Patient with Severe Crohnʼs Disease Became a Father While on Methotrexate and Infliximab Therapy

To the Editor: Inflammatory bowel disease (IBD) is often diagnosed in people of reproductive age. Mesalamine, which is required to maintain disease remission, is regarded as safe for pregnant women.1 Methotrexate is used in IBD patients failing to respond to mesalamine maintenance therapy, especially if they suffer from joint pain. All patients on methotrexate are advised to avoid conceiving while on this drug because of its potentially teratogenic effects and the risk of miscarriage.2 Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-α), classified as a pregnancy class B drug, which means that animal studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women.3 We report the case of a 44-year-old man with Crohn's disease (CD) who fathered a healthy child while on methotrexate and infliximab therapy. CD had been diagnosed 14 years earlier, when ileocolonic involvement and a perianal fistula were identified. The patient became steroid-dependent in 2006. He had persistently active perianal disease with persistent drainage and recurrent wrist, ankle, and sacro-iliac pain. Joint pain was more severe in the morning, with no significant swelling, and it failed to respond to analgesics. Weekly methotrexate 25 mg subcutaneously was started and the joint symptoms subsided with this treatment, but the patient started to complain of many liquid stools and crampy abdominal pain, and biochemical tests showed an increase in inflammatory markers with moderate anemia and drainage from the fistula. Surgical evaluation under deep sedation and magnetic resonance ruled out any perineal abscesses. Chest x-ray and purified protein derivate (PPD) testing excluded tuberculosis and infliximab was started at a dose of 5 mg/kg at weeks 0, 2, 6, and every 8 weeks thereafter. Dual immunosuppression effectively achieved clinical remission. In 2007, methotrexate was suspended because of several episodes of pharyngitis and the disease relapsed both at the intestinal level (with more than 10 bowel movements a day and mucopurulent drainage from the fistula) and in the joints (with peripheral and axial joint pain). Methotrexate was resumed at a dose of 10 mg/week and infliximab injection intervals reduced every 6 weeks. The patient's healthy 40-year-old wife became pregnant during this time, so she was indirectly exposed to both methotrexate and infliximab. She delivered a healthy baby weighing 2.8 kg. There is a report in the literature of a woman with a diagnosis of rheumatoid arthritis who miscarried while taking methotrexate and infliximab.4 As a competitive inhibitor of dihydrofolate reductase, methotrexate blocks the form of tetrahydrofolate from dihydrofolate and folic acid leading to death of rapidly dividing cell populations. Embryolethal and teratogenic effects of methotrexate have been demonstrated in several studies with congenital anomalies, primarily craniofacial malformations and distal limb reductions. A dose of 10 mg weekly is sufficient to induce abortion and central nervous system abnormalities, especially if the drug is taken between 6 and 8 weeks after conception. That is why female patients are advised to stop taking methotrexate at least 3 months before conception.5 No definitive data are available on the possible adverse influence of men exposed to methotrexate on pregnancy, or on the drug's effect on male fertility. Methotrexate is often administered together with other chemotherapeutic agents, so it is difficult to establish its real effect. Small studies reporting on methotrexate used alone suggest no negative effects on fertility.6,–8 All the studies reporting a reduced fertility were conducted while patients were actively taking the drug. No DNA damage was induced in the sperm chromosomes of 4 patients taking methotrexate.9 Several cases reports described women who used infliximab during pregnancy. Data extracted from infliximab postmarketing surveillance database on exposure before or during pregnancy show that in 96 pregnancies 67% result in live births, 15% in miscarriages, and 19% in therapeutic termination. This study establishes that no differences statistically significant were found compared to women with CD not exposed to infliximab. In this cohort were 10 women indirectly exposed to infliximab through their partner.3 Three men took infliximab prior to conception and during the first trimester, together with other drugs (6-mercaptopurine, metronidazole, mesalamine, methotrexate, and corticosteroids). Only 1 woman had a miscarriage: she had Addison's disease, a previous miscarriage, and was taking corticosteroids. Although in vitro studies have shown that infliximab alters sperm motility and morphology, these changes do not coincide with infertility.10 High levels of TNF-α are detected in the male genital tract in the active stages of IBD and negatively influence sperm function.11 Experimental data have shown that spermatozoa exposed to high doses of TNF-α undergo functional and genomic changes.12 Infliximab can reverse the toxic action of TNF-α in human spermatozoa, however, improving their motility and membrane integrity, and reducing DNA breakdown.12 Asthenoazoospermia has nonetheless been described in men taking anti-TNF-α therapy.14 Further studies are needed to establish the compound effects of methotrexate and infliximab on spermatogenesis. Almost all human studies are retrospective and this considerably limits the advice that can be gleaned from them. On the other hand, the deliberate use of methotrexate is not to be encouraged in patients planning a pregnancy because of its prolonged effects on fertility and the (albeit limited) data on defects in the newborn. Infliximab, on the other hand, is considered a safe therapeutic option for inducing and maintaining remission in pregnant CD patients with active disease.