Folic Acid Supplementation: Reducing the Risk of Neural Tube Defects

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Folic Acid Supplementation Reducing the Risk of
Neural Tube Defects

• Pregnancy Foresight Project, Swedish Medical
  Center, Seattle, WA
• Based on a presentation developed by, and with
  permission from, Karla Damus, RN, MSPH, PhD
• Dept Ob/Gyn and Womens Health
• Albert Einstein College of Medicine
• Senior Research Associate - March of Dimes
• kdamus_at_marchofdimes.com

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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 infants life and throughout the
  womans childbearing years
• Folic acid supplementation is a key preconception
  factor in preventing neural tube defects

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Most Pregnancies Are Unplanned!

• About half of all pregnancies are unplanned
• Unplanned pregnancies are most common among teens
• Depending on the age of the woman, the percentage
  of unplanned pregnancies varies from 33 78

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Unintended Pregnancies United States, 1994
Percent
Source National Survey of Family Growth,
1995 Prepared by March of Dimes Perinatal Data
Center, 1998
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Part I

• Definition and Epidemiology of
• Neural Tube Defects

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

• Occur in about 1-2/1000 births in the US
• Most babies with NTDs are born to women with no
  risk factors
• Racial/ethnic variation in incidence of NTDs

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Secular trends of spina bifida at birth per
10,000 births, North America, 1890-1990.
30
25
Boston Providence
20
Rate per 10,000 births
15
Atlanta
10
Rochester
5
NY
U.S.
1930
1940
1890
1900
1910
1920
1950
1960
1970
1980
1990
Year
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Prevalence of Anencephaly and Spina
BifidaMetropolitan Atlanta Congenital Defects
Program1968 - 2001
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Multivitamin Change - 1973
Prenatally Diagnosed Cases
Hospital-based LB SB Babies
20
Prenatal Diagnosis - 1984
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Before Fortification
After Fortification
Rate per 10,000
10

5
0
68
71
74
77
80
83
86
89
92
95
98
01
Year of Birth
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Relative Risk for Spina Bifida By
Race/Ethnicity, U.S., 1983-1990
Based on 16 state-based birth defects
surveillance systems Source CDC, Teratology,
July/August 1997 Prepared by March of Dimes
Perinatal Data Center, 1999
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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
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NTDs Among Hispanic Infants

• Hispanic infants, particularly US-born Mexicans
  are at greatest risk for NTDs
• In 6 selected states, Hispanic infants had a
  significantly higher rate of NTDs than
  non-Hispanic white infants

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Part II

• Folic Acid Supplementation to Prevent NTDs

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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

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Definitions

• FOLIC ACID (FA) pteroylglutamic acidsynthetic,
  used in fortified foods supplements
• FOLATES pteroyl - poly - glutamic acidappear
  naturally in foods or are formed in vivo

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Structure of Tetrahydropteroylpoly-g-glutamate
Folates
Folic Acid
Source Shane. Folate Chemistry and Metabolism.
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Folic Acid (FA) and Its Relationship to NTDs

• FA deficiency described as tropical macrocytic
  anemia in the 1930s
• Pure FA isolated from spinach in 1945 (folium-
  Latin for leaf)
• NTDs linked to antifolates, 1950s
• RBC folate decrease in NTD mothers, 1976
• Essentially all clinical studies of FA, 1981-99
  reported a 50-85 decrease in NTDs

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Multivitamin Folic Acid Neural Tube Defect
Studies, 1980-1999
'80-Smithells
'81-S. Wales
'88-Atlanta
'89-W. Australia
'89-CA/Illinois
'89-Boston
'90-Cuba
'91-UK-MRC
Randomized trials
'92-Hungary
Non-randomized trials
'93-New England
Observational studies
'95-California
'99-P.R. China
1.0
0.0
0.2
0.4
0.6
0.8
1.2
1.4
1.6
1.8
2.0
2.2
2.4
Risk Ratio With 95 Confidence Intervals
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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

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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

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NTD rate per 1,000 births by red cell folate
12
10
8
NTD Rate per 1,000 Births
6
4
2
0
400
600
800
200
Red Cell Folate, ng/mL

Daly et al., JAMA, 19952741698 1702.

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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

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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
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Dietary Folates/FA
Food Avg. µg in serving
Bioavailability ()
orange juice 109 43 spinach 102 63 turnip
greens 85 ? Asparagus 101 ? pinto beans 147
? beef liver 184 50 fortified bread (slice)
35 100 fortified
noodles 192 100 fortified brkf. Cereal 100 or
400 100
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Consumption of Folic Acid Dietary
Folate Effect on Red Cell Folate, Ireland 1996.
Mean percentage change
Red cell folate mcg/L Pre- / post- intervention
Intervention method
Supplement 400 mcg FA
351 - 492
40 p
Fortified food 400 mcg FA
326 - 498
52 p
Dietary folate 400 mcg folate
366 - 394
11, NS
345 - 399
Dietary advice
16, NS
326 - 335
Controls
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Cuskelly et al., Lancet 1996.
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Drugs that Interfere with Folic Acid

• Valproic acid (Depakene)- anitconvulsant
• Phenobarbital, phenytoin (Dilantin),
  carbamazapine (Tegretol), primidone (Mysoline)-
  anit-seizure
• Cimetidine (Tagamet)- for heartburn and reflux
• Beta blockers and calcium-channel blockers used
  for HBP and certain disorders
• Cholestyramine (Locholest, Questran)-
  cholesterol
• Antibiotic combination of trimethoprim and a
  sulfonamide (Bactrim, Septra) commonly used for
  UTI
• Triamterene (Dyrenium)- diuretic for HBP
• Sulfasalazine (Azulfidine)- for ulcerative
  colitis other inflammatory conditions

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Conditions that Require More Folic Acid

• History of NTD affected pregnancy (4.0mg daily)
• History of NTD
• Diabetes
• Alcoholism, alcohol abuse
• Smoking
• Illicit drug use
• Obesity
• Absorption disorders
• Infection with HPV
• Some prescribed medications
• Some OTC (NSAIDs)

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Folic Acid Deficiency May Reduce Risk of Health
Problems

• Spontaneous pregnancy loss (recurrent)
• Low birth weight and prematurity
• Atherosclerotic vascular disease (stroke, CAD)
• Colorectal and cervical cancer
• Acute Leukocytic Leukemia
• Alzheimers Disease

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SummaryFolic Acid - Neural Tube Defect Science

• Increasing blood/RBC folate concentration
  decreases the risk of NTDs
• Consumption of 400 micrograms of folic acid daily
  prior to conception - as part of a healthy diet -
  decreases the risk of NTDs in all populations up
  to 70
• Ethnic and genetic variations in NTD risk remain
  poorly characterized

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China-U.S. Collaborative Folic Acid Project
for NTD Prevention, 1993-1996.
Beijing
Hebei Province
Shanxi Province
Jiangsu Province
Shanghai
Zhejiang Province
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China Folic Acid Community Intervention Program
to Prevent the Occurrence of Neural Tube
Defects, 1993 - 1996
Intervention 400 mcg folic acid supplement
daily
No Pills
Pills
5.0
4.0
85
3.0
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NTD Rate/1000
2.0
1.0
0.0
North
South
Berry RJ, et al., NEJM 1999 3411485-90
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Multivitamin Use/Folic Acid Congenital Heart
Defects, 1995-2000
Birth Defect Type
Randomized trial
Observational studies
All heart defects
Outflow tract
Septal defects
Coarctation
Risk Ratio and 95 CI
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Multivitamin Use/Folic Acid Selected Non-NTD,
Non-CHD Birth Defects
All defects except NTD
Randomized trial
Czeizel
Non-randomized trial
Observational studies
Hayes
Oro-facial clefts
Shaw
Tolarova
Czeizel
Werler
CL /- CP
CP alone
Shaw
Limb
Yang
Werler
Li
Urinary tract
Werler
1.0
0.0
0.2
0.4
0.6
0.8
1.2
1.4
1.6
1.8
2.0
5.0
Risk Ratio and 95 CI
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Part III

• Educating Physicians and Patients about Folic
  Acid Supplementation

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Three Approaches for Changing Behavior
Women
Professional Education
Community Action
Mass Media
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Folic Acid to Prevent NTDs

• 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

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March of Dimes Folic Acid Campaign Evaluation

• National telephone surveys conducted by Gallup in
  1995, 1997, 1998, 2000 and 2002
• Surveys designed to evaluate womens 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)

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MOD FA Campaign Evaluation, cont.

• 1995 Survey N2010
• 1997 Survey N2001
• 1998 Survey N2115
• 2000 Survey N2000
• 2002 Survey N2004
• 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

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Folic Acid AwarenessHave You Heard of Folic Acid?
Percentage of women ages 18-45
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Folic Acid-Specific KnowledgeMarch of Dimes
Folic Acid Survey
Percentage of women ages 18-45
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Daily Use of Vitamin Containing Folic Acid
March of Dimes Folic Acid Survey
Percentage of women ages 18-45
Goal for non-pregnant women
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Characteristics of Women Taking Daily Supplement
with Folic AcidMarch of Dimes Folic Acid Survey,
2002
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Source of Information on Folic AcidMarch of
Dimes Folic Acid Survey, Selected Years
Percentage of women aware of folic acid
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Reasons Why Women Do Not Take a Multivitamin
Daily March of Dimes Folic Acid Survey, 2002
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Things Women Reported Might Encourage them to
Take a Multivitamin DailyMarch of Dimes Folic
Acid Survey, 2002
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Folic Acid Knowledge and Behavior 1995 and 2002
Percentage of women ages 18-45
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Summary

• Between 1995 and 2002, folic acid awareness among
  women of childbearing age increased from 52 to
  80, meeting the March of Dimes goal for this
  objective
• Despite an increase in awareness, in 2002
• 1 in 5 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
• In 2002, 1 in 3 women (33) reported consuming a
  multivitamin containing folic daily

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Summary (contd)

• When asked where they learned about folic acid
• More than half of women reported the media as
  their source of information
• Only 25 of women identified their health care
  provider
• More than one-third (34) said they would be more
  likely to take a vitamin supplement daily if
  their health care provider advised them to do so

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Summary (contd)

• In 2002, nearly one in four women (24) did not
  take a multivitamin daily because they forget to
  take them
• Most women (90) who did not take a multivitamin
  daily said they would be very likely or somewhat
  likely to do so if their health care provider
  recommended it

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Folic Acid Education in Washington State

• Surveyed physicians and patients at 6 Family
  Practice and Obstetric clinics
• Rural and urban settings
• Included 34 physicians, 120 pregnant women, 104
  non-pregnant women

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Folic Acid Education in Washington State

• 74 of physicians do not discuss folic acid
  supplementation with their non-pregnant patients
• 53 of non-pregnant patients did not recall a
  discussion of folic acid supplementation

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Folic Acid Education in Washington State

• More than 80 of physicians discuss folic acid
  supplementation with their pregnant patients
• More than 80 of pregnant patients recall a
  discussion of folic acid supplementation with
  their physician

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Folic Acid Education in Washington State

• Folic acid education is reaching the wrong
  group of women, i.e. supplementation during
  pregnancy is too late to prevent NTDs
• Goal must be to reach pregnancy
  non-contemplators, and those seeking to become
  pregnant

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Part IVFolic Acid Supplementation in the
Hispanic Community

• Sociocultural Issues

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NTDs The Hispanic Community

• NTDs more common in Hispanic community than
  other US ethnic groups
• Primary Care Providers should focus extra
  attention on educating Hispanic community about
  preconception folic acid supplementation

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Focus Groups Findings in the Hispanic Community

• A summary of the salient points and
  recommendations for Primary Care Providers

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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

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Hispanic Women Challenges

• Hispanic women less likely to have heard the
  folic acid message, in Spanish or English
• Less likely to know about importance of folic
  acid before pregnancy
• Hispanic women less likely to take vitamin
  supplement, though there is considerable
  variation in this behavior
• Fear of weight gain from vitamins

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Hispanic Women Opportunities

• Hispanic women receptive to message of before
  pregnancy,
• Very willing to make behavior change for health
  of future babies
• Women 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

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Hispanic Women Opportunities for the Primary
Care Provider

• Emphasize importance of good diet, healthy
  mothers and healthy babies
• Advise women that vitamins do not cause weight
  gain
• Vitamins (i.e. folic acid) before pregnancies are
  particularly important for mothers-to-be

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Hispanic Women Opportunities for the Primary
Care Provider

• Vitamins can improve the health of the mother
  even when she is not pregnant
• Literate and low literate Hispanic women like
  messages in posters and fotonovelas
• Waiting room, exam rooms, and bathrooms good
  place for posters and fotonovelas

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Women Folic Acid From Freshmen Through the
Forties

• The take-home message for all women during their
  reproductive years

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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.
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