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Figure 1.  Box Plots
Box Plots

Box plots representing the percentage of infant-to-mother plasma concentrations for carbamazepine, carbamazepine-10,11-epoxide (10,11-dihydro-10-hydoxy-carbamazepine metabolite), levetiracetam, lamotrigine, oxcarbazepine, and zonisamide. Box plots show the median and the 25th and 75th percentiles. Whiskers represent 1.5 times the interquartile range. Circles not connected by vertical lines or lying on horizontal whiskers represent outliers.

Figure 2.  Associations of Mother and Infant Drug Concentrations
Associations of Mother and Infant Drug Concentrations

Plots presenting the association between mother and infant drug concentrations for lamotrigine (A) and levetiracetam (B), obtained from mothers who were breastfeeding and infants who were breastfed. The solid line represents the univariate line of best fit between the infant and mother concentrations. Concentrations less than the lower limit of quantification are represented as half the value of the lower limit. For lamotrigine, the Pearson correlation coefficient was 0.58 (P < .001); for levetiracetam, 0.48 (P = .09).

Table 1.  Demographic Characteristics of Breastfeeding Women With Antiepileptic Drug Concentrations Available for Mother and Infant, Stratified by Druga
Demographic Characteristics of Breastfeeding Women With Antiepileptic Drug Concentrations Available for Mother and Infant, Stratified by Druga
Table 2.  Numbers of Mothers and Infants and Observed Concentration Ranges
Numbers of Mothers and Infants and Observed Concentration Ranges
Table 3.  Multiple Linear Regression Model Parameter Estimates for Lamotrigine and Levetiracetam Concentrations in Infants and Information on All Variables
Multiple Linear Regression Model Parameter Estimates for Lamotrigine and Levetiracetam Concentrations in Infants and Information on All Variables
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    Original Investigation
    December 30, 2019

    Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

    Author Affiliations
    • 1Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis
    • 2Department of Neurology & Neurological Sciences, Stanford University, Stanford, California
    • 3The Emmes Corporation, Rockville, Maryland
    • 4Department of Neurology, Northwestern University, Chicago, Illinois
    • 5Department of Neurology, Emory University, Atlanta, Georgia
    • 6Minnesota Epilepsy Group, Saint Paul
    • 7Department of Neurology, University of Southern California, Los Angeles
    • 8University of Cincinnati, Cincinnati, Ohio
    • 9Neurology, Columbia University, New York, New York
    • 10Department of Neurology, University of Washington, Seattle
    • 11Department of Psychiatry, University of Wisconsin at Madison, Madison
    • 12Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 13Department of Neurological Surgery, University of Washington, Seattle
    JAMA Neurol. 2020;77(4):441-450. doi:10.1001/jamaneurol.2019.4443
    Key Points

    Question  What is the extent of drug exposure via breastfeeding in infants whose mothers are receiving antiepileptic drug therapy?

    Findings  In this prospective cohort study, the median percentage of infant-to-mother concentration for 7 antiepileptic drugs ranged from 0.3% to 44.2% in 164 infant-mother concentration pairs. For infants with mothers receiving lamotrigine therapy, infant concentrations were associated with maternal concentrations.

    Meaning  In this study, the overall drug exposure was low in infants who were breastfed by mothers with epilepsy who were receiving antiepileptic drug therapy, and the findings add further support to breastfeeding by these mothers.

    Abstract

    Importance  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 Measures  The 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.

    Introduction

    The American Academy of Pediatrics recommends breastfeeding as the sole nutrition for the first 6 months of life, given the multiple benefits to both the child and mother.1,2Quiz Ref ID Benefits for children who are breastfed include a reduced risk of severe lower respiratory tract infections, atopic dermatitis, asthma, acute otitis media, nonspecific gastroenteritis, obesity, type 1 and 2 diabetes, childhood leukemia, sudden child death syndrome, and necrotizing enterocolitis, as well as possible positive cognitive effects.3-5 Benefits for mothers who breastfeed include reduced risks for type 2 diabetes, breast cancer, ovarian cancer, and maternal postpartum depression.3,4,6 However, no consensus exists for the safety of breastfeeding when the mother is receiving antiepileptic drugs (AEDs). Animal studies show many AEDs can have adverse effects on developing neurons in immature brains that are similar to alcohol.7-12 Human studies are sparse, and physicians are often uncomfortable recommending that women taking AEDs breastfeed their children. For infants born to women receiving AEDs, a major part of AED exposure is in utero, via placental passage.13 However, relative to maternal AED blood concentrations, the amount of AED exposure in the child via breastfeeding is uncertain for most AEDs.14 Previous studies from our group have reported no adverse neurodevelopmental effects in infants breastfed by mother taking AEDs, as measured by child IQ scores at age 3 years,15 and even positive effects at age 6 years.16 Another prospective cohort study of children of women with epilepsy who were receiving AEDs in Norway also found that breastfeeding is not associated with adverse neuropsychological outcomes at age 3 years.17 Overall, there is a lack of systematic studies on children who are breastfed that measure both infant AED concentrations and outcomes.

    Quiz Ref IDLamotrigine and levetiracetam are the 2 most commonly prescribed AEDs in women with epilepsy who are pregnant or breastfeeding.18,19 Breastfeeding studies pertaining to AEDs have small sample sizes, with the 3 largest studies (to our knowledge) of lamotrigine, levetiracetam, and phenobarbital reporting on 12, 10, and 18 mother-child blood-sample pairs, respectively.20-22 Additionally, many AEDs, such as lamotrigine and levetiracetam, have variable pharmacokinetics during pregnancy and the early postpartum period, which could complicate assessment of exposure via breastfeeding.23-27 Some studies have focused on breast milk concentrations as surrogate markers for actual AED concentrations in children.28,29 However, breast milk concentrations do not take into account differences in infant pharmacokinetic processes, such as absorption, ontogeny of metabolic and elimination profiles,30-35 or the timing of sampling with respect to the mother’s dose of AEDs.36-38 Additionally, such studies inherently assume that all of the drug partitioned into breast milk is available for infant consumption, which gives a skewed estimate of the relative infant dosage. Thus, data from these studies could misrepresent AED exposure in children through breastfeeding. Our study measured infant AED blood concentrations, providing a direct assessment of the amount of drug available in the infant’s blood. The primary goal of this study was to measure blood concentrations of AEDs in mothers with epilepsy and the infants they breastfed to provide direct, objective information on the extent of AED exposure via breastfeeding. Additionally, a secondary goal was to identify factors that could influence AED exposure via breast milk in the infant.

    Methods
    Study Design

    Quiz Ref IDThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of outcomes for women with epilepsy and their children during pregnancy and in the postpartum period. The study was approved by the institutional review board at each participating institution. Pregnant women with epilepsy between the ages of 14 and 45 years whose pregnancies had progressed to less than 20 weeks’ gestational age and who had measured IQ scores greater than 70 points were enrolled into the MONEAD study and followed up through pregnancy and 9 postpartum months. Each woman provided written informed consent. Children were enrolled in the MONEAD study at birth.

    Blood samples were collected from infants who were breastfed and their mothers at the same visit between 5 and 20 weeks after birth. Sampling in infants was limited to 1 sample to reduce discomfort in the infants and encourage participation by mothers. Breastfeeding data were collected as the volume of ingested breast milk delivered via graduated feeding bottles each day and the total duration of all daily breastfeeding sessions to calculate the total number of hours at the breast each day.

    Sample Collection and Analysis

    Each mother’s whole blood sample was collected, plasma-processed, and separated, and total AED concentrations were measured via validated liquid chromatography–mass spectrometry assays at the University of Minnesota (Minneapolis) in the MONEAD Pharmacokinetics Core Laboratory.39 Infant blood samples were collected as dried blood spots via filter paper from a free-flowing drop of blood from the plantar surface of the infant’s warmed heel. The sample-collection cards are designed to allow for the equal distribution of blood (eFigure 1 in the Supplement). Because it was important for the mothers to receive the results of the infant’s blood concentrations in a timely manner, all measurements of dried blood spots were performed in a Clinical Laboratory Improvement Amendments/College of American Pathologists–certified laboratory (MedTox Laboratories, New Brighton, Minnesota).40 Infant dried blood-spot concentrations were adjusted according to the ratios of whole blood to plasma as determined in adults (plasma equivalents). All dried blood–spot samples were processed and concentrations measured within 1 week of collection. The plasma-equivalent lower limits of quantification (LLoQs) were reported as 0.1 μg/mL for lamotrigine, 1.8 μg/mL for levetiracetam, 0.7 μg/mL for carbamazepine, 0.1 μg/mL for carbamazepine-10,11-epoxide, 1.6 μg/mL for topiramate, 13.1 μg/mL for valproic acid, 1.0 μg/mL for zonisamide, and 0.1 μg/mL for oxcarbazepine (measured as the 10,11-dihydro-10-hydroxy-carbamazepine metabolite). For 1 assay, zonisamide samples were run on different days, and 2 of the 4 runs had a higher LLoQ (12.5 μg/mL).

    Because the mother and infant samples were analyzed in different laboratories, a cross-validation between laboratories was performed. The MONEAD Core Laboratory spiked blank whole-blood samples at 2 different target concentrations of the main study drugs (carbamazepine, levetiracetam, and lamotrigine). Spiked samples were spotted onto cards via the free-flowing drop method. Samples were run in triplicate and assessed for accuracy and precision. Samples were analyzed at MedTox Laboratories and the Pharmacokinetics Core Laboratory (at the University of Minnesota, Minneapolis). For carbamazepine, the mean accuracy was 101.7% for the low control samples and 99.8% for the high control samples, and the coefficient of variation was less than 3%. The accuracy for levetiracetam was within 11% of the target concentration, with a coefficient of variation of less than 6.5%. For lamotrigine, the accuracy was 116.7% for the low control samples and 104.7% for the high control samples, with a coefficient of variation of less than 2.5%. In summary, the interlaboratory values were within a 20% coefficient of variation, with most values being within 10%, indicating all samples met the criteria for acceptable repeated sampling.41

    Statistical Analysis

    For calculations of exposure for descriptive analyses, infant AED concentrations were reported as the percentage of maternal AED plasma concentrations: ([infant AED concentration]/[maternal AED concentration]) × 100. For infants with concentrations less than the LLoQ, half of the concentration of the LLoQ was used as the infant AED concentration.42 Because infant AED concentrations were normalized by maternal AED concentrations, it was important to consider the time between infant and maternal plasma sampling. For all AEDs, the median time between the mother’s blood sample and infant’s blood sample ranged between −0.38 hours and 0.9 hours. (Negative values indicate that sampling was performed first in the infant.) Two infant-mother pairs in the levetiracetam group had a time between the 2 samplings of −360.25 hours (−15.01 days) and −261.58 hours (−10.90 days). These 2 pairs were considered outliers and were not included in any analysis. Additionally, women whose last recorded dosage of AEDs was more than 6 hours from the expected dose time based on their dosing regimen were categorized as having missed their last dose. A descriptive analysis was performed in this subset to examine the association of missed-last-dose status with concentrations in infants. To test for differences in concentrations in infants between monotherapy and polytherapy exposures, a t test was used.

    To study the association of covariates with infant AED plasma concentrations, multiple linear regression was performed with AED plasma concentration in infants as the outcome and the following variables included: the mother’s AED plasma concentration, a breastfeeding categorical variable (low, medium, or high), the infant’s age, the time between the mother’s dose and the infant’s feeding time, the time between the infant’s feeding and the infant’s plasma sample, the time between the mother’s dose and the mother’s plasma sampling, and the time between the blood-sample collection from mothers and infants. A P value less than .05 was the cutoff for a significant covariate. For the breastfeeding categories, data were reported in 2 fields: the volume of milk in ounces and the length of time that the infant was breastfed in hours over 24 hours.

    To create a single variable that semiquantitatively described the overall amount of daily breast milk delivery, a data-driven method was developed. Women were categorized into low, medium, and high categories, with a roughly equal number of women in each category, based on a combination of the 2 breastfeeding variables, using cutoff points at equal percentiles for hours breastfed and ounces of breast milk to create the 3 equally sized groups. A scatterplot with the mean number of hours breastfed per day over the entire duration since delivery on the x-axis and ounces of breast milk provided on the y-axis is shown in eFigure 2 in the Supplement. A woman was classified in the low group if her values for total hours breastfed and the amount of breast milk fell below the line drawn between 3 hours of breastfeeding and 9 ounces breast milk, high if her values for breastfeeding time and amount of breast milk were on or above the line between 5 hours of breastfeeding and 24 ounces of breast milk, and medium if her values fell between those 2 lines.

    Statistical analyses were completed with SAS version 9.4 (SAS Institute). Data were collected from December 2012 to October 2016 and analyzed from May 2014 to August 2019.

    Results

    The study enrolled 351 pregnant women with epilepsy and their 345 infants. Of the 345 infants, 222 infants (64.3%) were breastfed after delivery and 146 (42.3%) had AED concentrations available from a visit 5 to 20 weeks after birth. No infants received donor breast milk. Because of polytherapy, there was more than 1 AED concentration available for some infants, resulting in 174 blood-concentration data points from 146 infants. After excluding mothers with missing concentration data and the 2 outliers, 164 matching infant-mother concentration pairs were available for analysis from 135 mothers and their 138 infants (including 3 pairs of twins). The infant cohort included 179 female children (51.9%) and had a median (range) age of 13 (5-20) weeks; mothers had a median (range) age of 32 (18-47) years, and 118 of 135 (87.4%) were white.

    Most of the mothers (111 of 135 women [82.2%]) were receiving monotherapy. Of those receiving polytherapy, only 2 were taking an inducing medication (carbamazepine) and 1 an inhibiting medication (valproate). There were no differences in blood concentrations in infants who were breastfed from mothers receiving monotherapy vs polytherapy. Demographic factors were found to be comparable across AEDs (Table 1). Information on total recruitment and infant and maternal concentrations can be found in Table 2.

    Sixty-eight of 138 infants (49.3%) had AED concentrations that were less than the LLoQ. No infants who were breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, or topiramate had drug concentrations greater than the LLoQ. (Notably, the LLoQ for valproic acid is 10 to 20 times higher than that of the other AEDs, which is reflective of the higher target concentration of valproic acid used in adults.)

    Quiz Ref IDMost levetiracetam and zonisamide concentrations in infants were less than the LLoQ (45 of 63 infants [71.4%] and 3 of 5 infants [60.0%], respectively), although most lamotrigine concentrations in infants (62 of 70 [88.6%]) were greater than the LLoQ. (It should be noted that the LLoQ was lower for lamotrigine than for some of the other AED concentrations.) If the LLoQ value for lamotrigine (0.1 μg/mL) is adjusted to be similar to levetiracetam (1.8 μg/mL) to provide a more direct comparison of these 2 AEDs, the percentage of infants with lamotrigine concentrations greater than the LLoQ decrease to 38 of 70 (54.3%; data not shown).

    Across all drug categories, 12 women had a missed last dose. Of these women, 6 were taking lamotrigine, 3 were taking carbamazepine, 2 were taking oxcarbazepine, and 1 was taking zonisamide. None of the 6 infants with mothers taking lamotrigine who had a missed last dose had concentrations less than the LLoQ. The concentration in the 1 infant whose mother had missed a zonisamide dose was less than the LLoQ. No infants who were breastfed had concentrations greater than the LLoQ for carbamazepine or oxcarbazepine, regardless of mothers’ missed last doses.

    The AED concentrations in infants as the percentage of maternal plasma concentration for AEDs with data for more than 2 mother-infant pairs are shown in Figure 1. The data also included 3 pairs of twins (2 pairs of twins from mothers taking levetiracetam monotherapy and the third pair from a mother taking oxcarbazepine monotherapy), with all 6 infants having concentrations less than the LLoQ. The median percentage of infant-to-mother concentration was 28.9% (range, 0.6%-90.3%) for lamotrigine, 5.3% (range, 2.1%-20.4%) for levetiracetam, 44.2% (range, 35.2%-125.3%) for zonisamide, 5.7% (range, 3.7%-8.4%) for carbamazepine, 5.4% (range, 0.9%-9.6%) for carbamazepine epoxide, 0.3% (range, 0.2%-0.9%) for oxcarbazepine, 17.2% (range, 12.4%-22.0%) for topiramate, and 21.4% (range, 17.9%-24.9%) for valproic acid (Figure 1).

    In multiple linear regression models, data from 52 infant-mother pairs in which mothers were taking lamotrigine and 16 in which mothers were taking levetiracetam with complete information on all factors were used in the model. For the lamotrigine model, only maternal lamotrigine concentrations were significantly associated with plasma lamotrigine concentrations in infants (Pearson correlation coefficient, 0.58; P < .001; Figure 2). None of the covariates, including the time variables, were associated with infant plasma lamotrigine concentrations after taking maternal concentrations into account. For the levetiracetam model, the variable for time between the mother’s AED dose and the mother’s plasma sample was removed to make the model identifiable. We found that none of the factors considered in the levetiracetam model were significant. A summary of the model parameters is shown in Table 3. This analysis was not performed for the other AEDs because there were too few concentrations in infants that were greater than the LLoQ.

    Discussion

    Overall, AED concentrations in infants who were breastfed were low compared with the AED concentrations in their mothers. The median percentages for infant compared with maternal concentrations ranged from 0.3% to 44.2% for the 7 AEDs. Most infant blood concentrations in infants who were breastfed by mothers taking carbamazepine, oxcarbazepine, valproic acid, levetiracetam, and topiramate were less than the respective LLoQs. Only lamotrigine and levetiracetam sample sizes were sufficient to study the effect of covariates on infant AED concentrations. The only factor significantly associated with plasma lamotrigine concentrations in infants was maternal lamotrigine concentrations; none of the covariates collected were associated with levetiracetam concentrations in infants.

    Median lamotrigine concentrations in infants were 28.9% of the maternal plasma levels. These results are in agreement with the literature, which report median infant-to-maternal concentration values of 14% to 30% from smaller lamotrigine studies.20,43-46 The variability in concentrations for lamotrigine was larger than those seen with levetiracetam. It is possible that the variability could be associated with the differences in elimination of the 2 medications. Lamotrigine is metabolized to its N-glucuronide metabolite by the uridine 5′-diphospho-glucuronosyltransferase enzymes. The expression of these enzymes, the enzymes responsible for metabolism of lamotrigine, do not reach adult levels until approximately 2 years of age.47,48 The variability in the rate of maturity of enzymes could result in larger differences in lamotrigine concentrations among infants.

    Only 28.6% of the levetiracetam concentrations in infants (18 of 63 samples) were greater than the LLoQ, with the median levetiracetam level in infants being 5.3% of maternal plasma concentrations. The range of percentage of infant-to-mother concentration ratio was also relatively small (2.1%-20.4%). This observation is in line with previous reports of low infant levetiracetam concentrations compared with maternal concentrations.21,49Quiz Ref ID Although breast milk concentrations were not measured in this study, it has been reported that levetiracetam milk concentrations range from 75% to 155% of the maternal plasma concentrations.21,49 Despite extensive partitioning into milk, levetiracetam concentrations in infants are relatively low compared with lamotrigine. This may be explained by the fact that levetiracetam is not extensively metabolized by liver enzymes and infants have a relatively larger kidney size for their body mass, leading to higher clearance compared with adults.35,50,51 In addition, the shorter half-life (ie, faster elimination) of levetiracetam compared with lamotrigine could result in more variable levetiracetam concentrations in infants who were breastfed.

    For the remaining 4 of the 5 AEDs (oxcarbazepine, carbamazepine, topiramate, and zonisamide), the number of infants in each of these groups is relatively small; however, they represent a larger sample size than available previously for oxcarbazepine,52 carbamazepine,53 topiramate,54 and zonisamide,55 to our knowledge. This study reports low percentages in infant-to-mother concentrations, which are comparable with previous reports for carbamazepine,53,56,57 oxcarbazepine,52,58,59 valproic acid,57,60,61 zonisamide,55,62 and topiramate.54 Because the LLoQ for all of the study AEDs is 10% to 30% lower than the values used in adult suggested therapeutic ranges, our findings support that the concentrations in infants are substantially lower than the concentrations measured in the mothers. Prior studies at delivery demonstrated that umbilical-cord concentrations were nearly equal to maternal concentrations, suggesting extensive placental passage to the fetus.13,63 Therefore, the amount of AED exposure via breast milk is likely substantially lower than fetal exposure during pregnancy and appears unlikely to confer any additional risks beyond those that might be associated with exposure in pregnancy, especially given prior studies showing no adverse neurodevelopmental effects of breastfeeding while taking AEDs.

    It should be noted that infant values less than the LLoQ were represented as half of LLoQ to include values that would be less than the detection level and indicate that they are greater than the lower level of detection. Thus, higher LLoQs can result in higher percentages of infant-to-mother concentrations for some AEDs when infant values are less than the LLoQ.

    Limitations

    There are several limitations in this study. The MONEAD study is observational and susceptible to issues inherent in clinical practice. The amount of AED in the breast milk in the included women is not known, but this study made use of the heel-stick method in the infant, providing a direct measure of drug concentrations in the infant along with measurements of drug concentration in the mothers. Because drug concentration is a direct measure of drug exposure, the extent of drug exposure in the infant is not dependent on knowing the level of the drug in breast milk.38 However, it should be noted that relative infant dosage calculations cannot be performed, because breast milk concentrations of AEDs were not quantified. The number of samples in infants was limited to only 1 sample per infant, and determination of concentrations could only be assessed at 1 point between feedings; therefore, results may not reflect total exposure to the infant over time. Concentrations for the mothers and infants were measured in 2 different laboratories, and this could lead to increased variability. However, a cross-validation was performed to verify the range of variability between laboratories, and the variability was acceptable. The number of mother-infant samples available for medications other than lamotrigine or levetiracetam is small and precludes firm conclusions on transfer via breast milk for these AEDs. In addition, there were different LLoQs for AEDs with similar suggested therapeutic adult ranges. Therefore, the number of infant samples with measurable concentrations could be overrepresented for AEDs with lower LLoQs.

    Conclusions

    In summary, to our knowledge, this study provides direct information about AED drug exposure in the largest number of infants who were breastfed reported to date. Overall results indicate that AED drug exposure in infants, compared with their mothers who were taking AED therapy, is low. Our findings may explain why prior studies have found no adverse neurodevelopment effects of breastfeeding while the mother is taking an AED. The infants in the MONEAD study will be followed up until the age of 6 years to determine longer-term outcomes. On the basis of infant exposure via breastfeeding from maternal AEDs, the results of this study add support to the general safety of breastfeeding by mothers with epilepsy who take AEDs.

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    Article Information

    Accepted for Publication: October 11, 2019.

    Corresponding Author: Angela K. Birnbaum, PhD, Department of Experimental and Clinical Pharmacology, College of Pharmacy, Room 463, 717 Delaware St SE, University of Minnesota, Minneapolis, MN 55414 (birnb002@umn.edu).

    Published Online: December 30, 2019. doi:10.1001/jamaneurol.2019.4443

    Author Contributions: Drs Birnbaum and Karanam had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Birnbaum, Meador, May, Pennell.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Birnbaum, Karanam, Penovich, Brown, May.

    Critical revision of the manuscript for important intellectual content: Birnbaum, Meador, Brown, May, Gerard, Gedzelman, Penovich, Kalayjian, Cavitt, Pack, Miller, Stowe, Pennell.

    Statistical analysis: Birnbaum, Karanam, Brown, May.

    Obtained funding: Meador, Pack, Pennell, Birnbaum.

    Administrative, technical, or material support: Cavitt, Pack, Miller, Pennell.

    Supervision: Birnbaum, Meador, May, Kalayjian, Cavitt, Pennell.

    Conflict of Interest Disclosures: Dr Birnbaum has received research support from the National Institutes of Health, Epilepsy Foundation, Supernus Pharmaceuticals, and Veloxis Pharmaceuticals and is also a coinventor of a patent for intravenous carbamazepine (Lundbeck Pharmaceuticals). Dr Meador has received research support from the National Institutes of Health and Sunovion Pharmaceuticals and travel support from UCB Pharma; the Epilepsy Study Consortium pays Dr Meador’s university for his research consultant time for Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. Dr Gerard received research support from Sage Pharmaceuticals and Sunovion Pharmaceuticals and received speaker and travel funds from UCB Pharma. Dr Penovich has served on speakers’ bureaus for Eisai, Sunovian, GW Pharmaceuticals, Aquestive Therapeutics, and UCB. Dr Cavitt received research support from the National Institute of Neurological Disorders and Stroke and GW Pharmaceuticals. Dr Pack received royalties for the website UpToDate. Dr Miller has received grant and research support from the National Institutes of Health, Medtronic, the US Centers for Disease Control and Prevention, SK Biopharmaceuticals, Eisai, and Xenon Pharma and has a financial relationship with Therma Neurosciences Inc involving advisory board participation and patents. Dr Pennell has received research support from the National Institutes of Health and the Epilepsy Foundation and honoraria and travel support from American Epilepsy Society, American Academy of Neurology, Epilepsy Foundation, National Institutes of Health, and academic institutions for continuing medical education lectures. No other disclosures were reported.

    Funding/Support: This work was supported by National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Development (grants U01-NS038455 [Drs Meador and Pennell]), U01-NS050659 [Dr May], and 2U01-NS038455 [Drs Meador, Pennell, and May]).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Authors: MONEAD Investigator Group: Executive Committee: Kimford J. Meador, MD (Stanford University, Stanford, California, Multiple principal investigator and executive committee director); Page B. Pennell, MD (Harvard University, Brigham & Women’s Hospital, Boston, Massachusetts, multiple principal investigator and codirector of semiology core); Ryan May, PhD (the Emmes Corporation, multiple principal investigator and director of data and statistical center); Angela Birnbaum, PhD (University of Minnesota, Minneapolis, director of pharmacokinetics core); Morris J. Cohen, EdD (Pediatric Neuropsychology International, codirector of neuropsychology center); Maurice Druzin, MD (Stanford University, Stanford, California, codirector of obstetrics [OB] core); Richard Finnell, PhD (Baylor College of Medicine, Houston, Texas, consultant on teratogenicity); Jacqueline French, MD (New York University, New York, codirector, semiology core); Gregory Holmes, MD (University of Vermont, consultant); David W. Loring, PhD (Emory University, Atlanta, Georgia, codirector, neuropsychology center and chair, publications committee); Frederick T. McElrath, MD (Harvard University, Brigham & Women’s, Boston, Massachusetts, codirector of OB core); Lorene Nelson, PhD (Stanford University, Stanford, California, consultant); Zachary Stowe, MD (University of Wisconsin, director of psychiatric core); Linda Van Marter, MD (Harvard University, Brigham & Women’s, Boston, Massachusetts, director of neonatal core); Peter Wells, PharmD (University of Toronto, consultant); Mark Yerby, MD (Oregon Health Sciences University, consultant); Eugene Moore, BS (Emory University, Atlanta, Georgia, multisite research project manager). Data and Statistical Center: Ryan May, PhD (The Emmes Corporation, multiple principal investigator and director of data and statistical center); Dominic Ippolito, MS (The Emmes Corporation, project manager), Anjali Nair, MS (The Emmes Corporation, data manager/protocol monitor), Becky Ayre, BS (The Emmes Corporation, data manager/protocol monitor), Julia Skinner, MS (The Emmes Corporation, SAS programmer), Lisa Davis, BA (The Emmes Corporation, administrative coordinator), Linda Hendrickson (The Emmes Corporation, administrative coordinator), Nilay Shah, MD (The Emmes Corporation, medical monitor), Brenda Leung, BS (The Emmes Corporation, programmer analyst), Michelle Arias, BA (The Emmes Corporation, clinical systems analyst). MONEAD Site Investigators: Augusta University: Suzanne Strickland, MD (Augusta University, site principal investigator); Erin Latif, MD (Augusta University, OB co-investigator); Yong Park, MD (Augusta University, OB co-investigator); Delmaris Acosta-Cotte, MA (Augusta University, site neuropsychologist); Patty Ray, PhD (Augusta University, research assistant); Columbia University: Alison Pack, MD (Columbia University, site principal investigator); Kirsten Cleary, MD (Columbia University, OB co-investigator); Joyce Echo, PhD (Columbia University, site neuropsychologist); Annette Zygmunt, PhD (Columbia University, site neuropsychologist); Camilla Casadei, BA (Columbia University, research assistant); Emory University, Atlanta, Georgia: Evan Gedzelman, MD (Emory University, Atlanta, Georgia, site principal investigator); Mary Dolan, MD (Emory University, Atlanta, Georgia, OB co-investigator); Kim Ono, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Donald Bearden, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Christine Ghilian, PhD (Emory University Children’s Healthcare of Atlanta, Atlanta, Georgia, site neuropsychologist); Diane Teagarden, MSN (Emory University, Atlanta, Georgia, co-investigator); Melanee Newman, RN (Emory University, Atlanta, Georgia, research assistant); Geisinger Clinic: Paul McCabe, MD (Geisinger Clinic, site principal investigator); Michael Paglia, MD (Geisinger Clinic, OB co-investigator); Cora Taylor, PhD (Geisinger Clinic, site neuropsychologist); Rosemarie Delucca, RN (Geisinger Clinic, research assistant); Kristina Blessing MSW (Geisinger Clinic, research assistant); Harvard University, Boston, Massachusetts, and affiliated hospitals: Page Pennell, MD (Brigham & Women’s Hospital, Boston, Massachusetts, site principal investigator); Frederick T. McElrath, MD (Brigham & Women’s Hospital, Boston, Massachusetts, OB co-investigator); Linda Van Marter, MD (Brigham & Women’s Hospital, Boston, Massachusetts, director of neonatal core); Katrina Boyer, PhD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Ellen Hanson, PhD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Amy Young, PsyD (Boston Children’s Hospital, Boston, Massachusetts, site neuropsychologist); Paige Hickey, BS (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Jolie Strauss, MA (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Hayley Madeiros, BS (Boston Children’s Hospital, Boston, Massachusetts, site psychometrist); Li Chen, BA (Brigham & Women’s Hospital, Boston, Massachusetts, research assistant); Stephanie Allien, PAC (Brigham & Women’s Hospital, Boston, Massachusetts, research physician’s assistant); Yvonne Sheldon, RN (Brigham & Women’s Hospital, Boston, Massachusetts, neonatal research nurse); Taylor Weinau, BS (Brigham & Women’s Hospital, Boston, Massachusetts, OB research assistant). Henry Ford Hospital, Detroit, Michigan: Gregory L. Barkley, MD (Henry Ford Hospital, Detroit, Michigansite principal investigator); Marianna Spanaki-Varelas, MD PhD (Henry Ford Hospital, Detroit, Michigan, OB co-investigator); Andrea Thomas, MS (Henry Ford Hospital, Detroit, Michigan, site neuropsychologist); Jules Constantinou, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Nazin Mahmood, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Vibhangini Wasade, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Shailaja Gaddam, MD (Henry Ford Hospital, Detroit, Michigan, co-investigator); Andrew Zillgitt, DO (Henry Ford Hospital, Detroit, Michigan, co-investigator); Taimur Anwar, MD (Henry Ford Hospital, Detroit, Michigan, OB co-investigator); Carla Sandles, CCRP (Henry Ford Hospital, Detroit, Michigan, research assistant); Theresa Holmes, BA (Henry Ford Hospital, Detroit, Michigan, research assistant); Johns Hopkins University, Baltimore, Maryland: Emily Johnson, MD (Johns Hopkins University, Baltimore, Maryland, site principal investigator); Gregory Krauss, MD (Johns Hopkins University, Baltimore, Maryland, prior site principal investigator) Shari Lawson, MD (Johns Hopkins University, Baltimore, Maryland, OB co-investigator); Alison Pritchard, PhD (John Hopkins University, Baltimore, Maryland, site neuropsychologist); Matthew Ryan, MS (John Hopkins University, Baltimore, Maryland, site neuropsychologist); Pam Coe, MS (John Hopkins University, Baltimore, Maryland, research assistant); Minnesota Epilepsy Group: Patricia Penovich, MD (Minnesota Epilepsy Group, St Paul, site principal investigator); Katie Reger, PhD (Minnesota Epilepsy Group, St Paul, site neuropsychologist); Jenny Pohlman, MBS (Minnesota Epilepsy Group, St Paul, research assistant); Alisha Olson, RN (Minnesota Epilepsy Group, St Paul, research assistant); New York University: Jacqueline French, MD (New York University, New York, site principal investigator); William Schweizer, MD (New York University, New York, OB co-investigator); Chris Morrison, PhD (New York University, New York, site neuropsychologist); William MacAllister, PhD (New York University, New York, site neuropsychologist); Tobi Clements, BA (New York University, New York, research assistant); Northwell Health: Sean Hwang, MD (Northwell Health, site principal investigator); Hima Bindu Tam, MD (Northwell Health, OB co-investigator); Yael Cukier, PhD (Northwell Health, site neuropsychologist); Erica Meltzer, MD (Northwell Health, site neuropsychologist); Jacqueline Helcer PhD (Northwell Health, site neuropsychologist); Connie Lau, MS (Northwell Health, research assistant; Northwestern University, Chicago, Illinois: Elizabeth Gerard, MD (Northwestern University, site principal investigator); William Grobman, MD (Northwestern University, Chicago, Illinois, OB co-investigator); Joseph Coda, PsyD (Northwestern University, Chicago, Illinois, site neuropsychologist); Emily Miller, MD (Northwestern University, Chicago, Illinois, OB co-investigator); Irena Bellinski, RN (Northwestern University, Chicago, Illinois, research assistant); Elizabeth Bachman, MPH (Northwestern University, Chicago, Illinois, research assistant); Stanford University, Stanford, California: Kimford Meador, MD (Stanford University, Stanford, California, site principal investigator); Maurice Druzin, MD (Stanford University, Stanford, California, OB co-investigator); Casey Krueger PhD (Stanford Healthcare, Stanford, California, site neuropsychologist); Jordan Seliger, MA (Stanford University,Stanford, California, research assistant); University of Alabama at Birmingham: Jennifer DeWolfe, DO (University of Alabama at Birmingham, site principal investigator); John Owen, MD (University of Alabama at Birmingham, OB co-investigator); Matthew Thompson, PsyD (University of Alabama at Birmingham, site neuropsychologist); Cheryl Hall, LPN (University of Alabama at Birmingham, research assistant); University of Arizona: David Labiner, MD (Arizona Health Sciences Center, Tucson, site principal investigator); James Maciulla, MD (University of Arizona, Tucson, OB co-investigator); Jennifer Moon, PsyD (University of Arizona, Tucson, site neuropsychologist); Kayla Darris, BA (University of Arizona, Tucson, research assistant); University of Cincinnati, Cincinnati, Ohio: Jennifer Cavitt, MD (University of Cincinnati, Cincinnati, Ohio, site principal investigator); Michael Privitera, MD (University of Cincinnati, Cincinnati, Ohio, co-investigator); Kellie Flood-Schaffer, MD (University of Cincinnati, Cincinnati, Ohio, OB co-investigator); George Jewell, PhD (University of Cincinnati, Cincinnati, Ohio, site neuropsychologist); Lucy Mendoza, CCRP (University of Cincinnati, Cincinnati, Ohio, research assistant); University of Miami, Miami, Florida: Enrique Serrano, MD (University of Miami, Miami, Florida, site principal investigator); Yasin Salih, MD (University of Miami, Miami, Florida, OB co-investigator); Christin Bermudez, PhD (University of Miami, Miami, Florida, site neuropsychologist); Michelle Miranda, PhD (University of Miami, Miami, Florida, site neuropsychologist); Naymee Velez-Ruiz, MD (University of Miami, Miami, Florida, co-investigator); Pedro Figueredo, MD (University of Miami, Miami, Florida, research assistant); University of Pittsburgh, Pittsburgh, Pennsylvania: Anto Bagic, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, site principal investigator); Alexandra Popescu Urban MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Satya Gedela, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Christina Patterson, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, co-investigator); Arundhathi Jeyabalan, MD (University of Pittsburgh, Pittsburgh, Pennsylvania, OB co-investigator); Krestin Radonovich PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Melissa Sutcliffe, PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Susan Beers, PhD (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Carrie Wiles, MS (University of Pittsburgh, Pittsburgh, Pennsylvania, site neuropsychologist); Sandra Alhaj, BS (University of Pittsburgh, Pittsburgh, Pennsylvania, research assistant); University of Southern California: Laura Kalayjian, MD (University of Southern California, Los Angeles, site principal investigator); Alice Stek, MD (University of Southern California, Los Angeles, OB co-investigator); Sonia Perez, PhD (University of Southern California, Los Angeles, site neuropsychologist); Rachel Sierra, RC (University of Southern California, Los Angeles, research assistant); University of Washington: John W. Miller, MD (University of Washington, Seattle, site principal investigator); Jennie Mao, MD (University of Washington, Seattle, OB co-investigator); Vaishali Phatak PhD (University of Washington, Seattle, site neuropsychologist); Michelle Kim PhD (University of Washington, Seattle, site neuropsychologist); Andrea Cheng-Hakimian, MD (University of Washington, Seattle, co-investigator); Gina DeNoble MS (University of Washington, Seattle, research assistant); Wake Forest University Health Sciences, Winston-Salem, North Carolina: Maria Sam, MD (Wake Forest University Health Sciences, Winston-Salem, North Carolina, site principal investigator); Lamar Parker, MD (Wake Forest University Health Sciences, Winston-Salem, North Carolina, OB co-investigator); Melissa Morris MA (Wake Forest University Health Sciences, Winston-Salem, North Carolina, site neuropsychologist); Jessica Dimos, BS (Wake Forest University Health Sciences, Winston-Salem, North Carolina, research assistant); multisite: Danielle Miller, MA (project traveling neuropsychologist).

    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Meeting Presentation: This paper was presented as a poster at the American Epilepsy Society meeting; December 3, 2016; Houston, Texas.

    Additional Contributions: The investigators thank the children and families who have given their time to participate in the MONEAD study. The authors thank all the members of the MONEAD study for their contributions. (These authors were compensated as part of the National Institutes of Health grant that funded this study.)

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