title: Prenatal antiepileptic exposure associates with neonatal DNA methylation differences.
abstract: Antiepileptic drugs (AEDs) are used to treat a variety of neuropsychiatric illnesses commonly encountered in women during their reproductive years, including epilepsy and bipolar disorder. Despite their widespread use, the impact of prenatal exposure on fetal development remains obscure. To evaluate whether AEDs taken by pregnant mothers influence DNA methylation patterns in their neonates, DNA was extracted from the umbilical cord blood of 201 neonates whose mothers were treated for neuropsychiatric illness during pregnancy and interrogated across 27,578 CpG sites using the Illumina HumanMethylation27 BeadChip. The association of each methylation value with the cumulative duration of prenatal AED exposure was examined using a linear mixed model. The average methylation level across all CpG sites was calculated for each subject, and this global methylation measure was evaluated similarly. Neonates with a longer duration of AED exposure in pregnancy showed a decrease in average global methylation (p = 0.0045). Further, DNA methylation of CpG sites in 14 genes significantly decreased with the duration of prenatal AED exposure even after adjusting for multiple comparisons (FDR < 0.05). For a small subset (n = 19) of these neonates, a second tissue, placenta, was available in addition to cord blood. Methylation of 3 of these 14 CpG sites was also significantly decreased in placental tissue. These novel data suggest decreased DNA methylation in neonates of mothers who took AEDs during pregnancy. The long-term stability and potential impact of these changes warrant further attention, and caution may be warranted before prescribing AEDs to pregnant women.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. aksmit3@emory.edu
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.forename: D Jeffrey
authors.initials: DJ
authors.lastname: Newport
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.forename: James W
authors.initials: JW
authors.lastname: Schroeder
authors.forename: Page B
authors.initials: PB
authors.lastname: Pennell
authors.forename: Bettina T
authors.initials: BT
authors.lastname: Knight
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cubells
authors.forename: Zachary N
authors.initials: ZN
authors.lastname: Stowe
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Brennan
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D002220:Carbamazepine / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology; D018899:CpG Islands; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000473:pathology; D004341:Drug Evaluation; D005260:Female; D005312:Fetal Blood / Q000187:drug effects*; D015894:Genome, Human / Q000187:drug effects*; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn / Q000097:blood*; D008297:Male; D010920:Placenta / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid