregnancies through maternal choice and careful clinical counselling. Pre-pregnancy pulmonary status was poorer in women who continued than in those who delayed or stopped (Table 1). Of those who stopped, 85% (n = 5) restarted because of pulmonary deterioration by the third trimester. Prenatal CF complications included at least one episode of minor hemoptysis in 21% (n = 9/41) of women, at least one infective exacerbation in 55% of pregnancies (n = 26/47), and noninvasive ventilation in one woman. Other pregnancy-associated complications included one case of ovarian hyperstimulation syndrome, one case of sub-segmental pulmonary embolism, and two cases of pregnancy-induced hypertension. Excluding 10 first trimester terminations, 10 current pregnancies, and one patient relocation, obstetric outcomes available for 26 pregnancies confirmed a live birth rate of 85% (n = 22/26) and a 15% first-trimester miscarriage rate (n = 4). Obstetric complications included preterm delivery rate of 23% (n = 6/26), including two cases of COVID infection resulting in two neonatal intensive care unit admissions, one case of endometritis after cesarean section, and a fourthdegree perineal tear. There were no ectopic pregnancies, maternal or neonatal deaths, or reports of infant cataracts or congenital malformations. Median gestational age was 37/40 weeks (range 29-40). Mode of delivery was via cesarean section in 45% (n = 10/22, of which twowere emergency) and vaginal in 55% (n = 12/22), of which 83% (n = 10/12) were via induction of labor for diabetes (CF or gestational) indication. Deliveries were supported and occurred equally at local obstetric units and in tertiarycare obstetric hospital settings (50%, n = 11/22). Patient-experience survey responses cited high levels of confidence in health optimization and prioritization during pregnancy and praised excellent inter-health care provider communication and peer-to-peer emotional support provided among expectant mothers in the virtual prenatal exercise groups. Table 1. Baseline demographic and clinical characteristics of elexacaftor/tezacaftor/ivacaftoreligible expectant mothers according to therapeutic decision (Table Presented) Conclusion(s): In the absence of clinical trial safety data, the novel approach of a dedicated CF-maternal health multidisciplinary team clinic with local obstetric outreach support has ensured regular specialist clinical and emotional peer-to-peer support for this cohort of women eligible for ELX/ TEZ/IVA to ensure optimal outcomes and experiences of their pregnancies, where appropriate, close to home.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Remote respiratory sampling and unusual Pseudomonas growths in adults with cystic fibrosis: Is there a link?

P71 Table 1 2019 cohort n=20 2021 cohort n=46 p value* Remote samples 0 (0) 31 (67.4) - Age – years, mean (SD) 36.90 (9.65) 36.98 (13.25) NS Sex – Female n (%) 14 (70) 28 (60.9) NS F508del/F508del mutation n (%) 6 (30) 19 (41) NS Maintenance inhaled antibiotic therapy n (%) 13 (65) 27 (58.7) NS CFTR modulator therapy n (%) 7 (35) 40 (87) <0.001 Unusual Pseudomonas species (n) Pseudomonas putida (4)Pseudomonas fluorescens (4)Pseudomonas rhodesiae (2)Pseudomonas synxantha (2)Other (8) Pseudomonas putida (12)Pseudomonas fluorescens (11)PseudomonasMonteilii (4)Pseudomonas libanensis (3)Pseudomonas proteolytica (3)Other (13) <0.001(See text) Clinical intervention n (%)Patient symptomatic and new therapy prescribedPatient well and no action takenPatient well and new therapy prescribedNew long-term prophylaxis initiatedIncomplete data 5 (25)3 (15)7 (35)0 (0)5 (25) 10 (21.7%)15 (32.6)8 (17.4)4 (8.7)13 (28.2) NSNSNSNSNS Regrowth of unusual Pseudomonas species on subsequent samples n (%) 1 (5) 2 (4.3) NS *Tests performed = Mann Whitney Test for processing time,t test for mean age, Chi square for ratios (Yates’ correction where data size less than 5). NS=not significantConclusionDespite nearly 50% reduction in respiratory sampling (likely a result of Covid19 and the introduction of the CFTR modulator ‘Kaftrio’), our study demonstrated more than a 2-fold increase in growths of unusual Pseudomonas species in 2021. We found an association with longer processing times, which were more common with remote sampling. Mechanisms underlying this, such as contamination, require further investigation. Importantly, our data suggest that growths may be transient and treatment not always indicated. Our results suggest caution should be exercised when interpreting samples with long processing times, but further prospective studies are required.

Implementing tablet-based ototoxicity screening in adults with cystic fibrosis

Introduction: People with cystic fibrosis (PwCF) regularly receive antibiotics for treatment of lung infections, which can include intravenous aminoglycosides (IVAG) resulting in potential ototoxicity. Sound booth audiometry is costly, time-consuming, and requires further outpatient visits and audiologists. A quality improvement project delivered by specialist pharmacists to implement a tablet audiometry ototoxicity monitoring programme was launched in PwCF receiving IVAG therapy. Objectives: To implement a tablet ototoxicity screening programme in adults with CF. Methods: PwCF receiving IVAG completed tablet-based audiometry (0.25– 16 kHz) (Shoebox MD) alongside validated ototoxicity questionnaires at the beginning and end of treatment. Following a clinical pathway, clinicians undertook shared decision-making processes regarding continuation of AG if abnormality was detected, alongside referral for sound-booth audiometry. Results: Data were collected from April–Dec 2021. Thirty-eight patients (median [IQR] age 28.5 ([15.5] years;mean [SD] ppFEV1 62.3 [26.5]) were screenedwhowere on IVAG. Fifteen patients (39%)were referred for formal audiometry due to abnormal baseline results, of which 5 had symptoms of hearing loss identified through questionnaires. 3% (1/38) stopped AG therapy due to identified potential ototoxic risk. Twenty-two patients received screening at beginning and end of IVAG therapy: significant ototoxic effects were seen in 2 of these patients (9%);20 patients (91%) had no significant change from baseline audiometry. Conclusions: We present pilot results to show feasibility of tablet-based ototoxicity screening. More IV courses were completed at home than anticipated (due to Covid19) limiting end of IV testing. Further 3-month testing is planned to detect potential delayed ototoxic change. Nevertheless, our results show tablet audiometry to be an effective and practical screening tool used by non-audiologists for accurate, early identification of hearing loss and ototoxicity.