Folic Acid: What’s New? Karla Damus, RN, MSPH, PhD Dept Ob/Gyn and Women’s Health Albert...

Folic Acid:Folic Acid:What’s New?What’s New?

Karla Damus, RN, MSPH, PhDDept Ob/Gyn and Women’s HealthAlbert Einstein College of Medicine

March of Dimes Birth Defects [email protected]

March of Dimes Birth Defects Foundation

Mission:• To improve infant outcomes by preventing infant mortality

and birth defects

The Continuum of Reproductive Health• Improving health of infants requires focusing on the entire

spectrum of reproductive health which extends from prior to conception through the first year of an infant’s life and throughout the woman’s childbearing years

• Preconceptional health is the cornerstone of healthy infants, children, families and communities

Infant MortalityUnited States, 1915-1998

0

20

40

60

80

100

120

1915 1925 1935 1945 1955 1965 1975 1985 1995

Rate per 1,000 live births

Source: National Center for Health Statistics, final mortality data

Prepared by March of Dimes Perinatal Data Center, 2000

Ten Leading Causes of Infant MortalityUnited States, 1998

11.2

11.7

19.1

20.7

24.4

32.9

34.1

71.6

104.0

157.6

0 20 40 60 80 100 120 140 160 180

Pneumonia/Influenza

Hypoxia/Birth Asphyxia

Accidents

Infections

Placenta, Cord Comp.

RDS

Maternal Preg.Comp.

SIDS

Preterm/LBW

Birth Defects


Source: National Center for Health Statistics, 1998 final mortality data


Leading Cause-Specific Infant Mortality RatesUnited States, 1988 and 1998

208.2

83.6

140.1

36.1

81.4

157.6

104.0

71.6

32.934.1

0

50

100

150

200

250

Birth Defects Preterm /LBW

SIDS MaternalPreg. Comp.

RDS

1988 1998


Source: National Center for Health Statistics, 1988 and 1998 final mortality data


Leading Cause-Specific Infant Mortality RatesBy Maternal Race, United States, 1998

154.2

71.359.5

26.9 26.3

180.2

277.6

137.9

73.3 71.8

0

50

100

150

200

250

300

Birth Defects Preterm /LBW

SIDS MaternalPreg. Comp.

RDS

White Black


Source: National Center for Health Statistics, 1998 period linked birth/infant death data


Leading Causes of Infant DeathsUnited States, 1998

Prematurity/LBW14.5% Circulatory 5.1%

Genitourinary 5.9%

Musculoskeletal 7.3%

Nervous Sys. 12.2%

Other 10.7%

Chromosomal 15.2%

Respiratory 15.5%

Heart 28.2%

RDS4.6%

Mat. Comp. ofPreg 4.8%

SIDS10.0%

All Other Causes44.2%

Birth Defects22.0%

Source: National Center for Health Statistics, 1998 period linked birth/infant death data


Prevalence of NTDs in US

• Neural tube defects (NTDs) are a group ofmalformations of the developing brain andspine, including anencephaly and spina bifida

• about 2500 births/yr in U.S. (1 in 1500 births)

• Birth defects are the leading cause of infant mortality causing 1 out 5 infant deaths

• About 7% of infant deaths due to birth defects are due to NTDs

Neural Tube Defects

Anencephaly: absence of the majority of the brain and surrounding area at birth.

Spina Bifida (“open spine”): defect of the spine that can cause paralysis of varying degrees.

Data not available for these states

Preliminary Neural Tube Defect Ratesby State, 1992-1996

Relative Risk for Spina Bifida By Race/Ethnicity, U.S., 1983-1990

RACE/ETHNICITY ADJUSTED RELATIVE RISK (95% CI)

White 1.00

Black 0.80 (0.72-0.88)

Hispanic 1.41 (1.26-1.58)

Asian/Pacific Islander 0.51 (0.38-0.70)

Native American 1.13 (0.74-1.74)

*Based on 16 state-based birth defects surveillance systemsSource: CDC, Teratology, July/August 1997Prepared by March of Dimes Perinatal Data Center, 1999

NTDs Among Hispanic Infants

• Hispanic infants, particularly US-born Mexicans are at greatest risk for NTDs.

• In a total of 6 selected states, Hispanic infants had a significantly higher rate of NTDs than non-Hispanic white infants.

• Not all birth defects surveillance programs collect data on Hispanic ethnicity.

Infant Deaths due to NTDs by Race/Ethnicity, United States, 1996

7.9

9.9

16.317.9

9.5

16.8 16.8

02

468

10121416

1820

Blacknon-

Hispanic

Whitenon-

Hispanic

Hispanic Mexican PuertoRican

Cuban Central /So.

American


Source: National Center for Health Statistics, 1996 period linked birth/infant death filePrepared by March of Dimes Perinatal Data Center, 1999

Healthy People 2010 MCH Objectives Related to Folic Acid and Neural Tube Defects

• Reduce the incidence of spina bifida and other NTDs to no more than 3 per 10,000 live births– 1996 Baseline: 6

• Increase the proportion of women who consume 400 mcg of folic acid daily to at least 80%– 1997 Baseline: 30%

• (Developmental) Increase mean red blood cell folate among women 18-44 years– Potential data source: National Health And Nutrition Examination Survey (NHANES)

What is Folic Acid

• Folate is a water-soluble B vitamin derived from folate polyglutamates

• Found in green leafy vegetables, organ meats, some fresh fruits

• Susceptible to destructive oxidation with 50-95% destroyed in canning and cooking

Definitions

• FOLIC ACID (FA) = pteroylglutamic acid

synthetic, used in fortified foods & supplements

• FOLATES = pteroyl - poly - glutamic acid

appear naturally in foods or are formed in vivo

Folic Acid (FA): Background

• FA deficiency described as"tropical macrocytic anemia"in 1930's

• Pure FA isolated from spinachin 1945 (folium Latin for leaf)

• Antifolates found to cause neuraltube defects (NTD's) in 1950's

Folic Acid (FA) Deficiency

• FA deficiency redefined in 1990's• hematological, embryonic, fetal, pregnancy health

• Now clear that FA deficiency is common

• FA deficiency predisposes to:

• NTD’s

• Other birth defects (cleft lip +/- palate, cardiac, etc)

• Low birth weight and prematurity

• Atherosclerotic vascular disease (stroke, CAD)

• Colorectal and cervical cancer

'81-S. Wales'80-Smithells

'90-Cuba'91-UK-MRC'92-Hungary

'88-Atlanta'89-W. Australia'89-CA/Illinois'89-Boston

'93-New England

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

Multivitamin & Folic AcidNeural Tube Defect Studies, 1980-1999

Risk Ratio With 95% Confidence Intervals

'95-California

Randomized trialsNon-randomized trialsObservational studies

2.4

'99-P.R. China

NTDs Relationship to FA Status

• NTD’s linked to antifolates, 1950's

• RBC folate in NTD mothers, 1976

• Essentially all clinical studies of FA, 1981-99: 50-85% in NTD’s

• Biochemical basis of NTD’s not known ( DNA; homocysteine ?)

FA: Role in Metabolism

Coenzyme in 1-carbon transfer reactions:

• biosynthesis of purines & pyrimidines (DNA/RNA)

• biosynthesis of serine & methionine

• degradation of histidine

• degradation of homocysteine

Folic Acid Recommendations

USPHS September, 1992• All women of childbearing potential should

consume 0.4 mg (400 micrograms) of folic acid daily

Food & Nutrition Board of IOM, 1998• Men (14 yr & older) 400 µg any source

• Women (14 yr & older) 400 µg synthetic + food

• Pregnancy 600 µg synthetic + food

• Lactation 500 µg any source

SummaryFolic Acid - Neural Tube Defect Science

• Increasing blood/RBC folate concentration decreases the risk of NTD’s

• Consumption of 400 micrograms of folic acid daily prior to conception - as part of a healthy diet - decreases the risk of NTD’s in all populations up to 70%

• Ethnic and genetic variations in NTD risk remain poorly characterized

Bioavailability of Food Folates

• Folates are lost from foods by:- preparation (heat, oxidation, leaching into

water)- inhibition of essential gut enzymes by inhibitors in food, extremes in pH and rapid transit time

• Under controlled conditions, 30-80% of folate is absorbed

• One careful 92-day metabolic study found no more than 50% bioavailability of various food folates

FA to Prevent NTDs

• Diet

• Fortification of grain products with folic acid

• Multivitamin with 0.4 mg FA from beforeconception through first 28 daysRemember: > 50% pregnancies unplanned

Dietary Folates/FA

orange juice

spinach

turnip greens

asparagus

pinto beans

beef liver

fortified bread (slice)

fortified noodles

fortified brkf. Cereal

Food Avg. µg in serving Bioavailability (%)

109

102

85

101

147

184

35

192

100 or 400

43

63

50

100

100

100

Consumption of Folic Acid & Dietary Folate:Effect on Red Cell Folate, Ireland 1996.

Intervention method

Red cell folate mcg/L Pre- / post- intervention

Meanpercentage

change

Supplement400 mcg FA

Fortified food400 mcg FA

Dietary folate400 mcg folate

Dietary advice

Controls

351 - 492

326 - 335

345 - 399

366 - 394

326 - 498

+ 40, p<0.05

+ 52, p<0.05

+ 11, NS

+ 16, NS

+ 5

Cuskelly et al., Lancet; 1996.

China-U.S. Collaborative Folic Acid Project for NTD Prevention, 1993-1996.

Shanghai

Shanxi Province

Zhejiang Province

Jiangsu Province

Hebei ProvinceBeijing

Intervention = 400 mcg Intervention = 400 mcg folic acid supplement dailyfolic acid supplement daily

0.00.0

1.01.0

2.02.0

3.03.0

4.04.0

5.05.0

NorthNorth SouthSouth

41% 41%

NT

D R

ate

/10

00

NT

D R

ate

/10

00 85%85%

No PillsNo Pills PillsPills

Berry RJ, et al., NEJM 1999; 341:1485-90

China Folic Acid Community Intervention ProgramChina Folic Acid Community Intervention Program to Prevent the Occurrence of Neural Tube Defects, 1993 -

1996

Summary of Folic Acid - Neural Tube Defect Science

• Increasing blood/RBC folate concentration decreases the risk of NTD’s

• Consumption of 400 micrograms of folic acid daily prior to conception decreases the risk of NTD’s in all populations up to 85%

• Racial and ethnic variations in NTD risk• Genetic variations in NTD risk remain

uncharacterized

Multivitamin Use/Folic AcidCongenital Heart Defects, 1995-2000

Randomized trial

Observational studies

Outflow tract

Birth Defect Type

Septal defects

All heart defects

Coarctation

Scanlon

Czeizel

Botto

Botto

Czeizel

Botto

Shaw

Czeizel

Werler

Werler

Botto0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.05.0

Risk Ratio and 95% CI

Multivitamin Use/Folic AcidSelected Non-NTD, Non-CHD Birth Defects

Risk Ratio and 95% CI

Oro-facial clefts

Limb

Urinary tract

All defectsexcept NTD

Randomized trialNon-randomized trialObservational studies

Czeizel

ShawYang

Li

ShawHayes

Tolarova Czeizel

Werler

Werler

Werler

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 5.0

CL +/- CPCP alone

March of DimesNational Folic Acid Campaign: 1999-2002

• March of Dimes Campaign goal is to reduce NTD’s by at least 30% by 2002

• Behavior modification campaign is outcome driven, with three strategies:– professional education– community action– mass media

• National Council on Folic Acid (see March of Dimes website for members www.modimes.org)

• Since 1998, March of Dimes is the lead agency• Partners in campaign

Three Approaches for Changing Behavior

Folic Acid to Prevent NTD’s

• Behavior Strategy; Multivitamin containing 400 micrograms folic acid - as part of a healthy diet - beginning before conception

• Remember: neural tube closes by day 28 pregnancy

• Legislative Strategy; Increase consumption of folic acid by fortification of grain products with folic acid - required of “enriched grain products” since January 1998

• Remember: > 50% pregnancies unplanned

Mass Media:

Increase awareness of folic acid benefits

• TV PSA’s - Traffic Baby, Before you know it, Ready-Not, Stork 1 & 2, Shopping Carts

• Print PSA’s

• Latina Print Materials

• Have conducted continuing evaluation of awareness, knowledge, and behavior

• Let’s look at several TV PSA’s now

March of Dimes Folic Acid Campaign Evaluation

• National telephone surveys conducted by Gallup in

1995, 1997, 1998 and 2000

• Surveys designed to evaluate women’s changing

awareness and reported behaviors related to folic

acid and other pre-pregnancy health issues

• Targeted English speaking women of reproductive

age (18 to 45 years)

March of Dimes Folic Acid Survey

• National telephone surveys conducted by the Gallup Organization in 1995, 1997, 1998 and 2000 commissioned by the March of Dimes and supported by the CDC

• Surveys were designed to ascertain women’s awareness and reported behaviors related to folic acid and other pre-pregnancy health issues

• Targeted English speaking women of reproductive age (18 to 45 years)

• 1995 Survey: N=2010

• 1997 Survey: N=2001

• 1998 Survey: N=2115

• 2000 Survey: N=2000

– oversampled women who were pregnant in past 2 years

• Based on these sample sizes 95% confident that the margin of error attributable to sampling and other random effects could be +/- 3 percentage points

• The margin of error is greater for any subset analyses

• Error bias can also be introduced into opinion polls due to question wording and practical difficulties in obtaining responses from telephone interviews

Folic Acid AwarenessHave You Heard of Folic Acid?

52

66 6875

80

0

25

50

75

100

1995 1997 1998 2000 2001 Goal

Percentage of women ages 18-45

Folic Acid-Specific KnowledgeMarch of Dimes Folic Acid Survey

4

1013 14

2

6 710

20

30

0

5

10

15

20

25

30

1995 1997 1998 2000 2001 Goal

Prevents birth defects Should be taken before pregnancy


Daily Use of Vitamin Containing Folic Acid March of Dimes Folic Acid Survey

2832 32

34

25

30 29

40

32

0

10

20

30

40

1995 1997 1998 2000 2001 Goal*

All Women Women Not Pregnant


* Goal for non-pregnant women

Characteristics of Non-Pregnant Women Taking Daily Supplement with Folic Acid

March of Dimes Folic Acid Survey, 2000

39

35

32

23

37

30

14

36

31

26

0 10 20 30 40 50

$50,000 +

$40-49,999

$25-39,999

<$25,000

Any College

HS Grad

<HS

35-45

25-34

18-24

Percentage of non-pregnant women ages 18-45

Source of Information on Folic AcidMarch of Dimes Folic Acid Survey

30

10

22 23 24

1315

19 20

31

35 36

0

5

10

15

20

25

30

35

40

1995 1997 1998 2000

Magazine/Newspaper Radio/Television Health care providers

Percentage of women aware of folic acid

Health Professional Research Results: Women want to hear from health care providers

Doctors respond to questions, but often don’t have time to do proactive counseling

Nurses and nutritionists are

willing and able to counsel

women about folic acid

Important to have information

specific to health disciplines

Health Care Provider Education:

Women want to hear about folic acid from their health care provider

• Health Care Provider Resource Kit

• Association of Schools of Public Health Grant

• Grand Rounds

• New Display Board

12.124.0 28.726.8

0

20

40

60

Rarely Sometimes Most times Always

50.0

OB/GYN Baseline SurveyPatient Folic Acid Recommendations

Percent

2001Goal

Selected Responses from March of Dimes Provider Survey on Folic Acid

1998 Ob/Gyn 1999 ACNM 1999 AWHONN 1999 NANN

n=463 n=136 n=319 n=276Folic acid helps to: prevent birth defects 97.4 99.3 98.4 100.0 prevent low birthweight 30.7 40.7 51.1 64.4 prevent cardiovascular disease 40.0 48.9 45.8 46.4 prevent stroke 30.2 43.7 50.2 52.1 prevent fibroids (false) 44.1 23.7 12.9 5.7 prevent colorectal cancer 24.4 43.7 39.8 40.9 decrease homocysteine 37.2 43.7 37.0 37.5

USPHS daily rec 400 mcg 69.9 87.5 51.7 34.3Always recommend folic acid 28.7 45.9 42.6 65.2Always provide preconcep care 15.0 25.0 11.3 6.0Know grains fortified at 140 mcg 14.9 5.3 4.1 2.4Not likely to get fa from diet alone 55.9 63.0 69 67.6Begin fa at least 1 mo prior to preg 89.0 97.0 90.6 86.350% of preg in US unintended 38.0 39.8 26.0 24.3Provider takes MV daily 25.7 35.3 43.0 43.5

Percent of Correct Responses

MOD Folic Acid Surveys Summary

• While awareness of the benefits of folic acid is increasing slightly, only 3 in 4 women were aware of folic acid in 2000– Only 1 in 7 women knew that folic acid can

prevent birth defects

– 9 out of 10 women did not know that folic

acid should be taken prior to to pregnancy

• Only 1 in 3 women reported consuming a multivitamin containing folic daily

• When asked where they learned about folic acid:

– More than half of women reported the media as their source of information

– Only 1 in 5 women identified their health care provider

• Increases in the proportion of women who consume 400 micrograms of folic acid daily will require continued efforts in:

– Health professional education

– Community action

– Mass media

Targeting High-Risk Populations: Hispanic Women’s Initiative

• Partnering of 4 chapters with the National Alliance of Hispanic Health Community Based Organizations (CBO’s) in:

*Chicago

*Los Angeles

*San Diego

*Phoenix

• Implement a Media and a Word-of-mouth campaign

Focus Group Findings: Hispanic Women

• Sense of fatalism

• Highlighting Latinas’ greater risk creates an

overwhelming emotional response

• “Vitamins” are perceived negatively

• Most women accept that one day they will

get pregnant

• 18-24 year olds are attracted to health and

beauty message

Hispanic Women: Challenges

• Hispanic women less likely to have heard the message, in Spanish or English

• Less likely to know about importance of folic acid before pregnancy

• Hispanic women less likely to take vitamin supplement (even though they report their diet is “worse” in US)

• Some have later entry to prenatal care

• Fear of weight gain from vitamins

Hispanic Women: Opportunities

• Welcome contemplator message of “before”, link message to family’s health

• Very willing to make behavior change for health of future babies

• Acknowledge diet is worse in US and need to make changes

• Younger Hispanic women link general health to beauty

• Open to hear weight gain has no basis in fact

Community Action:

Keep community aware of and focused on health benefits of folic acid

• State Councils

• Campus/Youth Action Kits

• Community Action Kits

National Council on Folic AcidMember Organizations

• Professional Associations

• Government Agencies

• Health and Human Services Non-Profits

• Industry Associations

Reaching the GoalWhat Will It Take?

•Multi-year commitment

•Multi-faceted and comprehensive

approaches

•Incorporating the message in everything

we do in our communities and our

professions

The March of Dimes, the Centers for Disease Control & all members of the National Council on Folic Acid recommends that --

All women of childbearing potential consume 400 micrograms of folic acid every day as part of a healthy diet

Secular trends of spina bifida at birth per 10,000 births, North America, 1890-1990.

10

20

30

Year

1890 1900 1910 19201930 19401950 1960 1970 1980 1990

5

15

25

Rat

e pe

r 10

,000

birt

hs

BostonProvidence

Rochester

NY

Atlanta

U.S.

?

Prevalence of Anencephaly and Spina Bifida, Livebirths, Atlanta, 1968 - 1997

0

5

10

15

20

25

Rat

e pe

r 10

,000

Year68 72 76 80 84 88 92 9670 74 8278 86 90 94 98 00

Multivitamin Change - 1973

PrenatalDiagnosis - 1984

?

Prevalence of Anencephaly and Spina Bifida, Births and Terminated Pregnancies,

Atlanta, 1968 - 1997

0

5

10

15

20

25

Rat

e pe

r 10

,000

Year

Adjusted ASB Rate

BirthsTerminated Pregnancies

68 72 76 80 84 88 92 9670 74 8278 86 90 94 98 00

Prevalence of Anencephaly and Spina Bifida, Births and Terminated Pregnancies,

Atlanta, 1968 - 1997

0

5

10

15

20

25

Rat

e pe

r 10

,000

Year

Adjusted ASB Rate

Terminated Pregnancies

68 72 76 80 84 88 92 9670 74 8278 86 90 94 98 00

Births

Fortification 1998

??

Folic Acid: What’s New? Karla Damus, RN, MSPH, PhD Dept Ob/Gyn and Women’s Health Albert...

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