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What is teratogenesis?
Production of birth defects
What are malformations?
non-reversible morphological defects present at birth
What are congenital anomalies?
Present at birth
What are teratogens?
Physical or chemical agents that can cause malformations when pregnant people are exposed to them
How prevalent are birth defects?
Present in 2-3% of all live births
What are the top 10 causes of infant mortality (descending order)?
- Birth defects
- Preterm/Low birth weight
- Maternal pregnancy complications
- Placenta/ Cord complications
- Hypoxia/Birth Asphyxia
What is the leading cause of infant mortality?
Why are birth defects so common?
- Improvements in obstetrical care (decrease in deaths from prematurity and maternal pregnancy complications)
- Increase in medication and social drug use
- Contribution of environmental contaminants to teatogenesis
Why does the incidence of birth defects increase at an age of 2 years?
At an age of 2 years, incidence of birth defects increases to 4-6% due to the discovery of internal organ defects
How many deaths do birth defects cause in children less than one year old?
More than 1/3 of all deaths in infants <1 year old
Why are so many birth defects discovered later in life?
Defects may be symptom-less at birth and only manifested later
How many birth defects are due to known genetic causes?
20-25% are due to known genetic causes such as single gene defects and chromosomal aberrations
What is susceptibility to teratogenesis influenced by?
Susceptibility to teratogenesis is heavily influenced by genetics of mother and infant
What is the largest contributor to unsuccessful pregnancy?
What happens during the first trimester?
Conception (formation of zygote)-->Implantation-->Ovum divide and differentiate, form tissues and organs (organogenesis) (3-8 weeks)
When is the fetus most susceptible for birth defects?
- During the organogenic period
- Max. vulnerability for fetus is 17-57 days post-fertilization
When does the neural tube close?
- Within 28 days of gestation
- When most women do not know they are pregnant
Why is adequate nutrition (particularly folate) essential for women capable of becoming pregnant?
Because the neural tube closes within 28 days of gestation, when most women do not even know they are pregnant
What do trophoblast cells do?
- Trophoblast cells secrete proteolytic enzymes, which erode the epithelial uterine lining and creates an implantation site for the blastocyst
- Trophoblast forms a cord of cells that extend into the endometrium and attach there to start forming the placenta
In the first 20-25 days of pregnancy, how does the embryo get its nutrients?
- Embryo relies on nutrients from digested maternal uterine cells and diffusion of blood components
- Fluid and nutrients are absorbed by phagocytisis
- Known as hystiotrophic nutritional phase
When does gastrulation occur?
2-3 weeks into the preganancy
What happens during gastrulation?
- 1. Primitive streak: future axis of the embryo, marks the begining of gasturaltion, 3 layers of the embryo (ectoderm, mesoderm and endoderm)
- 2. Nerulation: ectoderm differentiates into neural plate and later, neural tube (CNS is one of the first organs to develop)
- 2. Mesoderm and endoderm cells migrate internally to form organs and tissues
What does the ectoderm become?
Brain, CNS, skin
What does the mesoderm become?
Voluntary muscles, cardiovascular and excretory systems
What does the endoderm become?
Digestive and respiratory systems, glandular organs
What is gastrulation characterized by?
Cell migration through primitive streak
When does organogenesis occur?
3-8 weeks into pregnancy
What is organogenesis characterized by?
Cell proliferation, cell migration, cell-cell interactions and tissue re-modeling
When does the fetal/neonatal phase occur?
8 weeks to birth
What happens during the fetal period?
- Fetal growth period
- Little differentiation of organs takes place except external genitalia
- Tissue differentiation, growth and physical maturation
- Functional and growth abnormalities can occur rather than morphological defects
- Abnormalities in reproduction system can occur
What are the 3 classes of teratogens?
- Medications (seizure medications, Accutane, thalidomide, lithium, chemotherapy drugs)
- Social drugs (alcohol, cocaine, cigarettes)
- Environmental Agents (organic solvents, heavy metals, pesticides, PCBs)
Which teratogen is responsible for the most fetal abnormalities?
- Responsible for prematurity, small gestational age, miscarriage, severe CNS defects and other congenital abnormalities
How do hot tubs effects fetuses?
- sustained exposure to hot tubs raises cor body temperature
- Animal studies show increased risk of birth defects with sustained core body temperature elevations
What birth defects can high levels of iodine cause?
- Congenital goitre
- Mental and physical retardation
What birth defects can high levels of fluoride cause?
Spina Bifida Occulta
What birth defects can high levels vitamin D cause?
- Facial abnormalities
- Mental retardation
What birth defects can high levels of vitamin A cause?
What birth defect can extreme protein deficiency cause?
Microcephaly (circumference of the baby's head is 2SD less than expected)
What birth defects can vitamin A deficiency cause?
- Eye abnormalities, microcephaly
- Similar to that of vitamin A excess
What birth defects can vitamin D deficiency cause?
- Fetal rickets
- Hypoplasia of tooth enamel
- Decreased bone density
- Growth failure, due to decreased availability of calcium
How does smoking cause birth defects?
- Decreases vitamin E stores
- Nonspecific birth defects and spontaneous abortions
What birth defects does a vitamin K deficiency cause?
What causes a folate deficiency?
- Caused by poor diet
- Maternal drug intake
- Genetic susceptibility to abnormalities in folate metabolism
What birth defects does an iodine deficiency cause?
Cretinism, syndrome of mental and physical retardation- potbelly, large tongue, facial characteristics of Down's syndrome
How is copper deficiency caused in pregnant women?
Can be caused by pregnant women undergoing treatments with copper chelating agents
What is acrodermatitis enteropathica?
- Rare disease
- Inability to absorb Zn
- Rashes, hair loss, diarrhea and poor growth
- Increased risk of birth defects and pregnancy complications
What is Menkes Kinky Hair syndrome?
- Genetic inborn errors of copper metabolism
- Major developmental abnormalities in brain
- Bones and blood vessels
- Treatment with copper chelating drugs such as penicillamine causes infants to be born with severe connective tissue defects
How can drugs cause nutrient deficiencies?
- Methotrexate is a folate antagonist (30% risk of NTD)
- Coumarin is a vitamin K antagonist (7% risk of congenital heart disease, Coumadin syndrome)
- Anticonvulsant-induced folate and Zn deficiencies
What is the leading cause of birth defects and intellectual handicap in North America?
Fetal Alcohol Syndrome
What are some characteristics of FAS?
- Craniofacial dimorphism
- Growth retardation (head circumference, weight, height <10th percentile)
- Decreased fat stores
- Retarded phychomotor and intellectual developement
When is the fetus most sensitive to FAS?
3rd trimester (and first 12 months after birth)
What are the common facial abnormalities associated with FAS?
- Short palpebral fissures
- Elongated mid-face
- Thin upper-lip
- Retrognathia; receding jaw
How does alcohol effect the fetus?
- After absorption, alcohol is evenly distributed to all body fluids, crosses blood-brain and placental barriers until equilibrium with mother's blood
- Detoxification and clearance are less developed in embryo/fetus
- Mother may not experience alcohol-related symptoms while embryo/fetus may be affected adversely
- Fetus and embryo developing CNS is more susceptible to alcohol related effects than is the adult brain
- women have 50% less alcohol dehydrogenase than men
- Alcohol crosses placenta freely
What are the mechanisms of developmental toxicity of alcohol?
- Alcohol has caloric value and replaces calories from other sources
- Effect on folic acid and Zn metabolism
- Acetylaldehyde and free radical toxicity
- Excessive cell death (apoptosis) in sensitive cell populations
- Placental toxicity
- Fetal hypoxia (inadequate supply of oxygen)
How do protein and Zn malnutrition effect FAS?
Protein and Zn malnutrition enhane the deleterious effects of alcohol
How does acetylaldehyde effect the fetus?
- Alcohol is metabolized into acetylaldehyde (toxic at uM concentrations vs mM concentrations for alcohol)
- Acetylaldehyde is converted to acetic acid by aldehyde dehydrogenase
How does chronic consumption of alcohol effect the fetus?
Chronic consumption prolongs the inflammatory proces (free radicals)
What are neural tube defects?
- A collective term describing congenital abnormalities of the fetal spine and CNS
- Include defects of the neural tube, which are caused by disruptions in the orderly formation of the neural tube during early gestation
- The brain and spinal cord develop from the neural tube and NTD cause various CNS disorders
What is the worldwide incidence of NTDs?
What are the most common NTDs?
Spina bifida and anencephaly
What is anencephaly?
- brain is not enclosed
- die shortly after bith
What is spina bifida?
- Failure of spine to close properly in the 1st month of gestation
- Lack of bone encasement of the spine-> permanent spinal cord and spinal nerve damage
- Inability to walk, abnormal bladder and bowel function, fatality
- Creates a lesion on the spinal column
What are the causes of NTDs?
- Genetics: much greater risk when mother previously had an offspring with NTD (only 12% of NTD have an identifiable genetic cause)
- Multifactorial inheritance
- Single gene (autosomal recessive) disorders
- Chromosomal Aneuploidy (trisomy 13)
- Teratogens (valprioc acid, thalidomide)
- Maternal insulin dependent DM
- Sever overweight
What is the most common cause of NTDs?
Folate deficiency or folate metabolism disorder
How many NTDs are related to folate deficiency or abnormal folate metabolism?
How was the MRC study conducted?
- Pregnant women and women planning a pregnancy were given capsules for 12 weeks
- Folate dose: 4mg
- Large sample size, double blind randomized controlled trial
- 71% reduction in NTD
Why was the MRC study stopped early?
Ethics were put into question due to success of folate supplementation on NTD
How does folate effect homocysteine levels?
- Most common cause of increased homocysteine due to impeded homocysteine e-methylation due to folate deficiency (insufficient N5-methyl-THF)
- High doses of vitamin A suppress this enzyme
How does secondary accumulation of SAH (S-adenosyl-L-homocysteine) create birth defects?
- High levels of homocysteine create a secondary accumulation of SAH
- Leads to inhibition of DNA methyltransferase reactions, DNA hypomethylation, and altered gene expression
How does increased homocysteine effect oxidative stress and cause birth defects?
- During fetal organogenesis can result in damage to mitochondrial and nuclear DNA, to protein structure and function, or to membrane lipids and signal transduction pathways
- Decrease the functional activity of methionine synthase through limiting the availability of vitamin B-12 by decreasing folate stores
What is the evidence for hyperhomocysteinemia in NTD (3 points)?
- Mother with NTD infants show lower plasma folate levels and an elevated homocysteine levels indicating that defects in the folate-dependant homocysteine pathway
- Families with NTDs tend to have in-bor error of metabolism (shortage of methyltetrahydrofolate reductase)
- Folic acid supplementatiom overcomes the metabolic defect, normalizes red blood cell folate concentrations and decreases blood homocysteine
How do the plasma homocysteine levels in a pregnant woman compare to those in a non-pregnant woman?
Plasma homocysteine concentrations are 30-60% lower in pregnancy
How are concentrations of maternal and fetal homocysteine lowered?
Lowered by folic acid supplementation
What is homocysteine a risk factor for?
- Spontaneous abortion
- Recurrent early miscarriages
How is maternal homocysteine related to birth weight?
Maternal homocysteine at preconception, 8 weeks and at birth is inversely related to birth weight
Why is folic acid fortification and supplementation better than just obtaining it from food?
The synthetic monoglutamate form of folate is more stable and bioavailable than the polyglutamate form as typically found in foods
What does folic acid fortification and supplementation do?
Increase RBC concentration
What happens when the polyglutamate form of folic acid is converted to the monoglutamate form?
It is converted by conjugases in the GI tract and a methyl group is attached- this methyl group renders absorption
What is the recommended supplementation of folic acid?