Is phenytoin (antiepileptic medication) safe to use during the third trimester of pregnancy?

Phenytoin Safety in the Third Trimester

Phenytoin is NOT safe in the third trimester and carries significant risks to the fetus, but if seizure control cannot be achieved with safer alternatives, it may be continued at the lowest effective dose with intensive monitoring, as the risks of uncontrolled seizures can be equally dangerous to both mother and fetus. 1, 2

Primary Concerns with Third Trimester Use

Phenytoin is a known teratogen that increases the risk of major malformations (orofacial clefts, cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (microcephaly), and mental deficiency when used throughout pregnancy. 2 The FDA drug label explicitly states that prenatal exposure increases risks for congenital malformations and adverse developmental outcomes, with an overall malformation rate of approximately 10% in children of epileptic women treated with antiepileptic drugs—two to three-fold higher than the general population. 2

Critical Third Trimester Complications

Neonatal Bleeding Disorder

A potentially life-threatening bleeding disorder related to decreased vitamin K-dependent clotting factors occurs in newborns exposed to phenytoin in utero. 2, 3 This requires:

• Maternal vitamin K (phytomenadione) supplementation beginning 4 weeks before expected delivery 3
• Immediate vitamin K administration to the neonate after birth 2, 3

Pharmacokinetic Changes

Phenytoin clearance increases dramatically during the third trimester (mean ratio 2.5:1 compared to pre-pregnancy), requiring dose escalation to maintain therapeutic levels. 4 This creates a clinical dilemma:

• Plasma drug clearance peaks in the third trimester 5, 4
• Dose increments are necessary to maintain therapeutic concentrations and prevent seizures 5
• However, higher doses increase teratogenic risk 1, 6

Management Algorithm if Phenytoin Must Be Continued

Immediate Actions

• Do not abruptly discontinue phenytoin, as this could provoke severe seizures with grave consequences for both mother and fetus 7
• Consult immediately with neurology and maternal-fetal medicine to evaluate switching to safer alternatives 7

Monitoring Requirements

• Monitor saliva or plasma phenytoin concentrations monthly or as clinically indicated throughout the third trimester 2, 5, 3
• Saliva phenytoin correlates closely with plasma unbound concentrations (r=0.98) and is easier to obtain 5
• The saliva:plasma ratio increases to maximal values at delivery 5

Dosing Strategy

• Use the lowest effective dose in monotherapy 1, 7
• Anticipate need for dose increases during third trimester to maintain seizure control 5, 4
• Plan for immediate postpartum dose reduction within 2-8 weeks after delivery to avoid maternal toxicity 5

Vitamin K Prophylaxis

• Begin maternal phytomenadione (vitamin K) supplementation 4 weeks before expected delivery date 3
• Administer vitamin K to neonate immediately after birth 2, 3

Folic Acid Supplementation

• High-dose folic acid supplementation is recommended throughout pregnancy 7
• Standard recommendation is 5 mg/day, ideally started preconceptionally 3

Common Pitfalls to Avoid

The most dangerous pitfall is abrupt discontinuation of phenytoin upon discovering pregnancy or entering the third trimester. 7 Uncontrolled seizures pose immediate risks including:

• Maternal trauma from falls
• Fetal hypoxia during convulsions
• Status epilepticus with potential maternal and fetal mortality

Another critical error is failing to anticipate postpartum toxicity. 5 After delivery, phenytoin clearance rapidly returns to pre-pregnancy values within 2-8 weeks, and maintaining the higher third-trimester dose will result in toxic levels and clinical symptoms. 5

Postpartum Considerations

Phenytoin is compatible with breastfeeding according to standard recommendations. 7 However, close monitoring of both maternal levels and infant for any adverse effects is warranted.

Dose reductions are necessary after delivery to avoid clinical symptoms of maternal toxicity as clearance normalizes. 5 Continue monitoring saliva or plasma concentrations during the puerperium. 5