{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:59:55Z","timestamp":1790315995071,"version":"4.1.0"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periconceptional folic acid supplementation prevents neural tube defects and may influence offspring neurodevelopment, but evidence for domain-specific learning difficulties remains unclear. We examined whether maternal-reported first-trimester initiation of folic acid supplementation was associated with parent-reported learning difficulties in offspring assessed at ages 4\u20137\u202fyears.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>This retrospective cohort study used data from the Dutch Perined-Lifelines birth cohort. We excluded preterm birth (&amp;lt;37\u202fweeks), high-dose folic acid exposure (4.0\u202fmg), and supplementation initiated after the first trimester. Exposure was retrospective maternal-reported folic acid supplementation timing and categorized as before conception\/prepregnancy through the first trimester and first trimester only. Outcomes were parent-reported binary indicators of poor concentration, reading disability, difficulty with calculating, and difficulty keeping up at school without clinical diagnoses or standardized neuropsychological assessments. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for child age, sex, body rate, stress rate, and preschool sleeping problems.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 3,216 children, 2,314 (71.9%) were in the preconception group and 902 (28.1%) in the first-trimester-only group. In adjusted models, first-trimester-only supplementation was not associated with poor concentration, reading disability, or difficulty keeping up at school but was nominally associated with higher odds of parent-reported difficulty with calculating (OR\u202f=\u202f1.60; 95% CI: 1.02\u20132.50).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Maternal-reported first-trimester initiation of folic acid supplementation was nominally associated with parent-reported difficulty with calculating assessed at ages 4\u20137, but the retrospective observational design, potential misclassification, and residual confounding preclude causal interpretation. Prospective studies with biomarkers and standardized developmental assessments are warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpubh.2026.1937716","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:32:26Z","timestamp":1790314346000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Maternal folic acid supplement timing and learning difficulties in children assessed at ages 4 to 7 years"],"prefix":"10.3389","volume":"14","author":[{"given":"Hanbin","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong","place":["Hong Kong, Hong Kong SAR, China"]},{"name":"National Institute for Family Planning","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, National Children\u2019s Medical Center, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingren","family":"Luo","sequence":"additional","affiliation":[{"name":"Center of Clinical Research, National Children\u2019s Medical Center, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center of Clinical Research, National Children\u2019s Medical Center, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0140-6736(91)90133-A","article-title":"Prevention of neural tube defects: results of the medical research council vitamin study","volume":"338","year":"1991","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.jogc.2022.04.004","article-title":"Guideline no. 427: folic acid and multivitamin supplementation for prevention of folic acid-sensitive congenital anomalies","volume":"44","author":"Wilson","year":"2022","journal-title":"J Obstet Gynaecol Can"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3945\/an.111.000992","article-title":"Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate\u2019s 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folic acid supplements and risk of autism spectrum disorders in children","volume":"309","author":"Sur\u00e9n","year":"2013","journal-title":"JAMA"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"3443","DOI":"10.3390\/nu17213443","article-title":"The effect of maternal folic acid supplementation on neurodevelopmental disorders in offspring: an umbrella review of systematic reviews and meta-analyses","volume":"17","author":"Yu","year":"2025","journal-title":"Nutrients"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"e142611","DOI":"10.1001\/jamapediatrics.2014.2611","article-title":"Folic acid supplements during pregnancy and child psychomotor development after the first year of life","volume":"168","author":"Valera-Gran","year":"2014","journal-title":"JAMA Pediatr"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1093\/ije\/dyu229","article-title":"Cohort profile: LifeLines, a three-generation cohort study and biobank","volume":"44","author":"Scholtens","year":"2015","journal-title":"Int J Epidemiol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e0225973","DOI":"10.1371\/journal.pone.0225973","article-title":"Cohort profile: the Dutch perined-lifelines birth cohort","volume":"14","author":"Salavati","year":"2019","journal-title":"PLoS One"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.1056\/NEJM199212243272602","article-title":"Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation","volume":"327","author":"Czeizel","year":"1992","journal-title":"N Engl J Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1001\/jama.2023.12876","article-title":"Folic acid supplementation to prevent neural tube defects: US preventive services task force reaffirmation recommendation statement","volume":"330","year":"2023","journal-title":"JAMA"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3945\/ajcn.110.004416","article-title":"Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood autism risks from genetics and environment) case-control study","volume":"96","author":"Schmidt","year":"2012","journal-title":"Am J Clin Nutr"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1186\/s12916-019-1432-4","article-title":"Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT offspring trial)","volume":"17","author":"McNulty","year":"2019","journal-title":"BMC Med"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1093\/advances\/nmy120","article-title":"The importance of maternal folate status for brain development and function of offspring","volume":"10","author":"Naninck","year":"2019","journal-title":"Adv Nutr"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41539-021-00099-3","article-title":"Developmental brain dynamics of numerical and arithmetic abilities","volume":"6","author":"Vogel","year":"2021","journal-title":"NPJ Sci Learn"}],"container-title":["Frontiers in Public 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