ASSOCIATE PROFESSORIOLANDA BLIDARU, MD, PhD

Teratogens• Teratos = monster (Greek)

• Any agent (drug, infection, physical condition / deficiency) that acts on embryo or fetus producing permanent alteration of morphology or function (Shepard, 1998).

Causes of congenital malformation

Unknown or multifactorial: 70%Genetic: 20%Environmental: 10%

Drugs & chemicals: 5%Infection: 2%Maternal disorders: 2%Irradiation: 1%

Factors affecting the teratogenic effect of the drug

A. Fetal factorsI. Developmental stage1. Preimplantation period (first 2 weeks):

Death or no effect.2. Embrionic period (2-nd → 8-th week):

Malformation3. Fetal period (after 9 weeks): Functional

defects, Growth retardationII. Genetic susceptibility :• Species differences: ex. Thalidomide• Individual differences: metabolism of the drug

B. Drug factorsI. The route, dose & duration of

administrationII. Effect of combined agents III. Access to fetoplacental unit: • Lipid solubility• Molecular weight: > 600 not cross the placenta• Protein binding• Thickness of the placental membrane

Food & Drug Administration

classification (1980)• 5 categories• Updated

1. Category A: • Controlled studies in humans

demonstrated no fetal risk.• E.g.: Prenatal vitamins,KCL, citrate

& gluconate, Thyroxin

2. Category B: •Animal studies indicate no fetal risk; no controlled studies in humans.•E.g.: Penicillins, Terbutaline,Acetaminophen, Cyclizine, Antacids,Prednisone, Insulin, Ampicillin,Clindamycin, Nitrofurantoin, Metronidazole, Miconazole, Spiramycin.

3. Category C: • Animal studies indicate fetal risk;

no human studies. • These drugs are administered only when

their benefits outweighs the potential fetal harm.

• E.g. Furosemide, Rifampicin, β-blockers,Phenothiazine, Methyl-Dopa,Nifedipine,Heparins, Aminophyllin, Gentamycin,Chloroquin, Acyclovir, Cyclosporin,.

4. Category D:• There is evidence of fetal risk in

humans but the benefits may outweigh the risk.

• These drugs are given only in serious disease because no alternative.

• E.g.Phenytoin, Valproic Acid, Diazepam, Imipramine,

Captopril, Thiazides, Spironolactone, Coumarine,Chlorpropamide, Tetracyclin, Streptomycin, Quinine, Methotrexate, Vinblastin, Azathioprine.

5. Category X: • There is clear human risk that

outweigh the benefits.• These drugs are contraindicated.• E.g. Estrogen, Androgens,Aminopterin, Isotretinoin,Thalidomide

Fetal alcohol syndrome

IUGR

Behavior disturbance

Brain defects

Cardiac defects

Spinal defects

Craniofacial anomalies

Phocomelia (limb reduction defects)

Bone defects

Anomalies of ear, CVS

Fetal anticonvulsant syndrome

Craniofacial abnormalities

Broad nasal bridge

Epicanthal fold

Limb defects

Growth deficiency

Mental Deficiency

Diazepam 1st trimester: cleft lip.