{
  "abstract": "Background High-dose folic acid supplementation is recommended for women using antiseizure medication (ASMs) to reduce risk of major congenital anomalies (MCAs) in offspring, but evidence is lacking.Methods We conducted a sequential target trial emulation using nationwide register data from Denmark, Iceland, Norway, and Sweden (1997–2020). Eligible women using ASMs were included and classified as initiators or non-initiators based on whether they filled prescription for high-dose folic acid within one week of inclusion. Risk difference (RD) and risk ratio (RR) for MCAs diagnosed before one year of age in offspring were estimated for initiators of high-dose folic acid (4 or 5 mg/day) supplementation in three periconceptional periods (13-52 weeks before, 1-12 weeks before, and 1-12 weeks after pregnancy onset) compared with non-initiators.Results We included 18 255, 13 619, and 12 365 eligible pregnancies and identified 1047 (5.7%), 521 (3.8%) and 1778 (14.4%) initiators of high-dose folic acid in the three periods, respectively. Initiation of high-dose folic acid 1–12 weeks before pregnancy was associated with a lower prevalence of MCA in offspring (2.6% vs 4.8% among non-initiators), corresponding to an absolute risk reduction of 2.2 percentage points (95% CI 0.5 to 3.5) and a 45% relative risk reduction (RR=0.55, 95% CI 0.25 to 0.91). No risk reduction was observed with initiation 1–12 weeks after (RR=1.27, 95% CI 0.94 to 1.64) or 13–52 weeks before (RR=0.99, 95% CI 0.65 to 1.36) pregnancy onset.Conclusions Initiation of high-dose folic acid in the 12 weeks before pregnancy was associated with a reduced risk of MCA in offspring of women using ASMs while initiation in the 12 weeks after pregnancy onset was not.Research protocol registration https://osf.io/vph2n/?view_only=c9361e4996eb4c4da32fc878f2fbf5b9.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, Aarhus University Hospital, Affiliated Member of Epi-Care, Aarhus, Denmark",
        "Department of Clinical Medicine, University of Bergen, Bergen, Norway"
      ],
      "name": "Yuelian Sun"
    },
    {
      "affiliations": [
        "Department of Clinical Medicine, University of Bergen, Bergen, Norway",
        "National Center for Epilepsy, Oslo University Hospital, Oslo, Norway"
      ],
      "name": "Silje Alvestad"
    },
    {
      "affiliations": [
        "Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway",
        "Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway"
      ],
      "name": "Jacqueline M Cohen"
    },
    {
      "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": [
        "Department of Clinical Medicine, University of Bergen, Bergen, Norway",
        "Department of Neurology, Haukeland University Hospital, Bergen, Norway"
      ],
      "name": "Nils Erik Gilhus"
    },
    {
      "affiliations": [
        "Department of Clinical Medicine, University of Bergen, Bergen, Norway"
      ],
      "name": "Håkon M Vegrim"
    },
    {
      "affiliations": [
        "Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Torbjörn Tomson"
    },
    {
      "affiliations": [
        "Department of Neurology, Aarhus University Hospital, Affiliated Member of Epi-Care, Aarhus, Denmark",
        "Department of Clinical Medicine, Aarhus University, Aarhus, Denmark"
      ],
      "name": "Jakob Christensen"
    },
    {
      "affiliations": [
        "Department of Data and Analytics, Finnish Institute for Health and Welfare, Helsinki, Finland",
        "Teratology Information Service, Emergency Medicine and Services, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"
      ],
      "name": "Maarit K Leinonen"
    },
    {
      "affiliations": [
        "Department of Data and Analytics, Finnish Institute for Health and Welfare, Helsinki, Finland",
        "Institute of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden"
      ],
      "name": "Mika Gissler"
    },
    {
      "affiliations": [
        "Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland"
      ],
      "name": "Helga Zoega"
    },
    {
      "affiliations": [
        "Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institute, Solna, Sweden"
      ],
      "name": "Neda Razaz"
    },
    {
      "affiliations": [
        "National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark"
      ],
      "name": "Julie Werenberg Dreier"
    },
    {
      "affiliations": [
        "Department of Clinical Medicine, University of Bergen, Bergen, Norway",
        "Department of Neurology, Haukeland University Hospital, Bergen, Norway"
      ],
      "name": "Marte-Helene Bjørk"
    }
  ],
  "title": "Timing of high-dose folic acid supplementation in the periconceptional period among women taking antiseizure medications and risk of major congenital anomalies: a target trial emulation",
  "uid": "76d2a000-cd4b-5cb3-93b1-8f1526401cea"
}