Lamotrigine in breast milk and nursing infants: determination of exposure

Abstract

Objective: Although lamotrigine use during pregnancy has substantially increased over the past decade secondary to accumulated reproductive safety data, systematic data on lamotrigine during breastfeeding remains sparse. We sought to characterize the determinants of lamotrigine concentrations in breast milk and nursing-infant plasma.

Patients and methods: Women who enrolled in a prospective investigation of perinatal medication pharmacokinetics, were treated with lamotrigine, and chose to continue lamotrigine while breastfeeding were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient and serial samples over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Lamotrigine concentrations in all of the samples were determined by using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted.

Results: Thirty women and their nursing infants participated in the study, providing a total of 210 breast milk samples. The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants.

Conclusions: Consistent with previous investigations of medications in breast milk, the lamotrigine milk/plasma ratio is highly variable. The rate of lamotrigine excretion into human breast milk is similar to that observed with other antiepileptic drugs. These data expand the extant literature on lamotrigine in breastfeeding and demonstrate relatively comparable nursing-infant exposure to lamotrigine compared with other antiepileptic drugs.

FIGURE 1

Gradient for lamotrigine excretion into human breast milk: mean ratio of lamotrigine concentration to the minimum breast milk concentration in each set of samples plotted by the aliquot of breast milk obtained from 17 women. These 17 women submitted breast milk samples (≥3 samples each; n =94) for determination of gradient effects from foremilk to hindmilk. The data shown represent breast milk samples collected from a single breast 8 to 12 hours after maternal ingestion of lamotrigine. These data were significantly defined by a second-order polynomial regression (R =0.83; F =8.05; df = [2,7]; P <.02).

FIGURE 2

Time course of lamotrigine excretion into human breast milk: mean ratio of lamotrigine concentration to the minimum breast milk concentration in each set of samples plotted by the time after maternal ingestion of lamotrigine aliquot of breast milk obtained from 16 women. These 16 women submitted breast milk samples (≥3 samples each; n =107) for determination of the time course of excretion into breast milk. These data were best fit by a second-order polynomial regression, although the regression analysis did not achieve statistical significance (R =0.86; F =4.36; df =[2,3]; P <.13).