Teratogens LT Flashcards
1
Q
Teratogens act by
A
- Producing cell death
- Altering normal growth of tissues
- Interfering with normal cellular differentiation
⇒Abnormalities in form or function of fetus
- Fetal loss
- Growth restriction
- Birth defects
- Impaired Neuro
- Fetal ALcohol Syndrome (altered neuro connections)
2
Q
Enviornmental teratogens account for
A
4-6% of birth defects
3
Q
Enviornmental teratogens include
A
- Maternal ilness
- DM
- PKU
- TORCH
- Physical agents
- Radiation
- Heat
- Drugs
- Thalidomide
- Antiepileptic
- Chemicals
- Hg
4
Q
TORCH infections
A
- Toxo
- Others- syphilis, VZV, Parvo B19
- Rubella
- Cytomegalo
- Herpes
5
Q
Factors that influence response to teratogen
A
- Genetic Succeptibility
- Dose
- Route
- Timing
- Concourrent exposures/maternal illnesses
- Absorption of mom
6
Q
Genetic succeptibility to teratogen
A
- genetic makeup of BOTH fetus and mom
- different that genetic conditions that directly cause defects
7
Q
Example of genetic succeptibility
A
- Defect in folate metabolism predisposes to a higher risk for developing structural abnormalities such as NT defects, cleft lip and palate and cardio malformations
- MTHFR gene mutation
- Risk of these malformations depends on the prescence of altered folate metabolism (MTHFR gene mutation) AND inadequate folate intake by mom
- ie risk can be reduced by suplementing folate to mom in preconceptional and early pregnancy period
8
Q
Genetic succeptibility and interaction with antiepileptic drugs
A
Fetuses with low epoxide hydrolase activity + exposure to antiepileptic drugs→higher levels of teratogenic oxidative metabolites
9
Q
Epidemiology of postaxial polydactyly
A
-
MORE common in African americans (1%)
- Caucasians (0.1%)
10
Q
Epidemiology of NT defects
A
- MORE common in caucasians than African Americans
11
Q
Epidemiology of pyloric stenosis and cleft lip
A
- MALES > Females
12
Q
Example of role of route exposure in teratogenecity
A
- Absorption and action of drug differ if adminstered dermally or systemically
-
Systemic route
- abnormalities
- fluconazole→potentially teratogenic
- Retinoic acid
- oral/systemic
-
Dermal
- safe
- fluconazole and retinoic acid are safe if adminstered dermally
13
Q
Dose of a drug and teratogenicity
Threshold Effects
A
Threshold Effects:
- a dose below which the drug is unlikely to increase the incidence of embryonic death, growth rstriction, functional impairment
- 1-3 orders of magnitude below teratogenic dose
14
Q
The use of teratogenic doses in animals
A
- Used when no human doses are available
- Teratogenic dose less than 10X the max theraputic dose in humans
- TERATOGENIC
- Teratogenic dose more than 100X the max theraputic dose in humans
- SAFE
15
Q
Teratogenicity among different species
A
-
Thalidomide
- Teratogenic in humans
- Safe in rabbits
-
Many drugs
- Teratogenic when given at 10 to 1000 times the normal dose adminstered to humans (100 fold difference is necesary to deem a drug safe)
-
Meclizine
-
When given to mice casues cleft palate due to apetite supression
- __Therefore, force feeding the mice would prevent the occurence of cleft palate
-
When given to mice casues cleft palate due to apetite supression
16
Q
The duration of dose adminstration and amount admisntered
A
- Some drugs are teratogenic when given at one large dose
- ie spreading out this dose wouyld make it safe
- eg. Daily intake of one alcoholic drik for a week is safer than binge drinking seven alcoholic drinks in a day
- Another drug is teratogenic when it exposure is prolonged
- ie giving it all at once would make it safe
- eg. Occasional very high maternal glucose is safer than persistent high glucose levels
17
Q
Drug drug interactions
A
- Synergistic drugs
- Independent
- Protective against the teratogenic effects of the other
- Folic acid is protective in patients taking antiepileptic (valproate, carbamazepine)
- Still try to avoid giving valproate
18
Q
Preimplantation and implantation
A
days 5-11
19
Q
Formation of the three germ layers
A
by day 16
20
Q
Formation of neural plate
A
by day 19
21
Q
Closure of neural tube
A
by day 27
22
Q
Appearance of limb buds
A
by day 30
23
Q
Formation of branchial arches, clefts, pouches, optic vesicle
A
between weeks 4-5
24
Q
Formation of mature heart and kidneys
A
by week 5-7
25
Achievement of mature limb architecture
by week 8
26
Sexual differentiatoin of internal and external genitalia
by weeks 7-10
27
Rotation of the intestines and return into the abdominal cavity
in week 10
28
Result of significant exposure during first 10-14 days after fertilization
Cell death
* if significant leads to spontaneous abortion
* If only a few die, other cells will compensate for their roles
* **All or none theory**
* ****Eg, significant exposure to radiation results in either pregnancy loss or no abnormalities
29
Teratogenecity and the embryonic period
**Embryonic period**
* From fertilization to the 8th week postconception (10 W of gestation)
* Most vulnerable to insult since organ systems are developing
30
Teratogenecity and the Fetal period cause
* Cell death
* Retardation of cell growth
* Inhibition of normal differentiation
**⇒**fetal growth restriction or disorders of the CNS not apparent at birth
*Eyes, genetalia, CNS, hematopoetic systems all develop during fetal period*
31
ACE-I as teratogens
**During second and third trimesters**
* FDA *Category D*
* Block Ang1→Ang2 in fetal kidney causing:
* Hypotension
* Renal tubular dysplasia
* Anuria/oligohydramnios
* Growth restriction
* Calvarial defects\
**During first trimerster**
* FDA *Category C*
* Congenital heart defects
32
Misoprostol as a teratogen
* PGE1 analogue
* In **First trimester**
* ****Severe vascular disruptions
* Terminal Limb defects
* Moebius syndrome
* Induce abortion
* also in second trimester
* To induce labor
* Safe
* Uterine cervix ripening
33
Thalidomide is only teratogenic
days 21-36 postconception (limb bud development)
34
Mechanism of teratogenesis
Radiation
cell death
35
Mechanism of teratogenesis
Thioureas, iodides
blocking of metabolic processes
36
Mechanism of teratogenesis
Fetal alcohol spectrum disorder
**APOPTOSIS**
**NOTE:** drugs can also be teratogenic by altering cell growth, proliferation,migration and interactions
37
Toxic mutagenesis
* Exposure prior to conception
* **Females**
* ****DNA replication occurs during *oogenesis* as a fetus
* Ie before ovulation
* **Males**
* ****Spermatogenesis is continuous throughout reproductive life
* Chemo
* Radiation
38
Infections and teratogenicity
* Fever associated with infections is teratogenic (possibly)
* Affects fetus and neonate
* malformations
* congenital infections
* disability
* death
* TORCH
* Lymphocytic choriomeningitis virus LCMV
39
How are maternal ilnesses teratogenic
diffusion of a metabolite or antibody across the placenta where it is toxic to the fetus
40
IDDM associated with
* 2-3 fold increase in risk of congenital anomalies
* Congenital heart disease
* Cleft palate
* Colobomas
* Spina bifida
* **Less common**
* ****Caudal regression
* Focal femoral hypoplasia
41
Uncontrolled PKU (diet)
* MIcrocephaly
* Intellectual disability
* Congenital heart disease
42
Androgen producing tumors
Virilization of female fetus
43
Myasthenia gravis teratogenicity
Transient neonatal myasthenia
44
Maternal Grave’s disease causes
Fetal and neonatal thyrotoxicosis
45
Immune thrombocytopenia results in
Fetal and neonatal thrombocytopenia
46
Maternal SLE causes
Fetal heart block
47
Maternal obesity is associated with
Birth defects
48
Heat exposure teratogenicity
**Heat exposure**
* Hot tub/sauna
* Maternal fever
* Elevation of maternal core temperature by 1.5°C in **first trimester for atleast 24 hrs**
* ****increased risk of NT defects
* microcephaly
* mental retardation
* hypertonia
* hypotonia
* seizures
49
Exposure to ionizing radiation during pregnancy
**Produces**
* fetal death
* growth disturbances
* somatic abnormalities
* mutation
* chromosome fragmentation
* malignancy
*Note:* not at levels of diagnostic imaging but still make sure imaging is absolutely necessary
50
The US Food and Drug Administration (FDA) requires that all prescription drugs be tested in animal models, usually one rodent and one nonrodent model. Testing establishes both the lowest observed adverse effect level (LOAEL) and the no observed adverse effect level (NOAEL). If the human exposure level is 100 times lower than the NOAEL, adverse effects in humans are considered
unlikely. However, results from animal models may not always apply to humans. As an
example, thalidomide is strongly teratogenic in humans, but weakly teratogenic in animals, while the opposite is true for aspirin. A study of drugs approved by the FDA from 2000 to 2010 found that the teratogenic risk in human pregnancy was "undetermined" for 98% of the drugs approved for human use.
51
Teratogenic medications
* ACE-I
* Anticonvulsants
* Antineoplastics
* Thalidomide
* Methylene blue
* Misoprostol
* Penicillamine
* Fluconazole
* Lithium
52
Read this
53
Teratogenicty of Folic Acid antagonists
**Trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, primidone, methotrexate**
* neural tube defects
* possibly
* CV defects
* oral clefts
* urinary tract defects
54
Oral isoterinoin
* Used to treat severe acne
* associated with ear anomalies
* microtia with or without atresia of ear canal
* CNS malformations
* hydrocephalus
* Neuronal brain migration defects
* cerebellum abnormalities
* severe intellectual disability
* seizures
* Optic N/retinal abnormalities
* Conotruncal heart defects
* thymic defects
* dysmorphic features
55
Statins during pregnancy
* Completely **contraindicated**
* Severe birth defects
* due to disruption of chol biosynthesis
* important for cell membrane morphogenesis
* limb malformations
* congenital heart disease
* CNS abnormalities
56
Alcohol consumption during pregnancy
**Substantial quantities**
* ND-PAE
* neurobehavioral disorder-prenatal alcohol exposure
* ARBD
* alcohol related birth defects
* fetal alcohol syndrome
* may be normal
57
Cigarette smoking during pregnancy
* Effect on placenta
* poor fetal growth
* limb deficiency
* due to vasoactive effect of compounds found in cigarettes
* Prenatal exposure→impaired function of:
* Endo
* Repro
* Resp
* CV
* Neuro
58
High plasma levels of lead during pregnancy
* Neurobehavioral effects in infants and children
* studies on parental lead exposure and congenital malformations
* No consistent increase in risk or pattern of defects
* lack biological indices of exposure at developmentally significant times
