Scientific opinion on the tolerable upper intake level for folate

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. 2023 Nov 13;21(11):e08353. doi: 10.2903/j.efsa.2023.8353

Reference Study Country Duration Funding	Design	Subject characteristics at baseline ^a	Intervention ^a	Endpoint assessed	Results
Figueiredo et al. (2009) AFPPS USA 3 yr (trial) + 3–5 yr (trial follow‐up with continued folic acid treatment) Enrolment 1994–98 Fortification started 1996, and was mandatory 1998 Public, Supplements by private company	Report of secondary findings based on additional analysis of the colorectal adenoma trial (Cole et al., 2007) RCT 3 × 2 factorial design Inclusion criteria: 21–80 yrs with histologically confirmed adenoma removed. Participants had a complete colonoscopy, with removal of all known polyps, within 3 months of enrolment Exclusion criteria: familial polyposis syndromes, intestine cancer, malabsorption syndromes, conditions worsened by supplemental aspirin or folic acid, conditions treated with aspirin, NSAIDs or folate. Cobalamin deficient individuals were excluded. Prostate cancer: only men in AFPPS. 651 randomised of which 643 were included below Randomised and started (ITT)/completed first trial phase/consented continued follow‐up/consented continued treatment G1: 327/318/303/235 G1a: 112/NR/NR/NR/NR G1b: 108/NR/NR/NR/NR G1c: 107/NR/NR/NR/NR G2: 316/306/292/237 G2a: 109/NR/NR/NR/NR G2b: 105/NR/NR/NR/NR G2c: 102/NR/NR/NR/NR	Age 57.4 +/−9.2 P‐folate (nmol/L) G1: 23.2 G2: 22.7 RBC‐folate (nmol/L) G1: 388.6 G2: 404 Other relevant sources of heterogeneity None in general, but herein lower baseline plasma cobalamin in G1 (G2 = 348.1 pmol/L; G1 = 317.0 pmol/L, difference = 31.1 pmol/L, 95% CI = 1.8 to 60.4 pmol/L, p = 0.04)	Folic Acid Doses: G1: 1000 μg/day G1a: 1000 μg/day + 81 mg/day Aspirin G1b: 1000 μg/day + 325 mg/day Aspirin G1c: 1000 μg/day + Aspirin placebo G2: Placebo G2a: Placebo + 81 mg/day Aspirin G2b: Placebo + 325 mg/day Aspirin G2c: Placebo + Aspirin placebo Background dietary folate (μg/day) G1: 337 G2: 350 Compliance: NR	Prostate cancer self‐reported; medical records obtained and diagnosis confirmed by histopathology	Type of analysis extracted: ITT Prostate cancer cases G1: 25 G2: 9 Estimated probability of being diagnosed with prostate cancer over 10 yrs: G1: 9.7% (95% CI 6.5–14.5) G2: 3.3% (95% CI 1.7–6.4) Age‐adjusted HR: 2.63 (95% CI 1.23–5.65) Multivariable‐adjusted HR: 2.58 (95% CI 1.14–5.86)

Reference

Study Country

Duration Funding

Design

Subject characteristics at baseline ^a

Intervention ^a

Endpoint assessed

Results

Figueiredo et al. (2009)

AFPPS

USA

3 yr (trial) + 3–5 yr (trial follow‐up with continued folic acid treatment)

Enrolment 1994–98 Fortification started 1996, and was mandatory 1998

Public, Supplements by private company

Report of secondary findings based on additional analysis of the colorectal adenoma trial (Cole et al., 2007)

RCT 3 × 2 factorial design

Inclusion criteria: 21–80 yrs with histologically confirmed adenoma removed. Participants had a complete colonoscopy, with removal of all known polyps, within 3 months of enrolment

Exclusion criteria: familial polyposis syndromes, intestine cancer, malabsorption syndromes, conditions worsened by supplemental aspirin or folic acid, conditions treated with aspirin, NSAIDs or folate. Cobalamin deficient individuals were excluded.

Prostate cancer: only men in AFPPS. 651 randomised of which 643 were included below

Randomised and started (ITT)/completed first trial phase/consented continued follow‐up/consented continued treatment

G1: 327/318/303/235

G1a: 112/NR/NR/NR/NR

G1b: 108/NR/NR/NR/NR

G1c: 107/NR/NR/NR/NR

G2: 316/306/292/237

G2a: 109/NR/NR/NR/NR

G2b: 105/NR/NR/NR/NR

G2c: 102/NR/NR/NR/NR

Age

57.4 +/−9.2

P‐folate (nmol/L)

G1: 23.2

G2: 22.7

RBC‐folate (nmol/L)

G1: 388.6

G2: 404

Other relevant sources of heterogeneity

None in general, but herein lower baseline plasma cobalamin in G1 (G2 = 348.1 pmol/L; G1 = 317.0 pmol/L, difference = 31.1 pmol/L, 95% CI = 1.8 to 60.4 pmol/L, p = 0.04)

Folic Acid

Doses:

G1: 1000 μg/day

G1a: 1000 μg/day + 81 mg/day Aspirin

G1b: 1000 μg/day + 325 mg/day Aspirin

G1c: 1000 μg/day + Aspirin placebo

G2: Placebo

G2a: Placebo + 81 mg/day Aspirin

G2b: Placebo + 325 mg/day Aspirin

G2c: Placebo + Aspirin placebo

Background dietary folate (μg/day)

G1: 337

G2: 350

Compliance: NR

Prostate cancer self‐reported; medical records obtained and diagnosis confirmed by histopathology

Type of analysis extracted: ITT

Prostate cancer cases

G1: 25

G2: 9

Estimated probability of being diagnosed with prostate cancer over 10 yrs:

G1: 9.7% (95% CI 6.5–14.5)

G2: 3.3% (95% CI 1.7–6.4)

Age‐adjusted HR: 2.63 (95% CI 1.23–5.65)

Multivariable‐adjusted HR: 2.58 (95% CI 1.14–5.86)

Abbreviations: AFPPS, Aspirin/Folate Polyp Prevention Study; CI, Confidence Interval; G, Group; HR, Hazard ratio; ITT, Intention‐to‐treat; NR, Not reported; P, Plasma; RBC, Red blood cell; RCT, Randomised controlled trial; yr, year; yrs, years.

^{^a}

Values reported as mean ± standard deviation or median (inter quartile range) unless otherwise indicated.