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Folic acid

Classification: A

Drug products: Folacin®, Folarell, Folix, Folsyra EQL Pharma, Folsyra Evolan, Folsyra Orifarm, Folsyra Pilum, Folsyra Vitabalans, Folsäure Injektopas, Folvidon

ATC code: B03BB01

Substances: folic acid, folic acid hydrated

Summary

Higher folic acid intake is associated with reduced ischemic stroke risk in men but not in women. There are contradictory data concerning the effect of folic acid on cancer incidence and whether there are sex differences or not. Large meta-analyses shown no reduced incidence of overall cancer or for colon cancer, neither in men nor in women. Results from observational studies vary between cancer forms, some describe no sex differences while others describe effect only in one sex. The clinically relevance is unclear.

Additional information

Pharmacokinetics and dosing

Based on data from a European population study (2889 men, 2557 women), the level of folate in plasma does not differ significantly between men and women [1]. Serum concentrations of folate biomarkers were measured in the US population in 2011-2012 (4463 men, 4493 women). Concentrations of 5-methylTHF concentrations were higher in women, while concentrations of the oxidation product of 5-methylTHF, that lacks biologic activity, were similar in men and women [2].Women who plan to become pregnant or are pregnant are recommended a folic acid intake of at least 400 µg/day to prevent neural tube defects on the fetus [3].

Effects

Stroke preventionMeta-analyses assessing the efficacy of folic acid supplementations for prevention of cardiovascular and cerebrovascular events have reported contradictory findings [4-7]. One meta-analysis performed a sex-stratified analysis showing a relative stroke risk of 0.84 (95% CI 0.74-0.94; p=0.03) in men predominant trials, while women predominate trials showed no change in relative risk (RR 1.11, 95% CI 0.84-1.49). The authors suggest this sex difference could be due to higher stroke event rates in men which increases study power to detect treatment effects. Another  reason might be sex differences in severity and treatment-responsiveness of hyper-homocysteinemia causing higher baseline homocysteine concentration in men and greater reductions in homocysteine levels in men [6]. Same findings have been reported in observational studies; higher folic acid intake was associated with reduced ischemic stroke risk in male US health professionals (43 732 men, RR 0.71, 95%CI 0.52-0.96, p=0.05) [8] and in male Finnish smokers (RR 0.80, 95% CI 0.70-0.91, p=0.001) [9], but not in female US nurses (83 272 women; RR 1.01, 95% CI 0.79-1.29, p=0.8) [10].

Cancer incidenceThe effect of folic acid on overall cancer incidence was analyzed in a meta-analysis with data from 13 placebo-controlled trials of folic acid for prevention of colorectal cancer (3 studies, n=2652) or cardiovascular disease (10 studies, n=46 969). The daily dose ranged between 0.5-5 mg folic acid (one trial 40 mg) and the average treatment duration was 5.2 years. The plasma folate was quadrupled (57.3 nmol/L for the folic acid group vs 13.5 nmol/L for the placebo group), but no effect on cancer incidence was observed, neither in men nor in women [11].Another meta-analysis of eight RCTs (n=34 598) found no effect of folic acid supplementation (0.5-2.5 mg) on colorectal cancer risk (RR 1.00, 95% CI 0.82-1.22, p=0.974), neither in men nor women [12]. Most observational studies report similar findings [13-17], while some report an association between low folic acid intake and colorectal cancer risk only in men [18, 19].High folic acid intake is associated with reduced risk of oral cavity and pharynx cancer [20] and head and neck cancer [21] in both men and women. High folic acid intake is associated with reduced risk of lung cancer only in men [22], and associated with increased risk of skin cancer only in women [23].

DeathAn observational study report that lower levels of folate are associated with higher risk of death in men and women, higher risk of death in cardiovascular diseases in men, and higher risk of death in tumor disease in women [24].

DepressionA meta-analysis of three randomized trials (n=247) showed beneficial effects of folic acid in depression [25]. One of the included trials (20 men, 40 women) reported an improved Hamilton depression rating scale in women, but not in men treated with folic acid [26].Observational studies are inconsistent whether patient’s sex influence the association between folate levels (or folic acid intake) and depressive symptoms. Low folate levels are associated with elevated depressive symptoms in US women [27, 28] and in elderly Latina women [29]. Contrary to this, Japanese studies found an association between low folate levels (or folic acid intake) and increased prevalence of depressive symptoms in men but not in women [30, 31]. One analysis in elderly >65 years found no association between folic acid intake and risk of depressive symptoms in men nor in women [32].

Adverse effects

See above, no further studies with a clinically relevant sex analysis regarding adverse effects of folic acid has been found.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Changes in folic acid intake as a result of fortification have been estimated in several countries. The 1998 FDA fortification policy contributed to an increased folic acid intake by approximately 100 µg/day in the US population, but consumption rates varied between ethnic groups with lower rates among Blacks and Mexican Americans [33]. Also, in a Brazilian study, folic acid intake increased after food fortification. Only 1.76% had folate deficiency, with no sex differences observed for any of the age groups [34].

Updated: 2020-08-28

Date of litterature search: 2017-12-10

References

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Authors: Carl-Olav Stiller, Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson