Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

Abstract

There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.OBJECTIVE To provide direct, objective information on antiepileptic drug exposure through breast milk.DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019.EXPOSURES Antiepileptic drug exposure in infants who were breastfed. MAIN OUTCOMES AND MEASURESThe percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle.RESULTS A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants.CONCLUSIONS AND RELEVANCE Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

Umbilical Cord, Maternal Milk, and Breastfed Infant Levetiracetam Concentrations Monitoring at Delivery and during Early Postpartum Period

“…The result is supported by the comparison of the distribution of these two paired ratios in Figure 2 , in which the moving of the infant/maternal serum concentration ratio to the lower values (i.e., “to the left”) is apparent. The mean and median, respectively of infant/maternal serum concentration ratio we observed was higher than in the studies by Tomson et al [ 4 ] and Birnbaum et al [ 17 ] in the “colostrum” subgroup (2–4 days postpartum) and in the study of Birnbaum et al [ 17 ] in the “milk” subgroup (7–31 days postpartum). Compared to Birnbaum et al’s study [ 17 ], we collected venous blood samples (not dried blood spots) from breastfed infants who were younger with a median age of 3 days (range 2–31 days) versus a median age of 13 weeks (range 6–20 weeks).…”

“…The mean and median, respectively of infant/maternal serum concentration ratio we observed was higher than in the studies by Tomson et al [ 4 ] and Birnbaum et al [ 17 ] in the “colostrum” subgroup (2–4 days postpartum) and in the study of Birnbaum et al [ 17 ] in the “milk” subgroup (7–31 days postpartum). Compared to Birnbaum et al’s study [ 17 ], we collected venous blood samples (not dried blood spots) from breastfed infants who were younger with a median age of 3 days (range 2–31 days) versus a median age of 13 weeks (range 6–20 weeks). Moreover, we analyzed both colostrum and milk concentrations simultaneously compared to Birnbaum et al’s study [ 17 ] in which milk concentrations were not measured.…”

“…The method was quality controlled in external quality control Instand (Germany) twice a year. For statistical calculations half of the LLoQ was used for infants with concentrations less than the LLoQ [ 17 , 20 ].…”

“…However, the effects of pregnancy on LEV disposition vary considerably between individuals and monitoring of LEV levels during pregnancy and after delivery is recommended [ 5 , 6 ]. An extensive transfer of LEV from mother to fetus and into breast milk was reported by some authors in small study groups or case-reports [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Despite this, breastfed infants had measured insignificant serum concentrations, and LEV is usually considered compatible with breastfeeding [ 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Further Evidence Breastfeeding by Women With Epilepsy Is Safe: Are Mothers Getting the Message?

“…Birnbaum et al measured temporally matched maternal and breastfed infant serum AED levels in 164 pairs 5 to 20 weeks postpartum. 9 A total of 82% of the women were on a monotherapy AED regimen. The most common AEDs were lamotrigine (n ¼ 73) and levetiracetam (n ¼ 63) and small numbers of mothers taking carbamazepine, oxcarbazepine, topiramate, valproate, and zonisamide.…”