Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy

Abstract

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

Keywords: folic acid supplement use; neural tube defects; obesity.

Figure 1

Folate related one-carbon metabolism. DHF: dihydrofolate; DHFR: dihydrofolate reductase; THF: tetrahydrofolate; MTHFR: methylene tetrahydrofolate reductase; 5-MTHF: 5-methyltetrahydrofolaat; MS: methionine synthase; SAM: S-adenosyl-methionine; SAH: S-adenosyl-homocysteine; AHCY: S-adenosylhomocysteine hydrolase.

Figure 2

Overview potential underlying (patho)physiological pathways of folate deficiency and NTDs in obese women.

Figure 3

Illustration of the gap between recommended period of folic acid supplement use, and window of opportunity for the health care provider to advice on folic acid supplement use.