Teratogens II Flashcards
What is a teratogen?
an agent that can cause abnormalities of form or function in a fetus exposed to the agent
What is the general population risk for structural anomalies in pregnancies?
~2-5%
Teratogenic agents cause approximately ____% of congenital malformations.
7
What are possible teratogenic exposures?
drugs, infectious agents, physical agents, maternal health factors/disease, environmental agents
List prescription medications that are potential teratogenic exposures.
valproic acid, carbamazepine, phenobarbital, lithium, Coumadin
List infectious agents that are potential teratogenic exposures.
rubella, cytomegalovirus, varicella, herpes simplex, toxoplasma, syphilis
What are the three kinds of bias that could invalidate epidemiology data.
ascertainment bias
observer bias
recall bias
What is ascertainment bias?
increased likelihood to report adverse outcomes over normal outcomes
What is recall bias?
more likely to recall exposures if adverse outcomes happened
amount of time since exposure affects recall
List environmental agents that are considered potential teratogenic exposures.
organic mercury compounds, lead, radiation, polychlorinated biphenyl, herbicides, industrial solvents
List examples of possible teratogenic effects.
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
What is teratogenic effect related to?
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
What were the FDA Pregnancy Risk Categories prior to 2015?
A B C D X
Describe a Category A drug.
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)
Describe a Category B drug.
animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women
Describe a Category C drug.
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
Describe a Category D drug.
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
Describe a Category X drug.
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
What replaced the risk letter categories for defining teratogen risk in 2015?
narrative sections and subsections including:
pregnancy (including labor and delivery)
lactation (including nursing mothers)
females and males of reproductive potential
What were Shepart’s Criteria for Teratogenicity?
- proven exposure to agent at critical time(s) in prenatal development
- consistent findings by 2 or more epidemiologic studies of high quality
- careful deliniation of the clinical cases
- rare environmental exposure associated with rare defect
- teratogenicity in experimental animals important but not essential
- the association should make biological sense
- proof in an experimental system that the agent acts in an unaltered state
Implantation takes place within _____ post-fertilization in the _____ period.
~1-2 weeks
all or none
When is the fetal period?
3-9 months
What factors are protective in the all-or-nothing period?
placenta is not fully functional (but diffusion can still occur)
limited O2 to embryo decreases amount of free radicals the embryo is exposed to
What is DES?
diethylstilbestrol
synthetic nonsteroidal estrogen used for prevention of miscarraige, preterm delivery, and other pregnancy complications
known teratogen- no longer used in US and Europe
Describe the teratogenic effects of DES on pregnant women.
increased risk of preterm delivery, spontaneous abortion, ectopic pregnancy, preeclampsia, stillbirth, infertility, breast cancer, and early menopause
Describe the teratogenic effects of DES on “daughters”.
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
Describe the teratogenic effects of DES on “sons”.
urogenital tract anomalies (including urinary difficulties and decreased fertility) have been reported
Name examples of the drugs/agents where dose has been proven to be a major determinant of teratogenicity in humans.
valproic acid
lamotrigine
methotrexate
ionizing radiation
Teratogens affect morphogenesis, development, and differentiation through ____, _____, or ______.
cell death
failed cell interactions
alterations in the movement of cells
_____ is known as the “prototype teratogen”.
Thalidomide
What is thalidomide?
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
Describe the teratogenic effect of thalidomide.
limb reduction defects, facial hemangiomata, esophageal and duodenal atresia, teratology of Fallot, renal agenesis, anomalies of the ear
What is the sensitive time period for the production of human thalidomide birth defects?
21-37 days from conception
Provide examples of why mode of exposure may matter in teratogenic effect.
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
Women with epilepsy have a ____X higher risk for fetal malformations than the general population, even when they are not taking anticonvulsants.
2-3
What is the primary fetal malformation associated with mothers with epilepsy?
increased risk for oral clefts and heart defects
What features in fetuses are associated with exposure to anticonvulsants in-utero?
broad depressed nasal bridges short nose with anteverted nares long philtrum maxillary hypoplasia fingernail hypoplasia
What is Fetal Valporate Syndrome?
rare condition that is caused by exposure of the fetus to valporic acid or sodium valproate during the first three months of pregnancy
What are some suggested mechanisms of teratogenic action of Valporic Acid?
Folic acid deficiency theory
arene oxide intermediate theory
oxidative stress theory
inhibition of histone deacetylase theory
What maternal health conditions may be teratogenic?
Type I DM
severe phenylalanine hydroxylase deficiency (Classic PKU)
Myasthenia gravis
Describe the teratogenic effects of maternal PAH on a fetus.
intellectual disability, variable microcephaly, poor behavior, congenital heart defects, tracheoesophageal fistula, intrauterine growth restriction
Type I or II DM in women before pregnancy that is poorly controlled is associated with major birth defects in _____% of pregnancies.
5-10
Gestational DM usually develops in the _____ of pregnancy, and is associated with risk for ______ anomalies.
second half
macrosomia, increased prenatal and perinatal mortality, and perinatal complications (but no congenital anomalies)
In patients with myasthenia gravis, transfer of IgG antibodies across the placenta can result in transient neonatal myasthenia in ___% to ____% of newborns.
10
20
Provide examples of recreational drugs with known teratogenic effects.
alcohol
cigarette smoke
cocaine
toluene
What teratogenic effects are associated with smoking?
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
Why is alcohol teratogenic?
fetal livers are unable to process alcohol because they lack alcohol dehydrogenase activity and other antioxidants
What diagnosis fall under the umbrella of Fetal Alcohol Spectrum Disorders (FASDs)?
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
List the teratogenic effects associated with alcohol.
permanent brain damage, congenital anomalies, prenatal and/or postnatal growth restriction and characteristic facial features, and cognitive, behavioral, emotional, and adaptive functioning deficits
What are examples of environmental teratogens?
lead and radiation
Describe the teratogenic effects of lead on fetuses.
CNS system damage, hydroceles, skin tags, hemangiomas, lymphangiomas, undecended testicles (in males), and stillbirth
What are examples of teratogenic infectious agents?
congenital rubella or German measles
congenital cytomegalovirus (herpes virus)
congenital toxoplasmosis
zika virus
List mechanical forces that impact fetal structural development.
malformations of the uterus that restrict fetal movement
oligohydraminos
amniotic bands
What are the 8 recommended areas for risk assessment of pregnant women as per the ACOG)?
- reproductive awareness
- environmental toxins and teratogens
- nutrition and folic acid
- genetics
- substance use disorders, including tobacco and alcohol
- medical conditions and medications
- infectious diseases and vaccinations
- psychosocial issues including screening for intimate partner violence
What are potential paternal exposures that can affect fetuses?
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
