Safety of vedolizumab and ustekinumab in the treatment of pregnant women with inflammatory bowel disease – a multicentre retrospective-prospective observational study
Barbora Pipek1, Dana Ďuricová2, Martin Bortlík3, Jan Březina4, Tomáš Douda Orcid.org 5, Tomáš Drašar6, Pavel Drastich7, Přemysl Falt Orcid.org 8,9, Pavel Kohout Orcid.org 10, Václav Leksa11, Aleš Novotný Orcid.org 12, Jan Ulbrych13, Milan Lukáš2, Luděk Bouchner14, Pavel Klvaňa15, Jan Škorpík16, Marek Veinfurt17, Blanka Zbořilová17, Katarína Mitrová18
1 Centrum péče o zažívací trakt, Vítkovická nemocnice a. s., Ostrava
2 Klinické a výzkumné centrum pro střevní záněty, Klinické centrum ISCARE a. s. a 1. LF UK v Praze
3 Gastroenterologické oddělení, Nemocnice České Budějovice, a. s.
4 Klinika hepatogastroenterologie, Transplantcentrum, IKEM, Praha
5 II. interní gastroenterologická klinika LF UK a FN Hradec Králové
6 IBD Centrum Turnov, Krajská nemocnice Liberec, a.s.
7 Klinika hepatogastroenterologie, IKEM, Praha
8 II. interní klinika – gastroenterologická a geriatrická, LF UP a FN Olomouc
9 Katedra interních oborů, LF UK v Hradci Králové
10 Interní klinika 3. LF UK a Thomayerovy nemocnice, Praha
11 Interní oddělení, Pardubická nemocnice, Nemocnice Pardubického kraje, a. s.
12 IV. interní klinika – klinika gastroenterologie a hepatologie 1. LF UK a VFN v Praze
13 II. interní klinika LF MU a FN u sv. Anny v Brně
14 Interní oddělení, FN Plzeň
15 Beskydské Gastrocentrum, Interní oddělení, Nemocnice ve Frýdku-Místku, p.o.
16 Oddělení gastroenterologie, Nemocnice Jihlava, příspěvková organizace
17 Gastroenterologické oddělení, Karlovarská krajská nemocnice a.s.
18 Klinické a výzkumné centrum pro idiopatické střevní záněty ISCARE a.s. a 1. LF UK Praha
Background: Inflammatory bowel disease (IBD) is mostly diagnosed in young women of fertile age, and a significant number of patients become pregnant while they have the disease. The remission of the illness, which is often achieved by intensive anti inflammatory treatment, has been found to be the most important factor of a successful pregnancy. Vedolizumab (VDZ) and ustekinumab (UST) are newer types of monoclonal antibodies with different mechanisms of effect when compared to anti-TNF treatment. VDZ is a monoclonal antibody against the α4ß7 integrin receptor, and UST against interleukin 12/23; both have expanded the spectrum of the biological treatment of IBD in recent years. Aims: To present the results of a multicentre observational study. The primary aim was to assess the safety of vedolizumab and ustekinumab for pregnancy, foetal development and the neonatal outcome. The secondary aim was to measure the drug concentration in maternal and cord blood at the time of delivery. Methods: It was a multicentre, retrospective-prospective observational study. Data on patients’ demographics, clinical characteristics and pregnancy were collected by the treating physician using a predefined questionnaire, data on newborn outcome were obtained from medical documentation. The ELISA method was used to measure the VDZ and UST concentrations. Results: The study took place in 15 IBD clinical centres in the Czech Republic. 79 women with 85 completed pregnancies were included in the study, and they were exposed to VDZ or UST during pregnancy. 36 women were treated with vedolizumab (median age 32 years) and 49 with ustekinumab (median age 30.5 years). In the group with VDZ, live births occurred with 32 women (88.9%), and there were two early spontaneous abortions up to the eighth week of gestation in addition to two instrumentally aborted pregnancies (4, 11.1%). 31 children (93.9%) in the group with VDZ were born at term with a median birth weight of 3,097.5 grams. In the ustekinumab group, 39 women (79.6%) had live births, there were nine early abortions and one instrumentally aborted pregnancy (10, 20.4%). 38 (97.4%) children were born at term with a median birth weight of 3,265 grams. The drug levels of VDZ and UST at birth were measured in 44 neonate-mother pairs (21 VDZ, 23 UST). The median level of VDZ in maternal venous blood was 7.2 mg/l, and in cord blood it was 4.7 mg/l (infant / maternal ratio 0.66). With UST, the median maternal level was 4.7 mg/l, and in neonates it was 7.9 mg/l (infant / maternal ratio 1.65). Conclusion: The results found in a group of women that were being treated for IBD and were exposed to at least one dose of biologic treatment with UST or VDZ during pregnancy are consistent with previously published evidence showing no adverse events, and they confirm the safety profile of new biologics in pregnancy. Due to the still limited number of enrolled patients, further studies are needed on the outcomes of pregnancies with new biologics drugs.
Keywordsvedolizumab, ustekinumab, pregnancy, transplacentární přenos
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1. van der Woude CJ, Ardizzone S, Bengtson MB et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis 2015; 9(2): 107–124. doi: 10.1093/ecco-jcc/jju006.
2. Lukáš M. Idiopatické střevní záněty: nové trendy a mezioborové souvislosti. Praha: Grada Publishing 2020.
3. Bortlik M, Machkova N, Duricova D et al. Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-α therapy during pregnancy: three-center study. Scand J Gastroenterol 2013; 48(8): 951–958. doi: 10.3109/00365521.2013.812141.
4. Sandborn WJ, Gasink C, Gao LL et al. Ustekinumab induction and maintenance therapy in refractory Crohn‘s disease. N Engl J Med 2012; 367(16): 1519–1528. doi: 10.1056/NEJMoa1203572.
5. Sandborn WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn‘s disease. N Engl J Med 2013; 369(8): 711–721. doi: 10.1056/NEJMoa1215739.
6. Feagan BG, Rutgeerts P, Sands BE et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369(8): 699–710. doi: 10.1056/NEJMoa1215734.
7. Mitrova K, Pipek B, Bortlik M et al. Differences in the placental pharmacokinetics of vedolizumab and ustekinumab during pregnancy in women with inflammatory bowel disease: a prospective multicentre study. Therap Adv Gastroenterol 2021; 14: 17562848211032790. doi: 10.1177/17562848211032790.
8. Wils P, Seksik P, Stefanescu C et al. Safety of ustekinumab or vedolizumab in pregnant inflammatory bowel disease patients: a multicentre cohort study. Aliment Pharmacol Ther 2021; 53(4): 460–470. doi: 10.1111/apt.16192.
9. Terjung B, Schmelz R, Ehehalt R et al. Safety of vedolizumab in the treatment of pregnant women with inflammatory bowel disease: a targeted literature review. Therap Adv Gastroenterol 2020; 13: 1756284820952592. doi: 10.1177/1756284820952592.
10. Moens A, van Hoeve K, Humblet E et al. Outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab. J Crohns Colitis 2019; 13(1): 12–18. doi: 10.1093/ecco-jcc/jjy142.
11. Mahadevan U, Vermeire S, Lasch K et al. Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease. Aliment Pharmacol Ther 2017; 45(7): 941–950. doi: 10.1111/apt.13960.
12. Rowan CR, Cullen G, Mulcahy HE et al. Ustekinumab drug levels in maternal and cord blood in a woman with Crohn‘s disease treated until 33 weeks of gestation. J Crohns Colitis 2018; 12(3): 376–378. doi: 10.1093/ecco-jcc/jjx141.
13. Lund T, Thomsen SF. Use of TNF-inhibitors and ustekinumab for psoriasis during pregnancy: a patient series. Dermatol Ther 2017; 30(3). doi: 10.1111/dth.12454.
14. de Lima A, Zelinkova Z, Mulders AG et al. Preconception care reduces relapse of inflammatory bowel disease during pregnancy. Clin Gastroenterol Hepatol 2016; 14: 1285–1292. doi: 10.1016/j.cgh.2016.03.018.
15. Pham-Huy A, Sadarangani M, Huang V et al. From mother to baby: antenatal exposure to monoclonal antibody biologics. Expert Rev Clin Immunol 2019; 15(3): 221–229. doi: 10.1080/1744666X.2019.1561282.
16. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. Am J Gastroenterol 2009; 104(1): 228–233. doi: 10.1038/ajg.2008.71.
17. Restellini S, Biedermann L, Hruz P et al. Update on the management of inflammatory bowel disease during pregnancy and brestfeeding. Digestion 2020; 101(Suppl 1): 1–6. doi: 10.1159/000502886.
18. Klenske E, Osaba L, Nagore D et al. Drug levels in the maternal serum, cord blood and breast milk of a ustekinumab-treated patient with Crohn’s disease. J Crohns Colitis 2019; 13(2): 267–269. doi: 10.1093/ecco-jcc/jjy153.
19. Rowan CR, Cullen G, Mulcahy HE et al. Ustekinumab drug levels in maternal and cord blood in a woman with Crohn’s disease treated until 33 weeks of gestation. J Crohns Colitis 2018; 12(3): 376–378. doi: 10.1093/ecco-jcc/jjx141.
20. Mahadevan U, Long MD, Kane SV et al. Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology 2021; 160(4): 1131–1139. doi: 10.1053/j.gastro.2020.11.038.
21. Julsgaard M, Christensen LA, Gibson PR et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology 2016; 151(1): 110–119. doi: 10.1053/j.gastro.2016.04.002.
22. Bortlik M, Machkova N, Duricova D et al. Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti- TNF-α therapy during pregnancy: three-center study. Scand J Gastroenterol 2013; 48(8): 951–958. doi: 10.3109/00365521.2013.812141.
23. Mahadevan U, Wolf DC, Dubinsky M et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013; 11(3): 286–292. doi: 10.1016/j.cgh.2012.11.011.
24. Moens A, van der Woude CJ, Julsgaard M et al. Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNC or conventional therapy: results of the European CONCEIVE study. Aliment Pharmacol Ther 2020; 51(1): 129–138. doi: 10.1111/apt.15539.
25. Bar-Gil Shitrit A, Ben Ya’acov A, Meir Livovsky D et al. Exposure to vedolizumab in IBD pregnant women appears of low risk for mother and neonate: a first prospective comparison study. Am J Gastroenterol 2019; 114(7): 1172–1175. doi: 10.14309/ajg.0000000000000186.
26. Geldhof A, Volger S, Lin CB et al. Pregnancy outcomes in women with psoriasis, psoriatic artritis, Crohn‘s disease and ulcerative colitis treated with ustekinumab. J Crohns Colitis 2020; 14(Suppl 1): S460. doi: 10.1093/ecco-jcc/jjz203.666.
27. Mahadevan U, Long MD, Kane SV et al. Pregnancy and neonatal outcomes after fetal exposure to biologics ant thiopurines among women withinflammatory bowel disease. Gastroenterology 2021; 160(4): 1131–1139. doi: 10.1053/ j.gastro.2020.11.038.
28. Flanagan E, Gipson PR, Wrick EK et al. Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure. Aliment Pharmacol Ther 2020; 52(10): 1551–1562. doi: 10.1111/apt.16102.
29. Julsgaard M, Baumgart D, Jorgensen SMD et al. Vedolizumab levels in mothers and newborns, clearance on neonates, susceptibility to infection, and achievement of developmental milestones. United European Gastroenterol J 2020; 8: 16.