1. TM 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

2. TM Outline Background: NTD prevention using folic acid Ways to achieve adequate folate levels for prevention Blood folate results Neural tube defect prevalence Concluding remarks

3. TM 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

4. TM Risk Reduction Folic Acid – Neural Tube Defect Studies 1980-1999 Randomized trials Non-randomized trials Observational studies Percent Risk Reduction / Increase with 95% CI '81-S. Wales T '80-England T '90-Cuba T '91-UK-MRC T '88-Atlanta '89-W. Australia '89-CA/Illinois '89-Boston 100 % 80 % 60 % 40 % 20 % 0% 120 % 500 600 Decreased risk Increased risk 4000 μg FA '92-Hungary '93-New England '95-California '99-P.R. China S N 400 μg FA 800 μg MV

5. TM 1992 U.S. Public Health Service Folic Acid Recommendation - 400 micrograms (0.4mg) folic acid daily - All women capable of becoming pregnant should consume - to reduce their risk of a pregnancy affected by spina bifida or other neural tube defects (NTDs)

6. TM 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

7. TM Promote supplement use: CDC, IOM, MoD, NCFA, states, local agencies - use health communication and education efforts Ways of achieving adequate folic acid

8. TM Use and Knowledge of Folic Acid Women of Childbearing Age Women of Childbearing Age Took folic acid daily Heard of folic acid Knew FA should be taken before pregnancy Knew FA can prevent birth defects 32% 79% 7% 13% March of Dimes Birth Defects Foundation, Gallup Polls 1995, 2003 20031995 28% 52% 9% 2%

9. TM 28% 32% 34% 29% 33% 32% 0 10 20 30 40 50 1995199719982000200120022003 Percent women taking vitamin with folic acid daily All women age 18-45 Percent

10. TM Promoted supplement use: CDC, IOM, MoD NCFA, states, local agencies - use health communication and education efforts Ways of achieving adequate folic acid Mandated fortification: FDA (1998) 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 - Approve the use of health claims on products that contain “significant” amounts of folic acid Added folic acid: Breakfast cereal manufacturers Added folic acid: Breakfast cereal manufacturers - Folic acid increased to 100% DV - Folic acid increased to 100% DV

11. TM Median serum and red blood cell folate levels, before and after folic acid fortification, U.S. women, aged 15-44 years, NHANES SOURCE: CDC/NCHS, National Health and Nutrition Examination Surveys, 1988-94 and 1999-2000 4.0 0 5 10 15 20 ng/mL Serum folate 13.0 BeforeAfter ng/mL 159.9 263.6 0 50 100 150 200 250 300 350 Red blood cell folate BeforeAfter

12. TM Change in U.S. NTD birth prevalence per 10,000 by fortification status (NCHS Birth Certificate Data, 45 states) PR (95% CI) 11% 1.031.16 Anencephaly 23% 2.022.62 Spina bifida % decline After Mandatory (0.70-0.84) 0.77 (0.78-0.95) 0.89 Before None

13. TM Change in U.S. NTD prevalence per 10,000 by fortification status (NBDPN, 24 programs) PR (95% CI) 14% 2.12.5 Anencephaly 33% 3.55.1 Spina bifida % decline After Mandatory (0.63-0.73) 0.67 (0.78-0.95) 0.86 Before None

14. TM Evaluation of the change in NTD prevalence, U.S. U.S. Actual NTD % decline 50%-70% Goal - NTD % decline 20%-30%

15. TM 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

16. 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

17. 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.

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