birth defects

Birth Defects: Protection Against Environmental

Agents by Folic Acid

March 29, 2004Kelly Volcik

School of Public HealthHuman Genetics Center

Birth Defects: Protection by Folic Acid

• Birth defects– Causes, types, prevention

• Folate– Background, biochemistry

• Studies– Past, present, future

Birth Defects

• Abnormalities of structure, function, or metabolism present at birth

• Result in physical/mental disability, or are fatal

• Leading cause of death within 1st year of life

• >4,000 known birth defects

• Occur in 1 / 28 births

What Causes Birth Defects?

• Genetic and/or environmental factors

• ~60 - 70% of birth defects have unknown causes

Genetic Causes of Birth Defects

• Missing or abnormal gene

• Number and structure of chromosomes

Environmental Causes of Birth Defects

• Most commonly result of mother’s health and exposure

• Infections– Rubella, CMV

• Medications– Accutane, Thalidomide, AEDs

• Drugs/Alcohol

• Chemicals, Radiation, Water contamination, Air Pollution, Heavy metals

Environmental + Genetic Causes of Birth Defects

• Multifactorial inheritance

– Neural tube defects

– Cleft lip/palate

– Heart defects ?

Common Birth Defects:Neural Tube Defects

• Failure of the neural tube to close

• Occur within 1st month of pregnancy

• Spina Bifida: spinal column does not completely close around spinal cord

• Anencephaly: incompletely developed or absent brain

• Occur in 1 / 2,000 live births


Common Birth Defects: Cleft Lip/Palate

• Occur in 1 / 700-1,000 births

• Cleft lip: opening between upper lip and nose

• Cleft palate: opening between roof of mouth and nasal cavity

• Surgically repaired after birth


Common Birth Defects:Heart Defects

• Abnormal develop of the heart– Atrial & ventricular septal defects

– Coarctation of the aorta

• Most common: occur in 1 / 100 births


Common Birth DefectsMultifactorial Inheritance

• Cerebral palsy

• Clubfoot

• Renal agenesis

• Hypospadias

• Congenital hernia

• Congenital hip dislocation

• Congenital hypothyroidism

• Gastrointestinal defects

• Congenital deafness

• Musculoskeletal disorders

Can Birth Defects Be Prevented?

• Daily multivitamin use− 400µg folic acid

• Avoid alcohol, smoking and drugs

• Take only doctor-approved medications− Prescription, OTC, herbal

• Pre-pregnancy visit with health care provider– Family history, medical problems

Can Birth Defects Be Diagnosed Before Birth?

• Ultrasound– Structural defects

• Amniocentesis and Chorionic Villus Sampling (CVS)

− Chromosomal abnormalities

Can Birth Defects Be Treated Before Birth?

• Prenatal therapy– Inherited disorders of body chemistry

• Prenatal surgery– Lung tumors, congenital diaphragmatic hernia

• Prenatal blood transfusions– Rh disease, heart rhythm disturbances

What is Folate?

• Water-soluble B-complex vitamin

• Folate– Occurs naturally in food– Polyglutamate

• Folic acid – Vitamin supplements – Fortified foods

50% absorbed

100% absorbed

85% absorbed

Folate Structure

Pteridine Ring Pteroic Acid Glutamic Acid

Residues

Folate Derivatives

10-FormylTHF

5-MethylTHF 5,10-MethyleneTHF 5,10-MethenylTHF

Tetrahydofolate (THF)

Functions of Folate Biochemistry

• Folate derivatives carry and transfer various forms of one-carbon (1C) units

– Biosynthesis of nucleic acids and amino acids

– Methylation of DNA, protein, lipids, etc.

Folate Pathway

Major Points of Folate Biochemistry

• Overall effect – Transfer of 1C units to

essential biosynthesis reactions

– Regenerate THF for 1C transfer

• Metabolic regulation− Ensure appropriate distribution of metabolites among pathways− Prevent accumulation of Hcy & other potentially toxic intermediates

DNA

Synthesis

THFMethyl’n

Hcy

Folate Transport Mechanisms

• 2 mechanisms transport folates from plasma to cell interior, as well as across the placenta

– Carrier-mediated: RFC1: integral membrane protein; functions during high folate concentrations (passive diffusion)

– Receptor-mediated: FR1&2: membrane-attached folate receptors; crucial for assimilation, distribution & retention of food folates; have high affinity for folate, especially 5-MTHF (active transport)

How Do I Get Folate?

Take a multivitamin─ 400µg of folic acid

• Eat a healthy diet─ Fruits, green leafy vegetables, beans, corn, peas, bananas, orange juice

Eat fortified cereal and grain products− Total®, Special K®, Product 19®

Can You Take Too Much Folate?

• No known toxic level

• Recommend consuming <1,000µg

• May hide diagnosis of vitamin B-12 deficiency

Who is at Risk of Having Low Folate Levels?

• People with poor eating habits/dieting disorders

• Cigarette smokers

• Alcohol and drug abusers

• Women who use birth control pills

• Genetic variation

Consequences of Folate Deficiency

• Result of low dietary intake, genetic error of folate metabolism, lifestyle exposures

1. DNA Hypomethylation− Gene overexpression, uncontrolled cell growth,

genomic instability

2. Hyperhomocysteinemia− Excessive accumulation of Hcy

3. Base Misincorporation− Decrease in thymine synthesis; replaced by uracil− DNA strands prone to nicks, breaks and vulnerable

to mutagen insertion

Folate and Birth Defect Prevention

History of NTDs & Folate Deficiency

• 1976, 1980: Smithells et al. suggest folic acid deficiency may predispose to NTDs; possible prevention by vitamin supplementation

• 1981-1992: 8 / 9 studies show 50-70% reduction in NTDs with folic acid intake

• 1992: U.S. Public Health Service and National Research Council recommend all women of child-bearing age consume 400µg of folate daily to reduce risk of NTDs


• March 1996: FDA authorizes addition of synthetic folic acid to grain products

• January 1998: FDA makes folic acid fortification mandatory (140µg folic acid / 100g product)

• 1998 IOM Food and Nutrition Board Folic Acid Recommendations:

− Men (14y +) 400 µg− Women (14y +) 400 µg− Pregnancy 600 µg− Previous NTD 4000 µg


• NTD Surveillance and Folic Acid Intervention – Texas-Mexico Border, 1993-1998

• Anencephaly cluster in Cameron County, Tx– 19.7 / 10,000 live births

• Baseline NTD rate high along Texas-Mexico border– 13.4 / 10,000 live births– Reflective of large Hispanic population (91%)

• Provide folic acid to high-risk women in 14 border counties


• NTD Surveillance and Folic Acid Intervention – Texas-Mexico Border, 1993-1998

• 360 NTD-affected births/terminations

• Enrolled women were provided NTD risk-reduction education/counseling & vitamins/folic acid

• Pregnancy outcomes after folate intervention:– 89% took folic acid before conception– 79% of pregnancies resulted in non-NTD-affected birth– 16% resulted in miscarriage, 4% in elective abortion– 1% resulted in NTD-affected birth


• Prevalence of NTDs during transition to mandatory folic acid fortification in the U.S. (2 independent studies)

• Prevalence of SB decreased 23 – 31%

• Prevalence of Anencephaly decreased 11 – 16%

NTDs (Birth Defects) & FolateGenetic Studies

• Errors of folate metabolism may be involved in the etiology of NTDs (birth defects)

• Role of maternal and/or fetal metabolic error?

Genetic Polymorphisms & Birth Defect Risk

• Variation in genes encoding enzymes of the folate pathway

• Variation in genes encoding folate transporters

Genetic PolymorphismsFolate Pathway Enzymes

• MTHFR (C677T)− risk in moms (up to OR=6.1) & infants (up to OR=7.2)

for NTDs– risk in moms (OR=3.3) & infants (OR=13.4) for NTDs

if mom’s folate levels low– risk in infants for CL/P (OR=2.1)

• MS (A2756G)

− risk in moms (OR=3.1) & infants (OR=3.2) for SB− risk in moms (OR=3.5) & infants (OR=3.8) for DS

• TS (TSER, 6bp deletion)

− risk in infants (OR=3.6 – 4.7) for SB

Genetic PolymorphismsFolate Transporters

• RFC1 (A80G)

– risk in moms (OR=2.7) & infants (OR=2.4) for NTDs

– risk in infants (OR=2.1) for heart defects if mom did not take vitamins

– risk in infants (OR=1.6) for heart defects if mom took vitamins

• FRs− Variants rare− Genetic variation leading to incorrect functioning may result in fetal death

Genetic PolymorphismsAdditional Associations

• Variation in folate pathway enzymes shown to be associated with increased risk of many other diseases

− diabetes

− breast cancer

− colon cancer

− renal disease

− arthritis

− Alzheimer’s

− schizophrenia

− atherosclerosis

− stroke

− coronary artery disease

NTDs (Birth Defects) & Folate Genetic Study Conclusions

• Cause of most NTDs (birth defects) unknown

• Due to low folate, high homocysteine, both, or other downstream effects?

• Studies have shown folate-related genes to contribute to NTD (birth defect) pathogenesis

• Large-population CDC study suggests folic acid protects against all major birth defects

Environmental Agents & Birth Defect Prevention

─ Obesity and diabetes

─ Maternal hyperthermia

─ Drug/Alcohol use

─ Medications

─ Smoking

• Birth defects most commonly result from maternal health and exposure

Environmental AgentsObesity & Diabetes

• Women with BMI ≥ 29 kg/m2 – risk for NTDs (OR=1.9)

• Women weighing more than 240 lbs– risk for NTDs (OR=4.0)

• Women with IDDM– risk for CNS defects (OR=15.5)– risk for cardiovascular system defects (OR=18.0)

* Folic acid loses protective benefit in overweight/obese mothers - No reduced risk of NTDs in women weighing >154 lbs

Environmental AgentsHyperthermia

• Women who had fevers and did not take vitamins

– risk for NTDs (OR=3.1) – risk for CL/P (OR=2.9)– risk for limb deficiency defects (OR=2.6)– risk for heart defects (OR=2.4)

• Women who had fevers and took vitamins− risk for NTDs (OR=2.3) − risk for CL/P (OR=1.5)− risk for limb deficiency defects (OR=2.0)− risk for heart defects (OR=1.8)

Environmental AgentsDrugs/Alcohol

• Maternal alcohol use– risk for CL/P, 1-3 drinks/mo (OR=1.5)– risk for CL/P, 4-10 drinks/mo (OR=3.1)– risk for CL/P, >10 drinks/mo (OR=4.7)

* vitamin use did not alter results– Well-established risk for fetal alcohol syndrome

• Maternal drug use (cocaine, marijuana, ecstacy)− No definitive reports− risk heart and renal malformations, stillbirth, SGA

low birth weight, microcephaly

Environmental AgentsMedications

• Maternal use of AEDs– 2-15x risk for congenital malformations– Different AEDs lead to different malformations– Protective effect of folate dependent upon AEDs– Suggest women with epilepsy take more folic acid

• Maternal use of corticosteroids− risk for CL/P (OR=1.3 – 6.6)

• Maternal use of oral contraceptives − risk for CL/P (OR=1.0 – 1.4)− risk for congenital urinary tract anomalies (OR=4.8)

Environmental AgentsSmoking

• Clefts

• NTDs

• Clubfoot

• Limb defects

• Mental retardation

• Craniostenosis

• Congenital heart defects

• Urogenital anomalies

• Increased risk associated with multiple malformations

Environmental AgentsSmoking

• Women who smoked and did not take vitamins – risk for CL/P (OR=2.8)

– risk for heart defects (OR=2.2)– risk for limb deficiency defects (OR=1.5)

• Women who smoked and took vitamins− risk for CL/P (OR=1.5) − risk for heart defects (OR=1.0)− risk for limb deficiency defects (OR=0.8)

Additional Environmental Agents

• Water contamination, Air pollution– Tap water consumption: 3-fold risk birth defects,

4-fold risk spontaneous abortion– Carbon monoxide & ozone: 3-fold risk heart

defects

• Chemicals– Paint, dry-cleaning chemicals, pesticides– Organic solvents

• Toluene – found in gasoline, sweeteners, plastics, cigarette smoke

Additional Environmental Agents

• Heavy metals– Lead exposure during pregnancy – low birth weight,

premature, miscarriage, stillbirth, mental retardation

• Radiation– X-ray exposure during pregnancy – microcephaly,

CL/P, spinal & eye defects, limb deformities, mental retardation

– UV light – photolysis of folate by sunlight; risk NTDs if mom exposed to UV light from tanning beds

Additional Health Benefits of Folate During Pregnancy

• Gestational hypertension (preeclampsia)– Characterized by edema; may indicate detachment of

the placenta from the uterus; if untreated, can lead to coma and seizures

– ~50% reduction in risk

• Gestational hyperhomocysteinemia− Increased risk for placental abruption, intrauterine

fetal death, small for gestational age− ~68% reduction in homocysteine levels

Additional (Potential) Health Benefits of Folate

• Lowers risk of heart disease and stroke– Reduces homocysteine levels– Improves endothelial function & decreases BP in smokers

• Improves mind and mood conditions– Depression, dementia, memory loss, low mental acuity

• Protects against some forms of cancer– Colon, lung, cervical, breast

Complex Questions Remain

• What are the mechanisms of folic acid protection?

• What are the mechanisms of folic acid resistance and how can they be treated?

• What are the downstream/alternate pathways involved in folate/homocysteine metabolism?

• What are optimal fortification/supplement/blood levels?

• How can these data and concepts translate into population screening for prevention?

Birth Defect Prevention Measures

• Folate supplementation

• Healthy lifestyle

• Genetic counseling; diagnostic testing

References

• www.modimes.org

• www.cdc.gov

• www.cbdmp.org

• www.sbaa.org

• Barber RC, et al. 1999. Molecular Genetics & Metabolism. 66:1-9.

• Shaw GM, et al. 2002. Epidemiology. 13(6):625-630.

• Lorente C, et al. 2000. American Journal of Public Health. 90(3):415-419.

• Munger RG, et al. 1996. Teratology. 54:27-33.

• Yerby MS. 2003. Neurology. 61:S23-26.

• Shepard TH, et al. 2002. Teratology. 65:153-161.

References

• McInnes RR, et al. 2002. Clinical Genetics. 61:248-256.

• Werler MM, et al. 1996. JAMA. 275:1089-1092.

• Shaw GM, et al. 1996. JAMA 275:1093-1096.

• Becerra JE, et al. 1990. Pediatrics. 85(1):1-9.

• Shaw GM, et al. 2000. Am Journal of Medical Genetics. 93:188-193.

• Green NS. 2002. Journal of Nutrition. 132:2356S-2360S.

• Williams LF, et al. 2002. Teratology. 66:33-39.

• MMWR Weekly. 2000. 49(1):1-4.

• Plus many more! ☺

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