In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Bélizna, C.; Meroni, Pier Luigi; Shoenfeld, Yehuda; Devreese, Katrien; Alijotas‐Reig, Jaume; Esteve-Valverde, Enrique; Chighizola, Cecilia Beatrice; Pregnolato, Francesca; Cohen, Hannah; Fassot, Céline; Mattera, Patrick Martin; Peretti, Pascale; Levy, Alexandre; Bernard, Laurence; Saïet, Mathilde; Lagarce, Laurence; Briet, Marie; Rivière, Marianne; Pellier, Isabelle; Gascoin, Géraldine; Rakotonjanahary, Jose; Borghi, María Orietta; Stojanovich, Ljudmila; Djoković, Aleksandra; Stanisavljević, Nataša; Bromley, Rebecca; Elefant-Amoura, Elisabeth; Buisson, Nadia Bahi; Sala, Taylor Pindi; Kelchtermans, Hilde; Makatsariya, Alexander; Bidsatze, Viktoria; Khizroeva, J. Kh.; Latino, José Omar; Udry, Sebastián; Henrion, Didier; Loufrani, Laurent; Guihot, Anne‐Laure; Muchardt, Christian; Hasan, Milena; Ungeheuer, Marie Noëlle; Voswinkel, Jan; Damian, Laura; Pabinger, Ingrid; Gebhart, Johanna; Pedrera, Rosario Lopez; Tervaert, Jan Willem Cohen; Tincani, Anǵela; Andréoli, Laura

doi:10.1016/j.autrev.2020.102525

Cited by 26 publications

(15 citation statements)

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“…In order to explain this possible increased frequency of NPD in these children, different possible risk factors have been implicated, such as auto-antibodies and drugs assumed during pregnancy and Azathioprine (AZA). A recent literature review regarding therapy with AZA during pregnancy concluded that it does not seem to increase the risk of congenital abnormalities in the offspring, but more long-term studies are needed to analyze the association with NPD in children exposed in utero, while considering all the potential confounding factors including maternal disease and familiar, social and economic context (Belizna et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the potential role of drugs commonly prescribed in SLE pregnancies, special attention was raised on Azathioprine (AZA) and its metabolites (Belizna et al, 2020). AZA is an immunosuppressive drug widely used in SLE patients, especially to maintain remission, and is considered safe during pregnancy as supported by international guidelines (Skorpen et al, 2016;Andreoli et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Neuropsychiatric Outcome of Children Born to Women With Systemic Lupus Erythematosus and Exposed in Utero to Azathioprine: A Case-Control Study

et al. 2020

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Objective: The long-term outcome of children born to SLE mothers still represents a controversial topic in literature, with some studies reporting a possible increased prevalence of different neurologic and psychiatric diseases (NPD), including neurodevelopmental disorders (ND), and in particular learning disorders (LD). Different risk factors have been advocated, such as the in utero exposure to auto-antibodies and drugs, particularly Azathioprine (AZA).Methods: A case-control study was designed to compare pregnancies treated with AZA (cases) with those not treated with AZA (controls). All the pregnancies had been prospectively followed in two Italian centers. The match was based upon renal involvement, antiphospholipid (aPL) status, maternal age at pregnancy (±5 years) and child’s age at the time of the study (±2 years). SLE mothers were interviewed by a telephone survey, particularly focused on the presence of a certified NPD in their children ≥6 years of age.Results: Twenty-seven cases and 65 controls were similar in terms of demographic, immunological and clinical features, except for a higher rate of SLE flares during pregnancy in cases (22.2% vs. 10.8%, p:0.191). The 92 children had a mean age of 14.0 years at the time of the survey; 11 had at least one NPD (12.0%). The frequency of each single NPD was similar to that of the general pediatric population and no association was found with either the in utero exposure to AZA, or other specific factors (auto-antibodies, disease activity, obstetric complications, prematurity).Conclusion: The long-term neuropsychiatric outcome of the children born to SLE mothers did not show neither an increased frequency of NPD as compared to the general pediatric population nor a specific pattern of NPD. The in utero exposure to AZA was not associated with the development of NPD in this case-control study of prospectively-followed pregnancies. NPD are complex conditions and large prospective studies are needed to capture the wide range of variables that may contribute to their development in the offspring of SLE women.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric Outcome of Children Born to Women With Systemic Lupus Erythematosus and Exposed in Utero to Azathioprine: A Case-Control Study

et al. 2020

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“…The majority of the reproductive research on medication safety on thiopurines in women with different autoimmune diseases focuses on adverse pregnancy and birth outcomes, 12,16‐20,22,23,25,38 and in general, there is a lack of data in examining the long‐term consequences after in utero drug exposure. Furthermore, most of the studies on the maternal safety of thiopurines during conception and pregnancy concern IBD, Systemic Lupus Erythematosus (SLE) and renal transplantation recipients 26‐28,39,40 . This study thus adds important evidence to this area, and it is the first and most comprehensive study on the risk of long‐term chronic diseases and congenital malformations with almost 9 years of follow‐up in the children exposed in utero to thiopurines.…”

Section: Discussionmentioning

confidence: 92%

The risk of chronic diseases and congenital malformations during childhood and adolescence after in utero exposure to thiopurines

Jølving

Anru

Nielsen

et al. 2021

Aliment Pharmacol Ther

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Summary Background Women with autoimmune diseases, particularly inflammatory bowel disease (IBD), often need to continue immunomodulatory therapies during pregnancy. While the evidence of birth and short‐term outcomes in children exposed in utero to these medicines is reassuring, long‐term safety data are lacking. Aim To assess any association between in utero exposure to thiopurines and diagnoses of chronic diseases (type 1 diabetes, coeliac disease, thyroid disease, rheumatoid arthritis, IBD and asthma) and congenital malformations during childhood and adolescence. Methods This nationwide cohort study was based on information using Danish registers and comprised all live‐born children from 1995 to 2015 (N = 1 308 778). Children exposed in utero to thiopurines were followed for a median of 8.9 years (25%‐75% percentiles 5.5‐12.4 years); children not exposed were followed for 13.9 years (25%‐75% percentiles 8.7‐19.0 years). Analyses were adjusted for a number of confounders including the type of maternal underlying disease. Results A total of 1047 children had been exposed to thiopurines in utero; 96 developed a chronic disease and 126 were diagnosed with congenital malformations during follow‐up. The adjusted hazard ratio for rheumatoid arthritis was 0.78 (95% CI 0.35‐1.73); for IBD, it was 1.45 (95% CI 0.64‐3.27); for asthma 0.94 (95% CI 0.73‐1.21), and for congenital malformations, it was 0.95 (95% CI 0.78‐1.15). For type 1 diabetes, coeliac disease, thyroid disease and ulcerative colitis, we had insufficient data to perform adjusted analysis. Conclusion We found no increased risk of seven common chronic diseases or congenital malformations during childhood and adolescence after gestational exposure to thiopurines.

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“…strains s22 and t15 possess many genes involved in xenobiotics biodegradation and metabolism that may play an important role in the detoxification of xenobiotics (Table S2). Strains s22 and t15 have a complete biodegradation pathway of azathioprine and 6-Mercaptopurine, which are oral immunosuppressants and have many pathogenic risks [ 54 , 55 ]. Additionally, it is intriguing that this novel species has a series of genes that catalyzes the first step of xenobiotics biodegradation.…”

Section: Resultsmentioning

confidence: 99%

Evolutionary, genomic, and biogeographic characterization of two novel xenobiotics-degrading strains affiliated with Dechloromonas

Zhang

Amanze

Sun

et al. 2021

Heliyon

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Xenobiotics are generally known as man-made refractory organic pollutants widely distributed in various environments. For exploring the bioremediation possibility of xenobiotics, two novel xenobiotics-degrading strains affiliated with Azonexaceae were isolated. We report here the phylogenetics, genome, and geo-distribution of a novel and ubiquitous Azonexaceae species that primarily joins in the cometabolic process of some xenobiotics in natural communities. Strains s22 and t15 could be proposed as a novel species within Dechloromonas based on genomic and multi-phylogenetic analysis. Pan-genome analysis showed that the 63 core genes in Dechloromonas include genes for dozens of metabolisms such as nitrogen fixation protein ( nifU ), nitrogen regulatory protein ( glnK ), dCTP deaminase, C4-dicarboxylate transporter, and fructose-bisphosphate aldolase. Strains s22 and t15 have the ability to metabolize nitrogen, including nitrogen fixation, NirS -dependent denitrification, and dissimilatory nitrate reduction. Moreover, the novel species possesses the EnvZ-OmpR two-component system for controlling osmotic stress and QseC-QseB system for quorum sensing to rapidly sense environmental changes. It is intriguing that this new species has a series of genes for the biodegradation of some xenobiotics such as azathioprine, 6-Mercaptopurine, trinitrotoluene, chloroalkane, and chloroalkene. Specifically, glutathione S-transferase ( GST ) and 4-oxalocrotonate tautomerase ( praC ) in this novel species play important roles in the detoxification metabolism of some xenobiotics like dioxin, trichloroethene, chloroacetyl chloride, benzo[a]pyrene, and aflatoxin B1. Using data from GenBank, DDBJ and EMBL databases, we also demonstrated that members of this novel species were found globally in plants (e.g. rice), guts (e.g. insect), pristine and contaminated regions. Given these data, Dechloromonas sp. strains s22 and t15 take part in the biodegradation of some xenobiotics through key enzymes.

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In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Cited by 26 publications

References 88 publications

Neuropsychiatric Outcome of Children Born to Women With Systemic Lupus Erythematosus and Exposed in Utero to Azathioprine: A Case-Control Study

Neuropsychiatric Outcome of Children Born to Women With Systemic Lupus Erythematosus and Exposed in Utero to Azathioprine: A Case-Control Study

The risk of chronic diseases and congenital malformations during childhood and adolescence after in utero exposure to thiopurines

Evolutionary, genomic, and biogeographic characterization of two novel xenobiotics-degrading strains affiliated with Dechloromonas

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