{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T12:17:53Z","timestamp":1780661873826,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T00:00:00Z","timestamp":1639094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003197","name":"Italian Medicines Agency","doi-asserted-by":"publisher","award":["FARM6KWTCT"],"award-info":[{"award-number":["FARM6KWTCT"]}],"id":[{"id":"10.13039\/501100003197","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Folic acid (FA) supplementation prevents neural tube defects (NTDs), but the effects on other reproductive outcomes are unclear. While common recommendation is 0.4 mg\/day in addition to regular nutrition, the most appropriate dose of FA is still under debate. We investigated the effects of a higher dose of periconception FA on reducing adverse reproductive outcomes. In this multicenter double-blind randomized controlled trial (RCT), 1060 women (aged 18\u201344 years and planning a pregnancy) were randomly assigned to receive 4.0 mg or 0.4 mg of FA daily. The primary outcome was the occurrence of congenital malformations (CMs). A composite outcome including one or more adverse pregnancy outcomes was also evaluated. A total of 431 women had a natural conception within 1 year. The primary outcome occurred in 8\/227 (3.5%) women receiving 4.0 mg FA and 9\/204 (4.4%) women receiving 0.4 mg FA (RR 0.80; 95%CI 0.31 to 2.03). The composite outcome occurred in 43\/227 (18.9%) women receiving 4.0 mg FA and 75\/204 (36.8%) women receiving 0.4 mg FA (RR 0.51; 95%CI 0.40 to 0.68). FA 4.0 mg supplementation was not associated with different occurrence of CMs, compared to FA 0.4 mg supplementation. However, FA 4.0 mg supplementation was associated with lower occurrence of other adverse pregnancy outcomes.<\/jats:p>","DOI":"10.3390\/nu13124422","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:29:33Z","timestamp":1639358973000},"page":"4422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Efficacy of 4.0 mg versus 0.4 mg Folic Acid Supplementation on the Reproductive Outcomes: A Randomized Controlled Trial"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3857-4133","authenticated-orcid":false,"given":"Renata","family":"Bortolus","sequence":"first","affiliation":[{"name":"Office for Research Promotion, Verona University Hospital, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-8635","authenticated-orcid":false,"given":"Francesca","family":"Filippini","sequence":"additional","affiliation":[{"name":"Office for Research Promotion, Verona University Hospital, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Cipriani","sequence":"additional","affiliation":[{"name":"Department of Woman, Newborn and Child, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6462-0079","authenticated-orcid":false,"given":"Daniele","family":"Trevisanuto","sequence":"additional","affiliation":[{"name":"Department of Woman\u2019s and Child\u2019s Health, University of Padua, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-3971","authenticated-orcid":false,"given":"Francesco","family":"Cavallin","sequence":"additional","affiliation":[{"name":"Independent Statistician, 36020 Solagna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3717-6205","authenticated-orcid":false,"given":"Giovanni","family":"Zanconato","sequence":"additional","affiliation":[{"name":"Department of Surgery, Odontostomatology and Maternal and Child Health, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0223-0032","authenticated-orcid":false,"given":"Edgardo","family":"Somigliana","sequence":"additional","affiliation":[{"name":"Department of Woman, Newborn and Child, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cesari","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Sant\u2019Antonio Abate Hospital, 21013 Gallarate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierpaolo","family":"Mastroiacovo","sequence":"additional","affiliation":[{"name":"International Centre on Birth Defects\u2014ICBD, 00195 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Parazzini","sequence":"additional","affiliation":[{"name":"Department of Woman, Newborn and Child, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"De-Regil, L.M., Pe\u00f1a-Rosas, J.P., Fern\u00e1ndez-Gaxiola, A.C., and Rayco-Solon, P. 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