{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:59:51Z","timestamp":1791547191847,"version":"4.3.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"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. Nutr."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study aimed to evaluate maternal serum levels of folate, vitamin B12, and their ratio on admission for labor and determine whether an imbalance between folate and vitamin B12, represented by a higher or lower serum folate to vitamin B12 ratio (SFVB12R), was associated with adverse pregnancy outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A retrospective cohort study of 11,549 pregnant women attending a district specialized hospital and who had serum folate (SF) and serum vitamin B12 (SVB12) levels measured at delivery was performed. The levels of SF, SVB12, and SFVB12R were defined as high (&amp;gt;95th percentile), normal (5\u201395th percentile), and low (&amp;lt;5th percentile). Information on pregnancy outcomes was retrieved from medical records. Linear regression was performed to examine the association of abnormal SF, SVB12, and SFVB12R levels with fetal growth indicators. Logistic regression was applied to estimate the association between abnormal SF, SVB12, and SFVB12R levels and pregnancy outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lower SF levels were associated with higher risks of intrahepatic cholestasis of pregnancy (ICP, OR 1.58; 95% CI 1.15\u20132.17), pre-eclampsia (PE, OR 1.89; 95% CI 1.28\u20132.81), and a lower risk of gestational diabetes mellitus (GDM, OR 0.40; 95% CI 0.23\u20130.70), whereas higher SVB12 levels were associated with a higher risk of ICP (OR 2.22; 95% CI 1.67\u20132.96), PE (OR 1.69; 95% CI 1.04-2.74), and GDM (OR 1.62; 95% CI 1.24\u20132.11). A higher SFVB12R increased birthweight (\u03b2 60.99; 95% CI 29.52\u201392.45) and was associated with a higher risk of large-for-gestational-age (LGA) newborns (OR 3.08; 95% CI 1.63\u20135.83); a lower SFVB12R decreased birthweight (\u03b2 \u221243.81; 95% CI \u221275.62, \u221212.00) and was associated with a lower risk of LGA newborns (OR 0.75; 95% CI 0.56\u20131.00), and with higher risks of ICP (OR 2.03; 95% CI 1.54\u20132.67) and pregnancy-induced hypertension (PIH, OR 1.81; 95% CI 1.09\u20133.00).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>An imbalance between folate and vitamin B12, represented by a higher or lower SFVB12R before delivery, was significantly associated with adverse pregnancy outcomes (ICP\/PIH\/LGA).<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnut.2022.947118","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T10:40:59Z","timestamp":1658745659000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Association of folate and vitamin B12 imbalance with adverse pregnancy outcomes among 11,549 pregnant women: An observational cohort study"],"prefix":"10.3389","volume":"9","author":[{"given":"Xiaosong","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoya","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e13064","DOI":"10.1111\/mcn.13064","article-title":"Maternal folate, one-carbon metabolism and pregnancy outcomes","volume":"17","author":"Jankovic-Karasoulos","year":"2021","journal-title":"Matern Child Nutr."},{"key":"B2","doi-asserted-by":"publisher","first-page":"151","DOI":"10.2337\/dc21-1018","article-title":"Gestational diabetes mellitus and the risks of overall and type-specific cardiovascular diseases: a population- and sibling-matched cohort study","volume":"45","author":"Yu","year":"2022","journal-title":"Diabetes Care."},{"key":"B3","doi-asserted-by":"publisher","first-page":"281","DOI":"10.2188\/jea.JE20140136","article-title":"Subsequent risk of metabolic syndrome in women with a history of preeclampsia: data from the health examinees study","volume":"25","author":"Yang","year":"2015","journal-title":"J Epidemiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nrendo.2016.127","article-title":"Long-term metabolic risk among children born premature or small for gestational age","volume":"13","author":"Mericq","year":"2017","journal-title":"Nat Rev Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","article-title":"One-Carbon metabolism in health and disease","volume":"25","author":"Ducker","year":"2017","journal-title":"Cell Metab."},{"key":"B6","first-page":"S101","article-title":"Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development","volume-title":"Food Nutr Bull.","author":"Molloy","year":"2008"},{"key":"B7","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.biochi.2015.12.003","article-title":"Early pregnancy B vitamin status, one carbon metabolism, pregnancy outcome and child development","volume":"126","author":"Sol\u00e9-Navais","year":"2016","journal-title":"Biochimie."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1007\/s00125-009-1499-0","article-title":"Low plasma vitamin B12 in pregnancy is associated with gestational 'diabesity' and later diabetes","volume":"52","author":"Krishnaveni","year":"2009","journal-title":"Diabetologia."},{"key":"B9","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1016\/j.clnu.2017.03.022","article-title":"High folate and low vitamin B12 status during pregnancy is associated with gestational diabetes mellitus","volume":"37","author":"Lai","year":"2018","journal-title":"Clin Nutr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1111\/1753-0407.12899","article-title":"Joint effects of folate and vitamin B12 imbalance with maternal characteristics on gestational diabetes mellitus","volume":"11","author":"Li","year":"2019","journal-title":"J Diabetes."},{"key":"B11","doi-asserted-by":"publisher","first-page":"217","DOI":"10.2337\/dc20-1607","article-title":"Association of maternal folate and vitamin B12 in early pregnancy with gestational diabetes mellitus: a prospective cohort study","volume":"44","author":"Chen","year":"2021","journal-title":"Diabetes Care."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2170","DOI":"10.1007\/s00125-021-05510-7","article-title":"Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study)","volume":"64","author":"Saravanan","year":"2021","journal-title":"Diabetologia."},{"key":"B13","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/ejcn.2013.289","article-title":"Imbalance of folic acid and vitamin B12 is associated with birth outcome: an Indian pregnant women study","volume":"68","author":"Gadgil","year":"2014","journal-title":"Eur J Clin Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.cca.2019.10.048","article-title":"Association of maternal D-dimer level in late pregnancy with birth outcomes in a Chinese cohort","volume":"501","author":"Yuan","year":"2020","journal-title":"Clin Chim Acta."},{"key":"B15","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/S2352-4642(19)30108-7","article-title":"Gestational age at birth and mortality from infancy into mid-adulthood: a national cohort study","volume":"3","author":"Crump","year":"2019","journal-title":"Lancet Child Adolesc Health."},{"key":"B16","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12986-019-0360-9","article-title":"Iron deficiency in late pregnancy and its associations with birth outcomes in Chinese pregnant women: a retrospective cohort study","volume":"16","author":"Yuan","year":"2019","journal-title":"Nutr Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"5759","DOI":"10.3390\/ijms22115759","article-title":"Interaction between metformin, folate and vitamin B12 and the potential impact on fetal growth and long-term metabolic health in diabetic pregnancies","volume":"22","author":"Owen","year":"2021","journal-title":"Int J Mol Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.3945\/ajcn.2008.27097","article-title":"A prospective study of micronutrient status in adolescent pregnancy","volume":"89","author":"Baker","year":"2009","journal-title":"Am J Clin Nutr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/mnfr.201200084","article-title":"Influence of maternal folate status on human fetal growth parameters","volume":"57","author":"van Uitert","year":"2013","journal-title":"Mol Nutr Food Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1097\/AOG.0000000000000343","article-title":"Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth","volume":"124","author":"Gaskins","year":"2014","journal-title":"Obstet Gynecol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3391","DOI":"10.1016\/j.clnu.2020.11.025","article-title":"Maternal folate levels during pregnancy and offspring brain development in late childhood","volume":"40","author":"Zou","year":"2021","journal-title":"Clin Nutr."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.3945\/ajcn.115.123083","article-title":"Prevalence of vitamin B-12 insufficiency during pregnancy and its effect on offspring birth weight: a systematic review and meta-analysis","volume":"103","author":"Sukumar","year":"2016","journal-title":"Am J Clin Nutr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1093\/aje\/kww212","article-title":"Associations of maternal vitamin B12 concentration in pregnancy with the risks of preterm birth and low birth weight: a systematic review and meta-analysis of individual participant data","volume":"185","author":"Rogne","year":"2017","journal-title":"Am J Epidemiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"619176","DOI":"10.3389\/fendo.2021.619176","article-title":"Maternal vitamin B12 status during pregnancy and its association with outcomes of pregnancy and health of the offspring: a systematic review and implications for policy in India","volume":"12","author":"Behere","year":"2021","journal-title":"Front Endocrinol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1093\/ajcn\/nqaa293","article-title":"Folate, vitamin B-12, and cognitive function in the Boston Puerto Rican health study","volume":"113","author":"Boumenna","year":"2020","journal-title":"Am J Clin Nutr."},{"key":"B26","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3390\/ijerph17020638","article-title":"Dietary folate intake and folic acid supplements among pregnant women from southern italy: evidence from the \u201cmamma & bambino\u201d cohort","volume":"17","author":"Barchitta","year":"2020","journal-title":"Int J Environ Res Public Health."},{"key":"B27","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1111\/j.1471-0528.2012.03321.x","article-title":"Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the generation R study","volume":"119","author":"Bergen","year":"2012","journal-title":"BJOG."},{"key":"B28","doi-asserted-by":"publisher","first-page":"R69","DOI":"10.1530\/REP-18-0130","article-title":"Effects of micronutrients on placental function: evidence from clinical studies to animal models","volume":"156","author":"Baker","year":"2018","journal-title":"Reproduction."},{"key":"B29","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s12020-019-02053-1","article-title":"Vitamin B12 insufficiency is associated with increased risk of gestational diabetes mellitus: a systematic review and meta-analysis","volume":"66","author":"Kouroglou","year":"2019","journal-title":"Endocrine."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e36","DOI":"10.2337\/dc15-2389","article-title":"Folic acid supplement intake in early pregnancy increases risk of gestational diabetes mellitus: evidence from a prospective cohort study","volume":"39","author":"Zhu","year":"2016","journal-title":"Diabetes Care."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.2337\/dc18-2198","article-title":"Prepregnancy habitual intakes of total, supplemental, and food folate and risk of gestational diabetes mellitus: a prospective cohort study","volume":"42","author":"Li","year":"2019","journal-title":"Diabetes Care."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.3945\/ajcn.112.056382","article-title":"High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a prospective observational cohort study","volume":"98","author":"Dwarkanath","year":"2013","journal-title":"Am J Clin Nutr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2100662","DOI":"10.1002\/mnfr.202100662","article-title":"Imbalanced folate and vitamin B12 in the third trimester of pregnancy and its association with birthweight and child growth up to 2 years","volume":"66","author":"Obeid","year":"2022","journal-title":"Mol Nutr Food Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/j.nut.2010.10.017","article-title":"Physiologic changes in homocysteine metabolism in pregnancy: a longitudinal study in Spain","volume":"27","author":"Ubeda","year":"2011","journal-title":"Nutrition."},{"key":"B35","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1111\/mcn.12062","article-title":"A prospective study of maternal fatty acids, micronutrients and homocysteine and their association with birth outcome","volume":"11","author":"Wadhwani","year":"2015","journal-title":"Matern Child Nutr."},{"key":"B36","doi-asserted-by":"publisher","first-page":"569","DOI":"10.3109\/09513590.2015.1031104","article-title":"Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia","volume":"31","author":"Chedraui","year":"2015","journal-title":"Gynecol Endocrinol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejmg.2014.10.004","article-title":"Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases","volume":"58","author":"Liew","year":"2015","journal-title":"Eur J Med Genet."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3982","DOI":"10.1038\/s41598-017-03888-2","article-title":"Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice","volume":"7","author":"Rosario","year":"2017","journal-title":"Sci Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.lfs.2017.10.017","article-title":"Combination of vitamin B12 active forms improved fetal growth in Wistar rats through up-regulation of placental miR-16 and miR-21 levels","volume":"191","author":"Shah","year":"2017","journal-title":"Life Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"4189","DOI":"10.1113\/JP272424","article-title":"mTOR folate sensing links folate availability to trophoblast cell function","volume":"595","author":"Rosario","year":"2017","journal-title":"J Physiol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1600646","DOI":"10.1002\/mnfr.201600646","article-title":"Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status","volume":"61","author":"Baker","year":"2017","journal-title":"Mol Nutr Food Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.placenta.2015.11.012","article-title":"Effect of folic acid on human trophoblast health and function in vitro","volume":"37","author":"Ahmed","year":"2016","journal-title":"Placenta."},{"key":"B43","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.biopha.2016.09.071","article-title":"Molecular and cellular effects of vitamin B12 forms on human trophoblast cells in presence of excessive folate","volume":"84","author":"Shah","year":"2016","journal-title":"Biomed Pharmacother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"17602","DOI":"10.1038\/s41598-019-54070-9","article-title":"Effect of imbalance in folate and vitamin B12 in maternal\/parental diet on global methylation and regulatory miRNAs","volume":"9","author":"Mahajan","year":"2019","journal-title":"Sci Rep."}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.947118\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T10:41:03Z","timestamp":1658745663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2022.947118\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,25]]},"references-count":44,"alternative-id":["10.3389\/fnut.2022.947118"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2022.947118","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,25]]},"article-number":"947118"}}