Congenital Birth Defects & Teratology Flashcards
What abnormalities can be present at birth?
- Malformation: misformed
- Deformation: formed then affected
- Dysplasia: expansion of immature cells
- Disruption: normal process e.g. cell migration is disrupted
What causes human birth defects in order of decreasing commonality?
UNKNOWN Multifactorial inheritance Environmental agents (drugs/viruses) Mutant genes Chromosomal abnormalities
What is teratogenesis?
Process whereby abnormality is induced in a developing organism during uterine life by foreign agents called teratogens
What is teratogenesis associated with?
Chemicals/pollutants/radiation Alcohol Dietary intake Viruses Medication
What influences the teratogenicity of a substance?
- It must contact embryo/foetus
- Period of development at exposure
- Exposure-time + dosage
- Foetus genotype influences susceptibility
What are the common teratogens?
- Alcohol > foetal alcohol syndrome
- Vitamin A > cleft palate, mandibular hypoplasia + heart defects
- Rubella/HSV > deafness, cataracts, retinal dysplasia+ microcephaly
- X-ray > microcephaly, spina bifida + cleft palate
- Valproate > neural tube defects, facial defects + limbs
What are the symptoms of foetal alcohol syndrome (FAS)?
Midline facial abnormalities via maxillary hypoplasia: No philtrum Thin top lip Heavy epicanthic folds Flattened nose
Mental/neural retardation (behavioural/developmental)
Heart defects
Short palpebral fissure
Heart defects
What infection agents are teratogens?
- Rubella > cataracts, cardiac defects + deafness
- Cytomegalovirus > microcephaly + microphthalmia
- Toxoplasma gondii > microcephaly, microphthalmia + hydrocephaly
- Syphilis > stillbirth + miscarriage
What environmental factors are teratogens?
- Ionising radiation (mainly affects)
- X-rays
- Pesticides, herbicides + fungicides
- Pollutants e.g. heavy metals + chemical effluent
How common is teratogen exposure?
Pregnant women take on average 4 drugs exc. nutritional supplements per pregnancy - 40% of these in critical period
How are pregnant women exposed to teratogens most commonly?
- Drugs used prior to pregnancy knowledge e.g. pain killers
- Drugs necessary for condition independent of pregnancy e.g. anti-epileptics
- Drugs necessary due to pregnancy specific condition e.g. thalidomide, diethylstilbestrol
- Environmental agents impossible to avoid e.g. crop sprays
How could many birth defects be prevented?
Appropriate avoidance or supplementation of nutrition
What are the common nutritional causes of congenital malformation?
Folate deficiency
Zinc (low OR high)
Glucose/ketone bodies from diabetic condition
Retinoid excess
When is the embryo/foetus most at risk of damage?
Weeks 3-8 (weeks 9-14 carries less risk but still susceptible) as core systems are developing by processes like cell division, organogenesis and midline union but also before the women knows she is pregnant
If problems occur at weeks 14-38 what defect commonly occurs?
Functional NOT structural where there is a direct toxic effect on cell of embryo that is either lethal or reduces growth e.g. retardation of mental development in FAS
When is sub-lethal damage repaired during pregnancy?
Weeks 1-2 as this is the pre-differentiation stage
What are Wilson’s 6 general principles of teratology?
- Final manifestations are death, malformation, growth retardation or functional disorder
- Susceptibility varies with developmental stage at exposure time
- Agents act in specific way on developing cells/tissues to initiate abnormal embryogenesis
- Manifestations increase in degree from no-effect to totally lethal as dose increases
- Access of adverse environmental influences to developing tissues on nature of agent
- Susceptibility depends on genotype of foetus and manner that it interacts with environmental factors
How can a substance be teratogenic?
- Mutation to DNA sequence
- Interruption of DNA/RNA synthesis
- Failure of normal cell migrations
- Chromosomal abnormalities causing structural/quantitative DNA
- Interference with cell differentiation
- Failure of normal cell-to-cell interactions
What teratogens can cause limb abnormalities?
- Thalidomide (anti-nauseant + sleeping pill)
- Retinoids (vit A derivatives)
- Mechanical issue via strangling of tissue by amniotic bands
What limb abnormalities exist?
Amelia: lack of limb Meromelia: part of limb Phocomelia: seal limbs Polydactyly: extra digits Syndactyly: webbed digits
What cardiac defects exist?
Ventricular-septal (can be neural crest cell associated)
Tetralogy of fallot
Transposition of great vessels
What is the common cause of cardiac defects?
Alcohol
What neural tube defects exist?
Spina bifida: meningocele +
myeloshisis (more severe)
Ancephaly: major portion of brain/skull missing
Sensory system defects of eye/ear
What are the causes of neural tube defects?
Multiple teratogens but folic acid deficiency commonly
What facial defects exist?
- Cleft palate (mainly female)/lip (mainly male) from abnormal neural crest cell migration (so often acc. with reduced brain size and cardiac defects)
- Macroglossia/macroglossia
- Treacher-Collins
- Pierre Robin syndrome
- Mandibulofacial maldevelopment/dysostosis (zygoma, mandible + maxilla)
- Downslanting palpebral fissure
- Malformed ears + possible conductive deafness
What are the causes of facial defects?
- Multiple teratogens e.g. anti-seizure drugs, retinoids and corticosteroids
- Maternal diabetes
- Autosomal dominant inheritance e.g. Treacher-Collins syndrome
How can you help mothers avoid teratogenicity?
Advice pre-conception regarding nutritional and lifestyle and avoid prescribing where possible or if its necessary prescribe safest and minimal therapeutic dose
What are the classifications of teratogens?
A: not shown to increase risk
B: animal studies not shown increased risk but no human studies
C: animal studies show adverse effects but no human studies e.g. Fluconazole
D: medication associated with defect in humans but may have benefits that outweigh risk e.g. ACE inhibitor/ARB
X: should not be used in human pregnancy e.g. Androgens
Give some examples of teratogenic drugs in class D.
ACE inhibitors Angiotensin II receptor antagonists Antineoplastic alkylating agents Aminoglycosides Aspirin Atenolol BZDs Carbazepine Lithium Penicillamine Barbiturates Tamoxifen Tetracycline
Give some examples of teratogenic drugs in class X.
Androgens Antineoplastics (antimetabolites e.g. folic acid antagonists) BZDs Progestins Raloxifene Statins Thalidomide Warfarin
Give some examples of teratogenic drugs in class C.
Corticosteroids
Fluconazole
