Drugs and Teratogenesis

Question 1

General Concepts

Answer 1

Organogenesis: 1st 8 weeks
CNS development: 3-20+ weeks
Mainly growth during second half of pregnancy

Question 2

Identification of Human Teratogens

Answer 2

Abrupt increase in the incidence of a defect coinciding with increased use of specific drug
Distinct pattern of malformation
Sufficient number of cases
Known exposure to agent in pregnancy
Absence of other factors

Question 3

Category A Drugs

Answer 3

Adequate and well-controlled studies fail to show risk to fetus

Question 4

Category B Drugs

Answer 4

Animal Reproduction studies fail to show risk to fetus and no adequate and well-controlled studies in pregnant women

Question 5

Category C Drugs

Answer 5

Animal reproduction studies show an adverse effect on fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use in pregnant women despite potential risks

Question 6

Category D Drugs

Answer 6

Positive evidence of human fetal risk based on human studies, but potential benefits may warrant use in pregnant woman despite potential risks

Question 7

Category X Drugs

Answer 7

Studies in animals or humans demonstrate fetal abnormalities and/or positive evidence of human fetal risk; risks in pregnant women clearly outweigh benefits

Question 8

Category N drugs

Answer 8

FDA has not classified the drug

Question 9

Male-Mediated Teratogenesis

Answer 9

Not extensively studied
Induction of genetic damage in sperm
Sperm acts as physical carrier of the agent
Seminal fluid transfer

Question 10

Thalidomide

Answer 10

Was once prescribed for pregnancy-associated nausea
Bilateral limb reduction
Defects in eyes, ears, kidney, and heart
Intercalates into guanine rich regions of DNA
Angiogenesis inhibition
Inhibits TNF alpha production

Question 11

Thalidomide Details

Answer 11

Uses: Multiple myeloma, leprosy
Heavily Regulated: Only prescribed by physicians registered in STEPS program, mandatory contraceptive measures (2 types), weekly pregnancy tests, short term supply of drug, patient registration, no refills

Question 12

Diethylstilbesterol (DES)

Answer 12

Oral synthetic non-steroidal estrogen analog
Use: To prevent miscarriage in 40s and 50s.
Delayed teratogen!
DES daughters 40x more likely to develop vaginal adenocarcinoma
DES sons show genital abnormalities
sons of DES daughters may have genital abnormalities

Question 13

Fetal Alcohol Syndrome (FAS)

Answer 13

1 in 750 births
Most common cause of mental retardation and birth defects
Characteristic facial features, low birth rate
Multiple critical points:
Craniofacial features 3 weeks post-conception, major malformations 3-9 weeks, CNS effect 3-20+ weeks, growth retardation 20-40 weeks

Question 14

Phentoin (dilantin)

Answer 14

Anti-epileptic
7-10% of babies suffer effects
Resembles FAS and referred to as fetal hydrantoin syndrome
Craniofacial abnormalities and mild mental retardation

Question 15

Nicotine

Answer 15

30% of women continue smoking 10 cigarettes per day.
nicotine found in fetal lung, kidneys, adrenal glands, intestines
Teratogenic effects: growth retardation, placenta development, association with cognitive impairment.
Mechanism: Nicotine restricts uterine blood vessels causing chronic hypoxia and malnutrition

Question 16

Retinoids

Answer 16

Vitamin A analogs regulate epithelial cell growth.

Play important role in development of pharyngeal arches.

Question 17

Accutane (Isotretinoin)

Answer 17

Craniofacial alterations: Absent or abnormal ears, cleft palate, small jaw
CNS abnormalities: Neural tube defects, poor cognitive performance
Cardiovascular malformations
Kidney Alterations
Thymic Aplasia

Question 18

Accutane (isotretinoin) Part 2

Answer 18

Miscarriage
Growth delay before and after birth
50% of children affected have IQ <85
2004 FDA establishes program modeled after thalidomide to prevent pregnant mothers from taking accutane.