Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth

Published:August 08, 2014DOI:


      The purpose of this study was to investigate oxidative stress as a mechanism of preterm birth in human subjects; we examined associations between urinary biomarkers of oxidative stress that were measured at multiple time points during pregnancy and preterm birth.

      Study Design

      This nested case-control study included 130 mothers who delivered preterm and 352 mothers who delivered term who were originally recruited as part of an ongoing prospective birth cohort at Brigham and Women’s Hospital. Two biomarkers that included 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane were measured in urine samples that were collected at up to 4 time points (median 10, 18, 26, and 35 weeks) during gestation.


      Urinary concentrations of 8-isoprostane and 8-OHdG decreased and increased, respectively, as pregnancy progressed. Average levels of 8-isoprostane across pregnancy were associated with increased odds of spontaneous preterm birth (adjusted odds ratio, 6.25; 95% confidence interval, 2.86–13.7), and associations were strongest with levels measured later in pregnancy. Average levels of 8-OHdG were protective against overall preterm birth (adjusted odds ratio, 0.19; 95% confidence interval, 0.10–0.34), and there were no apparent differences in the protective effect in cases of spontaneous preterm birth compared with cases of placental origin. Odds ratios for overall preterm birth were more protective in association with urinary 8-OHdG concentrations that were measured early in pregnancy.


      Maternal oxidative stress may be an important contributor to preterm birth, regardless of subtype and timing of exposure during pregnancy. The 2 biomarkers that were measured in the present study had opposite associations with preterm birth; an improved understanding of what each represents may help to identify more precisely important mechanisms in the pathway to preterm birth.

      Key words

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        • Martin J.A.
        • Centers for Disease Control and Prevention
        Preterm births: United States, 2007.
        MMWR Surveill Summ. 2011; 60: 78-79
        • Goldenberg R.L.
        • Culhane J.F.
        • Iams J.D.
        • Romero R.
        Epidemiology and causes of preterm birth.
        Lancet. 2008; 371: 75-84
        • Cha J.
        • Bartos A.
        • Egashira M.
        • et al.
        Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions.
        J Clin Invest. 2013; 123: 4063-4075
        • Kaga N.
        • Katsuki Y.
        • Obata M.
        • Shibutani Y.
        Repeated administration of low-dose lipopolysaccharide induces preterm delivery in mice: a model for human preterm parturition and for assessment of the therapeutic ability of drugs against preterm delivery.
        Am J Obstet Gynecol. 1996; 174: 754-759
        • Wei S.Q.
        • Fraser W.
        • Luo Z.C.
        Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review.
        Obstet Gynecol. 2010; 116: 393-401
        • 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
        • Dalle-Donne I.
        • Rossi R.
        • Colombo R.
        • Giustarini D.
        • Milzani A.
        Biomarkers of oxidative damage in human disease.
        Clin Chem. 2006; 52: 601-623
        • Wu L.L.
        • Chiou C.C.
        • Chang P.Y.
        • Wu J.T.
        Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics.
        Clin Chim Acta. 2004; 339: 1-9
        • Ferguson K.K.
        • McElrath T.F.
        • Meeker J.D.
        Environmental phthalate exposure and preterm birth.
        JAMA Pediatr. 2014; 168: 61-67
        • McElrath T.F.
        • Hecht J.L.
        • Dammann O.
        • et al.
        Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.
        Am J Epidemiol. 2008; 168: 980-989
        • Hornung R.W.
        • Reed L.
        Estimation of average concentration in the presence of nondetectable values.
        Appl Occup Environ Hyg. 1990; 5: 46-51
        • Meeker J.D.
        • Hu H.
        • Cantonwine D.E.
        • et al.
        Urinary phthalate metabolites in relation to preterm birth in Mexico city.
        Environ Health Perspec. 2009; 117: 1587-1592
        • Wood S.N.
        Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models.
        J Royal Stat Soc Series B Methodol. 2011; 73: 3-36
      1. Rosner B. Fundamentals of biostatistics. Boston, MA: Brooks/Cole; 2011:568-9.

        • Challis J.R.
        • Lockwood C.J.
        • Myatt L.
        • Norman J.E.
        • Strauss 3rd, J.F.
        • Petraglia F.
        Inflammation and pregnancy.
        Reprod Sci. 2009; 16: 206-215
        • Woods Jr., J.R.
        Reactive oxygen species and preterm premature rupture of membranes-a review.
        Placenta. 2001; 22: S38-S44
        • Burton G.J.
        • Yung H.W.
        • Cindrova-Davies T.
        • Charnock-Jones D.S.
        Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.
        Placenta. 2009; 30: S43-S48
        • Heazell A.E.
        • Moll S.J.
        • Jones C.J.
        • Baker P.N.
        • Crocker I.P.
        Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species.
        Placenta. 2007; 28: S33-S40
        • Hsieh T.T.
        • Chen S.F.
        • Lo L.M.
        • Li M.J.
        • Yeh Y.L.
        • Hung T.H.
        The association between maternal oxidative stress at mid-gestation and subsequent pregnancy complications.
        Reprod Sci. 2012; 19: 505-512
        • 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
        • 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
        • Scholl T.O.
        • Stein T.P.
        Oxidant damage to DNA and pregnancy outcome.
        J Matern Fetal Med. 2001; 10: 182-185
        • Kwiatkowski S.
        • Torbe A.
        • Dolegowska B.
        • et al.
        Isoprostanes 8-iPF2alpha-III: risk markers of premature rupture of fetal membranes?.
        Biomarkers. 2009; 14: 406-413
        • Pathak R.
        • Suke S.G.
        • Ahmed T.
        • et al.
        Organochlorine pesticide residue levels and oxidative stress in preterm delivery cases.
        Hum Exp Toxicol. 2010; 29: 351-358
        • 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
        • Negi R.
        • Pande D.
        • Kumar A.
        • Khanna R.S.
        • Khanna H.D.
        In vivo oxidative DNA damage and lipid peroxidation as a biomarker of oxidative stress in preterm low-birthweight infants.
        J Trop Pediatr. 2012; 58: 326-328
        • Okamura K.
        • Doi T.
        • Hamada K.
        • et al.
        Effect of repeated exercise on urinary 8-hydroxy-deoxyguanosine excretion in humans.
        Free Radic Res. 1997; 26: 507-514
        • Scholl T.O.
        Iron status during pregnancy: setting the stage for mother and infant.
        Am J Clin Nutr. 2005; 81: 1218S-1222S
        • Weissgerber T.L.
        • Wolfe L.A.
        • Davies G.A.
        • Mottola M.F.
        Exercise in the prevention and treatment of maternal-fetal disease: a review of the literature.
        Appl Physiol Nutr Metab. 2006; 31: 661-674
        • Hung T.H.
        • Lo L.M.
        • Chiu T.H.
        • et al.
        A longitudinal study of oxidative stress and antioxidant status in women with uncomplicated pregnancies throughout gestation.
        Reprod Sci. 2010; 17: 401-409
        • Shoji H.
        • Franke C.
        • Campoy C.
        • Rivero M.
        • Demmelmair H.
        • Koletzko B.
        Effect of docosahexaenoic acid and eicosapentaenoic acid supplementation on oxidative stress levels during pregnancy.
        Free Radic Res. 2006; 40: 379-384
        • Smith K.A.
        • Shepherd J.
        • Wakil A.
        • Kilpatrick E.S.
        A comparison of methods for the measurement of 8-isoPGF(2alpha): a marker of oxidative stress.
        Ann Clin Biochem. 2011; 48: 147-154
        • 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

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