Associations between iron-status and folate-status in US women of child-bearing age: A possible path to understanding birth defect risk in overweight/obese mothers

Iron and folate are two metabolically interwoven nutrients necessary for normal development and cell growth. Among the important consequences of deficiencies of one or both nutrients are increased risk of infertility in both males and females, increased risk of early pregnancy loss, and increased risk of birth defects and developmental deficits in offspring. In obesity, serum levels of both iron and folate are reduced, while intracellular folate stores are increased. Adequate red blood cell (RBC) folate is known to reduce the risk of folate-related birth defects on a population wide basis, but paradoxically, risk of birth defects is elevated in obese women despite their elevated concentrations of RBC folate. Understanding this obesity paradox is essential if the risk of birth defects in obesity is to be reduced. To date, no research has evaluated the associations among iron deficiency and serum folate deficiency and RBC folate excess in the child-bearing years (20 to 45 years). Nor has research looked at moderators or mediators of these associations. We have suggested a putative biologic mechanism that can explain the obesity/birth defects paradox and we have attempted to demonstrate the effects of true and/or functional iron deficiency on concentrations of RBC folate and reduced serum folate that are expected if that mechanism is in place. We used NHANES data to explore associations in a variety of pairs of iron and folate markers in 20- to 45-year-olds. We found significant associations for seven of twelve marker-pairs. Looking at females and males separately, six iron/folate associations were significant in women but not men, and two were significant in men but not in women. Gender moderation of these associations reached significance in only three marker-pairs, perhaps due to the small number of males in that study sample. We then looked specifically at women to better understand the association of obesity and folate-status. We explored the roles of iron and inflammation in mediating the association of obesity and folate. There were small but significant mediations by iron and inflammation. We looked for moderation of iron-folate associations by obesity, and by inflammation in a small female sample. There was no moderation by BMI, but some significant moderation by inflammation. There were observed changes in the size of conditional effects at increasing levels of both BMI and inflammation. This study has confirmed associations between iron and folate-status and their moderation by gender and inflammation. It also confirmed association between obesity and folate-status and mediation of that association by inflammation and iron-status. We hope to spark further research into the etiology and treatment of disturbances of folate metabolism in obesity, with the goal of better understanding the elevated risk of birth defects in obese women of child-bearing age and spurring development of better guidelines to reduce that risk.