{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:27:35Z","timestamp":1787243255994,"version":"build-2736575974"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center","award":["09120011910046"],"award-info":[{"award-number":["09120011910046"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>STUDY QUESTION<\/jats:title>\n                    <jats:p>Is periconceptional multiple-micronutrient supplement (MMS) use including folic acid (FA) compared to FA use only associated with increased embryonic growth, development, and birth weight in a high-risk population?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>SUMMARY ANSWER<\/jats:title>\n                    <jats:p>Women with MMS intake show no significant differences in first-trimester morphological embryo development, but increased first-trimester embryonic growth trajectories and fewer neonates born small for gestational age (SGA), less than the 3rd percentile (&amp;lt;p3), compared to women using only FA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                    <jats:p>Periconceptional maternal FA intake in the general population is associated with increased embryonic and fetal growth, and reduced risks of neural tube defects, other congenital malformations, low birth weight, and neonates born SGA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                    <jats:p>A prospective tertiary hospital-based cohort study (the Rotterdam Periconceptional Cohort) was conducted from January 2010 to December 2020.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                    <jats:p>We included 1076 women from the Rotterdam Periconceptional Cohort, before 10\u2009weeks of pregnancy with follow-up until delivery. Embryonic growth was assessed by measurement of crown-rump length (CRL) and embryonic volume (EV), and embryonic morphology was described by Carnegie stages using longitudinal three-dimensional ultrasound scans and virtual reality techniques. Birth outcomes were extracted from medical records. General characteristics and supplement use were extracted from research questionnaires.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                    <jats:p>This study showed increased embryonic growth trajectories (adjusted models, CRL: \u03b2 = 0.052, 95% CI 0.012\u20130.090, EV: \u03b2 = 0.022, 95% CI 0.002\u20130.042) in women using MMS compared to those using only FA. Moreover, a 45% reduced risk of a neonate-born SGA (&amp;lt;p3) was shown in women using MMS compared to FA users (adjusted OR = 0.546, 95% CI 0.308, 0.969). Embryonic morphological development (Carnegie stages) and the occurrence of miscarriages did not differ between women using MMS or solely FA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                    <jats:p>Following the heterogeneity of the composition and dose of MMS preparations, it is unclear which specific micronutrient, combination, or dose explains the increased embryonic growth trajectory and reduction in risk for SGA. This also hampers the possibility of differentiating between the effects of FA alone or as a component of MMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                    <jats:p>Our findings emphasize the importance of periconceptional maternal MMS use as a potential preventative intervention against reduced embryonic growth and neonates born SGA. Therefore, we recommend the periconceptional use of MMS in women at risk of inadequate micronutrient intake. However, awareness of potentially harmful side effects of high doses and combinations of micronutrients is essential, therefore the optimal composition and dose need to be investigated, and careful surveillance is recommended.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                    <jats:p>This research was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, and the ZonMw grant Open Competition 2018 (09120011910046). The authors declare that they have no conflict of interest.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                    <jats:p>NTR4356.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/humrep\/deae168","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T09:22:12Z","timestamp":1720516932000},"page":"1925-1933","source":"Crossref","is-referenced-by-count":7,"title":["Periconceptional maternal supplement intake and human embryonic growth, development, and birth outcomes: the Rotterdam Periconception Cohort"],"prefix":"10.1093","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-5579","authenticated-orcid":false,"given":"N","family":"Schenkelaars","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-6159","authenticated-orcid":false,"given":"S","family":"Schoenmakers","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3008-2567","authenticated-orcid":false,"given":"M","family":"Rousian","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-2931","authenticated-orcid":false,"given":"S P","family":"Willemsen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Erasmus MC, University Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5860-3993","authenticated-orcid":false,"given":"M M","family":"Faas","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen and University Medical Center Groningen , Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4353-5756","authenticated-orcid":false,"given":"R P M","family":"Steegers-Theunissen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"2024090414362601500_deae168-B1","author":"Alders","year":"2001"},{"key":"2024090414362601500_deae168-B2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/jcu.22207","article-title":"Design and validation of a 3D virtual reality desktop system for sonographic length and volume measurements in early pregnancy evaluation","volume":"43","author":"Baken","year":"2015","journal-title":"J Clin Ultrasound"},{"key":"2024090414362601500_deae168-B3","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s12445-020-0883-3","article-title":"Vitaminesuppletie in de zwangerschap","volume":"64","author":"Bakker","year":"2021","journal-title":"Huisarts Wet"},{"key":"2024090414362601500_deae168-B4","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/ije\/31.6.1235","article-title":"Fetal origins of adult disease: strength of effects and biological basis","volume":"31","author":"Barker","year":"2002","journal-title":"Int J Epidemiol"},{"key":"2024090414362601500_deae168-B5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0140-6736(13)60937-X","article-title":"Maternal and child undernutrition and overweight in low-income and middle-income countries","volume":"382","author":"Black","year":"2013","journal-title":"Lancet"},{"key":"2024090414362601500_deae168-B6","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/nure.12003","article-title":"A systematic review and meta-analysis of micronutrient intakes during pregnancy in developed countries","volume":"71","author":"Blumfield","year":"2013","journal-title":"Nutr Rev"},{"key":"2024090414362601500_deae168-B7","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1111\/1471-0528.12086","article-title":"A periconceptional energy-rich dietary pattern is associated with early fetal growth: the Generation R study","volume":"120","author":"Bouwland-Both","year":"2013","journal-title":"BJOG"},{"key":"2024090414362601500_deae168-B8","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1056\/NEJMoa064868","article-title":"Vitamins and perinatal outcomes among HIV-negative women in Tanzania","volume":"356","author":"Fawzi","year":"2007","journal-title":"N Engl J Med"},{"key":"2024090414362601500_deae168-B9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/nyas.14103","article-title":"The upper level: examining the risk of excess micronutrient intake in pregnancy from antenatal supplements","volume":"1444","author":"Gernand","year":"2019","journal-title":"Ann NY Acad Sci"},{"key":"2024090414362601500_deae168-B10","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nrendo.2016.37","article-title":"Micronutrient deficiencies in pregnancy worldwide: health effects and prevention","volume":"12","author":"Gernand","year":"2016","journal-title":"Nat Rev Endocrinol"},{"key":"2024090414362601500_deae168-B11","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.ajog.2018.12.023","article-title":"From population reference to national standard: new and improved birthweight charts","volume":"220","author":"Hoftiezer","year":"2019","journal-title":"Am J Obstet Gynecol"},{"key":"2024090414362601500_deae168-B12","first-page":"E13","article-title":"The Preconception Dietary Risk score; a simple tool to assess an inadequate habitual diet for clinical practice","volume":"9","author":"Huijgen","year":"2014","journal-title":"Clin Nutr e-SPEN"},{"key":"2024090414362601500_deae168-B13","first-page":"CD004905","article-title":"Multiple-micronutrient supplementation for women during pregnancy","volume":"3","author":"Keats","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"2024090414362601500_deae168-B14","doi-asserted-by":"crossref","first-page":"1218S","DOI":"10.1093\/ajcn\/71.5.1218s","article-title":"Physiology of pregnancy and nutrient metabolism","volume":"71","author":"King","year":"2000","journal-title":"Am J Clin Nutr"},{"key":"2024090414362601500_deae168-B15","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/humrep\/deu299","article-title":"Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group","volume":"30","author":"Kolte","year":"2015","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B16","first-page":"168","author":"Mannar","year":"2020"},{"key":"2024090414362601500_deae168-B17","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1001\/jama.2010.78","article-title":"Risk factors and outcomes associated with first-trimester fetal growth restriction","volume":"303","author":"Mook-Kanamori","year":"2010","journal-title":"JAMA"},{"key":"2024090414362601500_deae168-B18","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1159\/000289817","article-title":"Developmental stages in human embryos: revised and new measurements","volume":"192","author":"O\u2019Rahilly","year":"2010","journal-title":"Cells Tissues Organs"},{"key":"2024090414362601500_deae168-B19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1159\/000365794","article-title":"Multiple micronutrient needs in pregnancy in industrialized countries","volume":"65","author":"Parisi","year":"2014","journal-title":"Ann Nutr Metab"},{"key":"2024090414362601500_deae168-B20","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.fertnstert.2016.11.030","article-title":"Periconceptional maternal biomarkers of one-carbon metabolism and embryonic growth trajectories: the Rotterdam Periconceptional Cohort (Predict Study)","volume":"107","author":"Parisi","year":"2017","journal-title":"Fertil Steril"},{"key":"2024090414362601500_deae168-B21","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1016\/S0140-6736(21)00682-6","article-title":"Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss","volume":"397","author":"Quenby","year":"2021","journal-title":"Lancet"},{"key":"2024090414362601500_deae168-B22","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1093\/ije\/dyt127","article-title":"Mediation analysis in epidemiology: methods, interpretation and bias","volume":"42","author":"Richiardi","year":"2013","journal-title":"Int J Epidemiol"},{"key":"2024090414362601500_deae168-B23","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1093\/humrep\/det035","article-title":"First trimester brain ventricle fluid and embryonic volumes measured by three-dimensional ultrasound with the use of I-Space virtual reality","volume":"28","author":"Rousian","year":"2013","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B24","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1093\/humrep\/deq175","article-title":"An innovative virtual reality technique for automated human embryonic volume measurements","volume":"25","author":"Rousian","year":"2010","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B25","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1093\/ije\/dyab030","article-title":"Cohort profile update: the Rotterdam Periconceptional Cohort and embryonic and fetal measurements using 3D ultrasound and virtual reality techniques","volume":"50","author":"Rousian","year":"2021","journal-title":"Int J Epidemiol"},{"key":"2024090414362601500_deae168-B26","author":"Statistics CBo","year":"2021"},{"key":"2024090414362601500_deae168-B27","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0301-2115(02)00358-5","article-title":"Nutrient-gene interactions in early pregnancy: a vascular hypothesis","volume":"106","author":"Steegers-Theunissen","year":"2003","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2024090414362601500_deae168-B28","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1093\/humupd\/dmt041","article-title":"The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism","volume":"19","author":"Steegers-Theunissen","year":"2013","journal-title":"Hum Reprod Update"},{"key":"2024090414362601500_deae168-B29","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1093\/ije\/dyv147","article-title":"Cohort profile: the Rotterdam Periconceptional Cohort (Predict Study)","volume":"45","author":"Steegers-Theunissen","year":"2016","journal-title":"Int J Epidemiol"},{"key":"2024090414362601500_deae168-B30","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1017\/S0007114509288994","article-title":"Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study","volume":"102","author":"Timmermans","year":"2009","journal-title":"Br J Nutr"},{"key":"2024090414362601500_deae168-B31","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1093\/humrep\/det115","article-title":"Human embryonic growth trajectories and associations with fetal growth and birthweight","volume":"28","author":"van Uitert","year":"2013","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B32","doi-asserted-by":"crossref","first-page":"3188","DOI":"10.1093\/humrep\/det375","article-title":"Periconception maternal characteristics and embryonic growth trajectories: the Rotterdam predict study","volume":"28","author":"van Uitert","year":"2013","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev-publhealth-032315-021402","article-title":"Mediation analysis: a practitioner\u2019s guide","volume":"37","author":"VanderWeele","year":"2016","journal-title":"Annu Rev Public Health"},{"key":"2024090414362601500_deae168-B34","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1093\/humrep\/deh078","article-title":"Incidence of spontaneous abortion among pregnancies produced by assisted reproductive technology","volume":"19","author":"Wang","year":"2004","journal-title":"Hum Reprod"},{"key":"2024090414362601500_deae168-B35","first-page":"172","volume-title":"WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience","author":"World Health Organization","year":"2016"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/39\/9\/1925\/59018334\/deae168.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/39\/9\/1925\/59018334\/deae168.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T04:38:13Z","timestamp":1725511093000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/39\/9\/1925\/7716687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,18]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,7,18]]},"published-print":{"date-parts":[[2024,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deae168","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,9]]},"published":{"date-parts":[[2024,7,18]]}}}