{
  "abstract": "Abstract Objective To evaluate whether prenatal exposure to specific antiseizure drugs increases the risk of neurodevelopmental disorders in children.Design Population based cohort study.Setting Healthcare use data from publicly and commercially insured beneficiaries in the United States, 2000-21.Participants Pregnant patients with epilepsy linked to offspring.Interventions Dispensing of the antiseizure drug of interest during the second half of pregnancy (synaptogenesis period): carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproate, and zonisamide. The reference group consisted of pregnant patients with diagnosed epilepsy, but no antiseizure drug dispensation from three months before pregnancy until delivery.Main outcomes measures Any neurodevelopmental disorder, attention deficit hyperactivity disorder, autism spectrum disorder, behavioral disorder, developmental coordination disorder, intellectual disability, learning difficulty, and speech or language disorder identified using validated algorithms. Hazard ratios were estimated using Cox proportional hazard models with propensity score overlap weighting to adjust for potential confounders.Results The cohort included 8887 children who were prenatally unexposed. Exposed pregnancies ranged from 219 for lacosamide to 5261 for levetiracetam. Valproate and zonisamide showed associations with several outcomes (adjusted hazard ratio range 1.26-4.50), whereas levetiracetam and phenytoin were not associated with an increased risk of any outcome. Several drugs were associated with a two to fourfold risk increase for intellectual disability, but estimates were imprecise because of the small number of children with this disorder. Although no meaningful associations were found for topiramate and lamotrigine across most outcomes, there was a potential signal for intellectual disability (both drugs) and learning difficulty (topiramate only; hazard ratio 1.23 based on small numbers). Carbamazepine and oxcarbazepine showed a modest risk increase for attention deficit hyperactivity disorder and behavioral disorders (hazard ratio range 1.23-1.40). Results were robust across several sensitivity analyses, including using lamotrigine as an active comparator.Conclusions The findings strengthen the evidence for increased neurodevelopmental risks among children with prenatal valproate exposure and suggest the need for further evaluation of zonisamide. Signals for other antiseizure drugs, observed in the context of several comparisons and rare outcomes, require confirmation as data accumulate.",
  "authors": [
    {
      "affiliations": [
        "Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Loreen Straub"
    },
    {
      "affiliations": [
        "Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA"
      ],
      "name": "Sonia Hernandez-Diaz"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA"
      ],
      "name": "Brian T Bateman"
    },
    {
      "affiliations": [
        "Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Yanmin Zhu"
    },
    {
      "affiliations": [
        "Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Helen Mogun"
    },
    {
      "affiliations": [
        "Developing Brain Institute, Children’s National Hospital, Departments of Psychiatry, Pediatrics and Obstetrics and Gynecology, George Washington University School of Medicine, Washington, DC, USA"
      ],
      "name": "Katherine L Wisner"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA"
      ],
      "name": "Kathryn J Gray"
    },
    {
      "affiliations": [
        "Center for the Study of Children at Risk, Departments of Psychiatry and Pediatrics, Alpert Medical School of Brown University, and Women and Infants Hospital, Providence, RI, USA"
      ],
      "name": "Barry Lester"
    },
    {
      "affiliations": [
        "Department of Psychiatry, Harvard Medical School, Boston, MA, USA",
        "Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA, USA"
      ],
      "name": "Christopher J McDougle"
    },
    {
      "affiliations": [
        "Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Page B Pennell"
    },
    {
      "affiliations": [
        "Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Krista F Huybrechts"
    }
  ],
  "title": "Prenatal antiseizure drug exposure and risk of neurodevelopmental disorders in children: population based cohort study",
  "uid": "4e18b23f-88e8-5e97-9ac5-ee38819811ca"
}