Teratogens
Major defects are present in 2-3% at birth and in 4.5% by the age of 5 years, with a specific cause known in less than 50% of cases.
The 2007 International Conference on Fetal Programming and Developmental Toxicity has some things to say. Toronto Star article about it.
Definition and Criteria
- any agent or factor to which embryofetal exposure produces a permanent alteration in form or function of the offspring
criteria
- proven exposure to agent at critical time in development
- consistent findings by two or more high quality epidemiological studies
- careful delineation of the clinical cases attempting to prove relationship
- rare environmental exposure associated with rare defect
- association should make biological sense
assessment of relationship
- case reports often occur first, followed by epidemiological studies
- non-randomized, therefore significant risk of confounding factors
- voluntary reporting
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- often difficult to distinguish effect of drug and disease
- nor is it easy to determine natural prevalence and risk associated with exposure
categorization
categorization can be ambigous and change as new information becomes available, making counselling people difficult sometimes
category A:
- controlled studies do not demonstrate a risk to the fetus in the first trimester
category B:
- animal studies do not indicate risk, but there are no human studies, - or - adverse effects have been demonstrated in animals but not well-controlled human studies
category C:
- no adequate studies in animals or humans - or- adverse fetal effects in animals but no data available for humans
category D:
- evidence of fetal risk, but benefits outweigh risks
category X:
- proven fetal risks clearly outweight benefit
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Transfer from Mother to Fetus
- no direct communication between fetal and maternal blood
- by day 17, fetal and maternal blood vessels are functional and the placental circulation is established
- transfer is affected by:
- concentration of substance in maternal and fetal blood
- rate of maternal blood flow
- area available for exchange across villous trophoblast epithelium
- if active transfer, there must be specific receptors on trophoblast plasma membrane
- area of exchange across fetal capillaries in placenta
- presence of specific binding/carrier proteins in fetal/maternal circulation
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Actions and Effects of Teratogens
- susceptibility to a teratogen depends on the genotype and developmental stage of the embryo
- most critical stage is weeks 2-8
- before then, miscarriage will likely occur
- most organigenesis is complete by 13 weeks
- after 13 weeks, abnormalities are usually functional rather than structural
- they act in specific ways on the developing tissues:
- gene mutation
- chromosomal abnormalities
- alteration in substrates or precursors
- enzyme inhibition
- final manifestations of abnormal development are death, malformation, growth retardation and functional disorder
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Medications as Teratogens
thalidomide
- anxiolytic, sedative
- highlights importance of exposure timing
- days 21-27: primarily ear defects
- days 27-30: upper limb phocomelia
- days 30-33: lower limb phocomelia
warfarin (and other coumarin derivatives)
- 15-25% risk of serious abnormalities if given during first trimester; later use associated with placental separation, stillbirth, fetal hemorrhage
- nasal hypoplasia
- stippled bone epiphyses and broad, short hands with shortened phalanges
- ophthamologic abnormalities
- IUGR and developmental delay
- CNS abnormalities
-
anticonvulsants
overlap in abnormalities seen with various anticonvulsants; potential common epoxide metabolite responsible
increased rate of congenital abnormalities in offspring of epileptics
carbamazapine
- neutal tube defects (1-2%)
- mino craniofacial defects
- fingernail hypoplasia
- microcephaly
- developmental delay
- IUGR
phenytoin
- IUGR
- mental deficits
- microcephaly
- dysmorphic craniofacial features
- cardiac defects
- hypolastic nails and distal phalanges
- appears to be some genetic predisposition
valproic acid
- neural tube defects in 1%
Vitamin A and Derivatives
- current recommendation is that wmoen take no more than 5000 IU daily when pregnant
- spontaneous abortion
- Acutane (isoretinoin) is a Category X drug
- risk of malformations is 25-35%
- must confrim negative pregnancy and ensure two forms of contraception are used
- microtia and microphthalmia
- CNS defects
- thymic agenesis
- cardiovascular abnormalities
- mental deficits
- cleft lip and palate
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Alcohol and Drugs
Alcohol
- no safe level has been established, though there is possibly a threshold below which no problems arise
- still birth and FAS are most severe consequences
- prevalence of FAS in offspring of heavy drinkers in 10-50%
- Fetal Alcohol Syndrome
- prenatal and postnatal growth deficiency
- microcephaly
- CNS abnormalities, including structural abnormalities as well as below average function
- atypical facial appearance (mid facial hypoplasia)
- congenital heart defects and brain anomolies common
- Fetal alcohol Effect
- minor anomolies
- moderate growth deficiency
- mild mental deficits
- subtle behavioural abnormalities
Marijuana
- most commonly used recreational drug
- perinatal impact unclear
- no known congenital abnormalities, though smaller head circumference and possible decrease birth weight are possible
- multiple confounders: alcohol, cigarettes, other drugs
Cocaine
- effects likely due to vascular disruption or vasocinstriction
- anomalies possibly linked with cocaine include:
- segmental intestinal atresia
- limb reduction defects
- brain anomalies
- congenital heart defects
- urinary tract anomalies
- verbal performance and IQ appear unchanged, though visual-spatial skills and arithmetic skills may be lower
Heroin
- no increase in anomolies, though increased IUGR, perinatal death, developmental delay, and behavioural disturbances
- significant withdrawal symptoms
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Heavy Metals
lead
- relatively low levels of lead increases risk of spontaneous abortion
mercury
- severe congeital abnormalities
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Infectious Teratogens
measles
mumps
rubella
- very high risk before 11 weeks; trails down to 0 after 16 weeks
- microcephaly
- mental deficits
- cataracts
- deafness
- congenital heart disease
syphilis
- nonimmune hydrops (heart failure with effusion, asictes, or edema)
- IUGR
- reticuloendothelial abnormalities, including jaundice, hepatosplenomegaly, hepatitis
- skin rash
- rhinitis
- cataracts, chorioretinitis, glaucoma
- hydrocephalus, seizures, cranial nerve palsies
varicella
- risks low, 2-3%, even if occurring in first or second trimester
- anomalies include:
- skin scarring
- chorioretinitis
- cataracts
- microcephaly
- hypolasia of hands and feet
- muscle atrophy
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Radiation
- less than 5 rads has no teratogenic effect
- estimated fetal exposure from common medical procedures low:
- CT of abdomen and lumbar spine: 3.5 rads
- BE or SBS: 2-4 rads
- intravenous pyelogram: less than 1 rad
- MRI: no documented fetal effects
- high dose radiation: IUGR, microcephaly, MR
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