Folic acid supplementation adverse effects

There has been some discussion as to whether an adverse effect of folic acid on seizures represents a direct epileptogenic effect or results from interference with the effects of anticonvulsants. Initially, it was supposed that foUc acid provokes seizures, and the first report of an epileptic patient with megaloblastic anemia in whom folate therapy resulted in an exacerbation of seizures was published in 1960. Although several subsequent controlled studies failed to show any adverse effect on seizure frequency linked to folic acid supplementation, case reports and uncontrolled studies have documented worsening seizure frequency in some patients given folic acid, but the susceptibility factors at play have not been identified. 

Gastrointestinal adverse effects (stomatitis, anorexia, abdominal pain, dyspepsia, nausea, vomiting, diarrhea, and weight loss) are very common, particularly after oral administration of methotrexate (up to 50%), and often require dosage adjustment (3). Folic acid supplementation reduces the incidence of several gastrointestinal adverse effects. 

Water-soluble vitamins removed by hemodialysis (HD) contribute to malnutrition and vitamin deficiency syndromes. Patients receiving HD often require replacement of water-soluble vitamins to prevent adverse effects. The vitamins that may require replacement are ascorbic acid, thiamine, biotin, folic acid, riboflavin, and pyridoxine. Patients receiving HD should receive a multivitamin B complex with vitamin C supplement, but should not take supplements that include fat-soluble vitamins, such as vitamins A, E, or K, which can accumulate in patients with renal failure. 

Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing hence, dietary supplementation with 1 mg/d folic acid is recommended. 

In a meta-analysis of 307 patients with rheumatoid arthritis from seven randomized clinical trials, of whom 147 took folate supplementation, hematological adverse effects were not significantly reduced in the folate group (8). However, there was a 79% reduction in mucosal and gastrointestinal adverse effects in patients taking folic acid and a non-significant trend toward a reduction (42%) in patients taking folinic acid. Disease activity was not modified by low doses of folate. Finally, the authors noted that folinic acid is more expensive. 

Pyrimethamine is an inhibitor of dihydrofolate reductase and causes tetrahydrofolate deficiency. It is teratogenic in animals in rats it produces limb defects, cleft palate, and brachygnathia, and in chick embryos micromelia. Fetal death has been seen in rats and hamsters. However, in toxoplasmosis, pyrimethamine, with or without a sulfonamide, has been given to pregnant women without evidence of subsequent abnormalities. Supplementation with folic acid has been advocated to prevent or reduce adverse effects (SEDA-13,812), but it is not known if this could impair efficacy. 

An early review of newer case reports and placebo-controlled trials involving several hundred patients did not show an increase in fetal abnormalities (176). However, the relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors, such as trimethoprim, during the second or third month after the last menstrual period, compared with infants whose mothers had no such exposure, are 3.4 (95% Cl = 1.8, 6.4) and 2.6 (1.1, 6.1) respectively (177). Multivitamin supplements containing folic acid reduced the adverse effects of dihydrofolate reductase inhibitors. There have been two reports of severe spinal malformations in the fetuses of HIV-positive women treated with combination antiretroviral therapy and co-trimoxazole (178). 

Because it is a folic acid antagonist, methotrexate can induce a folic acid deficiency. This deficiency is thought to be partly responsible for methotrexate toxicity, and supplementation with folic acid has been shown to alleviate some adverse effects. Addition of folic acid to a methotrexate regimen for rheumatoid arthritis does not compromise drug efficacy. ... 

It appears reasonable to recommend supplementation with several B vitamins in physiological doses to many patients with epilepsy. Patients on inducer AEDs and VPA, and patients with an insufficient diet, are at risk for deficiency of several B vitamins. Moreover, the evidence that folic acid can prevent adverse effects in patients on AEDs is not much higher than the evidence for a protective effect of vitamins B2, Bg, B7 and B12 (Ranganathan and Ramar-atnam 2005). In animal studies, deficiency of vitamins B2 and Bg has been related to the occurrence of foetal malformations. Therefore, women of childbearing potential should supplement their diet with vitamin B2 and Bg, as well as folic acid. 

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