What is the Minimum Effective Dose of Folic Acid for Preventing NTDs

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

2
Minimum Effective DoseOutline

• Why is this a difficult question to answer?
• How can we estimate how much folic acid is
  needed?
• Actual experience with fortification
• Conclusions

3
Minimum Effective DoseWhy is This a Difficult
Question to Answer?
4
The Definitive Study

• Test reduced doses until NTD rates rise
• 400 µg ? Protective
• 300 µg ? Protective
• 200 µg ? Protective
• 100 µg ? Not Protective

UNETHICAL
5
What do we Know About Effective Dose?

• Clinical trial dosesdefinitely work, but too
  high
• MRC, 1991 4 mg
• Czeizel, 1992 800 µg
• Case control study dosespresumed to work, but
  are lower doses effective?
• Most U.S. studies reported on 400 µg

6
Complication Genetic Differences in Folate
Metabolism
Molloy AM, et al., Lancet, 1997 plt0.01
7
How Can We Estimate How Much Folic Acid is Needed?
8
Maternal Red Cell Folate vs. NTD Risk in Dublin

• Study Design
• Reviewed 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
9
Maternal RCF vs. NTD Risk in Dublin

• Continuous dose-response relationship
• RCF lt 150 ng/mL Risk ? 6.6/1000
• RCF gt 400 ng/mL Risk ? 0.8/1000

Daly L, et al., JAMA, 1995
10
Maternal RCF vs. NTD Risk in Dublin

• Curve continues down
• Risk ? 0.2/1000?

Daly L, et al., JAMA, 1995
11
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
12
How Much Folic Acid is Needed to Raise RCF to
Protective Levels?
13
NICHD/Trinity College/Health Research Board Trial

• Study design
• Randomized, 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
14
Results
Daly S, et al. Lancet, 1997
p lt 0.001
15
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
16
Results
Daly S, et al. Lancet, 1997
17

• Minimum estimate
• (considering non-compliance)
• 200 µg/d will
• decrease NTD rate by 41

18
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.
19
Quantifying the Effect of Folic Acid
Wald N, et al. Lancet, 2001.
20

• Predicted plasma folate levels were far lower
  than actual levels in NHANES 1999-2000
• The effects were inconsistent
• by age

21
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

22
Exposure Time Required to Reach Stable Folate
Levels

• 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
23
Was Duration of Exposure Sufficient to Produce
Stable Levels?
24
Differences May be Due to Inadequate Time for
Stabilization
Wald N, et al. Lancet, 2001.
25

• Studies used in Walds model led to an
  underestimation of folic acid effect on serum
  folate

26
What Are Current Exposure Levels?
27
Estimating DailyFolic Acid Intake After
Fortification
28
How Has Fortification Affected Folate Levels?
29
Serum Folate Levels Pre- and Post-Fortification
13.0
? 171
4.8
8.2
18.7
12.6
6.1
? 48
10.0
4.6
5.4
? 117
30
RCF Levels Pre- and Post-Fortification
264
? 65
104
160
327
? 40
94
233
31
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)

32
Actual Experience with Fortification
33
The Gold Standard

• How much has the additional
• 200 µg/day decreased NTD rates?

34
Estimates Vary Because of Ascertainment Problems
Stevenson RE, et al., Pediatrics, 2000
35
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
36
Estimated Effect

• Canada fortification at 150 µg /100 g grain ?
  50 reduction
• U.S. data with comparably ascertained cases are
  still not widely available

37
Conclusions
38
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

39
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 possiblehave we maxed
  out?

40
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 IOMs recommended limit
• For other women, who do not take supplements and
  who eat less fortified food, fortified OCs could
  be beneficial