Teratogens II

Question 1

What is a teratogen?

Answer 1

an agent that can cause abnormalities of form or function in a fetus exposed to the agent

Question 2

What is the general population risk for structural anomalies in pregnancies?

Answer 2

~2-5%

Question 3

Teratogenic agents cause approximately ____% of congenital malformations.

Answer 3

7

Question 4

What are possible teratogenic exposures?

Answer 4

drugs, infectious agents, physical agents, maternal health factors/disease, environmental agents

Question 5

List prescription medications that are potential teratogenic exposures.

Answer 5

valproic acid, carbamazepine, phenobarbital, lithium, Coumadin

Question 6

List infectious agents that are potential teratogenic exposures.

Answer 6

rubella, cytomegalovirus, varicella, herpes simplex, toxoplasma, syphilis

Question 7

What are the three kinds of bias that could invalidate epidemiology data.

Answer 7

ascertainment bias
observer bias
recall bias

Question 8

What is ascertainment bias?

Answer 8

increased likelihood to report adverse outcomes over normal outcomes

Question 9

What is recall bias?

Answer 9

more likely to recall exposures if adverse outcomes happened

amount of time since exposure affects recall

Question 10

List environmental agents that are considered potential teratogenic exposures.

Answer 10

organic mercury compounds, lead, radiation, polychlorinated biphenyl, herbicides, industrial solvents

Question 11

List examples of possible teratogenic effects.

Answer 11

miscarriage/fetal demise
intrauterine growth restriction
microcephaly
major/minor structural anomalies (1+)
metabolic dysfunction
cognitive dysfunction and/or intellectual disability
neurological dysfunction
altered behavior
increased risk for malignancy

Question 12

What is teratogenic effect related to?

Answer 12

type of agent
dose
gestational age at time of exposure
duration/mode of exposure
genetic susceptibilities carried by the woman and fetus
interactions of agents

Question 13

What were the FDA Pregnancy Risk Categories prior to 2015?

Answer 13

A
B
C
D
X

Question 14

Describe a Category A drug.

Answer 14

adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)

Question 15

Describe a Category B drug.

Answer 15

animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women

Question 16

Describe a Category C drug.

Answer 16

animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of this in pregnant women despite risk

Question 17

Describe a Category D drug.

Answer 17

there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite risk

Question 18

Describe a Category X drug.

Answer 18

studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits

Question 19

What replaced the risk letter categories for defining teratogen risk in 2015?

Answer 19

narrative sections and subsections including:
pregnancy (including labor and delivery)
lactation (including nursing mothers)
females and males of reproductive potential

Question 20

What were Shepart’s Criteria for Teratogenicity?

Answer 20

1. proven exposure to agent at critical time(s) in prenatal development
2. consistent findings by 2 or more epidemiologic studies of high quality
3. careful deliniation of the clinical cases
4. rare environmental exposure associated with rare defect
5. teratogenicity in experimental animals important but not essential
6. the association should make biological sense
7. proof in an experimental system that the agent acts in an unaltered state

Question 21

Implantation takes place within _____ post-fertilization in the _____ period.

Answer 21

~1-2 weeks

all or none

Question 22

When is the fetal period?

Answer 22

3-9 months

Question 23

What factors are protective in the all-or-nothing period?

Answer 23

placenta is not fully functional (but diffusion can still occur)
limited O2 to embryo decreases amount of free radicals the embryo is exposed to

Question 24

What is DES?

Answer 24

diethylstilbestrol
synthetic nonsteroidal estrogen used for prevention of miscarraige, preterm delivery, and other pregnancy complications
known teratogen- no longer used in US and Europe

Question 25

Describe the teratogenic effects of DES on pregnant women.

Answer 25

increased risk of preterm delivery, spontaneous abortion, ectopic pregnancy, preeclampsia, stillbirth, infertility, breast cancer, and early menopause

Question 26

Describe the teratogenic effects of DES on "daughters".

Answer 26

reproductive tract abnormalities (vaginal adenosis, cervical malformations, vaginal septae, uterine cavity anomalies, fallopian tube anomalies, and subsequent fertility problems) increased risk for clear cell adenocarcinoma of the vagina larger breasts increased risk of breast cancer

Question 27

Describe the teratogenic effects of DES on "sons".

Answer 27

urogenital tract anomalies (including urinary difficulties and decreased fertility) have been reported

Question 28

Name examples of the drugs/agents where dose has been proven to be a major determinant of teratogenicity in humans.

Answer 28

valproic acid lamotrigine methotrexate ionizing radiation

Question 29

Teratogens affect morphogenesis, development, and differentiation through ____, _____, or ______.

Answer 29

cell death failed cell interactions alterations in the movement of cells

Question 30

_____ is known as the "prototype teratogen".

Answer 30

Thalidomide

Question 31

What is thalidomide?

Answer 31

sedative common in the 1950s that was later used to treat morning sickness and anxiety resulted in over 10,000 children with congenital anomalies in 46 countries

Question 32

Describe the teratogenic effect of thalidomide.

Answer 32

limb reduction defects, facial hemangiomata, esophageal and duodenal atresia, teratology of Fallot, renal agenesis, anomalies of the ear

Question 33

What is the sensitive time period for the production of human thalidomide birth defects?

Answer 33

21-37 days from conception

Question 34

Provide examples of why mode of exposure may matter in teratogenic effect.

Answer 34

Vitamin A and vitamin A-like agents preformed vitamin A supplements taken orally can be teratogenic at high doses and taking oral Accutane is associated with anomalies, however topical retinoids have not been found to result in anomalies

Question 35

Women with epilepsy have a ____X higher risk for fetal malformations than the general population, even when they are not taking anticonvulsants.

Answer 35

2-3

Question 36

What is the primary fetal malformation associated with mothers with epilepsy?

Answer 36

increased risk for oral clefts and heart defects

Question 37

What features in fetuses are associated with exposure to anticonvulsants in-utero?

Answer 37

``` broad depressed nasal bridges short nose with anteverted nares long philtrum maxillary hypoplasia fingernail hypoplasia ```

Question 38

What is Fetal Valporate Syndrome?

Answer 38

rare condition that is caused by exposure of the fetus to valporic acid or sodium valproate during the first three months of pregnancy

Question 39

What are some suggested mechanisms of teratogenic action of Valporic Acid?

Answer 39

Folic acid deficiency theory arene oxide intermediate theory oxidative stress theory inhibition of histone deacetylase theory

Question 40

What maternal health conditions may be teratogenic?

Answer 40

Type I DM severe phenylalanine hydroxylase deficiency (Classic PKU) Myasthenia gravis

Question 41

Describe the teratogenic effects of maternal PAH on a fetus.

Answer 41

intellectual disability, variable microcephaly, poor behavior, congenital heart defects, tracheoesophageal fistula, intrauterine growth restriction

Question 42

Type I or II DM in women before pregnancy that is poorly controlled is associated with major birth defects in _____% of pregnancies.

Answer 42

5-10

Question 43

Gestational DM usually develops in the _____ of pregnancy, and is associated with risk for ______ anomalies.

Answer 43

second half | macrosomia, increased prenatal and perinatal mortality, and perinatal complications (but no congenital anomalies)

Question 44

In patients with myasthenia gravis, transfer of IgG antibodies across the placenta can result in transient neonatal myasthenia in ___% to ____% of newborns.

Answer 44

10 | 20

Question 45

Provide examples of recreational drugs with known teratogenic effects.

Answer 45

alcohol cigarette smoke cocaine toluene

Question 46

What teratogenic effects are associated with smoking?

Answer 46

increased risk for miscarriage, stillbirth, fetal demise, reduced fetal growth, abnormal placentation (placenta abruption, placenta previa), preterm delivery, and neonataldeath (including SIDs) most consistent effect is intrauterine growth restriction

Question 47

Why is alcohol teratogenic?

Answer 47

fetal livers are unable to process alcohol because they lack alcohol dehydrogenase activity and other antioxidants

Question 48

What diagnosis fall under the umbrella of Fetal Alcohol Spectrum Disorders (FASDs)?

Answer 48

fetal alcohol syndrome (FAS) partial FAS (pFAS) static encephalopathy/alcohol exposed (alcohol-related neurodevelopmental disorder (ARND) and neurobehavioral disorder Prenatal alcohol exposed (ND-PAE)) neurobehavioral disorder/alcohol exposed

Question 49

List the teratogenic effects associated with alcohol.

Answer 49

permanent brain damage, congenital anomalies, prenatal and/or postnatal growth restriction and characteristic facial features, and cognitive, behavioral, emotional, and adaptive functioning deficits

Question 50

What are examples of environmental teratogens?

Answer 50

lead and radiation

Question 51

Describe the teratogenic effects of lead on fetuses.

Answer 51

CNS system damage, hydroceles, skin tags, hemangiomas, lymphangiomas, undecended testicles (in males), and stillbirth

Question 52

What are examples of teratogenic infectious agents?

Answer 52

congenital rubella or German measles congenital cytomegalovirus (herpes virus) congenital toxoplasmosis zika virus

Question 53

List mechanical forces that impact fetal structural development.

Answer 53

malformations of the uterus that restrict fetal movement oligohydraminos amniotic bands

Question 54

What are the 8 recommended areas for risk assessment of pregnant women as per the ACOG)?

Answer 54

1. reproductive awareness 2. environmental toxins and teratogens 3. nutrition and folic acid 4. genetics 5. substance use disorders, including tobacco and alcohol 6. medical conditions and medications 7. infectious diseases and vaccinations 8. psychosocial issues including screening for intimate partner violence

Question 55

What are potential paternal exposures that can affect fetuses?

Answer 55

de novo mutations in sperm (from things such as radiation) alterations to libido/fertility presence of agent in semen directly affects embryonic/fetal development *note that no paternal exposures have been PROVEN to be teratogenic