ANTIEPILEPTIC DRUGS AND CONGENITAL MALFORMATIONS

· Most antiepileptic drugs are associated with an increased risk of congenital malformations (1). Although the evidence is not entirely conclusive, it is generally accepted that antiepileptic drug-induced congenital malformations are dose dependent, and is increased by multiple drug therapies, especially the combination of carbamazepine, valproate and Phenobarbital (2-4).

· Antiepileptic drugs are associated with an increased risk of midline cardiac defects, neural tube defects, and facial clefting, although the extent of these abnormalities is dependent on drug levels during distinct periods of embryogenesis.

· Specific drug-induced syndromes have been proposed, but the extensive overlap of dysmorphic features has prompted the more general definition of fetal antiepileptic drug syndrome (5,6).

· Phenytoin (Dilantin), Ethotoin (Perganone), Mephenytoin (Epilan, Isulton, Phenantoin, Sace Sedantional):

· Congenital heart defects (CHD)

· Cleft lip or palate.

· Gastrointestinal (GI) and genitourinary (GU) anomalies.

· Fetal hydantoin syndrome (short nose, flat nasal bridge, wide lips, up-turned nasal tip, hypertelorism, epicanthic folds, coloboma, low-set ears, low hairline, short neck, distal digital hypoplasia, absent nails, altered palmer crease, digital thumb, dislocated hip, IUGR) (7).

· Phenobarbital and mephobarbital (Mabaral):

· CHD.

· Cleft lip or palate.

· Fetal Phenobarbital syndrome (facial and skeletal anomalies similar to phenytoin) (8).

· Fetal Valproate Syndrome:

1. Antiepileptic drugs have been described in causing a variety of fetal anomalies including neural tube defects, respiratory and gastrointestinal tract anomalies, skeletal and cardiac defects (9,10).

2. Valproic acid (VPA) is associated with a higher prevalence of fetal anomalies than other antiepileptic agents including neural tube defects, cardiac anomalies and radial ray abnormalities.

3. Risk of neural tube defects during VPA therapy is 1-2%, carbamazepine (0.5-1%) and barbiturates and phenytoin (0.3-0.4%) (11).
The risk is dose related (12) (VPA crosses the placenta with fetal serum concentrations reaching higher levels than maternal serum concentrations)(13).

4. Fetal valproate syndrome.

• Facial anomalies (flat nasal bridge, epicanthic folds, small nose with anteverted nostrils, long upper lip, small mouth with down turned angles, low-set ears, hypertelorism).
• Congenital heart disease (varied lesions).
• Neural tube defects.
• Skeletal anomalies (radial aplasia and thumb abnormalities).
• Spinal abnormalities (open spinal defects).

5. Ultrasound (9-15).

• Limb abnormalities (47-65% of fetuses) (9).
• Radial aplasia.
• Radial deviation of the hand.
• Absence of the thumb (may be difficult to demonstrate due to the marked radial deviation of the hand).
• Open spinal defects.
• Carbamazepine (Tegretol, Epitol):
• Neural tube defects.
• Fetal carbamazepine syndrome (epicanthic folds, short nose, up-slanting palpebral fissures, long philtrum and distal digital hypoplasia (16).
• Ethosuximide (Zarontin), Methosuximide (Celontin), Phensuximide (Milontin):
• ? CHD.
• ? Cleft lip or palate.
• ? Hydrocephalus.
• Primidone (Mysoline, Sertan Primaclone):
• CHD.
• Cleft lip or palate.
• Microcephaly.
• Fetal primidone syndrome (hirsute foreheads, thick nasal roots, anteverted nostrils, long philtrum, straight thin upper lips, distal digital hypoplasia (17).

REFERENCES

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