NUTR 337-2

Production of birth defects

non-reversible morphological defects present at birth

Present at birth

Physical or chemical agents that can cause malformations when pregnant people are exposed to them

Present in 2-3% of all live births

• Birth defects
• Preterm/Low birth weight
• SIDS
• RDS
• Maternal pregnancy complications
• Placenta/ Cord complications
• Accidents
• Infections
• Pneumonia/Influenza
• Hypoxia/Birth Asphyxia

Birth defects

• 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

At an age of 2 years, incidence of birth defects increases to 4-6% due to the discovery of internal organ defects

More than 1/3 of all deaths in infants <1 year old

Defects may be symptom-less at birth and only manifested later

20-25% are due to known genetic causes such as single gene defects and chromosomal aberrations

Susceptibility to teratogenesis is heavily influenced by genetics of mother and infant

Post-implantation losses

Conception (formation of zygote)-->Implantation-->Ovum divide and differentiate, form tissues and organs (organogenesis) (3-8 weeks)

• During the organogenic period
• Max. vulnerability for fetus is 17-57 days post-fertilization

• Within 28 days of gestation
• When most women do not know they are pregnant

Because the neural tube closes within 28 days of gestation, when most women do not even know they are pregnant

• 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

• 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

2-3 weeks into the preganancy

• 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

Brain, CNS, skin

Voluntary muscles, cardiovascular and excretory systems

Digestive and respiratory systems, glandular organs

Cell migration through primitive streak

3-8 weeks into pregnancy

Cell proliferation, cell migration, cell-cell interactions and tissue re-modeling

8 weeks to birth

• 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

• Medications (seizure medications, Accutane, thalidomide, lithium, chemotherapy drugs)
• Social drugs (alcohol, cocaine, cigarettes)
• Environmental Agents (organic solvents, heavy metals, pesticides, PCBs)

• Alcohol
• Responsible for prematurity, small gestational age, miscarriage, severe CNS defects and other congenital abnormalities

• sustained exposure to hot tubs raises cor body temperature
• Animal studies show increased risk of birth defects with sustained core body temperature elevations

• Congenital goitre
• Mental and physical retardation

Spina Bifida Occulta

• Facial abnormalities
• Mental retardation

CNS abnormalities

Microcephaly (circumference of the baby's head is 2SD less than expected)

• Eye abnormalities, microcephaly
• Similar to that of vitamin A excess

• Fetal rickets
• Hypoplasia of tooth enamel
• Decreased bone density
• Growth failure, due to decreased availability of calcium

• Decreases vitamin E stores
• Nonspecific birth defects and spontaneous abortions

Coumadin syndrome

• Caused by poor diet
• Maternal drug intake
• Genetic susceptibility to abnormalities in folate metabolism

Cretinism, syndrome of mental and physical retardation- potbelly, large tongue, facial characteristics of Down's syndrome

Can be caused by pregnant women undergoing treatments with copper chelating agents

• Rare disease
• Inability to absorb Zn
• Rashes, hair loss, diarrhea and poor growth
• Increased risk of birth defects and pregnancy complications

• 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

• 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

Fetal Alcohol Syndrome

• Craniofacial dimorphism
• Growth retardation (head circumference, weight, height <10th percentile)
• Decreased fat stores
• Retarded phychomotor and intellectual developement

3rd trimester (and first 12 months after birth)

• Short palpebral fissures
• Elongated mid-face
• Thin upper-lip
• Retrognathia; receding jaw

• 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

• 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)

Protein and Zn malnutrition enhane the deleterious effects of alcohol

• Alcohol is metabolized into acetylaldehyde (toxic at uM concentrations vs mM concentrations for alcohol)
• Acetylaldehyde is converted to acetic acid by aldehyde dehydrogenase

Chronic consumption prolongs the inflammatory proces (free radicals)

• 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

0.5million/year

Spina bifida and anencephaly

• brain is not enclosed
• die shortly after bith

• 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

• 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

Folate deficiency or folate metabolism disorder

50-75%

• 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

Ethics were put into question due to success of folate supplementation on NTD

• 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

• High levels of homocysteine create a secondary accumulation of SAH
• Leads to inhibition of DNA methyltransferase reactions, DNA hypomethylation, and altered gene expression

• 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

• 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

Plasma homocysteine concentrations are 30-60% lower in pregnancy

Lowered by folic acid supplementation

• Preeclampsia
• Spontaneous abortion
• Recurrent early miscarriages

Maternal homocysteine at preconception, 8 weeks and at birth is inversely related to birth weight

The synthetic monoglutamate form of folate is more stable and bioavailable than the polyglutamate form as typically found in foods

Increase RBC concentration

It is converted by conjugases in the GI tract and a methyl group is attached- this methyl group renders absorption

400μg/day