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congenital malformations embryology 2006


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what are congenital malformations?
anatomical abnormalities present at birth
what's a teratology?
is from Greek teratos - monster
logia - study of
branch of embryology
studies abnormal development, causes of congenital malformations
what's a teratogenic agent or teratogen?
is anything that induces or increases incidence of congenital malformations
what percentage of newborns are born with malformations?
what does one's susceptibility to teratogens depend on?
2 things in general;
1. genotype of embryo
2. environmental influence
other things more specifically;
3. your species
4. your STRAIN of species
5. developmental stage when embryo exposed to teratogen
what's an example of species differences in terms of sensitivity to teratogens?
thalidomide teratogenesis
other animals are pretty resisitant to it
rabbits have to get higher doses than humans to have same effect
humans are pretty sensitive
what are the periods associated with developmental stages that influence how affected an embryo would be by teratogenesis?
3 periods
1. predifferentiation
2. organogenesis
3. fetal period
what's susceptibility of embryo during predifferentiation stage of development?
embryo's pretty refractory - pretty tough
resists mutation during cleavage, blastocyst, early germ layer stages
some things may cause problems when given during peri-implantation and gastrulation (trilaminar disc formation)
what period of development is the embryo at the highest susceptibility for mutation?
what specifically happens during organogenesis that makes embryos more susceptible to teratogens at that time?
besides obvious fact that organs are forming
agents have highest incidenct of malformations when given at this time
most organs have specific period of teratogenic susceptibility
what are the mechanisms by which teratogens create abnormal development?
not known
what issues affect the access teratogens have to developing tissues?
1. agent - what kind it is
is it physical or chemical
2. dose
what physical agents affect embryos, which do not and why?
physical agents are considered radiation, temperature variation or pH variation of maternal system
mom protects embryo from a lot of radiation just because her own tissue stands between the fetus and the radiation - rays must penetrate her body to reach embryo
ionizing radiation is dangerous because it will reach embryo, although intensity will be reduced
as for variations in body temperature of pH, usually mom's homeostatic mechanisms are enough to control most problems
what feature of chemical agents determines whether a development defect occurs?
how much reaches or accumulates in developing tissues
can placenta stop some chemical agents from reaching developing embryo?
no; but may slow process down and may reduce dosage
what are the four manifestations of deviant development?
1. death
2. malformation
3. growth restriction or growth retardation (GR)
5. functional deficit
when are the likeliness of death and malformations highest as opposed to growth restriction or functional deficiency?
death and malformtions more likely in early organogenesis
as development progresses, death and malformation less likely and growth restriction and functional deficiency more likely
why are growth restriction and functional deficiency more likely as embryo becomes fetus?
because growth and functional maturation are primary processes that remain vulnerable until birth
what kinds of things are considered congenital malformations?
gross structural defects
inborn errors of metabolism
physiological disturbances
developmental delays
cellular and molecular abnormalities
what determines whether malformations are major or minor?
major = anomalies with adverse effect on function
minor = anomalies with neither medical nor cosmetic consequences
what's another name for minor malformations?
anatomical variation
how can some major malformations be found?
through discovery of two or more minor malformations
what's the overall reported incidence of birth defects (percentage)?
what are common causes of birth defects?
65% from unknown causes
20% from known genetic transmission
10% known infectious agents, drugs, metabolic disorders, environmental agents
5% from chromosomal aberrations
what are some examples of infectious agents?
think TORCH
T = toxoplasmosis
O = nothing
R = rubella
C = cytomegalovirus
H = herpes simplex virus
what effect does rubella have on developing embryo?
causes Congenital Rubella Syndrome =
growth restriction, cardiovascular problems, cataracts, deafness which may have delayed onset, rash or cutaneous evidence of thrombocytopenia and erythropoiesis, altered ossification, hepatosplenomegaly, encephalitis
how does transmission of rubella differ with timing of exposure to embryo? based on trimesters
1st - about 80% affected
26 weeks - 25% affected
27-35 weeks - low numbers affected
what are the effects on embryo of exposure to cytomegalovirus or CMV?
neonatal deaths
neurodevelopmental abnormalities
hearing loss
growth restriction
what are the effects of embryonic exposure to HIV?
growth restriction
multiple confounding variables
what are the effects of embryonic exposure to parvovirus or B19?
severe nonimmune hydrops
tropism for bone marrow erythroid progenitors
chronic anemia
what's an example of a parasite that causes problems for the embryo?
toxoplasma gondii
causes toxoplasmosis
what's the effect of infection from toxoplasma gondii?
growth restriction
brain and retina
intracranial calcifications
what are the consequences of fetal alcohol syndrome?
growth restriction
facial anomalies
CNS dysfunction
what are the effects of cocaine use during pregnancy?
fetal death
growth restriction
persistent neruologic problems and learning deficits
vasoconstrictive effects?
what are the effects of smoking on embryo?
placental problems
growth restriction
what are the five categories of therapeutic drugs that could be given to women of childbearing age? what do they mean?
A = no risk or remote risk to fetus
B = animal studies don't show or suggest risk, well-controlled human studies fail to demonstrate risk
C = teratogenicity shown in animals but no controlled studies in humans or no studies in either animals or humans
D = evidence of human fetal risk but benefits of use make use of drug acceptable
X = studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and risk of use outweighs any possible benefit
what's the name for the effects on an embryo of thalidomide?
thalidomide embryopathy
what are the effects of exposure to thalidomide based on time of exposure - effect when exposed in early sensitive period vs. late sensitive period?
early sensitive period - ear and upper limb problems
late sensitive period - lower limb problems
what are the effects of anticonvulsants on embryos/fetuses/babies? what are these effects called?
name of problem = fetal hydantoin syndrome
double risk of malformations to babies born to epileptic women
effect of phenytoin or dilantin = craniofacial dysmorphia, microcephaly, skeletal defects, developmental delays
what are examples of retinoids or vitamin A derivative drugs?
accutane - treatment of cystic acne
also called isotretinoin

etretinate, also called Tegison - treatment of psoriasis
has a longer half-life - than what?
what are effects of retinoids on fetuses?
abortions, malformations including craniofacial, cardiac, thymic, CNS, ear, hydrocephalus
what are the effects of maternal ingestion of androgens?
would have female fetus with ambiguous genitalia if the ingestion happened during a critical period of differentiation
what's an example of a common metabolic disorder?
what are the effects of diabetic mother on fetus?
increased morbidity, macrosomia, congenital anomalies like congenital heart disease, musculoskeletal problems and CNS issues
what's an example of an exposure someone may have while at work?
methylmercury exposure
what are the consequences of occupational exposure to methylmercury?
neurotoxicity results in impaired maturation of CNS, postnatal neurologic deficits
growth restriction
renal toxicity
what are the effects of ionizing radiation on a fetus?
growth restriction
effects on CNS like mircocephaly, mental retardation, hydrocephalus, neurobehavioral abnormalities
optic defects like chorioretinitis, cataracts, blindness
other abnormalities like spina bifida, cleft palate, limb anomalies
what are the effects of intrauterine compression?
just called it amniotic band syndrome
what methods can be used to discover anomalies while mom is still pregnant?
1. amniocentesis and chorionic villus sampling (CVS)
2. maternal blood tests
3. serologic screening
4. ultrasound
what is the leading cause of infant mortality in U.S.?
birth defects
what percentage of all infant deaths are due to birth defects?
of about 120,000 babies born in US each year with a birth defect, how many will die during the first year?
teratogenic agents act via what kinds of mechanisms to cause pathogenesis?
5 main types of mechanisms:
1. chromosomal damage
2. lack of precursors, substrates
3. altered energy sources
4. enzyme inhibition
5. changed characteristics?
what are the categories of different kinds of manifestations of pathogenesis?
6 given by lecturer
1. cell death
2. failed cell interactions
3. reduced biosynthesis
4. impeded morphogenetic movement
5. tissue disruption
6. altered differentiation schedule
what factors influence the fetal dose of a teratogenic agent?
1. maternal metabolism
2. placental transfer
3. embryonic/fetal metabolism
what factors influence degree to which drugs can pass through the placenta?
1. lipids pass easily, water-soluble stuff not so easily
2. if plasma protein-bound, less likely to pass through placenta
3. if a large, organic ion, will have trouble passing through
anything with a MW over 1,000 daltons can't easily cross
is size an issue for most drugs crossing placenta?
no, most drugs are from 250-400 daltons
things around 600 daltons easily pass
what the hell is toxoplasmosis?
is parasitic infection that 85% of childbearing age women in U.S. are susceptible to
what happens to baby if mother ingests protozoan T. gondii or has toxoplasmosis?
lifelong disabilities
brain and retina most commonly diseased
triad of toxoplasmosis
1. hydrocephalus
2. chorioretinitis
3. intracranial calcifications

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