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Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy

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Abstract

Introduction

Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women.

Methods

We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic.

Results

The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy.

Conclusions

Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article.

References

  1. Shteinberg M, Haq IJ, Polineni D, Davies JC (2021) Cystic fibrosis. Lancet 397:2195–2211

    Article  CAS  PubMed  Google Scholar 

  2. https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2019-Patient-Registry-Annual-Data-Report.pdf (Accessed on 24 Oct 2021)

  3. Riordan JR, Rommens JM, Kerem B et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245(4922):1066–1073. https://doi.org/10.1126/science.2475911. (Erratum.In:Science1989;245:1437)

    Article  CAS  PubMed  Google Scholar 

  4. Sueblinvong V, Whittaker LA (2007) Fertility and pregnancy: common concerns of the aging cystic fibrosis population. Clin Chest Med 28:433–443

    Article  PubMed  Google Scholar 

  5. Gilljam M, Antoniou M, Shin J, Dupuis A, Corey M, Tullis DE (2000) Pregnancy in cystic fibrosis. Fetal and maternal outcome. Chest 118:85–91

    Article  CAS  PubMed  Google Scholar 

  6. Barak A, Dulitzki M, Efrati O, Augarten A, Szeinberg A, Reichert N, Modan D, Weiss B, Miller M, Katzanelson D, Yahav Y (2005) Pregnancies and outcome in women with cystic fibrosis. Isr Med Assoc J 7(2):95–98 (PMID: 15729959)

    PubMed  Google Scholar 

  7. Tan EK, Tan EL (2013) Alterations in physiology and anatomy during pregnancy. Best Pract Res Clin Obstet Gynaecol 27(6):791–802. https://doi.org/10.1016/j.bpobgyn.2013.08.001. (Epub 2013 Sep 4 PMID: 24012425)

    Article  PubMed  Google Scholar 

  8. Davis PB (2011) Therapy for cystic fibrosis–the end of the beginning? N Engl J Med 365:1734–1735

    Article  CAS  PubMed  Google Scholar 

  9. Hoy SM (2019) Elexacaftor/Ivacaftor/tezacaftor: first approval. Drugs 79:2001–2007

    Article  PubMed  Google Scholar 

  10. Zaher A, ElSaygh J, Elsori D, ElSaygh H, Sanni A (2021) A review of trikafta: triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Cureus 13:e16144

    PubMed  PubMed Central  Google Scholar 

  11. Veit G, Roldan A, Hancock MA et al (2020) Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination. JCI Insight 5:e139983

    Article  PubMed  PubMed Central  Google Scholar 

  12. Krasnowska EK, Pittaluga E, Brunati AM, Brunelli R, Costa G, De Spirito M, Serafino A, Ursini F, Parasassi T (2008) N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src. Free Radic Biol Med 45(11):1566–1572. https://doi.org/10.1016/j.freeradbiomed.2008.09.012. (Epub 2008 Sep 23 PMID: 18845245)

    Article  CAS  PubMed  Google Scholar 

  13. Middleton PG, Mall MA, Dřevínek P et al (2019) Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 381:1809–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Heijerman HGM, McKone EF, Downey DG et al (2019) Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet 394:1940–1948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Trimble AT, Donaldson SH (2018) Ivacaftor withdrawal syndrome in cystic fibrosis patients with the G551D mutation. J Cyst Fibros 17(2):e13–e16. https://doi.org/10.1016/j.jcf.2017.09.006. (Epub 2017 Oct 24 PMID: 29079142)

    Article  CAS  PubMed  Google Scholar 

  16. Vertex Pharmaceuticals Incorporated. Ivacaftor (Kalydeco) United States Prescribing Information. Available online: https://pi.vrtx.com/files/uspi_ivacaftor.pdf (accessed on 18 July 2020)

  17. Taylor-Cousar JL (2020) CFTR modulators: impact on fertility, pregnancy, and lactation in women with cystic fibrosis. J Clin Med 9:2706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Jain R, Kazmerski TM, Zuckerwise LC, et al (2021) Pregnancy in cystic fibrosis: Review of the literature and expert recommendations [published online ahead of print, 2021 Aug 26]. J Cyst Fibros. https://doi.org/10.1016/j.jcf.2021.07.019

  19. Vekaria S, Popowicz N, White SW, Mulrennan S (2020) To be or not to be on CFTR modulators during pregnancy: risks to be considered. J Cyst Fibros 19(2):e7–e8. https://doi.org/10.1016/j.jcf.2019.12.004

    Article  PubMed  Google Scholar 

  20. Trimble A, McKinzie C, Terrell M, Stringer E, Esther CR Jr (2018) Measured fetal and neonatal exposure to Lumacaftor and Ivacaftor during pregnancy and while breastfeeding. J Cyst Fibros 17(6):779–782. https://doi.org/10.1016/j.jcf.2018.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Riccio M, Carnevale G, Cardinale V, Gibellini L, De Biasi S, Pisciotta A et al (2014) The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells. J Hepatol 61(5):1097–1105. https://doi.org/10.1016/j.jhep.2014.06.016. (Epub 2014 Jun 19 PMID: 24953023)

    Article  CAS  PubMed  Google Scholar 

  22. Mainz JG, Michl RK, Beiersdorf N, et al. Successful Pregnancy of a Patient with Cystic Fibrosis Genotype F508del/ F508del and Progressed Pulmonary Destruction on lumacaftor/ivacaftor. Schwangerschaft einer F508del homozygoten CF-Patientin mit fortgeschrittener Lungendestruktion unter Therapie mit lumacaftor/ivacaftor. Klin Padiatr. 2019;231(5):271–273. doi:https://doi.org/10.1055/a-0973-8565

  23. Ladores S, Kazmerski TM, Rowe SM (2017) A case report of pregnancy during use of targeted therapeutics for cystic fibrosis. J Obstet Gynecol Neonatal Nurs 46(1):72–77. https://doi.org/10.1016/j.jogn.2016.08.011

    Article  PubMed  Google Scholar 

  24. Kaminski R, Nazareth D (2016) A successful uncomplicated CF pregnancy while remaining on Ivacaftor. J Cyst Fibros 15(1):133–134. https://doi.org/10.1016/j.jcf.2015.11.013

    Article  PubMed  Google Scholar 

  25. Nash EF, Middleton PG, Taylor-Cousar JL (2020) Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators—an international survey. J Cyst Fibros 19(4):521–526. https://doi.org/10.1016/j.jcf.2020.02.018

    Article  PubMed  Google Scholar 

  26. Taylor-Cousar JL, Jain R (2021) Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros 20(3):402–406. https://doi.org/10.1016/j.jcf.2021.03.006

    Article  CAS  PubMed  Google Scholar 

  27. Kendle AM, Roekner JT, Santillana EC, Kis LE, Cain MA (2021) Cystic fibrosis transmembrane conductance regulator modulators during pregnancy: a case series. Cureus 13(8):e17427. https://doi.org/10.7759/cureus.17427

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jain R, Taylor-Cousar JL (2021) Fertility, pregnancy and lactation considerations for women with CF in the CFTR modulator era. J Pers Med 11(5):418. https://doi.org/10.3390/jpm11050418

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jain R, Wolf A, Molad M, Taylor-Cousar J, Jr CRE, Shteinberg M (2022) Congenital bilateral cataracts in newborns exposed to elexacaftor-tezacaftor-ivacaftor in utero and while breast feeding. J Cyst Fibros 17:S1569-1993(22)01386-8

  30. Collins B, Fortner C, Cotey A, Esther CRJ, Trimble A (2022) Drug exposure to infants born to mothers taking elexacaftor, tezacaftor, and Ivacaftor. J Cyst Fibros 21(4):725–727

    Article  CAS  PubMed  Google Scholar 

  31. Murad MH, Asi N, Alsawas M, Alahdab F (2016) New evidence pyramid. Evid Based Med 21:125–127

    Article  PubMed  PubMed Central  Google Scholar 

  32. Heltshe SL, Godfrey EM, Josephy T, Aitken ML, Taylor-Cousar JL (2017) Pregnancy among cystic fibrosis women in the era of CFTR modulators. J Cyst Fibros 16:687–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jain R, Magaret A, Vu PT et al (2022) Prospectively evaluating maternal and fetal outcomes in the era of CFTR modulators: the MAYFLOWERS observational clinical trial study design. BMJ Open Respir Res 9(1):e001289

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Giuseppe Cimino*,1-2 Fiorentina Ascenzioni,3 Bruno Botta,4 Luca Cavinato,3 Andrea Cerrato,4 Gabriele Cianfoni,3 Valentina D’Ambrosio,2 Francesca De Luca,2 Paola Delporto,3 Maria Di Chiara,2 Paola Galoppi,2 Francesco Gasparrini,3 Francesca Ghirga,4 Antonella Giancotti,2 Aldo Laganà,4 Giulia Mazzoccanti,3 Alessandro Mondo,2 Carmela Maria Montone,4 Manuel Murciano,2,5 Francesco Pecorini,2 Maria Grazia Piccioni,2 Damiana Pompeo,2 Sara Sorrenti,2 Lorenzo Spiniello,2 Gianluca Terrin,2 Patrizia Troiani,1-2 Fabrizio Zullo,2 Roberto Brunelli**.2. *First author; **last author. 1. Cystic Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy. 2. Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Italy. 3. Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Italy. 4. Department of Chemistry and Technology of Drugs, “Department of Excellence 2018-2022”, Sapienza University of Rome, Italy. 5. Emergency and General Pediatrics Department, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy.

Funding

No funding source was obtained for this work.

Author information

Authors and Affiliations

  1. Cystic Fibrosis Regional Reference Center, A.O.U. Policlinico Umberto I, Rome, Italy

    Giuseppe Cimino

  2. Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Via del Policlinico, 155, 00161, Rome, Italy

    Giuseppe Cimino, Sara Sorrenti, Manuel Murciano, Paola Galoppi & Roberto Brunelli

  3. Emergency and General Pediatrics Department, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Manuel Murciano

  4. Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Rome, Italy

    Fiorentina Ascenzioni

  5. Department of Chemistry and Technology of Drugs, “Department of Excellence 2018–2022”, Sapienza University of Rome, Rome, Italy

    Bruno Botta

Authors
  1. Giuseppe Cimino
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  2. Sara Sorrenti
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  4. Paola Galoppi
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  5. Fiorentina Ascenzioni
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  6. Bruno Botta
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  7. Roberto Brunelli
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Consortia

On Behalf of the Sapienza University Working Group on Cystic Fibrosis in Pregnancy

  • Giuseppe Cimino
  • , Paola Galoppi
  • , Fiorentina Ascenzioni
  • , Luca Cavinato
  • , Andrea Cerrato
  • , Gabriele Cianfoni
  • , Valentina D’Ambrosio
  • , Francesca De Luca
  • , Paola Delporto
  • , Maria Di Chiara
  • , Paola Galoppi
  • , Francesco Gasparrini
  • , Francesca Ghirga
  • , Antonella Giancotti
  • , Aldo Laganà
  • , Giulia Mazzoccanti
  • , Alessandro Mondo
  • , Carmela Maria Montone
  • , Manuel Murciano
  • , Francesco Pecorini
  • , Maria Grazia Piccioni
  • , Damiana Pompeo
  • , Sara Sorrenti
  • , Lorenzo Spiniello
  • , Gianluca Terrin
  • , Patrizia Troiani
  • , Fabrizio Zullo
  •  & Bruno Botta

Contributions

CG: protocol/project development; data collection or management; manuscript editing. SS: data collection or management; data analysis; manuscript writing/editing. MM: data collection or management; data analysis; manuscript writing/editing. AF: protocol/project development; data collection or management; manuscript editing. BB: protocol/project development; data collection or management; manuscript editing. BR: protocol/project development; data collection or management; manuscript editing.

Corresponding author

Correspondence to Sara Sorrenti.

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The members of The Sapienza University Working Group on Cystic Fibrosis in Pregnancy are mentioned in Acknowledgements.

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Cimino, G., Sorrenti, S., Murciano, M. et al. Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy. Arch Gynecol Obstet 309, 9–15 (2024). https://doi.org/10.1007/s00404-023-06962-5

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  • DOI: https://doi.org/10.1007/s00404-023-06962-5

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