Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding

Abstract

The aim of this article is to critically review available data regarding the safety of immunomodulators and biological therapies during pregnancy and breast-feeding in women with inflammatory bowel disease. Methotrexate and thalidomide can cause congenital anomalies and are contraindicated during pregnancy (and breast-feeding). Although thiopurines have a Food and Drug Administration (FDA) rating D, available data suggest that these drugs are safe and well tolerated during pregnancy. Although traditionally women receiving azathioprine or mercaptopurine have been discouraged from breast-feeding because of theoretical potential risks, it seems that these drugs may be safe in this scenario. Treatment with cyclosporine for steroid-refractory ulcerative colitis (UC) during pregnancy can be considered safe and effective, and the use of this drug should be considered in cases of severe UC as a means of avoiding urgent surgery. Breast-feeding is contraindicated for patients receiving cyclosporine. Biological therapies appear to be safe in pregnancy, as no increased risk of malformations has been demonstrated. Therefore, the limited clinical results available suggest that the benefits of infliximab and adalimumab in attaining response and maintaining remission in pregnant patients might outweigh the theoretical risks of drug exposure to the fetus. Stopping therapy in the third trimester may be considered, as it seems that transplacental transfer of infliximab is low prior to this. Certolizumab differs from infliximab and adalimumab in that it is a Fab fragment of an antitumor necrosis factor alpha monoclonal antibody, and therefore it may not be necessary to stop certolizumab in the third trimester. The use of infliximab is probably compatible with breast-feeding.

Letter: thiopurines during pregnancy and intrauterine exposure to metabolites – author's reply

“…Indeed, there are previous reports that young subjects have higher TPMT activity compared to older ones: Serpe et al showed that TPMT activity is significantly higher in wild-type children than wild-type adults and, in particular, wild-type infants (0.08-2 years) had a 9% higher TPMT activity than other wild-type groups 2 ; McLeod et al reported similarly that in newborns TPMT activity and TPMT protein concentration in erythrocytes are 50% higher than in healthy adults. 3 Results consistent with these observations have been reported by other authors. 4,5 Moreover, a recent study showed that IBD patients 6 years of age or younger treated with thiopurines had an 85% increase in probability of response if taking a dose >3.0 mg/kg/day, that is considered the upper limit for the safe dose of this medication in the general adult population, compared to a dose of 2-3 mg/kg/ day.…”

“…1 Many previous review articles and guidelines have commented on the fact that the foetal liver lacks the enzyme 'inosinate pyrophosphorylase'. [2][3][4][5] Our use of the term 'inosinate phosphorylase' may have led to some confusion. 6 The articles quoted by de Boer et al 7,8 provide case reports where measurements of thiopurine metabolites were taken from the red blood cells of mother and infant, specifically 6-MMP and 6-TGN.…”

Is safety infliximab during pregnancy in patients with inflammatory bowel disease?

“…These findings bolster recommendations that pregnant patients should avoid IFX treatment after 30 weeks' gestation (7,8). Thus, the use of IFX should probably be limited to cases in which uncontrolled activity of IBD could expose both mother and child to risks greater than those deriving from its use (9).…”

The long-term risk of continuous immunosuppression using thioguanides in inflammatory bowel disease

“…On the basis of maximum concentration measured, the infant ingests MP of <0.008 mg/kg bodyweight/24 h. The authors concluded that breastfeeding during treatment with AZA seemed safe and should be recommended, considering the extensive beneficial effects to mother and child [Christiansen et al 2008]. A review of immunomodulators in pregnancy and breastfeeding came to the same conclusion [Gisbert, 2009]. More extensive studies are certainly warranted in this area.…”