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      Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

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          Abstract

          <div class="section"> <a class="named-anchor" id="ab-noi190103-1"> <!-- named anchor --> </a> <h5 class="title" id="d553404e482">Question</h5> <p id="d553404e484">What is the extent of drug exposure via breastfeeding in infants whose mothers are receiving antiepileptic drug therapy? </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-2"> <!-- named anchor --> </a> <h5 class="title" id="d553404e487">Findings</h5> <p id="d553404e489">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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-3"> <!-- named anchor --> </a> <h5 class="title" id="d553404e492">Meaning</h5> <p id="d553404e494">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. </p> </div><p class="first" id="d553404e497">This cohort study aims to provide direct, objective information on infants’ antiepileptic drug exposure through breast milk. </p><div class="section"> <a class="named-anchor" id="ab-noi190103-4"> <!-- named anchor --> </a> <h5 class="title" id="d553404e501">Importance</h5> <p id="d553404e503">There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-5"> <!-- named anchor --> </a> <h5 class="title" id="d553404e506">Objective</h5> <p id="d553404e508">To provide direct, objective information on antiepileptic drug exposure through breast milk. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-6"> <!-- named anchor --> </a> <h5 class="title" id="d553404e511">Design, Setting, and Participants</h5> <p id="d553404e513">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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-7"> <!-- named anchor --> </a> <h5 class="title" id="d553404e516">Exposures</h5> <p id="d553404e518">Antiepileptic drug exposure in infants who were breastfed.</p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-8"> <!-- named anchor --> </a> <h5 class="title" id="d553404e521">Main Outcomes and Measures</h5> <p id="d553404e523">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. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-9"> <!-- named anchor --> </a> <h5 class="title" id="d553404e526">Results</h5> <p id="d553404e528">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; <i>P</i> &lt; .001) but not levetiracetam concentration in infants. </p> </div><div class="section"> <a class="named-anchor" id="ab-noi190103-10"> <!-- named anchor --> </a> <h5 class="title" id="d553404e534">Conclusions and Relevance</h5> <p id="d553404e536">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. </p> </div>

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          Most cited references46

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          The Long-Term Public Health Benefits of Breastfeeding.

          Breastfeeding has many health benefits, both in the short term and the longer term, to infants and their mothers. There is an increasing number of studies that report on associations between breastfeeding and long-term protection against chronic disease. Recent research evidence is reviewed in this study, building on previous authoritative reviews. The recent World Health Organization reviews of the short- and long-term benefits of breastfeeding concluded that there was strong evidence for many public health benefits of breastfeeding. Cognitive development is improved by breastfeeding, and infants who are breastfed and mothers who breastfeed have lower rates of obesity. Other chronic diseases that are reduced by breastfeeding include diabetes (both type 1 and type 2), obesity, hypertension, cardiovascular disease, hyperlipidemia, and some types of cancer.
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            Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

            Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.
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              Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs.

              Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential. 2009 Massachusetts Medical Society
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                Author and article information

                Journal
                JAMA Neurology
                JAMA Neurol
                American Medical Association (AMA)
                2168-6149
                December 30 2019
                Affiliations
                [1 ]Experimental & Clinical Pharmacology, University of Minnesota, Minneapolis
                [2 ]Department of Neurology & Neurological Sciences, Stanford University, Stanford, California
                [3 ]The Emmes Corporation, Rockville, Maryland
                [4 ]Department of Neurology, Northwestern University, Chicago, Illinois
                [5 ]Department of Neurology, Emory University, Atlanta, Georgia
                [6 ]Minnesota Epilepsy Group, Saint Paul
                [7 ]Department of Neurology, University of Southern California, Los Angeles
                [8 ]University of Cincinnati, Cincinnati, Ohio
                [9 ]Neurology, Columbia University, New York, New York
                [10 ]Department of Neurology, University of Washington, Seattle
                [11 ]Department of Neurological Surgery, University of Washington, Seattle
                [12 ]Department of Psychiatry, University of Wisconsin at Madison, Madison
                [13 ]Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
                Article
                10.1001/jamaneurol.2019.4443
                6990802
                31886825
                a7184d97-273b-498c-b6be-791fe6fe275e
                © 2019
                History

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