{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T03:36:59Z","timestamp":1781581019621,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI13\/01559"],"award-info":[{"award-number":["PI13\/01559"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Identification of causal factors that influence fetal growth and anthropometry at birth is of great importance as they provide information about increased risk of disease throughout life. The association between maternal genetic polymorphism MTHFR(677)C&gt;T and anthropometry at birth has been widely studied because of its key role in the one-carbon cycle. MTHFR(677) CT and TT genotypes have been associated with a greater risk of low birth weight, especially in case of deficient intake of folic acid during pregnancy. This study aimed to analyze the association between the maternal MTHFR(677)C&gt;T genetic polymorphism and anthropometry at birth in a population with adequate folate consumption. We included 694 mother\u2013newborn pairs from a prospective population-based birth cohort in Spain, in the Genetics, Early life enviroNmental Exposures and Infant Development in Andalusia (GENEIDA) project. Women were genotyped for MTHFR(677)C&gt;T SNP by Q-PCR using TaqMan\u00a9 probes. Relevant maternal and newborn information was obtained from structured questionnaires and medical records. Results showed that maternal MTHFR(677)C&gt;T genotype was associated with newborn anthropometry. Genotypes CT or CT\/TT showed statistically significant associations with increased or decreased risk of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) based on weight and height, depending on the newborn\u2019s sex, as well as with SGA in premature neonates. The relationships between this maternal genotype and anthropometry at birth remained despite an adequate maternal folate intake.<\/jats:p>","DOI":"10.3390\/nu13030831","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T05:10:16Z","timestamp":1614748216000},"page":"831","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant\u2019s Anthropometry at Birth"],"prefix":"10.3390","volume":"13","author":[{"given":"Sof\u00eda","family":"Aguilar-Lacasa\u00f1a","sequence":"first","affiliation":[{"name":"Barcelona Biomedical Research Park (PRBB), Research Institute for Global Health (ISGlobal), Doctor Aiguader, 88, Barcelona, 08003 Barcelona, Spain"},{"name":"Department of Genetics, Faculty of Sciences, University of Granada, Fuente Nueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"L\u00f3pez-Flores","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Sciences, University of Granada, Fuente Nueva s\/n, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Gonz\u00e1lez-Alzaga","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"},{"name":"Andalusian School of Public Health (EASP), 18011 Granada, Spain"},{"name":"Campus Universitario de la Cartuja, Cuesta del Observatorio, 4, 18011 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Gim\u00e9nez-Asensio","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"},{"name":"Andalusian Public Foundation for the Biosanitary Research of Eastern Andalusia-Alejandro Otero (FIBAO), Licinio de la Fuente Building, Dr. Azpitarte, 4, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1427-7639","authenticated-orcid":false,"given":"F. David","family":"Carmona","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Sciences, University of Granada, Fuente Nueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2983-5418","authenticated-orcid":false,"given":"Antonio F.","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"},{"name":"Department of Legal Medicine and Toxicology, University of Granada School of Medicine, Health Sciences Technological Park, Avenida de la Investigaci\u00f3n, 11, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Felicidad","family":"L\u00f3pez Gallego","sequence":"additional","affiliation":[{"name":"Gynecology and Obstetrics Care Unit, Poniente Hospital, Ctra. de Almerimar, 04700 El Ejido-Almer\u00eda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e9e","family":"Romero-Molina","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"},{"name":"Statistics and Operations Research Department, Faculty of Sciences, University of Granada, Fuente Nueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Lacasa\u00f1a","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria (ibs.GRANADA), Av. de las Fuerzas Armadas, 2, 18014 Granada, Spain"},{"name":"Andalusian School of Public Health (EASP), 18011 Granada, Spain"},{"name":"CIBER Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Monforte de Lemos 3-5, Pabell\u00f3n 11, Planta 0, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"F7","DOI":"10.1136\/adc.2006.096214","article-title":"Neonatal anthropometric charts: What they are, what they are not","volume":"92","author":"Bertino","year":"2007","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1056\/NEJM199904223401603","article-title":"Birthweight in relation to morbidity and mortality among newborn infants","volume":"340","author":"McIntire","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1093\/ije\/dyq267","article-title":"Birthweight and mortality in adulthood: A systematic review and meta-analysis","volume":"40","author":"Risnes","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1210\/jc.2018-00917","article-title":"3D Cohort Study Group. Large-for-gestational-age may be associated with lower fetal insulin sensitivity and \u03b2-cell function linked to leptin","volume":"103","author":"Dong","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","first-page":"241","article-title":"High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study","volume":"58","author":"Murcia","year":"2017","journal-title":"Eur. J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sengpiel, V., Bacelis, J., Myhre, R., Myking, S., Pay, A.S.D., Haugen, M., Brants\u00e6ter, A.L., Meltzer, H.M., Nilsen, R.M., and Magnus, P. (2014). Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: A prospective observational cohort study. BMC Pregnancy Childbirth, 14.","DOI":"10.1186\/s12884-014-0375-1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.jand.2019.02.016","article-title":"Prepegnancy dietary patterns and their association with perinatal outcomes: A prospective cohort study","volume":"119","author":"Benaim","year":"2019","journal-title":"J. Acad. Nutri. Diet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bulloch, R.E., Wall, C.R., McCowan, L.M.E., Taylor, R.S., Roberts, C.T., and Thompson, J.M.D. (2020). The Effect of interactions between folic acid supplementation and one carbon metabolism gene variants on small-for-gestational-age births in the Screening for Pregnancy Endpoints (SCOPE) cohort study. Nutrients, 12.","DOI":"10.3390\/nu12061677"},{"key":"ref_9","unstructured":"World Health Organization (2016). Recommendations on Antenatal Care for a Positive Pregnancy Experience, World Health Organization."},{"key":"ref_10","doi-asserted-by":"crossref","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":"ref_11","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1159\/000364866","article-title":"Localization of folate metabolic enzymes, methionine synthase and 5,10-methylenetetrahydrofolate reductase in human placenta","volume":"78","author":"Shin","year":"2014","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.4103\/ijmr.IJMR_275_15","article-title":"Folic acid, one-carbon metabolism & childhood cancer","volume":"146","author":"Kumar","year":"2017","journal-title":"Indian J. Med. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/nyas.13499","article-title":"Safety of folic acid","volume":"1414","author":"Field","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ejcn.2013.232","article-title":"Vitamin B12: One carbon metabolism, fetal growth and programming for chronic disease","volume":"68","author":"Rush","year":"2014","journal-title":"Eur. J. Clin. Nutrit."},{"key":"ref_15","unstructured":"World Health Organization, and Food and Agricultural Organization of the United Nations (2004). Chapter 14. Vitamin B12. Vitamin and Mineral Requirements in Human Nutrition, FAO."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1097\/MOL.0000000000000259","article-title":"Choline metabolites: Gene by diet interactions","volume":"27","author":"Smallwood","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2188\/jea.JE20110039","article-title":"Effects of maternal 5,10-methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and tobacco smoking on infant birth weight in a japanese population","volume":"22","author":"Yila","year":"2012","journal-title":"J. Epidemiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s00404-017-4322-z","article-title":"Genetic polymorphism of MTHFR(677)C>T whit preterm birth and low birth weight susceptibility: A meta-analysis","volume":"295","author":"Wu","year":"2017","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00404-015-3894-8","article-title":"Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: A systematic review and meta-analysis","volume":"293","author":"Chen","year":"2016","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1093\/oxfordjournals.aje.a115694","article-title":"The ponderal index in term newborn siblings","volume":"132","author":"Khoury","year":"1990","journal-title":"Am. J. Epidemiol."},{"key":"ref_21","first-page":"406","article-title":"Anthropometric growth patterns of preterm and full-term newborns (24\u201342 weeks\u2019 gestational age) at the Hospital Materno-Infantil Vall d\u2019Hebron (Barcelona) (1997\u20132002","volume":"60","author":"Carrascosa","year":"2004","journal-title":"An. Pediatr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/oxfordjournals.aje.a114086","article-title":"Reproducibility and validity of a semiquantitative food frequency questionnaire","volume":"122","author":"Willett","year":"1985","journal-title":"Am. J. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1475-2891-12-26","article-title":"Reproducibility and validity of a food frequency questionnaire among pregnant women in a Mediterranean area","volume":"12","author":"Vioque","year":"2013","journal-title":"Nutr. J."},{"key":"ref_24","unstructured":"Gesti\u00f3n de Salud y Nutrici\u00f3n SL (2019) i-Diet Food Composition Database, Updated from original version of G. Mart\u00edn Pe\u00f1a FCD (i-diet.es)"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1093\/ajcn\/83.5.993","article-title":"Folate and human reproduction","volume":"83","author":"Tamura","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1455S","DOI":"10.3945\/ajcn.2010.28674E","article-title":"Folate bioavailability: Implications for establishing dietary recommendations and optimizing status","volume":"91","author":"Caudill","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_27","first-page":"1","article-title":"Mice: Multivariate imputation by chained equations in R","volume":"45","year":"2011","journal-title":"J. Statist. Softw."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"164","DOI":"10.5455\/medarh.2018.72.164-169","article-title":"The frequency of the 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in the population","volume":"72","author":"Nefic","year":"2018","journal-title":"Med. Arch."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/ajcn\/70.4.495","article-title":"Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome","volume":"70","author":"James","year":"1999","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/humu.10193","article-title":"Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation","volume":"21","author":"Sibani","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Steluti, J., Carvalho, A.M., Carioca, A.A.F., Miranda, A., Gatt\u00e1s, G.J.F., Fisberg, R.M., and Marchioni, D.M. (2017). Genetic variants involved in one-carbon metabolism: Polymorphism frequencies and differences in homocysteine concentrations in the folic acid fortification era. Nutrients, 9.","DOI":"10.3390\/nu9060539"},{"key":"ref_32","first-page":"1","article-title":"Maternal dietary intake of folate, vitamin B12 and MTHFR 677C>T genotype: Their impact on newborn\u2019s anthropometric parameters","volume":"9","author":"Chen","year":"2014","journal-title":"Genes Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3945\/ajcn.115.107219","article-title":"Genetic modifiers of folate, vitamin B-12, and homocysteine status in a cross-sectional study of the Canadian population","volume":"101","author":"Zinck","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/nutrit\/nuv107","article-title":"Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults","volume":"74","author":"Sechi","year":"2016","journal-title":"Nutr. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1111\/1471-0528.13202","article-title":"Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: A population study, systematic review and meta-analysis","volume":"122","author":"Hodgetts","year":"2015","journal-title":"BJOG"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.reprotox.2016.11.012","article-title":"Effect of folic acid supplementation on preterm delivery and small for gestationalage births: A systematic review and meta-analysis","volume":"67","author":"Zhang","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.3389\/fnins.2019.01284","article-title":"Folic acid and risk of preterm birth: A meta-analysis","volume":"13","author":"Li","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1093\/ajcn\/76.1.180","article-title":"Methylenetetrahydrofolate reductase 677C-T genotype modulates homocysteine responses to a folate-rich diet or a low-dose folic acid supplement: A randomized controlledtrial","volume":"76","author":"Pullin","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s12929-014-0077-z","article-title":"Folic acid supplementation in pregnancy and implications in health and disease","volume":"21","author":"Barua","year":"2014","journal-title":"J. Biomed. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s00431-017-3026-5","article-title":"Diet in pregnancy-more than food","volume":"176","author":"Danielewicz","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S424","DOI":"10.21037\/cdt.2019.02.03","article-title":"Folate supplementation for prevention of congenital heart defects and low birth weight: An update","volume":"9","author":"Obeid","year":"2019","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00394-015-1076-x","article-title":"The impact of MTHFR 677 C\/T genotypes on folate status markers: A meta-analysis of folic acid intervention studies","volume":"56","author":"Colson","year":"2017","journal-title":"Eur. J. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Golja, M.V., \u0160mid, A., Ku\u017eeli\u010dki, N.K., Trontelj, J., Ger\u0161ak, K., and Mlinari\u010d-Ra\u0161\u010dan, I. (2020). Folate insufficiency due to MTHFR deficiency is bypassed by 5-methyltetrahydrofolate. J. Clin. Med, 9.","DOI":"10.3390\/jcm9092836"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/j.toxrep.2019.09.012","article-title":"Safety evaluation of calcium L-methylfolate","volume":"6","author":"Niederberger","year":"2019","journal-title":"Toxicol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-014-0251-x","article-title":"In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver","volume":"13","author":"Drake","year":"2015","journal-title":"BMC Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13148-018-0468-1","article-title":"No evidence for association of MTHFR 677C>T and 1298A>C variants with placental DNA methylation","volume":"10","author":"Price","year":"2018","journal-title":"Clin. Epigenet."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/3\/831\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:31:53Z","timestamp":1760160713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/3\/831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,3]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["nu13030831"],"URL":"https:\/\/doi.org\/10.3390\/nu13030831","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,3]]}}}