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Assessing the Impact of Fortification on the Epidemiology of Neural Tube Defects

FDA Advisory Committee for Reproductive Health DrugsDecember 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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Risk Reduction Folic Acid – Neural Tube Defect Studies

1980-1999

Randomized trialsNon-randomized trialsObservational 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

4000μg FA

'92-Hungary

'93-New England

'95-California

'99-P.R. China SN

400μg FA

800μg MV

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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)

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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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• Promote supplement use: CDC, IOM, MoD, NCFA, states, local agencies

- use health communication and education efforts

Ways of achieving adequate folic acid

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Use and Knowledge of Folic AcidUse and Knowledge of Folic Acid Women of Childbearing AgeWomen of Childbearing Age

Took folic acid daily

Heard of folic acid

Knew FA should be takenbefore 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%

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28%32% 32% 34%

29%33% 32%

0

10

20

30

40

50

1995 1997 1998 2000 2001 2002 2003

Percent women taking vitamin with folic acid dailyAll women age 18-45

Per

cent

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• 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 - Add folic acid to all products made with “enriched” flour to contain 140 ug/100g “enriched” flour to contain 140 ug/100g

-- Approve the use of health claims on products Approve the use of health claims on products that contain “significant” amounts of folic acidthat 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

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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

20ng/mL

Serum folate

13.0

Before After

ng/mL

159.9

263.6

0

50

100

150

200

250

300

350Red blood cell folate

Before After

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Change in U.S. NTD birth prevalence per 10,000 by fortification status

(NCHS Birth Certificate Data, 45 states)

PR

(95% CI)

11%1.031.16Anencephaly

23%2.022.62Spina bifida

% decline

After

Mandatory

(0.70-0.84)

0.77

(0.78-0.95)

0.89

Before

None

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Change in U.S. NTD prevalence per 10,000 by fortification status

(NBDPN, 24 programs)

PR

(95% CI)

14%2.12.5Anencephaly

33%3.55.1Spina bifida

% decline

After

Mandatory

(0.63-0.73)

0.67

(0.78-0.95)

0.86

Before

None

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

U.S.

Actual NTD

% decline

50%-70%

Goal - NTD

% decline

20%-30%

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Folic Acid Preventable Neural Tube DefectsAre 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

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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 infolic 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

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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 allfolic-acid preventable birth defects.

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National Folic Acid Campaign to Prevent Birth Defects, 1999 -