ASSOCIATE PROFESSOR IOLANDA 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 factors I. Developmental stage 1. Preimplantation period (first 2 weeks): Death or no effect. 2. Embrionic period (2-nd → 8-th week): Malformation 3. Fetal period (after 9 weeks): Functional defects, Growth retardation II. Genetic susceptibility : Species differences: ex. Thalidomide Individual differences: metabolism of the drug

B. Drug factors I. The route, dose & duration of administration II. 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.