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Folic Acid Supplements May Have Adverse Epigenetic Effects

By Eddy Ball
January 2009

Lead author Siri Håberg
Lead author Siri Håberg (Photo courtesy of Siri Håberg)

Second author Stephanie London
Second author Stephanie London, who was Håberg's mentor at NIEHS (Photo courtesy of Steve McCaw)

A team of U.S. and Norwegian researchers, funded in part by NIEHS, report evidence of a possible downside to the practice of maternal folic acid supplementation in the first trimester of pregnancy to reduce the risk of neural tube defects and other congenital malformations. Their study, published online December 3 by the journal Archives of Disease in Childhood, found a six to nine percent increase in relative risk for wheeze and lower respiratory tract infections in exposed infants and toddlers - along with a 24 percent increase in risk for hospitalization for lower respiratory tract infections.

Citing the results of animal studies, the investigators speculated that the increased risk may be the result of epigenetic alteration of methylation levels impacting the development of the immune system of the fetus during the first trimester of pregnancy. "These findings are in agreement with the hypothesis that early childhood respiratory health may be affected by the possible epigenetic influences of methyl donors in maternal diet during pregnancy," the researchers concluded.

While the findings are preliminary and the protective effects of folic acid supplementation on neural tube defects are still thought to outweigh the possible adverse effects on early childhood airway inflammation, the study advances understanding of the complex effects of maternal diet on fetal development. The results also point to the need for further investigations into the evidence for recommending specific levels of maternal supplementation during early pregnancy.

The study ( Exit NIEHS was led by NIEHS Special Volunteer Siri Håberg, Ph.D., who is also affiliated with the Division of Epidemiology at the Norwegian Institute of Public Health. The team included NIEHS Genetics Epidemiology Group Principal Investigator Stephanie London, M.D., as second author, and three colleagues from the Norwegian Institute of Public Health and the University of Oslo.

The team used data on the first 32,077 children up to the age of 18 months born of mothers enrolled in the Norwegian Mother and Child Cohort Study (MoBa), a large population-based study with information on supplementation from several time points in pregnancy. Because food in Norway, unlike food in the U.S., is not fortified with folic acid, assessment of supplementation by MoBa subjects was much simpler to determine.

The researchers acknowledged that several other factors related to supplement use may potentially influence the risk of disease in the MoBa children and strengthen or weaken the associations found in the study. These included such variables as the socio-economic status and health of the mother, as well as genetic polymorphisms in folate metabolism among mothers and children.

Citation: Håberg SE, London SJ, Stigum H, Nafstad P, Nystad W ( Exit NIEHS. 2008. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child. doi:10.1136/adc.2008.142448 [Epub ahead of print].

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