What is the Minimum Effective Dose of Folic Acid for Preventing NTDs? James L. Mills, M.D., M.S....
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![Page 1: What is the Minimum Effective Dose of Folic Acid for Preventing NTDs? James L. Mills, M.D., M.S. Caroline Signore, M.D. NICHD.](https://reader036.fdocuments.in/reader036/viewer/2022062304/56649f4e5503460f94c6fae3/html5/thumbnails/1.jpg)
What is the Minimum Effective Dose of Folic Acid
for Preventing NTDs?
James L. Mills, M.D., M.S.
Caroline Signore, M.D.
NICHD
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Minimum Effective Dose:Outline
Why is this a difficult question to answer?
How can we estimate how much folic acid is needed?
Actual experience with fortification
Conclusions
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Minimum Effective Dose:
Why is This a Difficult Question to Answer?
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The Definitive Study
Test reduced doses until NTD rates rise
400 µg Protective
300 µg Protective
200 µg Protective
100 µg Not Protective
UNETHICAL
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What do we Know About Effective Dose?
Clinical trial doses—definitely work, but too high
MRC, 1991: 4 mgCzeizel, 1992: 800 µg
Case control study doses—presumed to work, but are lower doses effective?
Most U.S. studies reported on 400 µg
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Complication: Genetic Differences in Folate
Metabolism
MTHFR Genotype Mean RCF (µg/L)
CC 347
CT 314
TT 284*
Molloy AM, et al., Lancet, 1997; *p<0.01
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How Can We Estimate How Much Folic Acid is Needed?
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Maternal Red Cell Folate vs. NTD Risk in Dublin
Study DesignReviewed early pregnancy maternal RCF from nested case-control study of 84 cases NTD and 266 normal controls
Logistic regression analysis to examine relationship between RCF and NTD risk
Daly L, et al., JAMA, 1995
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Maternal RCF vs. NTD Risk in Dublin
Continuous dose-response relationship
RCF < 150 ng/mL Risk 6.6/1000
RCF > 400 ng/mL Risk 0.8/1000
Daly L, et al., JAMA, 1995
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Maternal RCF vs. NTD Risk in Dublin
Curve continues down
Risk 0.2/1000?
Daly L, et al., JAMA, 1995
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Maternal RCF vs. NTD Risk in Dublin
Curve flattens out (genetic Mendelian defects)
Risk 0.5/1000?
Unable to confirm optimal RCF level, but 400 ng/mL is highly protective
Daly L, et al., JAMA, 1995
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How Much Folic Acid is Needed to Raise RCF to
Protective Levels?
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NICHD/Trinity College/Health Research
Board Trial
Study designRandomized, placebo-controlled trial
121 patients randomized to receive placebo, 100 µg, 200 µg, or 400 µg folic acid/d
Compliance assessed by sign-in sheets over 6 mo. study period
Daly S, et al., Lancet, 1997
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Results
Group NInitial
Median RCF µg/L
Final Median
RCF µg/L
Median Change
µg/L
Placebo 19 335 311 -12
100 µg/d 22 309 375* 67
200 µg/d 28 311 475* 130
400 µg/d 26 350 571* 200
Daly S, et al. Lancet, 1997 * p < 0.001
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RCF and NTD Risk Calculation
Initial and post-treatment RCF values substituted into regression equation from L. Daly, et al. to derive estimated change in NTD risk
Daly S, et al. Lancet, 1997
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Results
Treatment
GroupN
Estimated Reduction in
NTD Risk
Placebo 19 0
100 µg/d 22 22%
200 µg/d 28 41%
400 µg/d 26 47%
Daly S, et al. Lancet, 1997
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Minimum estimate
(considering non-compliance):
~200 µg/d will
decrease NTD rate by 41%
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Literature Review and Calculation of Folic Acid Effect on Serum Folate
Mathematical model based on trials of folic acid supplementation on plasma folate
Calculated a dose-response equation
Wald N, et al. Lancet, 2001.
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Quantifying the Effect of Folic Acid
Effect of Dose of Folic Acid on Change in Serum Level by Age
0
5
10
15
20
25
30
0 0.2 0.4 0.6 0.8 1Dose (mg/day)
Ch
ang
e in
Ser
um
F
ola
te (
ng
/mL
)
Age 40-65
Age 20-35
Wald N, et al. Lancet, 2001.
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Predicted plasma folate levels were far lower than actual levels in NHANES 1999-2000
The effects were inconsistent
by age
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Explanations
Non-compliance would lead to an underestimation of effect
Studies selected for the model had insufficient duration of exposure to reach stable serum folate levels, resulting in an underestimation of effect
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Exposure Time Required to Reach Stable Folate Levels
0
2
4
6
8
10
12
14
Wee
ks
<=200 ug >=400 ug
Daily Dose of Folic Acid
Larger doses of folic acid require a longer
period to achieve steady serum or
plasma concentration
Quinlivan EP and Gregory JF, Am J Clin Nutr, 2003
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Was Duration of Exposure Sufficient to Produce Stable
Levels?
Adequate
Duration
Inadequate Duration
Mean Age
20-352 (33%) 4 (67%)
Mean Age
40-654 (50%) 4 (50%)
TOTAL 6 (43%) 8 (57%)
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Differences May be Due to Inadequate Time for Stabilization
Effect of Dose of Folic Acid on Change in Serum Level by Age
0
5
10
15
20
25
30
0 0.2 0.4 0.6 0.8 1Dose (mg/day)
Ch
ang
e in
Ser
um
F
ola
te (
ng
/mL
)
Age 40-65
Age 20-35
Wald N, et al. Lancet, 2001.
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Studies used in Wald’s model led to an underestimation of folic acid effect on serum folate
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What Are Current Exposure Levels?
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Estimating DailyFolic Acid Intake After
Fortification
0
100
200
300
Es
tim
ate
d F
olic
Ac
id (
ug
/da
y)
FDA, 199
3
Caudill,
2001
Choum
enko
vitc
h, 2
002
Quinl
ivan, 2
003
TheoreticalClinical
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How Has Fortification Affected Folate Levels?
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Serum Folate Levels Pre- and Post-Fortification
0 5 10 15 20
Serum Folate (ug/L)
Jacques
Lawrence
CDC
4.6
4.8
12.6
5.4
8.2
6.1
171%
48%
117%
13.0
18.7
10.0
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RCF Levels Pre- and Post-Fortification
0 100 200 300 400
Red Cell Folate (ng/mL)
Ray
CDC 65%
40%
104
94
160
233
264
327
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Summary
Fortification probably increases folic acid exposure by 200 µg/day or more
Serum and red cell folate levels have risen dramatically (by 171% and 65%, respectively)
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Actual Experience with Fortification
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The Gold Standard
How much has the additional
200 µg/day decreased NTD rates?
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Estimates Vary Because of Ascertainment Problems
Stevenson RE, et al., Pediatrics, 2000
Method of Detection Percent
Ultrasonography 55%
MSAFP 25%
AF AFP 3%
Delivery 17%
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Experience: Nova Scotia
Population based study of all NTDs from live births, stillbirths, and terminations
Compared pre- and post-fortification at 150 µg/100 g
Total NTD incidence fell by 54%2.58/1000 1.17/1000
Persad VL, et al., CMAJ, 2002
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Estimated Effect
Canada: fortification at 150 µg /100 g grain 50% reduction
U.S. data with comparably ascertained cases are still not widely available
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Conclusions
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Conclusions
It is difficult to pinpoint the lowest effective dose of folic acid
Data from Ireland indicate 200 µg/day will prevent at least 40% of NTDs
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Conclusions
Actual experience in Canada indicates estimated doses of 200+ µg/day will prevent 50% or more
In the U.S., ~50% prevention may be the maximum, or ~70% prevention may be possible—have we “maxed out?”
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Conclusions
Given food fortification and supplement use in the U.S., many women will not need fortified OCs
For women using supplements, fortified OCs might put them over the IOM’s recommended limit
For other women, who do not take supplements and who eat less fortified food, fortified OCs could be beneficial