Neural Tube Defects Among Mexican Neural Tube Defects Among Mexican Americans Living on the Texas-Mexico Border:Americans Living on the Texas-Mexico Border:
Effects of Folic Acid and Dietary FolateEffects of Folic Acid and Dietary Folate
Lucina Suarez, PhD
Kate Hendricks, MD
Texas Department of Health
Prepared by Zunera Gilani, 2002
Suggested ReadingsSuggested Readings Suarez L, Hendricks KA, Cooper SP, et al. Neural tube
defects among Mexican Americans living on the US-Mexico border : Effects of folic acid and dietary folate. Am J Epidemiol 2000; 152: 1017-23.
Shaw GM, Schaffer D, Velie EM,et al. Periconceptional vitamin use, dietary folate, and the occurrence of neural tube defects. Epidemiology 1995; 6: 219-26.
Harris JA, Shaw GM. Neural tube defects-why are rates high among populations of Mexican descent? Environ Health Perspect 1995; 103 (suppl 6): 163-4.
Hendricks KA, JS Simpson, Larsen RD. Neural tube defects along the Texas-Mexico border, 1993-1995.Am J Epidemiol 1999;149 : 1119-27.
Neural Tube DefectsNeural Tube Defects
NTDs are malformations of the developing brain and spinal cord
NTD closure occurs during the fourth week of embryosis
The most common NTDs are anencephaly and spina bifida
Numerous studies have shown a 50% to 100% reduction in NTDs by taking .4 mg of folic acid daily
NTD prevalence is higher among Mexican Americans (9-16 per 10,000) than non-Hispanic whites (6 per 10,000) and African Americans (5 per 10,000)
BackgroundBackgroundCameron County, on the Texas-Mexico border,
had the highest prevalence in the US since the 1970s--29 per 10,000 in 1991
Texas
MexicoCameron County
Brownsville
US Prevalence per 10,000 BirthsUS Prevalence per 10,000 Births
Hawaii 1988-94 7.2Iowa 1985-90 9.0California 1989-91 9.3Atlanta 1990-91 9.9Arkansas 1985-89 10.3South Carolina 1992-94 16.0
Prevalence in Mexican AmericansPrevalence in Mexican Americans(per 10,000 births) (per 10,000 births)
Cameron County, Texas 1990-92 21.2Texas-Mexico border 1993-95 14.9
Mexico-born 15.1
US-born 9.5California 1989-91
Mexico-born 16.0
US-born 6.8
Folic Acid SupplementsFolic Acid Supplements Estimated Risk Reduction from Clinical Trials
Author Location NTD Type Study SizeRisk Reduction
Laurence 1981 Wales Recurrence 111 57%
Smithells 1983 England Recurrence 1052 88%
Vergel 1990 Cuba Recurrence 214 100%
MRC 1991 Europe Recurrence 1195 72%
Kirke 1992 Ireland Recurrence 261 100%
Czeizel 1992 Hungary Occurrence 4156 100%
Milunsky 1989 USAOccurrence cohort
13870 73%
Folic Acid SupplementsFolic Acid SupplementsEstimated Risk Reduction from Case-Control Studies
Author Location Case:ControlRisk
Reduction
Winship, 1984 England 764:764 86%
Mulinare, 1988 Atlanta 181:1480 60%
Mills, 1989 Illinois-California 565:567 11%
Martinez-Frias, 1992 Spain 16736:16574 30%
Bower, 1992 Australia 75:150 89%
Werler, 1993 Boston-Philadelphia 232:1558 60%
Shaw, 1995 California 295:247 35%
Shaw 1995 : Results on Folic Acid Shaw 1995 : Results on Folic Acid Supplements by Race/EthnicitySupplements by Race/Ethnicity
OR 95% CI
Mexican American 1.0 0.4-2.1
Non-Hispanic White 0.6 0.4-1.1
African American 0.5 0.1-3.2
Shaw 1995: Results on Combined Shaw 1995: Results on Combined Folate Intake from Vitamins and DietFolate Intake from Vitamins and Diet
Folate µg Mexican American Non-Hispanic
<228 referent referent
228-399 1.0 (0.4-2.4) 0.6 (0.2-1.7)
400-999 0.8 (0.3-1.9) 0.6 (0.2-1.5)
≥1000 0.6 (0.2-2.0) 0.3 (0.1-0.8)
Specific Aims of Texas Border StudySpecific Aims of Texas Border Study
To determine the extent that preconception intake of:– supplemental folic acid– dietary folate alone– folic acid and folate from combined sources
reduces the risk of NTDs in Mexican American women
Case DefinitionCase Definition
Cases were ascertained through active surveillance of the 14 counties along the Texas-Mexico border (Jan 1995-May 2000)
Cases were identified from multiple sources including hospitals, birthing centers, midwives, genetic clinics, abortion clinics
Population-basedPopulation-basedCase-Control StudyCase-Control Study
Cases included all clinically apparent NTDs at all gestational ages prenatally diagnosed, induced or spontaneously aborted still or live born
Controls were randomly selected from normal live births, frequency matched by hospital and year
Measurement InstrumentsMeasurement InstrumentsIn-person interviews, English or Spanish,
one month postpartumExtensive mother questionnaire
health and reproductive history,
demographics, nutritional supplements,
drug use, environmental exposures98-item food frequency questionnaireExposure in the periconceptional period, 3 months
before to 3 months after conception
Main Exposure VariablesMain Exposure Variables
Folic acid supplements
prenatal vitamins, multivitamins or
single-ingredient folic acid tablets Dietary folate
based on food frequency questionnaireCombined supplemental folic acid and
dietary folate
Confounding VariablesConfounding Variables
maternal ageeducationannual incomecountry of birthcigarette smoking alcohol use
diabetesobesitygravidityprevious pregnancy loss prenatal care oral contraceptive use
Study Participation RatesStudy Participation Rates
Case women Control women
Identified for study 225 378
Completed interview 184 225
Refused interview 26 101
Moved 15 52
Distribution of CasesDistribution of Cases
NTD type 83 anencephaly84 spina bifida 17 encephalocele
Gestation41 <20 weeks70 >35 weeks
Pregnancy outcome94 live births 27 still births 4 miscarriages 59 elective
terminations
Demographic and Risk Factor Demographic and Risk Factor CharacteristicsCharacteristics
0
25
50
75
100
%
Cases
Controls
Crude ORs for NTD Risk FactorsCrude ORs for NTD Risk Factors
Risk Factor OR 95% CI
Age >25 years 0.9 0.6-1.3
Mexico-born 1.1 0.8-1.7
Education 7+ years 0.6 0.3-1.0
Cigarette smoking 1.8 1.0-3.0
Alcohol use 1.3 0.8-1.9
Diabetes 1.6 0.7-3.3
Obesity 1.8 1.1-2.8
Prior pregnancy loss 1.9 1.1-3.3
Daily Vitamin Use AmongDaily Vitamin Use Among
Case and Control WomenCase and Control Women
0
20
40
60
80
100
%
Case
Control
Use of Folic Acid-Containing VitaminsUse of Folic Acid-Containing Vitamins
0
20
40
60
80
100
-3 -2 -1 1+ 2+ 3+
Periconceptional Month
%
Single Folic AcidPrenatalMultivitamin
Frequency Distribution ofFrequency Distribution ofAverage Daily Dietary Folate IntakeAverage Daily Dietary Folate Intake
0
5
10
15
20
25
30
35
40
150 350 550 750 950 1150 1350 1550 2150Folate Intake (mcg)
Fre
quen
cy
Controls
Cases
Periconceptional Vitamin UsePericonceptional Vitamin Use
Vitamin Use
Case Women
Control Women
No. % No. %
None (6 month interval) 102 44.7 126 5.3
Preconception
Any use 1-3 months
before conception
11 6.0 10 4.4
Daily use every
month before conception
5 2.7 9 4.0
Postconception
(use 1-3 months after)
102 55.4 126 56.0
Effect of Preconceptional Use ofEffect of Preconceptional Use ofFolic Acid-Containing Vitamins on NTD RiskFolic Acid-Containing Vitamins on NTD Risk
OR 95% CI Crude 0.7 0.2-2.1 Adjusted 0.8 0.2-2.6
Odds ratios are compared to non-users aloneAdjusted for education, age, previous
pregnancy loss, and obesity
Effect of Dietary Folate on NTD RiskEffect of Dietary Folate on NTD Risk
Daily Folate Intake (mg/day) OR 95% CI
Adj OR†
95% CI
.925-.431 1.0‡ referent 1.0‡ referent
.432-.613 1.0 0.6-1.7 1.0 0.6-1.8
.614-.786 0.7 0.4-1.1 0.7 0.4-1.2
.787-2.10 0.7 0.4-1.3 0.8 0.4-1.4
Effect of Combined Dietary and Effect of Combined Dietary and
Supplemental FolateSupplemental Folate
Folate Intake
(mg/day) OR 95% CI Adj OR† 95% CI
<.400 1.0‡ referent 1.0‡ referent
.400-.999 0.8 0.5-1.3 0.9 0.5-1.4
≥1.000 0.7 0.3-1.3 0.7 0.3-1.4
Main FindingsMain Findings
Mild to no benefit in using folic acid containing vitamins (20% reduction)
30% risk reduction for combined intakes of ≥1.0 mg per day, adjusted for covariates
Underlying Population FactorsUnderlying Population Factors
Economically disadvantaged and medically underserved
Distinct gene admixture with Amerindian population
Traditional yet atypical dietary patternEnvironmental contaminants
– pesticides or fumonisinsHigher frequencies of specific folate pathway
gene polymorphisms
Potential BiasesPotential BiasesFood Frequency QuestionnaireFFQs less valid among low-educated
populationsFFQs overestimate absolute levels of folate
intakeReferenced a single period from 3 months
before to 3 months after conception (pregnancy influenced recall)
Potential BiasesPotential Biases
Differential recall period between cases and controls (ie, gestational age)
Differential participation rates (60% vs 82%)Controls demographically similar to source
population
Inconclusive results because of Inconclusive results because of methodological problemsmethodological problems
Almost no exposure to folic acidHomogeneous dietary exposuresSources of bias would push estimated
effects toward the null