Handbook of Genetic Counseling/Fetal Hydantoin Syndrome

Fetal Hydantoin Syndrome

Etiology

• Prenatal hydantoin (dilantin, phenytoin) exposure

History/Epidemiology

• Phenytoin= anticonvulsant first introduced in1938.
• Teratogenic effects were first recognized in 1964.
• Numerous studies have demonstrated increased risk for congenital defects, both major and minor.
• Study conducted from 1985-1992
  • 332 newborns exposed to phenytoin (hydantoin, dilantin) during the 1st trimester
  • A total of 15 (4.5%) had major birth defects, including:
    • Cardiovascular
    • Spina bifida
    • Hypospadias

Clinical Features

• Craniofacies:
  • Broad nasal bridge, wide anterior fontanelle, low hairline, broad alveolar ridge, short neck, hypertelorism, microcephaly, cleft lip/palate, low set ears, epicanthal folds, ptosis, coloboma, coarse scalp hair.
• Limbs:
  • Small or absent nails, hypoplasia of distal phalanges, altered palmar crease, digital thumb, dislocated hip
• Growth:
  • Mild to moderate growth deficiency, usually prenatal in onset
• Performance:
  • Occasional borderline to mild mental deficiency. Performance in childhood is usually better than that predicted in infancy
• Cardiovascular (occasional abnormalities):
  • Aortic valvular stenosis, coarctation of aorta, PDA, septal defects
• GI (occasional abnormalities):
  • Pyloric stenosis, duodenal atresia, anal atresia
• Other (occasional):
  • Small nipples that are widely spaced, umbilical and inguinal hernia.

Risks

• Risks of delivering a child with congenital defects is 2-3x greater for women taking dilantin than for the general population.
  • Increased risk could be caused by epilepsy, the drugs, or a combination of the two. It is thought that the drugs are the causative factor.
• Risks of child having full syndrome is about 10% and the risk for having some of the effects of the disorder is an additional 33%
• Some reports have shown that phenytoin is a transplacental carcinogen. Tumors were reported to occur after in utero exposure to phenytoin in a few cases.
• Phenytoin may induce folic acid deficiency in the epileptic patient by impairing GI absorption or by increasing hepatic metabolism. Therefore, the risk for having a baby with a spinal abnormality is increased.
• Some risk of early hemorrhagic disease of the newborn. Occurs during the 1st 24 hours after birth and can be fatal. Exact mechanism: unknown. Drug is thought to deplete already low levels of fetal vitamin K therefore suppressing the vitamin K-dependent coagulation factors II, VII, IX, and X. Proposed treatment regimen: taking oral vitamin K during last 2 months of pregnancy, C section if difficult labor or trauma is suspected, administering intravenous vitamin K to the newborn in the delivery room (this regimen hasn't been tested in clinical controlled trials, but are logical).
• Risk of not taking phenytoin: pregnant patient can have seizures and can cause the baby to have fetal hypoxia.

Breast Feeding

• Phenytoin is excreted into breast milk. Milk:plasma ratios range from 0.18 to 0.54.
• Little risk to the infant if maternal levels are kept in the therapeutic range
• Drowsiness and decreased sucking were observed in one infant, no other adverse effects have been reported.
• The American Academy of Pediatrics considers phenytoin to be compatible with breast feeding.

References

• www.reprotox.org
• Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 5th edition. Baltimore: Williams & Wilkins.
• Jones KL. Smith's Recognizable Patterns of Human Malformations. 5th edition. W.B. Saunders Company: Philadelphia. 1997.

Notes

The information in this outline was last updated in 2002.