Birth Defects: Protection Against Environmental Agents by Folic Acid

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Birth Defects Protection
Against Environmental Agents by Folic Acid
March 29, 2004 Kelly Volcik School of Public
Health Human Genetics Center
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Birth Defects Protection by
Folic Acid

• Birth defects
• Causes, types, prevention
• Folate
• Background, biochemistry
• Studies
• Past, present, future

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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
• gt4,000 known birth defects
• Occur in 1 / 28 births

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What Causes Birth Defects?

• Genetic and/or environmental factors
• 60 - 70 of birth defects have unknown causes

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Genetic Causes of Birth Defects

• Number and structure of chromosomes

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Environmental Causes of Birth
Defects

• Most commonly result of mothers health and
  exposure
• Infections
• Rubella, CMV
• Medications
• Accutane, Thalidomide, AEDs
• Drugs/Alcohol
• Chemicals, Radiation, Water contamination,
  Air Pollution, Heavy metals

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Environmental Genetic Causes of Birth Defects

• Multifactorial inheritance
• Neural tube defects
• Cleft lip/palate
• Heart defects

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Common Birth DefectsNeural 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
• Multifactorial inheritance

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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
• Multifactorial inheritance

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Common Birth DefectsHeart Defects

• Abnormal develop of the heart
• Atrial ventricular septal defects
• Coarctation of the aorta
• Most common occur in 1 / 100 births
• Multifactorial inheritance

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Common Birth DefectsMultifactorial Inheritance

• Cerebral palsy
• Clubfoot
• Renal agenesis
• Hypospadias
• Congenital hernia

• Congenital hip dislocation
• Congenital hypothyroidism
• Gastrointestinal defects
• Congenital deafness
• Musculoskeletal disorders

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Can Birth Defects Be Prevented?

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

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Can Birth Defects Be Diagnosed Before Birth?

• Ultrasound
• Structural defects

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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

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Birth Defects Protection
by Folic Acid

• Birth defects
• Causes, types, prevention
• Folate
• Background, biochemistry
• Studies
• Past, present, future

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What is Folate?

• Water-soluble B-complex vitamin
• Folate
• Occurs naturally in food
• Polyglutamate
• Folic acid
• Vitamin supplements
• Fortified foods

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Folate Structure
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Folate Derivatives
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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.

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Folate Pathway
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Folate Pathway
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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

THF
Methyln
DNA Synthesis
Hcy
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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 FR12 membrane-attached
  folate receptors crucial for assimilation,
  distribution retention of food folates have
  high affinity for folate, especially 5-MTHF
  (active transport)

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How Do I Get Folate?
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Can You Take Too Much Folate?

• No known toxic level
• Recommend consuming lt1,000µg
• May hide diagnosis of vitamin B-12 deficiency

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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

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Consequences of Folate Deficiency

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

• DNA Hypomethylation
• Gene overexpression, uncontrolled cell growth,
  genomic instability
• Hyperhomocysteinemia
• Excessive accumulation of Hcy
• Base Misincorporation
• Decrease in thymine synthesis replaced by uracil
• DNA strands prone to nicks, breaks and vulnerable
  to mutagen insertion

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Birth Defects Protection
by Folic Acid

• Birth defects
• Causes, types, prevention
• Folate
• Background, biochemistry
• Studies
• Past, present, future

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Folate and Birth Defect Prevention
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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

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History of NTDs Folate Deficiency

• 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

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History of NTDs Folate Deficiency

• 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

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History of NTDs Folate Deficiency

• 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

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History of NTDs Folate Deficiency

• 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

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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?

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Genetic Polymorphisms Birth Defect Risk

• Variation in genes encoding enzymes of the folate
  pathway
• Variation in genes encoding folate transporters

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Genetic PolymorphismsFolate Pathway Enzymes

• MTHFR (C677T)
• ? risk in moms (up to OR6.1) infants (up to
  OR7.2) for NTDs
• ? risk in moms (OR3.3) infants (OR13.4) for
  NTDs if moms folate levels low
• ? risk in infants for CL/P (OR2.1)

• MS (A2756G)
• ? risk in moms (OR3.1) infants (OR3.2) for
  SB
• ? risk in moms (OR3.5) infants (OR3.8) for
  DS

• TS (TSER, 6bp deletion)
• ? risk in infants (OR3.6 4.7) for SB

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Genetic PolymorphismsFolate Transporters

• RFC1 (A80G)
• ? risk in moms (OR2.7) infants (OR2.4) for
  NTDs
• ? risk in infants (OR2.1) for heart defects
  if mom did not take vitamins
• ? risk in infants (OR1.6) for heart defects
  if mom took vitamins

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

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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

• Alzheimers
• schizophrenia
• atherosclerosis
• stroke
• coronary artery disease

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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

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Environmental Agents Birth Defect
Prevention

• Birth defects most commonly result from
  maternal
• health and exposure

• Obesity and diabetes
• Maternal hyperthermia
• Drug/Alcohol use

• Medications
• Smoking

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Environmental AgentsObesity Diabetes

• Women with BMI 29 kg/m2
• ? risk for NTDs (OR1.9)
• Women weighing more than 240 lbs
• ? risk for NTDs (OR4.0)
• Women with IDDM
• ? risk for CNS defects (OR15.5)
• ? risk for cardiovascular system defects (OR18.0)

Folic acid loses protective benefit in
overweight/obese mothers - No reduced risk of
NTDs in women weighing gt154 lbs
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Environmental AgentsHyperthermia

• Women who had fevers and did not take vitamins
• ? risk for NTDs (OR3.1)
• ? risk for CL/P (OR2.9)
• ? risk for limb deficiency defects (OR2.6)
• ? risk for heart defects (OR2.4)

• Women who had fevers and took vitamins
• ? risk for NTDs (OR2.3)
• ? risk for CL/P (OR1.5)
• ? risk for limb deficiency defects (OR2.0)
• ? risk for heart defects (OR1.8)

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Environmental AgentsDrugs/Alcohol

• Maternal alcohol use
• ? risk for CL/P, 1-3 drinks/mo (OR1.5)
• ? risk for CL/P, 4-10 drinks/mo (OR3.1)
• ? risk for CL/P, gt10 drinks/mo (OR4.7)
  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

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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 (OR1.3 6.6)
• Maternal use of oral contraceptives
• ? risk for CL/P (OR1.0 1.4)
• ? risk for congenital urinary tract anomalies
  (OR4.8)

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Environmental AgentsSmoking

• Increased risk associated with multiple
  malformations

• Clefts
• NTDs
• Clubfoot
• Limb defects

• Mental retardation
• Craniostenosis
• Congenital heart defects
• Urogenital anomalies

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Environmental AgentsSmoking

• Women who smoked and did not take vitamins
• ? risk for CL/P (OR2.8)
• ? risk for heart defects (OR2.2)
• ? risk for limb deficiency defects (OR1.5)

• Women who smoked and took vitamins
• ? risk for CL/P (OR1.5)
• ? risk for heart defects (OR1.0)
• ? risk for limb deficiency defects (OR0.8)

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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

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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

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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

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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

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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?

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Birth Defect Prevention Measures

• Folate supplementation
• Healthy lifestyle
• Genetic counseling diagnostic testing

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References

• www.modimes.org
• www.cdc.gov
• www.cbdmp.org
• www.sbaa.org

• Barber RC, et al. 1999. Molecular Genetics
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• Munger RG, et al. 1996. Teratology. 5427-33.
• Yerby MS. 2003. Neurology. 61S23-26.
• Shepard TH, et al. 2002. Teratology. 65153-161.

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References

• McInnes RR, et al. 2002. Clinical Genetics.
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• Werler MM, et al. 1996. JAMA. 2751089-1092.
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• Plus many more! ?