What is the optimal therapeutic range for levetiracetam (Keppra) in pregnant women with a history of epilepsy?

Optimal Therapeutic Range for Levetiracetam During Pregnancy

For pregnant women with epilepsy, levetiracetam levels should be maintained at a minimum of 65% of preconception concentrations for patients who had seizures within 12 months before pregnancy, and at least 46% of preconception levels for seizure-free patients. 1

Pharmacokinetic Changes During Pregnancy

• Levetiracetam concentrations significantly decrease throughout pregnancy due to physiologically based pharmacokinetic changes 1, 2
• The most significant decrease in levetiracetam concentration/dose ratio occurs during the first trimester, with levels dropping by approximately 5.76 mg/L compared to pre-pregnancy values 2, 3
• By the third trimester, maternal plasma concentrations may be only 40% of baseline concentrations outside pregnancy 4
• This decrease is primarily due to increased clearance, with apparent clearance increasing by approximately 71.08 L/day during the first trimester 2

Monitoring Recommendations

• Therapeutic drug monitoring is essential for all pregnant women taking levetiracetam 1, 3
• Monitoring should begin before conception to establish baseline levels 3
• Monthly monitoring throughout pregnancy is recommended to adjust dosing as needed 1, 3
• More careful monitoring is warranted for women who had seizures within the year preceding pregnancy, as they are at higher risk for seizure deterioration 1

Dosing Adjustments

• Dose increases of up to 75% during pregnancy compared to preconception may be necessary to maintain therapeutic levels 3
• Dose adjustments should be based on:
  • Patient's seizure history (seizure-free vs. non-seizure-free) 1
  • Trimester of pregnancy 3
  • Measured levetiracetam concentrations 1, 3

Target Concentrations Based on Seizure History

• For patients who had seizures within 12 months before pregnancy (non-seizure-free group):

  • Maintain levetiracetam concentrations above 65% of preconception levels 1
  • Low concentrations in this group are significantly associated with increased seizure frequency (p=0.022) 1

• For patients who were seizure-free for more than 12 months before pregnancy:

  • Maintain levetiracetam concentrations above 46% of preconception levels 1

Postpartum Considerations

• Levetiracetam clearance decreases significantly after delivery 3
• Plasma concentrations increase abruptly in the postpartum period 3
• Dose reduction of approximately 24% compared to third-trimester dosing may be needed postpartum to avoid toxicity 3

Common Pitfalls and Caveats

• Extended-release formulations may be particularly problematic during pregnancy, as increased clearance can lead to periods of subtherapeutic concentrations and breakthrough seizures 5
• Twice-daily dosing may be preferable to once-daily dosing during pregnancy to maintain more consistent drug levels 5
• Approximately 30% of levetiracetam serum levels during pregnancy fall below standard laboratory reference ranges, highlighting the importance of individualized monitoring rather than relying on standard ranges 2
• The umbilical cord/maternal plasma concentration ratio averages 1.15, indicating significant fetal exposure 4