Before the arrival of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators women with CF and impaired lung function were experiencing a high risk of complications and mortality during and the years after pregnancy. The arrival of the highly efficient CFTR modulator, Elexacaftor-Tezacaftor-Ivacaftor (ETI) resulted in an improvement of lung function, quality of life and fertility. Here we report a case of successful pregnancy and uncomplicated delivery for a CF patient with severely impaired lung function receiving ETI prior to conception

Balmpouzis, Zisis

Baud, David

Faure van Rossum, Annabelle

Koutsokera, Angela

Mazza Stalder, Jesica

Mitropoulou, Georgia

Panchaud, Alice

Respiratory Medicine Case Reports

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Successful pregnancy in a cystic fibrosis patient with a severe impairment of lung function receiving Elexacaftor-Tezacaftor-Ivacaftor

Zisis Balmpouzis

Annabelle Faure van Rossum

David Baud

Alice Panchaud

Georgia Mitropoulou

Jesica Mazza Stalder

Angela Koutsokera

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Respiratory Medicine Case Reports 40 (2022) 101776Available online 8 November 20222213-0071/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/).Contents lists available at ScienceDirectRespiratory Medicine Case Reportsjournal homepage: www.elsevier.com/locate/rmcrCase ReportSuccessful pregnancy in a cystic fibrosis patient with a severeimpairment of lung function receiving Elexacaftor-Tezacaftor-IvacaftorZisis Balmpouzis a, b, *, Annabelle Faure van Rossum c, David Baud d, Alice Panchaud e, f,Georgia Mitropoulou a, b, Jesica Mazza Stalder a, 1, Angela Koutsokera a, b, 1a Adult Cystic Fibrosis and CFTR-related Disorders Center, Division of Pulmonology, Dept of Medicine, Lausanne University Hospital and University ofLausanne, Switzerlandb Lung Transplant Center, Division of Pulmonology, Dept of Medicine, Lausanne University Hospital and University of Lausanne, Switzerlandc Operative Gynecology and Obstetrics, Private Practice, Switzerlandd Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital, 1011, Lausanne, Switzerlande Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerlandf Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandA R T I C L E  I N F OKeywords:Cystic fibrosisImpaired lung functionPregnancyElexacaftor-Tezacaftor-IvacaftorA B S T R A C TBefore the arrival of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulatorswomen with CF and impaired lung function were experiencing a high risk of complications andmortality during and the years after pregnancy. The arrival of the highly efficient CFTR modula-tor, Elexacaftor-Tezacaftor-Ivacaftor (ETI) resulted in an improvement of lung function, qualityof life and fertility. Here we report a case of successful pregnancy and uncomplicated delivery fora CF patient with severely impaired lung function receiving ETI prior to conception.1. IntroductionIn individuals with cystic fibrosis (CF), mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene andsubsequent dysfunction of the CFTR protein lead to defective transport of chloride, bicarbonate ions and water across epithelial mem-branes. Although the respiratory and the digestive systems are affected the most, CFTR is also expressed in the reproductive systemwhere CFTR dysfunction is associated with male infertility and female subfertility [1].In women with CF, the reproductive system anatomy is preserved, however, CFTR is expressed in the cervix, the endometrium andthe fallopian tubes [1]. CFTR dysfunction results in thicker cervical mucus hampering sperm penetration and creates a pH-imbalanced environment in the uterus affecting sperm capacitation and fertilization [2]. Older maternal age and exocrine pancreaticinsufficiency are also risk factors for subfertility in women with CF [3]. Women with CF having a moderate-to-severe lung functionimpairment, defined as a forced expiratory volume in 1 s (FEV1) lower than 50% of the predicted value (pFEV1%), carry a higher riskof delivery by cesarean section and giving birth to infants with lower birth weight [4]. Ashcroft et al. [5] also found a positive correla-tion between lower FEV1 and the risk for preterm delivery and giving birth to infants with lower birth weight for the gestational age.The effect of pregnancy on maternal lung function remains controversial; recent studies did not find any difference in lung functiondecline and maternal survival following pregnancy [4,6], on the contrary an Italian study found a lung function (FEV1 and forced vi-* Corresponding author. Division of Pulmonology, Dept of Medicine, Lausanne University Hospital, Rue du Bugnon 46, 1011, Lausanne, Switzerland.E-mail address: zisis.balmpouzis@chuv.ch (Z. Balmpouzis).1 These authors contributed equally to this work.https://doi.org/10.1016/j.rmcr.2022.101776Received 11 September 2022; Accepted 6 November 2022Respiratory Medicine Case Reports 40 (2022) 1017762Z. Balmpouzis et al.tal capacity) and body mass index (BMI) decline the year following pregnancy [7]. Nevertheless the recently published expert recom-mendations for pregnancy in CF, suggest an optimization of lung function and ideally a pFEV1 higher than 60% before pregnancy [6].CFTR modulators are specifically designed to address the CFTR protein defect. Elexacaftor-Tezacaftor-Ivacaftor (ETI), a highly ef-fective CFTR modulator combination, is associated with an improvement in lung function and nutritional status, a decreased rate ofpulmonary exacerbations and improved quality of life [8]. In addition, CFTR modulators seem to also improve fertility in female CFpatients probably through modification of the consistency of cervical mucus and uterine fluids. Improved fertility and, consequently,unplanned pregnancies have been reported in women receiving CFTR modulator treatment [9]. Although animal data did not showany teratogenic or fetotoxic effects [10], and a series of 45 pregnancies of women receiving ETI seems reassuring [11], the currentlyavailable human safety data do not allow a reproductive risk assessment. Conversely, the little available evidence suggests effective-ness of the combined preparation for maternal health during pregnancy; 5 out of 6 mothers that stopped the CFTR modulators due tosafety concerns for the fetus experienced a respiratory deterioration [11].Here, we present a case of a successful pregnancy and vaginal delivery in a CF patient with severe lung function impairment(pFEV1 40%) treated with ETI. This is the first case of pregnancy while on ETI in Switzerland and the first detailed description of apregnancy in a patient receiving ETI with such low FEV1 levels.2. Case presentationThis is a 30-year old individual with CF having a Phe508del/Y1092X genotype, diffuse bronchiectasis colonized by Pseudomonasaeruginosa and exocrine pancreatic insufficiency. In 2017, following an infectious exacerbation, the patient experienced an importantpulmonary function decline (nadir FEV1 at 0.63 L, 23% of the predicted value) and had severe malnutrition (BMI 16 kg/m2). At thattime, the transthoracic echocardiogram (TTE) showed signs of pulmonary hypertension (dilated right ventricle and an estimated sys-tolic pulmonary artery pressure of 50 mmHg) and a patent foramen ovale. These results motivated a discussion for lung transplanta-tion, an option the patient declined. Over the following years, FEV1 remained stable at 0.8 L (30% of predicted), but the patient's con-dition was precarious especially during infectious exacerbations. On February 2019, she presented with her lowest recorded value ofFEV1 at 0.57L (21% of predicted), before receiving antibiotic treatment for an infectious exacerbation. In August 2020, ETI was initi-ated through the compassionate access program before its official approval in Switzerland on February 1, 2021. Following ETI initia-tion, the patient experienced a marked improvement of her general status and respiratory symptoms. The FEV1 increased up to 1.09L(40% of predicted) one month after starting ETI, nutritional status improved (BMI 18.2 kg/m2) and, since ETI start, the patient didnot present any exacerbations requiring systemic antibiotics.An unplanned pregnancy occurred in December 2021, around 4 months after ETI initiation, this being the first pregnancy for thispatient. After a detailed genetic workup of the couple and following an extensive discussion about the risks of maternal and fetal mor-bidity and mortality in this setting, the patient decided to continue with the pregnancy. Despite the current scarcity of reproductivesafety data, we pursued ETI considering the risk for maternal deterioration upon treatment cessation [11].Close obstetric follow up confirmed normal fetal anatomy, growth and development over the course of pregnancy. Before the 31stweek, the maternal pFEV1 remained between 35 and 40%, relatively stable compared to the values obtained immediately before thepregnancy (Fig. 1). Up to this time, the patient had not developed resting or nocturnal hypoxemia but the 6-min walking test showedexertional desaturation. In contrast to the TTE performed in summer 2017, the TTE carried out on the 13th and on the 31st week ofgestation did not show a patent foramen ovale nor signs of pulmonary hypertension. There was no argument for allergic bronchopul-monary aspergillosis (ABPA) at any time-point, the patient did not develop gestational diabetes and an iron deficiency with mild ane-mia was substituted intravenously (IV) at the 31st and the 32nd week of pregnancy.The course was uncomplicated until the 31st week when the patient presented symptoms of threatened preterm labour. She washospitalized at the obstetric ward and received atosiban, followed by nifedipine for tocolysis and betamethasone for fetal lung matu-ration with a favorable evolution. At the same time, she contracted a rhinovirus infection causing a productive cough and bronchialcongestion. A new oximetry showed nocturnal desaturation necessitating oxygen supplementation during sleep. The frequency of res-Fig. 1. Evolution of pulmonary function tests and weight over timeAbbreviations: ETI: elexacaftor, tezacaftor, ivacaftor; pFEV1%: forced expiratory volume in 1 s as percentage of the predicted value. The time-point zero refers to timeof ETI initiation (black vertical line). Time-points after ETI start are noted as positive months and time-points before ETI start as negative months. line indicatesthe estimated time of conception line indicates the time of delivery.Respiratory Medicine Case Reports 40 (2022) 1017763Z. Balmpouzis et al.piratory physiotherapy sessions was increased and inhaled formoterol/budesonide was also started. The patient refused concomitantantibiotic therapy and returned home after one week of hospital stay.On the 33rd week of gestation, she developed symptomatic polyhydramnios treated with amniocentesis and drainage of 2700 mlof amniotic fluid. After a surveillance period of 12 hours post drainage, the patient was able to return home.On the 36th week of pregnancy, she developed a spontaneous rupture of the membranes and gave birth to a healthy infant of 2.7kg through vaginal delivery. To date, 12 months after delivery, the infant growth and development are uncomplicated. After child-birth, the nocturnal hypoxemia of the mother corrected rapidly and oxygen therapy was stopped. Four months after delivery, theFEV1 increased to 1.07L, 40% of the predicted value, at a similar level as before pregnancy (Fig. 1). The patient has also regained herbaseline functional status.3. DiscussionOur case highlights the new challenges and opportunities clinicians and individuals with CF may face in the era of highly effectiveCFTR modulators regarding fertility and pregnancy. Considering that the majority of CF women receiving ETI are of childbearing age,family planning and contraception should be an integral part of the CF consultation before initiation of modulators and should be dis-cussed regularly thereafter. Clear communication in this regard is essential to decrease the risk of unplanned pregnancies and to allowinformed decision making for planned pregnancies. Furthermore, the improvements in quality of life, pulmonary function and thelower risk of exacerbations during treatment with highly effective CFTR modulators may allow childbearing to be (re)considered bymore CF women with decreased pulmonary function [12]. However, data about maternal mortality and morbidity as well as informa-tion about the short- and long-term safety of these treatments for the child remain scarce. Registries including fertility, fetal and ma-ternal outcomes will prove essential to improve our understanding and to optimize patient care in the new landscape of highly effec-tive CFTR modulators.4. ConclusionThe arrival of ETI has brought unprecedented changes to the CF care. The clear improvement of respiratory and nutritional statusand increased fertility have changed family planning and childbearing decisions for CF women receiving this treatment. Followingpregnant CF patients receiving ETI will be an increasingly frequent challenge that CF clinicians and obstetricians will face in the fol-lowing years.Statement of ethicsThe patient provided written informed consent for publication (available upon request).Funding sourcesNo funding was received for this case report.Author contributionZB collected the data and wrote the manuscript. AK and JMS revised the manuscript. All authors contributed in patient follow-up,critically revised the manuscript and approved the final version.Acknowledgementswe would like to thank Mrs Isabelle Huart RN and Caroline Dutoit RN, nurses of the Adult CF and CFTR-related disorders centerfor their implication in the care of this patient. We would like to thank the patient for allowing her data to be collected and reported inthis manuscript.References[1] E. Tizzano, M. Silver, D. Chitayat, J.-C. Benichou, M. Buchwald, Differential cellular expression of cystic fibrosis Transmembrane regulator in humanreproductive tissues, clues for the infertility in patients with cystic fibrosis, Am. J. Pathol. 144 (5) (1994) May.[2] A. Ahmad, A. Ahmed, P. Patrizio, Cystic fibrosis and fertility, Curr. Opin. Obstet. Gynecol. 25 (3) (2013) 167–172 https://doi.org/10.1097/GCO.0b013e32835f1745, Jun.[3] M. Shteinberg, A.B. Lulu, D.G. Downey, Z. Blumenfeld, et al., Failure to conceive in women with CF is associated with pancreatic insufficiency and advancingage, J. Cyst. Fibros. 18 (4) (2019) 525–529 https://doi.org/10.1016/j.jcf.2018.10.009, Jul.[4] Q. Reynaud, C. Rousset Jablonski, S. Poupon-Bourdy, et al., Pregnancy outcome in women with cystic fibrosis and poor pulmonary function, J. Cyst. Fibros. (1)(2020) 80–83 https://doi.org/10.1016/j.jcf.2019.06.003, Jan 19.[5] A. Ashcroft, S.J. Chapman, L. Mackillop, The outcome of pregnancy in women with cystic fibrosis: a UK population-based descriptive study, BJOG 127 (13)(2020) 1696–1703 https://doi.org/10.1111/1471-0528.16423, Dec.[6] R. Jain, T.M. Kazmerski, L.C. Zuckerwise, et al., Pregnancy in cystic fibrosis: review of the literature and expert recommendations, J.Cyst.Fibrosis. 21 (3)(2022) 387–395 https://doi.org/10.1016/j.jcf.2021.07.019, May.[7] B. Giordani, S. Quattrucci, A. Amato, M. Salvatore, R. Padoan, A case-control study on pregnancy in Italian Cystic Fibrosis women. Data from the ItalianRegistry, Respir. Med. 145 (2018) 200–205 https://doi.org/10.1016/j.rmed.2018.11.009, Dec.[8] P.G. Middleton, M.A. Mall, P. Drevinek, L.C. Lands, E.F. McKone, D. Polineni, et al., Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508delAllele, NEJM 381 (19) (2019) 1809–1819 https://doi.org/10.1056/NEJMoa1908639, Nov 7.[9] J.L. Taylor-Cousar, CFTR modulators: impact on fertility, pregnancy, and lactation in women with cystic fibrosis, J. Clin. Med. 9 (9) (2020) 2706 https://Respiratory Medicine Case Reports 40 (2022) 1017764Z. Balmpouzis et al.doi.org/10.3390/jcm9092706, Sep.[10] FDA. Highlights of Prescribing Information for TRIKAFTA™ (Elexacaftor, Tezacaftor and Ivacaftor Tablets; Ivacaftor Tablets), Co-packaged for Oral Use.[11] J.L. Taylor-Cousar, R. Jain, Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation, J.Cyst.Fibrosis. 20 (3)(2021) 402–406 https://doi.org/10.1016/j.jcf.2021.03.006, May.[12] T.M. Kazmerski, T. Gmelin, B. Slocum, S. Borrero, E. Miller, Attitudes and decision making related to pregnancy among young women with cystic fibrosis,Matern. Child Health J. 21 (4) (2017) 818–824 https://doi.org/10.1007/s10995-016-2181-z, Apr.

Successful pregnancy in a cystic fibrosis patient with a severe impairment of lung function receiving Elexacaftor-Tezacaftor-Ivacaftor [case report].

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Successful pregnancy in a cystic fibrosis patient with a severe impairment of lung function receiving Elexacaftor-Tezacaftor-Ivacaftor [case report].

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