The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception

Nørgård, Bente Mertz; Pedersen, Lars; Jacobsen, Jacob; Rasmussen, Steen; Sørensen, Henrik Toft

doi:10.1111/j.1365-2036.2004.01889.x

Cited by 71 publications

(34 citation statements)

References 23 publications

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“…Many, but not all, of the pharmacological effects of Aza are attributable to its cleavage to 6-mercaptopurine and the release of the methylnitroimidazole moiety plays an additional part in its biological activity (Calne, 1982). Aza can affect rapidly growing cells including bone marrow and gastrointestinal cells, and increase susceptibility to infection and hepatotoxicity (Norgad et al, 2004;Wu et al, 2006). Furthermore, Aza is mutagenic, genotoxic, teratogenic and several types of tumors are associated with prolonged treatment with it (Langer et al, 2003;Marcen et al, 2003;Karawya and El-Nahas, 2006).…”

Section: Introductionmentioning

confidence: 99%

Grape seed extract prevents azathioprine toxicity in rats

El-Ashmawy

Gad

Salama

2010

Phytotherapy Research

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Azathioprine (Aza) is an important drug commonly used in the therapy of autoimmune system disorders. It induces hepatotoxicity and hazard effects that restrict its use. The effects of administration of grape seed extract and folic acid on Aza toxicity by gavage (simultaneously) daily for 4 weeks were studied by determining the changes in some hematological parameters and liver histology. The glutathione level (GSH) and lipid peroxidation content as malondialdehyde (MDA) in the liver tissue were measured. The repeated intake of Aza (25 mg/kg body weight) induced anemia characterized by decreased erythrocyte and leukocyte counts and reticulocyte and hematocrit percentages, while the prothrombin time was significantly increased. Moreover, Aza caused a significant decrease in phagocytic activity and lymphocyte percentage. Aza induced hepatic damage as indicated by pronounced changes in the histological structure, a significant increase in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), and MDA content in the liver tissue. Meanwhile, the GSH activity was significantly decreased. Co-treatment with grape seed extract and Aza minimized the previously mentioned hazard effects of Aza and significantly protected the hepatic tissue by ameliorating the antioxidant activity. Folic acid administration, simultaneously, with Aza only improved the anemia. It may be concluded that grape seed extract is a useful herbal remedy, especially for controlling oxidative damages and is considered as a potent protective agent against Aza hepatotoxicity.

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Section: Introductionmentioning

confidence: 99%

Grape seed extract prevents azathioprine toxicity in rats

El-Ashmawy

Gad

Salama

2010

Phytotherapy Research

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“…Furthermore, 4 children with congenital abnormalities (underlying paternal diseases: glomerulonephritis and severe skin disease) were found in 54 pregnancies (7.4%) fathered by men treated with azathioprine or mercaptopurine compared with 4.1% in control pregnancies (95% CI 0.7–5.0) indicating that paternal use of azathioprine or mercaptopurine before conception might be associated with an increased risk of congenital abnormality [72] although more data are needed to determine whether the association is causal.…”

Section: Resultsmentioning

confidence: 99%

Pregnancy and Breastfeeding in Patients with Crohn’s Disease

et al. 2007

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Crohn’s disease commonly affects women of childbearing age. Available data on Crohn’s disease and pregnancy show that women with Crohn’s disease can expect to conceive successfully, carry to term and deliver a healthy baby. Control of disease activity before conception and during pregnancy is critical, to optimize both maternal and fetal health. Generally speaking, pharmacological therapy for Crohn’s disease during pregnancy is similar to pharmacological therapy for nonpregnant patients. Patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy. Sulfasalazine, mesalazine and corticosteroids are safe, azathioprine and 6-mercaptopurine are reasonably safe with few discordant data, infliximab seems safe as well, whereas methotrexate is contraindicated during pregnancy. During breastfeeding, mesalazine and prednisone are considered safe, azathioprine/6-mercaptopurine, budesonide and infliximab probably safe and methotrexate is contraindicated.

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“…67 Apart from a single small study that found an increased risk of spontaneous abortions and congenital anomalies among 13 thiopurine-exposed men, 68 multiple larger studies have failed to identify an increased rate of congenital anomalies with paternal thiopurine use. [69][70][71][72] The largest prospective study of 115 pregnancies fathered by men taking thiopurines at conception found no statistically significant increase in the rate of major congenital anomalies (3.0% exposed versus 2.2% unexposed). 72 However, the rate of elective abortions was higher in the exposed group.…”

Section: Methotrexatementioning

confidence: 96%

Use of Immunomodulators and Biologics Before, During, and After Pregnancy

McConnell

M²

2016

Inflammatory Bowel Diseases

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Immunomodulators and biologic medications, alone or in combination, form the core therapeutic strategy for managing moderate-to-severe inflammatory bowel disease (IBD). IBD incidence peaks during the prime reproductive years, raising concerns about the impact of disease and its treatment on fertility, maternal and fetal health during pregnancy, breastfeeding safety, and childhood development. Although IBD increases risk of pregnancy complications independent of disease activity, adverse pregnancy outcomes are more common when disease is active. To mitigate fetal risk, women should conceive while disease is quiescent. Aside from methotrexate, immunomodulators and biologics may be used during pregnancy to achieve and maintain disease control. Based on available safety data, there is no increased risk of congenital anomalies among infants exposed to these medications. Active thiopurine metabolites and most monoclonal antibodies cross the placenta and are detectable in neonates. They are detectable in breast milk in minute levels as well. The impact of this exposure on neonatal outcomes is discussed. Adjusted dosing schedules during gestation may reduce fetal drug exposure, though the maternal risks of such manipulation require careful consideration. Ongoing prospective studies will further inform risk assessment, including for newer medications such as the anti-integrin agents.

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The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception

Cited by 71 publications

References 23 publications

Grape seed extract prevents azathioprine toxicity in rats

Grape seed extract prevents azathioprine toxicity in rats

Pregnancy and Breastfeeding in Patients with Crohn’s Disease

Use of Immunomodulators and Biologics Before, During, and After Pregnancy

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