teratogens Flashcards
What is teratogenesis
dysgenesis of fetal organs either structurally or functionally (causing intellectual disability)
What is the most famous teratogen
Thiolinamide; originally used to Tx influenza, then used as anti-emetic and sleep aid
When is Thiolinamide teratogenic
34th - 50th day after LMP
What were the effects of Thiolinamide
Phocomelia (limb defects) 2/2 inhibiting angiogenesis during limb bud formation External ear defects Visceral anomalies (organ agenesis)
When is baby safe from teratogens
Ovum prior to fertilization is resistant
first 2 weeks (conception to implantation), ovum is usually resistant bc/ it is mostly separated from mom’s circulation
When does organogenesis occur
days 18-60 gestation; most gross deformities before day 36
GU/craniofacial: later
Palate sensitivity lasts appx 3 weeks
CNS: 2 weeks- near end of gestation
What is the “fetal phase”
End of embryonic state (9 weeks) to term
What do teratogens usually cause in the fetal phase
CNS dysfunction
IU growth retardation
Organ dysfunction
How is dosing related to teratogenesis
Effects occur more frequently at higher doses
What are the most accepted theories on the mechanisms of teratogenesis
- Antineoplastic agents are cytotoxic (depressed mitosis, promote cell death) and when the body tries to repair, you get uncoordinated growth (malformation)
- Directly interact with DNA and interfere w/ gene expression
- Affect angiogenesis
- Inhibit enzymes important for organ development
- Nutrient and vitamin deficiencies can be teratogenic (folate)
What are the FDA pregnancy categories
A: studies fail to demonstrate risk in first trimester (folic acid, levothyroxine)
B: animal studies fail to demonstrate risk (Amoxicillin, Insulin R and N)
C: animal studies show adverse effects on fetus, only use if benefit>risk (albuterol, fluoxetine, Sertraline)
D: dont use, evidence of human fetal risk (tetracyclines)
X: dont use, positive human fetal risk
How are animal studies related to human studies
Not all animal teratogens are harmful in humans BUT relatively all human teratogens are harmful to animals
What are the teratogenic drugs in this lecture (most important)
Carbamazepine Phenytoin Valporate Isotretinoin Oral anticoagulants (warfarin)
What does Carbamazepine cause
Neural tube defects
effects similar to phenytoin embryopathy
What does phenytoin cause
short fingers, short nose
What does valporate cause
neural tube defects from 1st trimester exposure small mouth developmental delay narrow forehead flat philtrum
What does isotretinoin cause
external ear defects/absence of ears congenital heart defects hydrocephalus mental retardation clefts hypertelorism (space between eyes is wide) 40% miscarriage
What does warfarin cause in first trimester exposure (6-9 weeks)
Fetal warfarin syndrome: nasal hypoplasia, calcific stippling of epiphysis, short stubby fingers
What does warfarin cause after the first trimester
CNS defects (in utero hemorrhage+scarring) Bone defects (dwarfism, scoliosis, skull defects) from inhibited gamma carboxylation of bone proteins
What risk factors can cause adverse pregnancy outcomes
Alcohol misuse and obesity
What does alcohol in pregnancy cause (fetal alcohol syndrome)
IUGR, microcephaly, mental retardation, facial abnormalities
What amount of alcohol is reported safe while pregnant
one drink per day (1 beer, 4 oz wine, 1 shot liquor 40% ethanol)
2-14 drinks per week are said to cause FAS
What do FAS babies look like
small head epicanthial folds short nose smooth philtrum underdeveloped jaw long nasal bridge thin upper lip
What do ACE and ARB cause
congenital renal failure
skull abnormalities
*Oligohydramnios causing limb contractures, skull and facial deformities
