{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T23:30:16Z","timestamp":1785540616733,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD083292"],"award-info":[{"award-number":["R01HD083292"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007520","name":"Nationwide Children's Hospital","doi-asserted-by":"publisher","award":["51139-0002-0320"],"award-info":[{"award-number":["51139-0002-0320"]}],"id":[{"id":"10.13039\/100007520","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg\/day of docosahexaenoic acid (DHA) was superior to 200 mg\/day in preventing both early preterm birth (less than 34 weeks\u2019 gestation) and preterm birth (less than 37 weeks\u2019 gestation). The goal of this secondary study is to compare the effects of 1000 mg\/day versus 200 mg\/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12\u201320 weeks\u2019 gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1\u03b2, TNF\u03b1, and INF\u03b3 were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (&lt;37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.<\/jats:p>","DOI":"10.3390\/nu13124248","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:56Z","timestamp":1638314576000},"page":"4248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth"],"prefix":"10.3390","volume":"13","author":[{"given":"Christina J.","family":"Valentine","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiman Q.","family":"Khan","sequence":"additional","affiliation":[{"name":"Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra R.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Sands","sequence":"additional","affiliation":[{"name":"Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Defranco","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron J.","family":"Gajewski","sequence":"additional","affiliation":[{"name":"Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3579-1685","authenticated-orcid":false,"given":"Susan E.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina M.","family":"Reber","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-5379","authenticated-orcid":false,"given":"Lynette K.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital, Columbus, OH 43215, USA"},{"name":"Department of Pediatrics, Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.cytogfr.2020.12.004","article-title":"The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth","volume":"59","author":"Prairie","year":"2021","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1471-0528.2006.01120.x","article-title":"The preterm parturition syndrome","volume":"113","author":"Romero","year":"2006","journal-title":"BJOG"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.plefa.2007.10.015","article-title":"Immunomodulation by omega-3 fatty acids","volume":"77","author":"Calder","year":"2007","journal-title":"Prostaglandins Leukot Essent Fat. Acids"},{"key":"ref_4","first-page":"CD003402","article-title":"Omega-3 fatty acid addition during pregnancy","volume":"11","author":"Middleton","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1097\/MPG.0000000000002375","article-title":"A Randomized Trial of Maternal Docosahexaenoic Acid Supplementation to Reduce Inflammation in Extremely Preterm Infants","volume":"69","author":"Valentine","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.plefa.2006.05.014","article-title":"Versatile roles of docosahexaenoic acid in the prenatal brain: From pro- and anti-oxidant features to regulation of gene expression","volume":"75","author":"Yavin","year":"2006","journal-title":"Prostaglandins Leukot Essent Fat. Acids"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.plefa.2008.09.016","article-title":"The relationship between the fatty acid composition of immune cells and their function","volume":"79","author":"Calder","year":"2008","journal-title":"Prostaglandins Leukot Essent Fat. Acids"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1053\/j.jrn.2007.05.011","article-title":"Gamma-tocopherol and docosahexaenoic acid decrease inflammation in dialysis patients","volume":"17","author":"Himmelfarb","year":"2007","journal-title":"J. Ren. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/07315724.2002.10719248","article-title":"Omega-3 fatty acids in inflammation and autoimmune diseases","volume":"21","author":"Simopoulos","year":"2002","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1093\/ajcn\/82.2.281","article-title":"Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals","volume":"82","author":"McCann","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.atherosclerosis.2009.03.006","article-title":"Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes","volume":"206","author":"Rizza","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/mnfr.201100710","article-title":"The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability","volume":"56","author":"Calder","year":"2012","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rogers, L.K., Graf, A.E., Bhatia, A., Leonhart, K.L., and Oza-Frank, R. (2013). Associations between maternal and infant morbidities and sRAGE within the first week of life in extremely preterm infants. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082537"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.phrs.2012.12.003","article-title":"DHA supplementation: Current implications in pregnancy and childhood","volume":"70","author":"Rogers","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.1167\/iovs.10-5339","article-title":"Docosahexaenoic acid improves the nitroso-redox balance and reduces VEGF-mediated angiogenic signaling in microvascular endothelial cells","volume":"51","author":"Matesanz","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ejogrb.2015.11.033","article-title":"Effects of omega-3 fatty acids in prevention of early preterm delivery: A systematic review and meta-analysis of randomized studies","volume":"198","author":"Kar","year":"2016","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"808","DOI":"10.3945\/ajcn.112.050021","article-title":"DHA supplementation and pregnancy outcomes","volume":"97","author":"Carlson","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1017\/S0007114507764747","article-title":"Dietary fat intakes for pregnant and lactating women","volume":"98","author":"Koletzko","year":"2007","journal-title":"Br. J. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100905","DOI":"10.1016\/j.eclinm.2021.100905","article-title":"Higher dose docosahexaenoic acid supplementation during pregnancy and early preterm birth: A randomised, double-blind, adaptive-design superiority trial","volume":"36","author":"Carlson","year":"2021","journal-title":"EClinicalMedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1055\/s-0036-1582397","article-title":"Inflammation in Complicated Pregnancy and Its Outcome","volume":"33","author":"Kalagiri","year":"2016","journal-title":"Am. J. Perinatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.clinbiochem.2009.11.002","article-title":"Soluble receptor for advanced glycation end products in physiological and pathological pregnancy","volume":"43","author":"Germanova","year":"2010","journal-title":"Clin. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ijoa.2015.12.006","article-title":"Cytokines in the perinatal period\u2014Part II","volume":"26","author":"Chau","year":"2016","journal-title":"Int. J. Obstet. Anesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"575197","DOI":"10.3389\/fimmu.2020.575197","article-title":"Maternal Immunological Adaptation During Normal Pregnancy","volume":"11","author":"Michalski","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12944-016-0241-4","article-title":"Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages","volume":"15","author":"Guenard","year":"2016","journal-title":"Lipids Health Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1084\/jem.20030800","article-title":"The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: A novel pathway for inflammatory cell recruitment","volume":"198","author":"Chavakis","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"917108","DOI":"10.1155\/2010\/917108","article-title":"The receptor for advanced glycation end products (RAGE) and the lung","volume":"2010","author":"Buckley","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1038\/modpathol.3800661","article-title":"The receptor for advanced glycation end products and its ligands: A new inflammatory pathway in lung disease?","volume":"19","author":"Morbini","year":"2006","journal-title":"Mod. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbaexp.2003.08.008","article-title":"Tissue-specific expression patterns of the RAGE receptor and its soluble forms--a result of regulated alternative splicing?","volume":"1630","author":"Schlueter","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.4049\/jimmunol.0903398","article-title":"sRAGE induces human monocyte survival and differentiation","volume":"185","author":"Wang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3716","DOI":"10.1096\/fj.08-109033","article-title":"A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10)","volume":"22","author":"Raucci","year":"2008","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1210\/jc.2010-1418","article-title":"Activation of the receptor for advanced glycation end products system in women with severe preeclampsia","volume":"96","author":"Oliver","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1515\/JPM.2008.080","article-title":"Detection of feto-maternal infection\/inflammation by the soluble receptor for advanced glycation end products (sRAGE): Results of a pilot study","volume":"36","author":"Hajek","year":"2008","journal-title":"J. Perinat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1515\/jpm.2011.055","article-title":"Clinical significance of serum sRAGE and esRAGE in women with normal pregnancy and preeclampsia","volume":"39","author":"Kwon","year":"2011","journal-title":"J. Perinat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1159\/000448141","article-title":"Accumulation of Advanced Glycation End Products Involved in Inflammation and Contributing to Severe Preeclampsia, in Maternal Blood, Umbilical Blood and Placental Tissues","volume":"82","author":"Chen","year":"2017","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1080\/14767058.2018.1481948","article-title":"Changes in circulating levels of carboxymethyllysine, soluble receptor for advanced glycation end products (sRAGE), and inflammation markers in women during normal pregnancy","volume":"32","author":"Uribarri","year":"2019","journal-title":"J. Matern. Fet. Neonat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2719460","DOI":"10.1155\/2016\/2719460","article-title":"Diagnostic Potential of Evaluation of SDF-1alpha and sRAGE Levels in Threatened Premature Labor","volume":"2016","author":"Rzepka","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"568042","DOI":"10.1155\/2015\/568042","article-title":"Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes","volume":"2015","author":"Rzepka","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.3109\/14767058.2012.663825","article-title":"The soluble receptor for advanced glycation end products can prospectively identify patients at greatest risk for preterm birth","volume":"25","author":"Bastek","year":"2012","journal-title":"J. Matern. Fet. Neonat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"660983","DOI":"10.3389\/fcimb.2021.660983","article-title":"Inflammatory Amplification: A Central Tenet of Uterine Transition for Labor","volume":"11","author":"Leimert","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ren, J., Qiang, Z., Li, Y.Y., and Zhang, J.N. (2021). Biomarkers for a histological chorioamnionitis diagnosis in pregnant women with or without group B streptococcus infection: A case-control study. BMC Pregnancy Childbirth, 21.","DOI":"10.1186\/s12884-021-03731-7"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118237","DOI":"10.1016\/j.lfs.2020.118237","article-title":"Upregulation of TNF-alpha and IL-6 induces preterm premature rupture of membranes by activation of ADAMTS-9 in embryonic membrane cells","volume":"260","author":"Li","year":"2020","journal-title":"Life Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Carlson, S.E., Gajewski, B.J., Valentine, C.J., Rogers, L.K., Weiner, C.P., DeFranco, E.A., and Buhimschi, C.S. (2017). Assessment of DHA on reducing early preterm birth: The ADORE randomized controlled trial protocol. BMC Pregnancy Childbirth, 17.","DOI":"10.1186\/s12884-017-1244-5"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4248\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:06Z","timestamp":1760168166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/12\/4248"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":42,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["nu13124248"],"URL":"https:\/\/doi.org\/10.3390\/nu13124248","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]}}}