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

Study LimitationsStudy Limitations

Low powerLow prevalence of exposureHomogeneous dietary exposure

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

RecommendationsRecommendations

Test this hypothesis in a Mexican American population more highly exposed to folic acid

Pursue all recommended prevention strategiesMotivate Mexican American women of

childbearing age to take folic acid routinelyFortify foods consumed by this population