Urinary oxidative stress biomarkers are associated with preterm birth: an Environmental Influences on Child Health Outcomes program study

Published:November 14, 2022DOI:


      Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States.


      We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin.

      Study Design

      This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F (F2-IsoP-M; the major 8-iso-prostaglandin-F metabolite), and prostaglandin-F were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models.


      Approximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11–1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16–1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94–1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis.


      Here, oxidative stress, as measured by 8-iso-prostaglandin-F, F2-IsoP-M, and prostaglandin-F in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

      Key words

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        • Welch B.M.
        • McNell E.E.
        • Edin M.L.
        • Ferguson K.K.
        Inflammation and oxidative stress as mediators of the impacts of environmental exposures on human pregnancy: evidence from oxylipins.
        Pharmacol Ther. 2022; 239108181
        • Longini M.
        • Perrone S.
        • Vezzosi P.
        • et al.
        Association between oxidative stress in pregnancy and preterm premature rupture of membranes.
        Clin Biochem. 2007; 40: 793-797
        • Ferguson K.K.
        • Meeker J.D.
        • McElrath T.F.
        • Mukherjee B.
        • Cantonwine D.E.
        Repeated measures of inflammation and oxidative stress biomarkers in preeclamptic and normotensive pregnancies.
        Am J Obstet Gynecol. 2017; 216: 527.e1-527.e9
        • Joo E.H.
        • Kim Y.R.
        • Kim N.
        • Jung J.E.
        • Han S.H.
        • Cho H.Y.
        Effect of endogenic and exogenic oxidative stress triggers on adverse pregnancy outcomes: preeclampsia, fetal growth restriction, gestational diabetes mellitus and preterm birth.
        Int J Mol Sci. 2021; 2210122
        • Menon R.
        • Fortunato S.J.
        • Milne G.L.
        • et al.
        Amniotic fluid eicosanoids in preterm and term births: effects of risk factors for spontaneous preterm labor.
        Obstet Gynecol. 2011; 118: 121-134
        • Fisher J.J.
        • Bartho L.A.
        • Perkins A.V.
        • Holland O.J.
        Placental mitochondria and reactive oxygen species in the physiology and pathophysiology of pregnancy.
        Clin Exp Pharmacol Physiol. 2020; 47: 176-184
        • Zavalza-Gómez A.B.
        Obesity and oxidative stress: a direct link to preeclampsia?.
        Arch Gynecol Obstet. 2011; 283: 415-422
        • Wang C.N.
        • Chen J.Y.
        • Sabu S.
        • et al.
        Elevated amniotic fluid F2-isoprostane: a potential predictive marker for preeclampsia.
        Free Radic Biol Med. 2011; 50: 1124-1130
        • Hussain T.
        • Murtaza G.
        • Metwally E.
        • et al.
        The role of oxidative stress and antioxidant balance in pregnancy.
        Mediators Inflamm. 2021; 2021: 9962860
        • Erez O.
        • Romero R.
        • Jung E.
        • et al.
        Preeclampsia and eclampsia: the conceptual evolution of a syndrome.
        Am J Obstet Gynecol. 2022; 226: S786-S803
        • Cappelletti M.
        • Presicce P.
        • Kallapur S.G.
        Immunobiology of acute chorioamnionitis.
        Front Immunol. 2020; 11: 649
        • Redline R.W.
        • Roberts D.J.
        • Parast M.M.
        • et al.
        Placental pathology is necessary to understand common pregnancy complications and achieve an improved taxonomy of obstetrical disease.
        Am J Obstet Gynecol. 2022; ([Epub ahead of print])
        • Hernández-Trejo M.
        • Montoya-Estrada A.
        • Torres-Ramos Y.
        • et al.
        Oxidative stress biomarkers and their relationship with cytokine concentrations in overweight/obese pregnant women and their neonates.
        BMC Immunol. 2017; 18: 3
        • Cathey A.L.
        • Eaton J.L.
        • Ashrap P.
        • et al.
        Individual and joint effects of phthalate metabolites on biomarkers of oxidative stress among pregnant women in Puerto Rico.
        Environ Int. 2021; 154: 106565
        • Ferguson K.K.
        • Chin H.B.
        Environmental chemicals and preterm birth: biological mechanisms and the state of the science.
        Curr Epidemiol Rep. 2017; 4: 56-71
        • Eick S.M.
        • Meeker J.D.
        • Brown P.
        • et al.
        Associations between socioeconomic status, psychosocial stress, and urinary levels of 8-iso-prostaglandin-F2α during pregnancy in Puerto Rico.
        Free Radic Biol Med. 2019; 143: 95-100
        • Irie M.
        • Asami S.
        • Nagata S.
        • Ikeda M.
        • Miyata M.
        • Kasai H.
        Psychosocial factors as a potential trigger of oxidative DNA damage in human leukocytes.
        Jpn J Cancer Res. 2001; 92: 367-376
        • Eick S.M.
        • Geiger S.D.
        • Alshawabkeh A.
        • et al.
        Associations between social, biologic, and behavioral factors and biomarkers of oxidative stress during pregnancy: findings from four ECHO cohorts.
        Sci Total Environ. 2022; 835: 155596
        • Skoczynska A.
        • Skoczynska M.
        • Turczyn B.
        • Wojakowska A.
        • Gruszczynski L.
        • Scieszka M.
        Exposure to arsenic in the air and 15-F2t-Isoprostane in urine in a sub-population of inhabitants of a copper smelter region.
        Expo Health. 2021; 13: 403-418
        • Palta P.
        • Szanton S.L.
        • Semba R.D.
        • Thorpe R.J.
        • Varadhan R.
        • Fried L.P.
        Financial strain is associated with increased oxidative stress levels: the Women’s Health and Aging Studies.
        Geriatr Nurs. 2015; 36: S33-S37
        • Morrow J.D.
        • Hill K.E.
        • Burk R.F.
        • Nammour T.M.
        • Badr K.F.
        • Roberts 2nd, L.J.
        A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism.
        Proc Natl Acad Sci U S A. 1990; 87: 9383-9387
        • Milne G.L.
        • Sanchez S.C.
        • Musiek E.S.
        • Morrow J.D.
        Quantification of F2-isoprostanes as a biomarker of oxidative stress.
        Nat Protoc. 2007; 2: 221-226
        • Kadiiska M.B.
        • Gladen B.C.
        • Baird D.D.
        • et al.
        Biomarkers of Oxidative Stress Study II: are oxidation products of lipids, proteins, and DNA markers of CCl4 poisoning?.
        Free Radic Biol Med. 2005; 38: 698-710
        • Milne G.L.
        Classifying oxidative stress by F2-isoprostane levels in human disease: the re-imagining of a biomarker.
        Redox Biol. 2017; 12: 897-898
        • Roberts L.J.
        • Morrow J.D.
        Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo.
        Free Radic Biol Med. 2000; 28: 505-513
        • Eick S.M.
        • Ferguson K.K.
        • Milne G.L.
        • et al.
        Repeated measures of urinary oxidative stress biomarkers and preterm birth in Puerto Rico.
        Free Radic Biol Med. 2020; 146: 299-305
        • Ferguson K.K.
        • McElrath T.F.
        • Chen Y.H.
        • Loch-Caruso R.
        • Mukherjee B.
        • Meeker J.D.
        Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth.
        Am J Obstet Gynecol. 2015; 212: 208.e1-208.e8
        • Peter Stein T.
        • Scholl T.O.
        • Schluter M.D.
        • et al.
        Oxidative stress early in pregnancy and pregnancy outcome.
        Free Radic Res. 2008; 42: 841-848
        • Venkatesh K.K.
        • Meeker J.D.
        • Cantonwine D.E.
        • McElrath T.F.
        • Ferguson K.K.
        Association of antenatal depression with oxidative stress and impact on spontaneous preterm birth.
        J Perinatol. 2019; 39: 554-562
        • Ferguson K.K.
        • Chen Y.H.
        • VanderWeele T.J.
        • McElrath T.F.
        • Meeker J.D.
        • Mukherjee B.
        Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy.
        Environ Health Perspect. 2017; 125: 488-494
        • Martin A.
        • Faes C.
        • Debevec T.
        • Rytz C.
        • Millet G.
        • Pialoux V.
        Preterm birth and oxidative stress: effects of acute physical exercise and hypoxia physiological responses.
        Redox Biol. 2018; 17: 315-322
        • Dennis E.A.
        • Norris P.C.
        Eicosanoid storm in infection and inflammation.
        Nat Rev Immunol. 2015; 15: 511-523
        • Peiris H.N.
        • Romero R.
        • Vaswani K.
        • et al.
        Prostaglandin and prostamide concentrations in amniotic fluid of women with spontaneous labor at term with and without clinical chorioamnionitis.
        Prostaglandins Leukot Essent Fatty Acids. 2020; 163: 102195
        • Maddipati K.R.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Eicosanomic profiling reveals dominance of the epoxygenase pathway in human amniotic fluid at term in spontaneous labor.
        FASEB J. 2014; 28: 4835-4846
        • van ’t Erve T.J.
        • Lih F.B.
        • Kadiiska M.B.
        • Deterding L.J.
        • Eling T.E.
        • Mason R.P.
        Reinterpreting the best biomarker of oxidative stress: The 8-iso-PGF(2α)/PGF(2α) ratio distinguishes chemical from enzymatic lipid peroxidation.
        Free Radic Biol Med. 2015; 83: 245-251
        • Dorjgochoo T.
        • Gao Y.T.
        • Chow W.H.
        • et al.
        Major metabolite of F2-isoprostane in urine may be a more sensitive biomarker of oxidative stress than isoprostane itself.
        Am J Clin Nutr. 2012; 96: 405-414
        • Rosen E.M.
        • van ’t Erve T.J.
        • Boss J.
        • et al.
        Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery.
        Free Radic Biol Med. 2019; 130: 419-425
        • Eick S.M.
        • Enright E.A.
        • Geiger S.D.
        • et al.
        Associations of maternal stress, prenatal exposure to per- and polyfluoroalkyl substances (PFAS), and demographic risk factors with birth outcomes and offspring neurodevelopment: an overview of the ECHO.CA.IL Prospective Birth Cohorts.
        Int J Environ Res Public Health. 2021; 18: 742
        • Ferguson K.K.
        • Rosario Z.
        • McElrath T.F.
        • et al.
        Demographic risk factors for adverse birth outcomes in Puerto Rico in the PROTECT cohort.
        PLoS One. 2019; 14e0217770
        • Swan S.H.
        • Sathyanarayana S.
        • Barrett E.S.
        • et al.
        First trimester phthalate exposure and anogenital distance in newborns.
        Hum Reprod. 2015; 30: 963-972
        • Blencowe H.
        • Cousens S.
        • Chou D.
        • et al.
        Born too soon: the global epidemiology of 15 million preterm births.
        Reprod Health. 2013; 10: S2
        • Rosner B.
        Fundamentals of biostatistics.
        7th ed. Brooks/Cole, Cengage Learning, Boston, MA2011
        • Eick S.M.
        • Barrett E.S.
        • van ’t Erve T.J.
        • et al.
        Association between prenatal psychological stress and oxidative stress during pregnancy.
        Paediatr Perinat Epidemiol. 2018; 32: 318-326
        • Marseglia L.
        • Manti S.
        • D’Angelo G.
        • et al.
        Oxidative stress in obesity: a critical component in human diseases.
        Int J Mol Sci. 2014; 16: 378-400
        • De Jacobis I.T.
        • Vona R.
        • Straface E.
        • et al.
        Sex differences in blood pro-oxidant status and platelet activation in children admitted with respiratory syncytial virus bronchiolitis: a pilot study.
        Ital J Pediatr. 2020; 46: 29
        • Lien Y.C.
        • Zhang Z.
        • Cheng Y.
        • et al.
        Human placental transcriptome reveals critical alterations in inflammation and energy metabolism with fetal sex differences in spontaneous preterm birth.
        Int J Mol Sci. 2021; 22: 7899
        • Willer C.J.
        • Li Y.
        • Abecasis G.R.
        METAL: fast and efficient meta-analysis of genomewide association scans.
        Bioinformatics. 2010; 26: 2190-2191
        • Zimmerman E.
        • Aguiar A.
        • Aung M.T.
        • et al.
        Examining the association between prenatal maternal stress and infant non-nutritive suck.
        Pediatr Res. 2021; ([Epub ahead of print])
        • Ashrap P.
        • Watkins D.J.
        • Milne G.L.
        • et al.
        Maternal urinary metal and metalloid concentrations in association with oxidative stress biomarkers.
        Antioxidants (Basel). 2021; 10: 114
        • Eaton J.L.
        • Cathey A.L.
        • Fernandez J.A.
        • et al.
        The association between urinary glyphosate and aminomethyl phosphonic acid with biomarkers of oxidative stress among pregnant women in the PROTECT birth cohort study.
        Ecotoxicol Environ Saf. 2022; 233: 113300
        • Welch B.M.
        • Keil A.P.
        • Buckley J.P.
        • et al.
        Associations between prenatal urinary biomarkers of phthalate exposure and preterm birth: a pooled study of 16 US cohorts.
        JAMA Pediatr. 2022; 176: 895-905
        • Bekkar B.
        • Pacheco S.
        • Basu R.
        • DeNicola N.
        Association of air pollution and heat exposure with preterm birth, low birth weight, and stillbirth in the US: a systematic review.
        JAMA Netw Open. 2020; 3e208243
        • Goin D.E.
        • Gomez A.M.
        • Farkas K.
        • et al.
        Occurrence of fatal police violence during pregnancy and hazard of preterm birth in California.
        Paediatr Perinat Epidemiol. 2021; 35 (469–8)
        • Mestan K.
        • Matoba N.
        • Arguelles L.
        • et al.
        Cord blood 8-isoprostane in the preterm infant.
        Early Hum Dev. 2012; 88: 683-689
        • Inayat M.
        • Bany-Mohammed F.
        • Valencia A.
        • et al.
        Antioxidants and biomarkers of oxidative stress in preterm infants with symptomatic patent ductus arteriosus.
        Am J Perinatol. 2015; 32: 895-904
        • Menon R.
        Oxidative stress damage as a detrimental factor in preterm birth pathology.
        Front Immunol. 2014; 5: 567
        • Weber D.
        • Stuetz W.
        • Bernhard W.
        • et al.
        Oxidative stress markers and micronutrients in maternal and cord blood in relation to neonatal outcome.
        Eur J Clin Nutr. 2014; 68: 215-222
        • Dhobale M.
        • Joshi S.
        Altered maternal micronutrients (folic acid, vitamin B(12)) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy.
        J Matern Fetal Neonatal Med. 2012; 25: 317-323
        • Tedesco R.P.
        • Galvão R.B.
        • Guida J.P.
        • et al.
        The role of maternal infection in preterm birth: evidence from the Brazilian Multicentre Study on preterm Birth (EMIP).
        Clinics (Sao Paulo). 2020; 75: e1508
        • Kazemier B.M.
        • Buijs P.E.
        • Mignini L.
        • et al.
        Impact of obstetric history on the risk of spontaneous preterm birth in singleton and multiple pregnancies: a systematic review.
        BJOG. 2014; 121: 1197-1208
        • Gavia-García G.
        • Rosado-Pérez J.
        • Arista-Ugalde T.L.
        • Aguiñiga-Sánchez I.
        • Santiago-Osorio E.
        • Mendoza-Núñez V.M.
        Telomere length and oxidative stress and its relation with metabolic syndrome components in the aging.
        Biology (Basel). 2021; 10: 253
        • Stefanovic V.
        • Andersson S.
        • Vento M.
        Oxidative stress - related spontaneous preterm delivery challenges in causality determination, prevention and novel strategies in reduction of the sequelae.
        Free Radic Biol Med. 2019; 142: 52-60
        • Xu C.
        • Liu W.
        • You X.
        • et al.
        PGF2α modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways.
        Mol Hum Reprod. 2015; 21: 603-614
        • Aung M.T.
        • Yu Y.
        • Ferguson K.K.
        • et al.
        Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers.
        Sci Rep. 2019; 9: 17049
        • Norwitz E.R.
        • Caughey A.B.
        Progesterone supplementation and the prevention of preterm birth.
        Rev Obstet Gynecol. 2011; 4: 60-72
        • Gopaul N.K.
        • Halliwell B.
        • Änggård E.E.
        Measurement of plasma F2-isoprostanes as an index of lipid peroxidation does not appear to be confounded by diet.
        Free Radic Res. 2000; 33: 115-127
        • Richelle M.
        • Turini M.E.
        • Guidoux R.
        • Tavazzi I.
        • Métairon S.
        • Fay L.B.
        Urinary isoprostane excretion is not confounded by the lipid content of the diet.
        FEBS Lett. 1999; 459: 259-262
        • Helmersson J.
        • Basu S.F.
        (2)-isoprostane and prostaglandin F(2 alpha)metabolite excretion rate and day to day variation in healthy humans.
        Prostaglandins Leukot Essent Fatty Acids. 2001; 65: 99-102
        • Catov J.M.
        • Bodnar L.M.
        • Olsen J.
        • Olsen S.
        • Nohr E.A.
        Periconceptional multivitamin use and risk of preterm or small-for-gestational-age births in the Danish National Birth Cohort.
        Am J Clin Nutr. 2011; 94: 906-912
        • Harville E.W.
        • Lewis C.E.
        • Catov J.M.
        • Jacobs Jr., D.R.
        • Gross M.D.
        • Gunderson E.P.
        A longitudinal study of pre-pregnancy antioxidant levels and subsequent perinatal outcomes in black and white women: the CARDIA Study.
        PLoS One. 2020; 15e0229002
        • Sánchez-Polán M.
        • Silva-Jose C.
        • Franco E.
        • et al.
        Prenatal anxiety and exercise. Systematic review and meta-analysis.
        J Clin Med. 2021; 10: 5501