{
  "abstract": "Objective To evaluate the association of paternal use of valproate during spermatogenesis compared with paternal use of lamotrigine or levetiracetam on offspring risk of neurodevelopmental disorders (NDDs).Methods Eligibility criteria: observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate vs lamotrigine or levetiracetam during spermatogenesis.Information sources: the databases PubMed, Embase, Cochrane Library and Web of Science were systematically searched from January 1995 to October 2025.Synthesis of results and risk of bias: a random-effects model was used to estimate pooled HRs and 95% CI, with heterogeneity assessed using I2 statistic for any NDD.We present a meta-analysis of observational, peer-reviewed studies reporting neurodevelopmental outcomes of children exposed to paternal monotherapy use of valproate versus lamotrigine or levetiracetam during spermatogenesis. Given the major regulatory implications of paternal valproate safety, the recent emergence of new population-based data, and the expectation of further large studies, we designed this work as a living systematic review and meta-analysis that will be updated as new eligible evidence becomes available.Results We identified three eligible studies based on data from (1) Norway and Sweden, (2) Norway and Taiwan and (3) Denmark. As two studies included Norwegian data, their results are referred to as ‘Norway 1’ and ‘Norway 2’ for clarity. In the meta-analysis of data from Denmark, Sweden and Norway 1, the pooled HR of offspring NDDs was 1.05 (95% CI 0.87 to 1.27; I 2=0.0%), and in meta-analysis of data from Denmark, Sweden and Norway 2, it was 1.03 (95% CI 0.85 to 1.24; I2=0.0%).In the meta-analysis including Taiwan, Denmark, Sweden and Norway 1, the pooled HR was 1.06 (95% CI 0.88 to 1.27; I2=0.0%), and when including data from Taiwan, Denmark, Sweden and Norway 2, the pooled HR was 1.04 (95% CI 0.87 to 1.25; I2=0.0%).Conclusions In this living meta-analysis, we found no evidence that paternal exposure to valproate compared with lamotrigine/levetiracetam during spermatogenesis was associated with increased risk of NDDs in offspring.",
  "authors": [
    {
      "affiliations": [
        "Department of Clinical Medicine, Aarhus University, Aarhus, Denmark",
        "Department of Neurology, Aarhus University Hospital, Affiliated Member of Epi-CARE, Aarhus, Denmark"
      ],
      "name": "Jakob Christensen"
    },
    {
      "affiliations": [
        "National Centre for Register-Based Research, Department of Public Health, Aarhus University, Aarhus, Denmark",
        "Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark"
      ],
      "name": "Betina B Trabjerg"
    },
    {
      "affiliations": [
        "PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway"
      ],
      "name": "Marleen M H J van Gelder"
    },
    {
      "affiliations": [
        "PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway",
        "Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA",
        "Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Lin-Chieh Meng"
    },
    {
      "affiliations": [
        "Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan",
        "Health Data Research Center, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Hsi-Yu Lai"
    },
    {
      "affiliations": [
        "Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway",
        "Department of Neurology, Haukeland University Hospital, Bergen, Norway"
      ],
      "name": "Jannicke Igland"
    },
    {
      "affiliations": [
        "Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Neda Razaz"
    },
    {
      "affiliations": [
        "Department of Clinical Neuroscience, Karolinska Institutet, and Department of Neurology, Karolinska University Hospital, Stockholm, Sweden"
      ],
      "name": "Torbjörn Tomson"
    },
    {
      "affiliations": [
        "Department of Neurology, Haukeland University Hospital, Bergen, Norway",
        "Norwegian Center for Headache Research (NorHead), Department of Clinical Medicine, University of Bergen, Bergen, Norway"
      ],
      "name": "Marte-Helene Bjørk"
    },
    {
      "affiliations": [
        "Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan",
        "Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan",
        "School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan"
      ],
      "name": "Fei-Yuan Hsiao"
    },
    {
      "affiliations": [
        "PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway",
        "Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway"
      ],
      "name": "Hedvig M E Nordeng"
    },
    {
      "affiliations": [
        "National Centre for Register-Based Research, Department of Public Health, Aarhus University, Aarhus, Denmark",
        "Centre for Integrated Register-based Research (CIRRAU), Aarhus University, Aarhus, Denmark"
      ],
      "name": "Julie Werenberg Dreier"
    }
  ],
  "title": "Risk of neurodevelopmental disorders associated with paternal use of valproate during spermatogenesis: a living meta-analysis—version 1",
  "uid": "25187b5c-6f1e-55d3-882c-b4ecc7df57f6"
}