What are the risks of fetal hydantoin syndrome in pregnant women taking Phenytoin (Dilantin)?

Risks of Fetal Hydantoin Syndrome in Pregnant Women Taking Phenytoin

Phenytoin (Dilantin) during pregnancy significantly increases the risk of fetal hydantoin syndrome, with approximately 10% of exposed infants developing the full syndrome and an additional 30% showing partial features. 1

What is Fetal Hydantoin Syndrome?

Fetal hydantoin syndrome (FHS) is a spectrum of congenital abnormalities caused by exposure to phenytoin during pregnancy. The syndrome includes:

Major Features:

• Craniofacial anomalies: Dysmorphic facial features 2
• Growth abnormalities: Prenatal and postnatal growth deficiencies 3
• Limb defects: Underdeveloped nails, digital hypoplasia 2, 1
• Neurodevelopmental issues: Mental deficiency/intellectual disability 3, 1

Less Common Features:

• Cleft lip and palate
• Microcephaly
• Ocular defects
• Cardiovascular anomalies
• Hypospadias
• Hernias (umbilical and inguinal)
• Significant developmental delays 4

Risk Assessment

The FDA label for phenytoin clearly states that prenatal exposure may increase risks for:

• Major malformations (orofacial clefts, cardiac defects)
• Minor anomalies (dysmorphic facial features, nail and digit hypoplasia)
• Growth abnormalities (including microcephaly)
• Mental deficiency 5

Research indicates:

• Approximately 10% of exposed infants develop the full fetal hydantoin syndrome 1
• An additional 31% display some features compatible with the syndrome 1
• The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs during pregnancy is about 10%, which is two to three times higher than in the general population 5

Management Recommendations for Pregnant Women with Epilepsy

1. Pre-conception Planning:

   • Initiate folic acid supplementation (4 mg daily) at least one month before conception and continue through the first trimester 6
   • Establish baseline therapeutic drug levels before pregnancy 6

2. Medication Selection:

   • Consider alternative medications: Lamotrigine and levetiracetam have lower teratogenic potential 6
   • If phenytoin must be used, aim for monotherapy at the lowest effective dose 6, 7

3. During Pregnancy:

   • Monitor plasma phenytoin concentrations regularly (every 4 weeks) 5
   • Adjust dosage as needed due to altered pharmacokinetics during pregnancy 5
   • Restore original dosage postpartum 5

4. Vitamin K Supplementation:

   • Administer vitamin K to the mother before delivery and to the neonate after birth to prevent potentially life-threatening bleeding disorders 5

Important Warnings

1. FDA Warning: The FDA label explicitly states that patients should be apprised of potential harm to the fetus if phenytoin is used during pregnancy 5

2. Risk of Malignancies: There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy 5

3. Genetic Factors: Susceptibility to fetal hydantoin syndrome appears to correlate with fetal levels of the microsomal detoxifying enzyme epoxide hydrolase 7

Clinical Decision Making

When managing epilepsy in women of childbearing potential:

1. First-line options: Consider lamotrigine or levetiracetam as they have lower teratogenic potential 6

2. If phenytoin is necessary:

   • Use the lowest effective dose
   • Monitor drug levels closely
   • Provide comprehensive counseling about the 10% risk of full syndrome and 30% risk of partial features 1

3. For women already pregnant on phenytoin:

   • Do not abruptly discontinue (risk of status epilepticus)
   • Consider transitioning to safer alternatives if seizure control allows
   • Implement close monitoring with regular ultrasounds and fetal assessments

Remember that while phenytoin poses significant risks, approximately 90% of infants exposed to anticonvulsants in utero will not show evidence of teratogenesis when managed appropriately 7.