Impact of anti-TNFα exposure in utero on the development of immune systems of exposed children – a controlled, multicentre observational study

Czech version

Authors: Ďuricová D. ¹; Dvořáková E. ¹; Hradský O. ²; Mitrová K. ^1,2; Durilová M. ³; Koželuhová J. ⁴; Kohout P. ⁵; Zárubová K. ²; Bronský J. ²; Hradská N. ⁶; Bronská E. ⁷; Adamcová M. ⁷; Machková N. ¹; Hrubá V. ¹; Bortlík M. ^1,8,9; Lukáš M. ¹; Malíčková K. ^1,10
Authors‘ workplace: Klinické a výzkumné centrum pro střevní záněty ISCARE I. V. F., a. s., Praha ¹; Pediatrická klinika 2. LF UK a FN Motol, Praha ²; Klinika dětské chirurgie 2. LF UK a FN Motol, Praha ³; Gastroenterologické a hepatologické oddělení, I. interní klinika LF UK a FN v Plzni ⁴; Interní klinika 3. LF UK a Thomayerovy nemocnice, Praha6 Privátní ordinace PLDD, Litovel ⁵; Privátní ordinace PLDD, Praha ⁷; Interní klinika 1. LF UK a ÚVN, Praha ⁸; Farmakologický ústav 1. LF UK a VFN, Praha ⁹; Ústav lékařské biochemie a laboratorní diagnostiky, 1. LF UK a VFN, Praha ¹⁰
Published in: Gastroent Hepatol 2018; 72(6): 479-485
Category:
doi: https://doi.org/10.14735/amgh2018479

Overview

Background:

Data on safety of in utero exposure to anti-tumor necrosis factor (TNF) α on long-term childhood development are sparse. Our aim was to assess the impact of in utero exposure to anti-TNFα on the postnatal development of immune systems of exposed children.

Methods:

Children (≥ 12 months of age) born to mothers with inflammatory bowel disease (IBD) (2007–2016) treated with anti-TNFα during pregnancy in three centres were included. Unexposed children of non-IBD mothers who came for mandatory check-up to the general pediatrician served as a control group. A predefined questionnaire was distributed by the pediatricians to collect data on the perinatal period, infectious complications, antibiotic use, and vaccination.

Results:

We included 72 exposed and 69 unexposed children (median age 35 months and 50 months, respectively). No significant difference in infectious complications ≤ 1^st year of life (23.9 vs. 17.4%, p = 0.36) or during the whole follow-up (p = 0.32) was found between exposed infants and controls. Concomitant immunosuppressive therapy during pregnancy and anti-TNFα levels in cord blood did not increase the infection rate ≤ 1st year of life (p > 0.05). Protective titers of antibodies to vaccination were found in > 95% of exposed children except for H. influenzae and mumps vaccines. However, these two vaccines had the lowest serologic response in the control group, too.

Conclusions:

Treatment with anti-TNFα during pregnancy seemed to be safe with regard to postnatal development of the immune systems of exposed children.

Key words: inflammatory bowel disease – anti-TNFα – gravidity – infections – vaccination

Submitted: 22. 11. 2018

Accepted: 28. 11. 2018

Sources

1. Burisch J, Munkholm P. The epidemiology of inflammatory bowel disease. Scand J Gastroenterol 2015; 50(8): 942– 951. doi: 10.3109/ 00365521.2015.1014407.

2. van der Woude CJ, Ardizzone S, Bengtson MBet 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.

3. Julsgaard M, Christensen LA, Gibson PR et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterol 2016; 151(1): 110– 119. doi: 10.1053/ j.gastro.2016.04.002.

4. Bortlik M, Duricova D, Machkova N et al. Impact of anti-tumor necrosis factor alpha antibodies administered to pregnant women with inflammatory bowel disease on long-term outcome of exposed children. Inflamm Bowel Dis 2014; 20(3): 495– 501. doi: 10.1097/ 01.MIB.0000440984.86659.4f.

5. de Lima A, Zelinkova Z, van der Ent C et al. Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety. Gut 2016; 65(8): 1261– 1268. doi: 10.1136/ gutjnl-2015-309321.

6. Chaparro M, Verreth A, Lobaton T et al. Long-term safety of in utero exposure to anti-tnfα drugs for the treatment of inflammatory bowel disease: results from the multicenter European TEDDY Study. Am J Gastroenterol 2018; 113(3): 396– 403. doi: 10.1038/ ajg.2017.501.

7. Mahadevan U, Martin CF, Sandler RS et al. PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic thera-py (Abstract 865). Gastroenterol 2012; 142 (5 Suppl 1): S149.

8. Kanis SL, de Lima-Karagiannis, van der Ent C et al. Anti-TNF levels in cord blood at birth are associated with anti-TNF type. J Crohns Colitis 2018; 12(8): 939– 947. doi: 10.1093/ ecco-jcc/ jjy058.

9. Mahadevan U, Martin CF, Kane SV et al. Do infant serum levels of biologic agents at birth correlate with risk of adverse outcomes? Results from the PIANO Registry. Gastroenterol 2016; 150 (4 Suppl 1): S91– S92.

10. Zinke M, Disselhoff J, Gartner B et al. Immunological persistence in 4– 6 and 7– 9 year olds previously vaccinated in infancy with hexavalent DTPa-HBV-IPV/ Hib. Hum Vaccin 2010; 6(2): 189– 193.

11. Beaulieu DB, Ananthakrishnan AN, Martin C et al. Use of biologic therapy by pregnant women with inflammatory bowel disease does not affect infant response to vaccines. Clin Gastroenterol Hepatol 2018; 16(1): 99– 105. doi: 10.1016/ j.cgh.2017.08.041.