Cuba Birth Certificate

							 Assessing the Impact of Fortification on the
   Epidemiology of Neural Tube Defects
      FDA Advisory Committee for Reproductive Health Drugs
                     December 15, 2003



     Joseph Mulinare, M.D., M.S.P.H.
      National Center on Birth Defects and
           Developmental Disabilities

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                   Outline

• Background: NTD prevention using folic acid

• Ways to achieve adequate folate levels for prevention

• Blood folate results

• Neural tube defect prevalence

• Concluding remarks




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            Neural tube defects


• Serious birth defects
  – spina bifida and anencephaly

• 1 of 1,000 pregnancies

• 300,000 yearly worldwide

• Increased consumption of folic
  acid can prevent 50%-70%

                                   From NEJM 1999
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Randomized trials                      Risk Reduction
Non-randomized trials     Folic Acid – Neural Tube Defect Studies
Observational studies                           1980-1999
                              Decreased risk                Increased risk
  '80-England T
  '81-S. Wales T
  '88-Atlanta
  '89-W. Australia
  '89-CA/Illinois
  '89-Boston
  '90-Cuba          T
  '91-UK-MRC T                                 4000μg FA
  '92-Hungary                                           800μg MV
  '93-New England
  '95-California
                          N
  '99-P.R. China
                                         S              400μg FA

                    100% 80% 60% 40% 20% 0% 120% 500 600
                          Percent Risk Reduction / Increase with 95% CI
         TM
     1992 U.S. Public Health Service
       Folic Acid Recommendation

                 - All women capable of becoming
                  pregnant should consume

                 - 400 micrograms (0.4mg) folic acid
                 daily

                 - to reduce their risk of a pregnancy
                 affected by spina bifida or other
                 neural tube defects (NTDs)




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     1992 U.S. Public Health Service
       Folic Acid Recommendation



              Increase consumption of folic acid/folate:

                    •Improve dietary habits
                    •Take daily folic acid supplement
                    •Consume fortified foods




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    Ways of achieving adequate folic acid

• Promote supplement use: CDC, IOM, MoD, NCFA, states,
         local agencies
            - use health communication and education efforts




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          Use and Knowledge of Folic Acid
                   Women of Childbearing Age

                                                     1995          2003
  Heard of folic acid                                 52%          79%
  Knew FA can prevent birth
  defects
                                                        9%         13%
  Knew FA should be taken
  before pregnancy                                      2%          7%

 Took folic acid daily                               28%           32%
March of Dimes Birth Defects Foundation, Gallup Polls 1995, 2003


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      Percent women taking vitamin with folic acid daily
                        All women age 18-45

          50


          40                    34%
                      32% 32%                 33%   32%
                28%                   29%
Percent




          30


          20


          10


           0
               1995 1997 1998 2000 2001 2002 2003

          TM
    Ways of achieving adequate folic acid

• Promoted supplement use: CDC, IOM, MoD NCFA, states,
         local agencies
            - use health communication and education efforts

• Mandated fortification: FDA (1998)
           - Add folic acid to all products made with
           “enriched” flour to contain 140 ug/100g

           - Approve the use of health claims on products
              that contain “significant” amounts of folic acid
• Added folic acid: Breakfast cereal manufacturers
           - Folic acid increased to 100% DV


    TM
   Median serum and red blood cell folate levels,
      before and after folic acid fortification,
                         U.S. women, aged 15-44 years, NHANES

ng/mL                                                                                              ng/mL
  20               Serum folate                        Red blood cell folate                       350
                                                                                263.6              300
  15                                                                                               250
                                13.0
                                                                159.9                              200
  10
                                                                                                   150
   5               4.0                                                                             100
                                                                                                   50
   0                                                                                               0
                Before           After                          Before          After
             SOURCE: CDC/NCHS, National Health and Nutrition Examination Surveys, 1988-94 and 1999-2000


        TM
Change in U.S. NTD birth prevalence per 10,000
             by fortification status
           (NCHS Birth Certificate Data, 45 states)


               Before          After           PR      %
               None          Mandatory      (95% CI) decline

                                              0.77
Spina bifida   2.62             2.02
                                            (0.70-0.84)
                                                           23%

                                              0.89
Anencephaly    1.16             1.03
                                             (0.78-0.95)
                                                           11%


      TM
  Change in U.S. NTD prevalence per 10,000
            by fortification status
                  (NBDPN, 24 programs)


               Before       After           PR      %
               None       Mandatory      (95% CI) decline

                                           0.67
Spina bifida    5.1           3.5
                                         (0.63-0.73)
                                                       33%

                                           0.86
Anencephaly     2.5           2.1
                                         (0.78-0.95)
                                                       14%


      TM
        Evaluation of the change
        in NTD prevalence, U.S.


            Actual NTD    Goal - NTD
             % decline    % decline



     U.S.   20%-30%        50%-70%




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      Folic Acid Preventable Neural Tube Defects
                   Are we done yet?

 4000 estimated NTD-affected pregnancies yearly

 2000 50% of NTD-affected pregnancies that are preventable
- ~1000 estimated 25% fewer NTD pregnancies.
            due to fortification

~1000 estimate NTD-affected pregnancies
          remaining that are folic acid preventable


     TM
               Concluding remarks:
• Blood folate levels have increased substantially
since food fortification began in 1998.

•   NTD prevalence has fallen 20% - 30% in the United States.

• Lower NTD rates are consistent with an increase in
folic acid content from food fortification.

• The need still exists to prevent the occurrence of an
additional 1,000 NTD-affected pregnancies…
1,000 additional babies who can be born healthy, without the
devastating effects caused by these serious birth defects


     TM
       Concluding remarks (contd):


• More options are needed to provide additional folic
acid to ALL reproductive-age women who are at risk for
having a folic-acid-preventable neural tube defect.


• We should be doing whatever is necessary to
safely increase the amounts of folic acid that women
of reproductive age need to get to eliminate all
folic-acid preventable birth defects.




  TM
      National Folic Acid Campaign
     to Prevent Birth Defects, 1999 -




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