LEC60: Teratology & Birth Defects

Question 1

% of infant deaths in north america attributed to birth defects?

Answer 1

> 20%

Question 2

% newborns w/ major structural anomalies

Answer 2

3%

Question 3

% newborns w/ single minor defect

Answer 3

14%

Question 4

% of birth defects detected by age 2

% by age 5

Answer 4

6% by age 2

8% by age 5

Question 5

when are major development defects most common, %

Answer 5

in early embryos

10-15%

Question 6

% of recognized prenancies that end in miscarriage

Answer 6

15%

Question 7

% of spontaneously aborted conceptuses w/ chromosomal abnormalities

Answer 7

50-60%

Question 8

incidence of major anomalies at birth? most to least common

Answer 8

10: 1000 brain
8: 1000 heart
4: 1000 kidneys
2: 1000 limbs
6: 1000 others

TOTAL: 30:1000

Question 9

overall incidence of major anomalies at birth and most common of those?

Answer 9

3%

most common: brain, 1% of major anomalies

Question 10

types of congential anomalies?

Answer 10

1) malformation
2) disruption
3) deformation
4) dysplasia

Question 11

malformation? ex?

Answer 11

intrinsically abnormal development process

ie cardiac abrnormality, VSD

Question 12

disruption? ex?

Answer 12

inference w/ an originally normal development process

fetus starts as normal, sthg happens that disrupts development process

Question 13

deformation? ex?

Answer 13

abnormal form resulting from mechanical forces

ie if no fluid around fetus, > clubbed feet, contractures of limbs

Question 14

dysplasia? ex?

Answer 14

abnormal organization of cells into tissues

ie kidneys dysplasia > multiple cysts replace them

Question 15

patterns of anomalies?

Answer 15

1) field defect
2) sequence
3) syndrome
4) association

Question 16

field defect?

Answer 16

disturbance in just 1 single developmental field

ie kidney, heart

Question 17

sequence?

Answer 17

single structural defect/mechanical factor

ie lack of fluid w/ ruptured membranes due to compression

ie potter’s sequence- bilateral renal agenesis

Question 18

syndrome?

Answer 18

multiple abnormalities that’re pathogenetically related

Question 19

association?

Answer 19

non-random occurrence of multiple anomalies in 2+ people

Question 20

most common cause of human birth defects?

Answer 20

unknown etiology (50-60%)

Question 21

second most common cause of birth defects?

Answer 21

multifactorial inheritance (20-25%)

Question 22

what is multifactorial inheritance?

Answer 22

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

Question 23

% of birth anomalies caused by genetic factors?

Answer 23

1/3 of all birth defects

Question 24

when are chromosomal abnormalities common?

Answer 24

in early zygotes/embryos

Question 25

what is numerical chromosomal abnormality?

Answer 25

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

Question 26

turner syndrome?

Answer 26

numerical chromosomal abnormality (45,X)

most common abnormality in spontaneous abortions

1/8000 live births

75% due to missing paternal X chromsome

Question 27

examples of autosomal trisomies?

Answer 27

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

Question 28

examples of sex chromosome trisomies?

Answer 28

1) 47, XXX: 15-25% mild MR
2) 47, XXY: Klinefelters, small testes, infertility
3) 47, XYY: normal appearance, tall

Question 29

mosaicism?

Answer 29

numerical chromosomal abnormality

2 cell lines w/ 2+ genotypes

Question 30

triploidy?

Answer 30

numerical chromosomal abnormality

failure of separation of 2nd polar body

dispermy

20% of all chromosomally abnormal spontaneous abortuses

Question 31

what are structural chromosome abnormalities?

Answer 31

chromosomal breakage and abnormal combination-

ie reciprocal translocation, terminal deletion, ring chromosome, duplication, paracentric inversion, isochromosome, robersonian translocation

due to drugs, chemicals, viruses

Question 32

characteristics of anomalies caused by mutant genes

Answer 32

7% of congenital anomalies

heritable

Question 33

achondroplasia

Answer 33

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

Question 34

what is a teratogen, what % of anomalies acct for, how do they occur?

Answer 34

any agent- drug, virus, alochol- that causes a congenital anomaly

causes 7-10% of anomalies

mechanisms often unclear

ie thalidomide

Question 35

basic principles in teratogenesis? aka factors that determine/impact teratogenic influence?

*HY*

Answer 35

*HY*

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

Question 36

when and what is critical pd of human development?

Answer 36

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

Question 37

when is susceptibility to teratogens greatest?

Answer 37

during organogenesis, 3-8 weeks! when organs are developing

Question 38

what occurs re: birth anomalies, during fetal pd?

Answer 38

8-38 weeks

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

Question 39

are all developing organs equally susceptible to teratogens at all times?

Answer 39

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

Question 40

do teratogens just effect 1 organ?

Answer 40

no, they can affect >1 organ

Question 41

high doses of radiation affects?

Answer 41

CNS and eye

Question 42

rubella as teratogen affects?

Answer 42

eye defects, deafness, cardiac anomalies

Question 43

thalidomide impact across pregnancy?

Answer 43

early: meromelia-absence of limbs
later: hypoplasia of limbs

after critical pd: no affect on limbs

Question 44

does dose matter re: teratogens?

Answer 44

yes- dose-response relatoinship whereby the greater the exposure, the more severe the phenotypic effect

Question 45

how do we know about safe doses of drugs for preg women?

Answer 45

animal research- dose used is usu at much higher levels than that used in humans

Question 46

what is phenytoin?

Answer 46

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

Question 47

fetal hydantoin syndrome

Answer 47

caused by phenytoin exposure among embryos genetically susceptible to defective development

wide-spaced eyes, long philtrim, epincanthal folds, gigital hypoplasia, neurodevelopmental problems

Question 48

what are criteria for calling something a teratogen? proof of teratogenicity?

Answer 48

1) frequency fo anomaly increased above background risk

OR

2) malformed infants have history of maternal exposure more often than normal infants

Question 49

are case reports sufficient data to prove teratogenicity?

Answer 49

no, unless agent and anomaly are exceedingly rare

Question 50

% of congenital anomalies caused by drugs/chemicals

Answer 50

< 2%! so actually pretty rare for drug to be teratogen

Question 51

is caffeine a teratogen?

Answer 51

no

although over 300 mg/day may cause low birth-weight, miscarriage if early on

Question 52

is alcohol a teratogen?

if so, incidence of teratogenic effects?

what are effects?

when does alc have greatest effect on fetus?

Answer 52

yes

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

Question 53

coumadin re: fetus

Answer 53

anticoagulant

known teratogen - can cause bleeding in fetus

antagonist of vitamin k; can cause IUGR, zeisures, nasal hypoplasia, stippled epiphysis, CNS defects (dandy-walker malformation)

Question 54

oral acne med teratogen?

Answer 54

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

Question 55

environment chemicals that can cause birth defects?

Answer 55

1) lead:

spontaneous abortions, IUGR, anoalies, functional deficits

2) polychlorinated biphenyls (PCBs):

IUGR, skin discoloration, contaminated waters

Question 56

when can hyperthermia cause defect? what happens?

Answer 56

early exposure to hot tub or sauna is assoc w/ increaesd risk for neural tube defects

Question 57

infectious agents as teratogens? what do they cause?

Answer 57

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

Question 58

is radiation teratogen? effect?

Answer 58

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

Question 59

are elctromagnetic fields teratogenic?

Answer 59

ie electric blankets, computers?

NO

Question 60

is ultrasound teratogenic?

Answer 60

NO

Question 61

is diabetes teratogenic?

Answer 61

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

Question 62

what are mechanical factors that might cause clubfoot, congenital hip dislocation?

Answer 62

oligohydramnios

uterine anomalies

fibroids

early amniocentesis

Question 63

what does it mean to be anomaly caused by multifactorial inheritance? what usu results?

Answer 63

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

Question 64

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

Answer 64

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!