Birth Defects
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Birth Defects Birth Defects Presentation Transcript

  • Birth Defects : Protection Against Environmental Agents by Folic Acid March 29, 2004 Kelly Volcik School of Public Health Human 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 1 st 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
    • Number and structure of chromosomes
    • Missing or abnormal gene
  • 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 1 st 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
  • 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
  • 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
  • Common Birth Defects Multifactorial 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?
    • Pre-pregnancy visit with health care provider
      • Family history, medical problems
    • Daily multivitamin use
      • 400 µ g folic acid
    • Avoid alcohol, smoking and drugs
    • Take only doctor-approved medications
      • Prescription, OTC, herbal
  • 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
  • Birth Defects: Protection by Folic Acid
    • Birth defects
      • Causes, types, prevention
    • Folate
      • Background, biochemistry
    • Studies
      • Past, present, future
  • 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
  • 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 THF Methyl’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 <1,000 µ g
    • 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
    • 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
  • Birth Defects: Protection by Folic Acid
    • Birth defects
      • Causes, types, prevention
    • Folate
      • Background, biochemistry
    • Studies
      • Past, present, future
  • 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 400 µ g of folate daily to reduce risk of NTDs
  • 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 (140 µ g folic acid / 100g product)
    • 1998 IOM Food and Nutrition Board Folic Acid Recommendations:
        • Men (14y +) 400 µ g
        • Women (14y +) 400 µg
        • Pregnancy 600 µ g
        • Previous NTD 4000 µ g
  • 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
  • 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
  • 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%
  • 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?
  • Genetic Polymorphisms & Birth Defect Risk
    • Variation in genes encoding enzymes of the folate pathway
    • Variation in genes encoding folate transporters
  • Genetic Polymorphisms Folate 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 Polymorphisms Folate 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 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
    • 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 Agents Obesity & Diabetes
    • Women with BMI ≥ 29 kg/m 2
      •  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 Agents Hyperthermia
    • 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 Agents Drugs/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 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 (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 Agents Smoking
    • Clefts
    • NTDs
    • Clubfoot
    • Limb defects
    • Mental retardation
    • Craniostenosis
    • Congenital heart defects
    • Urogenital anomalies
    • Increased risk associated with multiple malformations
  • Environmental Agents Smoking
    • 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! ☺