Folic acid supplements after first trimester linked to childhood asthma

ADELAIDE – Women who take folic acid supplements in late pregnancy may increase their child’s risk of developing asthma, an Australian study suggests. Folic acid supplementation during this crucial time of fetal immune system development may increase susceptibility to allergic lung diseases.

“Current recommendations worldwide advocate a daily intake of 400 micrograms of folic acid prior to pregnancy and in the first trimester for the prevention of neural tube defects,” write Dr Melissa J Whitrow and colleagues of the Research Centre for the Early Origins of Health and Disease, Adelaide, Australia, in the American Journal of Epidemiology.(1)

While the preventive effect on neural tube defects is undoubted, folate’s status as unequivocally beneficial has been challenged by recent studies in animals and infants, demonstrating an adverse effect of supplemental folic acid intake during pregnancy on respiratory health in early life.

Adding to the confusion, a recent study (2) involving over 8,000 individuals over the age of 2 has found an inverse correlation between folate levels and the risk of allergies. In the study, higher serum folate levels were associated with a lower risk of high total serum IgE concentrations, atopy, and wheezing.

The postulated proallergic effects of folic acid may be restricted to the supplementation of the maternal diet during pregnancy, rather than the consumption of folate in foods, where the compound takes a different form. Folic acid supplements, a potent source of methyl donors, can modify gene expression. In an animal model, it has recently been demonstrated that folate-induced DNA changes affect the expression of T-helper type 2 (Th2) cytokines during fetal development, in turn altering the inflammatory response and thus the risk of allergic airways disease in the child.

The Australian researchers looked at asthma rates among almost 500 children whose mothers had been followed since pregnancy. A little under 12% had developed asthma by age 3, and approximately the same percentage suffered from asthma at age 5.

After adjusting for confounding factors, the study found that supplemental folic acid in late pregnancy was associated with an increased risk of both asthma at 3.5 years and of persistent asthma. Reassuringly, folic acid supplements taken in pre- or early pregnancy (first trimester) were not associated with asthma at any age.

Children whose mothers took folic acid in late pregnancy from the 30th week on were one-quarter more likely to have asthma at age 3 compared with children whose mothers did not take folic acid at that point in pregnancy. They were also more likely to have persistent asthma symptoms from the age of 3 through to age 5.

The findings relate only to the synthetic folic acid supplements, the authors emphasise, and have no implications for the consumption of natural foods rich in folate (the naturally occurring form).

“We found an effect of folic acid when taken in supplement form but not when sourced from diet. A plausible explanation for this is the difference in bioavailability between forms; the polyglutamate form in foods has a lower bioavailability than the monoglutamate form in supplements.”

“The increased prevalence of allergic asthma in humans may in part be related to increased perinatal dietary supplementation with methyl donors. Our observation of an effect after the first trimester coincides with the development of the fetal immune system and the period during which there is a rise in fetal exposure to immunoglobulin E (IgE) and fetal IgE receptor activity.”

The next step will be to determine whether restricting folic acid intake in late pregnancy will have a beneficial impact on asthma prevention and thus the respiratory health of children, conclude the authors.

References:
1. Whitrow MJ et al.: Am J Epidemiol. 2009 Dec 15;170(12):1486-93
2. Matsui EC et al.: J Allergy Clin Immunol. 2009 Jun;123(6):1253-9