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Birth Defects: Protection Against Environmental Agents by Folic Acid

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Title: Birth Defects: Protection Against Environmental Agents by Folic Acid


1
Birth Defects Protection
Against Environmental Agents by Folic Acid
March 29, 2004 Kelly Volcik School of Public
Health Human Genetics Center
2
Birth Defects Protection by
Folic Acid
  • Birth defects
  • Causes, types, prevention
  • Folate
  • Background, biochemistry
  • Studies
  • Past, present, future

3
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

4
What Causes Birth Defects?
  • Genetic and/or environmental factors
  • 60 - 70 of birth defects have unknown causes

5
Genetic Causes of Birth Defects
  • Number and structure of chromosomes

6
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

7
Environmental Genetic Causes of Birth Defects
  • Multifactorial inheritance
  • Neural tube defects
  • Cleft lip/palate
  • Heart defects

?
8
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
  • Multifactorial inheritance

9
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

10
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
  • Multifactorial inheritance

11
Common Birth Defects Multifactorial Inheritance
  • Cerebral palsy
  • Clubfoot
  • Renal agenesis
  • Hypospadias
  • Congenital hernia
  • Congenital hip dislocation
  • Congenital hypothyroidism
  • Gastrointestinal defects
  • Congenital deafness
  • Musculoskeletal disorders

12
Can Birth Defects Be Prevented?
  • Pre-pregnancy visit with health care provider
  • Family history, medical problems

13
Can Birth Defects Be Diagnosed Before Birth?
  • Ultrasound
  • Structural defects

14
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

15
Birth Defects Protection
by Folic Acid
  • Birth defects
  • Causes, types, prevention
  • Folate
  • Background, biochemistry
  • Studies
  • Past, present, future

16
What is Folate?
  • Water-soluble B-complex vitamin
  • Folate
  • Occurs naturally in food
  • Polyglutamate
  • Folic acid
  • Vitamin supplements
  • Fortified foods

17
Folate Structure
18
Folate Derivatives
19
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.

20
Folate Pathway
21
Folate Pathway
22
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
23
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)

24
How Do I Get Folate?
25
Can You Take Too Much Folate?
  • No known toxic level
  • Recommend consuming lt1,000µg
  • May hide diagnosis of vitamin B-12 deficiency

26
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

27
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

28
Birth Defects Protection
by Folic Acid
  • Birth defects
  • Causes, types, prevention
  • Folate
  • Background, biochemistry
  • Studies
  • Past, present, future

29
Folate and Birth Defect Prevention
30
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

31
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

32
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

33
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

34
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

35
NTDs (Birth Defects) Folate Genetic Studies
  • Errors of folate metabolism may be involved in
    the etiology of NTDs (birth defects)
  • Role of maternal and/or fetal metabolic error?

36
Genetic Polymorphisms Birth Defect Risk
  • Variation in genes encoding enzymes of the folate
    pathway
  • Variation in genes encoding folate transporters

37
Genetic Polymorphisms Folate 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

38
Genetic Polymorphisms Folate 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

39
Genetic Polymorphisms Additional 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

40
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

41
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

42
Environmental Agents Obesity 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
43
Environmental Agents Hyperthermia
  • 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)

44
Environmental Agents Drugs/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

45
Environmental Agents Medications
  • 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)

46
Environmental Agents Smoking
  • Increased risk associated with multiple
    malformations
  • Clefts
  • NTDs
  • Clubfoot
  • Limb defects
  • Mental retardation
  • Craniostenosis
  • Congenital heart defects
  • Urogenital anomalies

47
Environmental Agents Smoking
  • 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)

48
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

49
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

50
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

51
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

52
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?

53
Birth Defect Prevention Measures
  • Folate supplementation
  • Healthy lifestyle
  • Genetic counseling diagnostic testing

54
References
  • www.modimes.org
  • www.cdc.gov
  • www.cbdmp.org
  • www.sbaa.org
  • Barber RC, et al. 1999. Molecular Genetics
    Metabolism. 661-9.
  • 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. 5427-33.
  • Yerby MS. 2003. Neurology. 61S23-26.
  • Shepard TH, et al. 2002. Teratology. 65153-161.

55
References
  • McInnes RR, et al. 2002. Clinical Genetics.
    61248-256.
  • Werler MM, et al. 1996. JAMA. 2751089-1092.
  • Shaw GM, et al. 1996. JAMA 2751093-1096.
  • Becerra JE, et al. 1990. Pediatrics. 85(1)1-9.
  • Shaw GM, et al. 2000. Am Journal of Medical
    Genetics. 93188-193.
  • Green NS. 2002. Journal of Nutrition.
    1322356S-2360S.
  • Williams LF, et al. 2002. Teratology. 6633-39.
  • MMWR Weekly. 2000. 49(1)1-4.
  • Plus many more! ?
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