Folic Acid: What’s New? Karla Damus, RN, MSPH, PhD Dept Ob/Gyn and Women’s Health Albert Einstein College of Medicine March of Dimes Birth Defects Foundation

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 Mortality United States, 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 Mortality United States, 1998 Rate per 100,000 live births Source: National Center for Health Statistics, 1998 final mortality data Prepared by March of Dimes Perinatal Data Center, 2000

Leading Cause-Specific Infant Mortality Rates United States, 1988 and 1998 Rate per 100,000 live births Source: National Center for Health Statistics, 1988 and 1998 final mortality data Prepared by March of Dimes Perinatal Data Center, 2000

Leading Cause-Specific Infant Mortality Rates By Maternal Race, United States, 1998 Rate per 100,000 live births Source: National Center for Health Statistics, 1998 period linked birth/infant death data Prepared by March of Dimes Perinatal Data Center, 2000

Leading Causes of Infant Deaths United States, 1998 Source: National Center for Health Statistics, 1998 period linked birth/infant death data Prepared by March of Dimes Perinatal Data Center, 2000

Prevalence of NTDs in US Neural tube defects (NTDs) are a group of malformations of the developing brain and spine, 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.

Open Neural Tube Defect Neural tube defects are fairly common. Here is a large meningomyelocele. Such defects can be suggested by a elevated maternal serum alpha-fetoprotein.

Anencephaly The eyes appear proptotic with anencephaly because of the lack of the skull. Note the low set external ear.

Data not available for these states Preliminary Neural Tube Defect Rates by State,

Relative Risk for Spina Bifida By Race/Ethnicity, U.S., *Based on 16 state-based birth defects surveillance systems Source: CDC, Teratology, July/August 1997 Prepared 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 Rate per 100,000 live births Source: National Center for Health Statistics, 1996 period linked birth/infant death file Prepared 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 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

Structure of Tetrahydropteroylpoly-  -glutamate Source: Shane. Folate Chemistry and Metabolism. Folates Folic Acid

Folic Acid (FA): Background FA deficiency described as "tropical macrocytic anemia" in 1930's Pure FA isolated from spinach in 1945 (folium Latin for leaf) Antifolates found to cause neural tube 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 Multivitamin & Folic Acid Neural Tube Defect Studies, Risk Ratio With 95% Confidence Intervals '95-California Randomized trials Non-randomized trials Observational 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, : 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

Summary 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 - 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

NTD rate per 1,000 births by red cell folate NTD Rate per 1,000 Births Red Cell Folate, ng/mL Daly et al., JAMA, 1995;274:1698 –

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 before conception through first 28 days Remember: > 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 (%) or

Consumption of Folic Acid & Dietary Folate: Effect on Red Cell Folate, Ireland Intervention method Red cell folate mcg/L Pre- / post- intervention Mean percentage change Supplement 400 mcg FA Fortified food 400 mcg FA Dietary folate 400 mcg folate Dietary advice Controls , p< , p< , NS + 16, NS + 5 Cuskelly et al., Lancet; 1996.

China-U.S. Collaborative Folic Acid Project for NTD Prevention, Shanghai Shanxi Province Zhejiang Province Jiangsu Province Hebei Province Beijing

Intervention = 400 mcg folic acid supplement daily NorthSouth 41% NTD Rate/ % No Pills Pills Berry RJ, et al., NEJM 1999; 341: China Folic Acid Community Intervention Program to Prevent the Occurrence of Neural Tube Defects,

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 Acid Congenital Heart Defects, Randomized trial Observational studies Outflow tract Birth Defect Type Septal defects All heart defects Coarctation Scanlon Czeizel Botto Czeizel Botto Shaw Czeizel Werler Botto Risk Ratio and 95% CI

Multivitamin Use/Folic Acid Selected Non-NTD, Non-CHD Birth Defects Risk Ratio and 95% CI Oro-facial clefts Limb Urinary tract All defects except NTD Randomized trial Non-randomized trial Observational studies Czeizel Shaw Yang Li Shaw Hayes Tolarova Czeizel Werler CL +/- CP CP alone

March of Dimes National Folic Acid Campaign: 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 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= Survey: N= Survey: N= 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 Awareness Have You Heard of Folic Acid? Percentage of women ages 18-45

Folic Acid-Specific Knowledge March of Dimes Folic Acid Survey Percentage of women ages 18-45

Daily Use of Vitamin Containing Folic Acid March of Dimes Folic Acid Survey Percentage of women ages * Goal for non-pregnant women

Characteristics of Non-Pregnant Women Taking Daily Supplement with Folic Acid March of Dimes Folic Acid Survey, 2000

Source of Information on Folic Acid March of Dimes Folic Acid Survey 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

OB/GYN Baseline Survey Patient Folic Acid Recommendations Percent 2001 Goal

Selected Responses from March of Dimes Provider Survey on Folic Acid

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 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

Daisy Fuentes is not pregnant. But she is taking folic acid just in case. A multivitamin with folic acid every day, as part of a healthy diet, helps prevent birth defects of the brain and spine. Start now, before you even think about getting pregnant. Some studies show it may also help protect women from cervical and colon cancer.

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 Acid Member Organizations Professional Associations Government Agencies Health and Human Services Non-Profits Industry Associations

Reaching the Goal What 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, Year Rate per 10,000 births Boston Providence Rochester NY Atlanta U.S.

? Prevalence of Anencephaly and Spina Bifida, Livebirths, Atlanta, Rate per 10,000 Year Multivitamin Change Prenatal Diagnosis ?

Prevalence of Anencephaly and Spina Bifida, Births and Terminated Pregnancies, Atlanta, Rate per 10,000 Year Adjusted ASB Rate Births Terminated Pregnancies

Prevalence of Anencephaly and Spina Bifida, Births and Terminated Pregnancies, Atlanta, Rate per 10,000 Year Adjusted ASB Rate Terminated Pregnancies Births Fortification 1998 ? ?