% of infant deaths in north america attributed to birth defects?
% newborns w/ major structural anomalies
% newborns w/ single minor defect
% of birth defects detected by age 2
% by age 5
6% by age 2
8% by age 5
when are major development defects most common, %
in early embryos
% of recognized prenancies that end in miscarriage
% of spontaneously aborted conceptuses w/ chromosomal abnormalities
incidence of major anomalies at birth? most to least common
overall incidence of major anomalies at birth and most common of those?
most common: brain, 1% of major anomalies
types of congential anomalies?
intrinsically abnormal development process
ie cardiac abrnormality, VSD
inference w/ an originally normal development process
fetus starts as normal, sthg happens that disrupts development process
abnormal form resulting from mechanical forces
ie if no fluid around fetus, > clubbed feet, contractures of limbs
abnormal organization of cells into tissues
ie kidneys dysplasia > multiple cysts replace them
patterns of anomalies?
1) field defect
disturbance in just 1 single developmental field
ie kidney, heart
single structural defect/mechanical factor
ie lack of fluid w/ ruptured membranes due to compression
ie potter's sequence- bilateral renal agenesis
multiple abnormalities that're pathogenetically related
non-random occurrence of multiple anomalies in 2+ people
most common cause of human birth defects?
unknown etiology (50-60%)
second most common cause of birth defects?
multifactorial inheritance (20-25%)
what is multifactorial inheritance?
birth defect caused by combination of genes and environment
ie neural tube defects- know partly genetic, but also can reduce incidence in those genetically predisposed for it if give folic acid while pregnant
% of birth anomalies caused by genetic factors?
1/3 of all birth defects
when are chromosomal abnormalities common?
in early zygotes/embryos
what is numerical chromosomal abnormality?
failure of chromosome pair or 2 chromatids to disjoin during mitosis or meiosis; due to disjunction
ie turner syndrome, autosomal trisomies like trisomy 21, sex chromosome trisomies, mosaicism, triploidy
numerical chromosomal abnormality (45,X)
most common abnormality in spontaneous abortions
1/8000 live births
75% due to missing paternal X chromsome
examples of autosomal trisomies?
1) trisomy 18- heart defects, clenched fingers
2) trisomy 13- midline defects ie anencephaly
^^ both are incompatible w/ life
3) trisomy 21- 75% embryos spontaneously abort, 20% stillborn
examples of sex chromosome trisomies?
1) 47, XXX: 15-25% mild MR
2) 47, XXY: Klinefelters, small testes, infertility
3) 47, XYY: normal appearance, tall
numerical chromosomal abnormality
2 cell lines w/ 2+ genotypes
numerical chromosomal abnormality
failure of separation of 2nd polar body
20% of all chromosomally abnormal spontaneous abortuses
what are structural chromosome abnormalities?
chromosomal breakage and abnormal combination-
ie reciprocal translocation, terminal deletion, ring chromosome, duplication, paracentric inversion, isochromosome, robersonian translocation
due to drugs, chemicals, viruses
characteristics of anomalies caused by mutant genes
7% of congenital anomalies
birth anomaly caused by G to A transition mutation at ntd 1138 of cDNA in FGFR3 gene on chromosome 4p
autosomal dominant- so if parent has it, have 50% chance of passing it on to fetus
if both parents are carriers, not compatible w/ life
what is a teratogen, what % of anomalies acct for, how do they occur?
any agent- drug, virus, alochol- that causes a congenital anomaly
causes 7-10% of anomalies
mechanisms often unclear
basic principles in teratogenesis? aka factors that determine/impact teratogenic influence?
1) timing of exposure - if occurs during critical period of particular organ system development, will cause effect
2) dosage of drug or chemical- severity of abnormality:[teratogen]
3) genotype (genetic constitution) of embryo- diff species or indivs may respond diff to same substance
when and what is critical pd of human development?
1st 2 weeks after conception - when egg is fertilized, implanting, membranes developing
"all or nothing" time - exposure causes either fetal/embryonic death or has no effect
when is susceptibility to teratogens greatest?
during organogenesis, 3-8 weeks! when organs are developing
what occurs re: birth anomalies, during fetal pd?
no major anomalies but can have physiologic changes, minor morphological abnormalities & functional disturbances
ie exposure to alcohol- won't cause structural defect in brain, but will cause physiological disturbance
are all developing organs equally susceptible to teratogens at all times?
no- pds of high and less sensitivity occur during embryonic and fetal periods
most likely to have abnormality occur if exposure is during a highly sensitive period for a given organ or other aspect of developing embryo
do teratogens just effect 1 organ?
no, they can affect >1 organ
high doses of radiation affects?
CNS and eye
rubella as teratogen affects?
eye defects, deafness, cardiac anomalies
thalidomide impact across pregnancy?
early: meromelia-absence of limbs
later: hypoplasia of limbs
after critical pd: no affect on limbs
does dose matter re: teratogens?
yes- dose-response relatoinship whereby the greater the exposure, the more severe the phenotypic effect
how do we know about safe doses of drugs for preg women?
animal research- dose used is usu at much higher levels than that used in humans
what is phenytoin?
drug that causes fetal hydantoin syndrome in 5-10% of exposed embryos - because only those embryos w/ GENETIC PREDISPOSITION to developing syndrome will have abnormalities
dose also important
fetal hydantoin syndrome
caused by phenytoin exposure among embryos genetically susceptible to defective development
wide-spaced eyes, long philtrim, epincanthal folds, gigital hypoplasia, neurodevelopmental problems
what are criteria for calling something a teratogen? proof of teratogenicity?
1) frequency fo anomaly increased above background risk
2) malformed infants have history of maternal exposure more often than normal infants
are case reports sufficient data to prove teratogenicity?
no, unless agent and anomaly are exceedingly rare
% of congenital anomalies caused by drugs/chemicals
< 2%! so actually pretty rare for drug to be teratogen
is caffeine a teratogen?
although over 300 mg/day may cause low birth-weight, miscarriage if early on
is alcohol a teratogen?
if so, incidence of teratogenic effects?
what are effects?
when does alc have greatest effect on fetus?
dose-dependent response to alc
1-2/1000 live births
fetal alc effects (FAE) = behavioral and learning difficulties
susceptible pd spans major pt of gestation
coumadin re: fetus
known teratogen - can cause bleeding in fetus
antagonist of vitamin k; can cause IUGR, zeisures, nasal hypoplasia, stippled epiphysis, CNS defects (dandy-walker malformation)
oral acne med teratogen?
retinoic acid - vitamin A
severe ear defects, cardiac and CNS defects, craniofacial, thymic aplasia, cleft palate, neuropsychological impairment, & spontaneous abortion
critical pd- 3rd-5th wk
environment chemicals that can cause birth defects?
spontaneous abortions, IUGR, anoalies, functional deficits
2) polychlorinated biphenyls (PCBs):
IUGR, skin discoloration, contaminated waters
when can hyperthermia cause defect? what happens?
early exposure to hot tub or sauna is assoc w/ increaesd risk for neural tube defects
infectious agents as teratogens? what do they cause?
micro-organisms can cross placenta, enter fetal blood stream- cause
spontaneous abortion, stillbirth, congenital anomalies, neonatal sequelae
get prenatal dx
rubella, CMV, herpes simplex, varicella, toxoplasmosis, syphylis are eg
is radiation teratogen? effect?
yes- high-levels of ionizing radiation cause cell death, chromosomal injury, anomalies, mental retardation
severity lreated to dose, dose rate, stage of embryologic development
greatest risk for severe mental retardation- 10-18 weeks GA
5 rads or less is safe! diagnostic levels of radiation aren't teratogenic
are elctromagnetic fields teratogenic?
ie electric blankets, computers?
is ultrasound teratogenic?
is diabetes teratogenic?
if poorly controlled, 2-3 fold increase in congenital anomalies if mom's diabetes is poorly controlled
can cause neural tube defects, cardiac defects, sacral agenesis, limb macrosomia, stillbirths
what are mechanical factors that might cause clubfoot, congenital hip dislocation?
what does it mean to be anomaly caused by multifactorial inheritance? what usu results?
combo of genetic & environmental factors
usu single major anomaly results- cleft lip, NTD, pyloric stenosis
risk of recurrence is based on frequency in general pop & categories of relatives- higher risk w/ closer-degree relative
which of following is true re: teratogens, birth defects?
1) teratogens don't have any effect after pd of organogenesis
2) teratogens can cause severe abnormalities during implantation
3) teratogens should show dose-response effect
4) chromosomal abnormalities are leading cause of birth defects
1) false bc can have minor functiona, physiologic effects
2) false- all or nothing response during implantation- either death of embryo or no effect at all
3) teratogens should show dose-response effect- true!
4) false- leading cause is unknown!