Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review

Abstract

Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus

“…Indeed, in countries with FA food fortification and FA supplementation guidelines for pregnancy, folate excess is more common than folate deficiency. A systematic review confirms that in the context of mandatory FA fortification, most women preconception, and through pregnancy, are exceeding the upper tolerable limit (~1000 μg/d) [ 76 ]. While direct consequences of nutrient deficiencies have been well documented [ 77 , 78 , 79 ], the effects of excess FA intake are less well elucidated and are more likely to have direct effects on one-carbon metabolism and ultimately complicated and indirect effects on maternal and fetal health, and pregnancy outcome.…”

Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts

“…The mandate was expected to increase daily FA intake by 100 μg. However, most pregnant women post-FA fortification mandate are exceeding the recommended total daily intake of 600 µg [ 7 , 8 ]. A recent systematic review of women taking FA supplements in countries with mandatory food fortification programs found that almost all women exceed the upper tolerable limit of FA (1000 μg/day) [ 7 ].…”

“…However, most pregnant women post-FA fortification mandate are exceeding the recommended total daily intake of 600 µg [ 7 , 8 ]. A recent systematic review of women taking FA supplements in countries with mandatory food fortification programs found that almost all women exceed the upper tolerable limit of FA (1000 μg/day) [ 7 ]. A possible explanation for the disparity between the expected and actual daily increase, at least in Australia, is that within a couple of years after the FA fortification mandate, the voluntary fortification of numerous food products with FA commenced, resulting in substantially higher intakes of FA than predicted from the fortification mandate alone.…”

Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells

“…Folic acid at lower doses is known to have beneficial effects as an antioxidant by reducing the homocysteine levels . However, higher doses of FA can act as a pro-oxidant. , Higher doses of folic acid are usually considered as the amount of FA received is much higher than the body usually can metabolize, and, because of this, it results in an unmetabolized form of folic acid (UMFA) in circulation . The recommended doses of folic acid as a prenatal multivitamin range from 400 to 500 μg in Australia to 800 μg/day in the U.S. and 1000 μg/day in Canada .…”

“…However, higher doses of FA can act as a pro-oxidant. , Higher doses of folic acid are usually considered as the amount of FA received is much higher than the body usually can metabolize, and, because of this, it results in an unmetabolized form of folic acid (UMFA) in circulation . The recommended doses of folic acid as a prenatal multivitamin range from 400 to 500 μg in Australia to 800 μg/day in the U.S. and 1000 μg/day in Canada . Accumulating evidence from recent studies suggests that excessive intake of folic acid in the form of supplements and fortification in cereals may cause increased levels of unmetabolized folic acid (UMFA) in blood serum either because of saturation and/or inhibition of dihydrofolate reductase. , The increased levels of UMFA can lead to disruption of the homocysteine to methionine conversion and therefore accumulation of unmetabolized homocysteine that can act as a pro-oxidant .…”