What is known concerning levetiracetam and breast-feeding?/nThe patient is pregnant and treated wit

Fråga: What is known concerning levetiracetam and breast-feeding?

The patient is pregnant and treated with levetiracetam (Keppra), estimated delivery in 6 weeks.

Sammanfattning: Levetiracetam is readily transferred to breast milk, and higher than negligible amounts have been measured in the plasma of breast-fed infants. Even though no short term side-effects have been reported in full term neonates, long term effects are unknown. Because of this, breast-feeding cannot be recommended. Should the mother choose to breast-feed during treatment, the baby should be monitored for sedation, and preferably also with plasma drug concentration measurements.

Svar: Levetiracetam is a small molecule with a molecular weight of about 170. It is not bound to plasma proteins (1,2). These properties are in general associated with increased probability of excretion in breast milk. Levetiracetam has a bioavailability of nearly 100 %, and is renally excreted to 95 %, with less than 25 % as inactive (mostly hydrolysed) metabolites. The half-life is 6-8 hours. At our laboratory, levetiracetam concentrations generally seen at therapeutic doses range between 35 and 120 uM.

Questions concerning levetiracetam and breast-feeding have previously been documented in Drugline, with recommendations not to breast-feed during levetiracetam treatment (1, 2). Since then, two studies reporting on levetiracetam milk transfer and serum concentrations in the breast-fed infants have been published (3,4).

In the first study, serum concentrations in seven breast-fed infants were measured 3-5 days after delivery, 15 uM for one infant and below the limit of quantification (10 uM) for six of the infants (3). The levels of levetiracetam remained low during follow-up. For one of the latter infants, a concentration of 77 uM was measured a few hours after delivery, probably relating to transplacental transfer. One infant had low levetiracetam serum concentrations for eight weeks (15-17 uM) and less than 10 uM after 4 months. The mean milk/maternal serum concentration ratio was 1.00 (range 0.76-1.33). All infants appeared to be healthy throughout the study.

In the second study, levetiracetam concentrations in plasma and breast milk were measured 4-23 days after delivery in eleven women and their infants (4). Plasma levels in infants ranged from 4 to 20 uM. The mean milk/maternal serum concentration ratio was 1.05. The mean infant/maternal plasma concentration ratio after nursing was 0.13 (range 0.07-0.22). No adverse effects related to breast-feeding were reported.

However, levetiracetam levels in serum were measured at drug fasting conditions of 10-12 hours (3) and 10-15 hours (4) after the last dose, respectively. Given that the half-life of levetiracetam is only 7-8 hours (1), infant exposure might have been underestimated.

There is one case report published concerning exposure to levetiracetam through breast milk (1). The infants mother had been treated with valproic acid and phenytoin during pregnancy, seven days after delivery in week 34 levetiracetam was added to her medication. The child became hypotonic and fed poorly. The breast milk concentration three hours after intake was three times higher (99 uM) than in maternal serum (32 uM). The infant had a serum concentration of 6.0 uM 96 hours after the mother had stopped treatment and was discharged healthy ten days later. In several studies, the most commonly reported side effects are irritability, somnolence, headache, infection, weight-loss, weight-gain, general behavior changes, aggression and sleep disturbances (5,6,7). In a child with phosphorylase-A-kinase-deficiency reversible colitis and apnoeas were reported (7).