Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia

Published:October 05, 2015DOI:


      Despite decades of research, and much progress in discernment of biomarkers in the maternal circulation, the pathogenesis of preeclampsia (PE) remains elusive. The pathophysiology of PE is believed to involve aberrant placentation and an associated increase in systemic inflammation. In this conceptualization, PE becomes more likely when the level of systemic inflammatory burden inherent in pregnancy itself exceeds the maternal capacity to compensate for this additional stress. If this is the case, then it is possible to hypothesize that conditions, such as infectious disease, that increase systemic inflammatory burden should also increase the risk of PE. As urinary tract infection (UTI) represents a common source of inflammation during pregnancy, we tested whether presence of UTI during pregnancy increased the odds of developing PE. Prior work has documented this association. However many of these studies were limited by small cohort sizes and insufficient control for covariates.


      The present study is a secondary analysis of a robust contemporary obstetrical cohort recruited to examine the ability of longitudinally sampled maternal angiogenic concentrations to predict PE. We hypothesize that the occurrence of UTI during a pregnancy is associated with the later occurrence of PE in that pregnancy. As PE is believed to be associated with aberrations in systemic angiogenic levels (placental growth factor and soluble isoform of VEGF receptor), we further hypothesize that there will be significant interactions between maternal angiogenic protein levels and the occurrence of UTI.

      Study Design

      Women aged ≥18 years (n = 2607) were recruited and followed up prospectively from the initiation of prenatal care through delivery at 3 regional academic centers. PE was defined by American Congress of Obstetricians and Gynecologists criteria and was independently validated by a panel of physicians. UTI was defined by the presence of clinical symptoms necessitating treatment in addition to supportive laboratory evidence. Multivariate logistic regression models were used and controlled for maternal age, race, parity, body mass index, hypertension, diabetes, in vitro fertilization, and smoking status.


      There were 129 women with diagnosed UTIs and 235 with PE. Patients with UTI in pregnancy had higher rates of PE (31.1% vs 7.8%, P < .001) compared to those without reported UTI. The mean gestational age (SD) for UTI diagnosis in PE cases and controls was 25.6 (10.4) and 21.9 (10.9) weeks, respectively (P = .08). The unadjusted odds ratio for PE in the setting of UTI was 5.29 (95% confidence interval, 3.54–7.89). After controlling for confounders, UTI was associated with an odds ratio for PE of 3.2 (95% confidence interval, 2.0–5.1).


      Presence of UTI in pregnancy, particularly in the third trimester, is strongly associated with PE. This association supports the hypothesis that the risk of PE is enhanced by an increased maternal inflammatory burden. Prophylaxis against UTI represents a potentially low-cost global intervention to slow or halt the development of PE.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy
        Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
        Obstet Gynecol. 2013; 122: 1122
        • Walker J.J.
        Pre-eclampsia. Lancet. 2000; 356: 1260-1265
        • Sibai B.M.
        • Caritis S.
        • Hauth J.
        What we have learned about preeclampsia.
        Semin Perinatol. 2003; 27: 239-246
        • Bilano V.L.
        • Ota E.
        • Ganchimeg T.
        • Mori R.
        • Souza J.P.
        Risk factors of pre-eclampsia/eclampsia and its adverse outcomes in low- and middle-income countries: a WHO secondary analysis.
        PLoS One. 2014; 9: e91198
        • Steegers E.A.
        • von Dadelszen P.
        • Duvekot J.J.
        • Pijnenbort R.
        Pre-eclampsia. Lancet. 2010; 376: 631-644
        • Redman C.W.
        • Sargent I.L.
        Latest advances in understanding preeclampsia.
        Science. 2005; 308: 1592-1594
        • Conde-Agudelo A.
        • Villar J.
        • Lindheimer M.
        Maternal infection and risk of preeclampsia: systematic review and metaanalysis.
        Am J Obstet Gynecol. 2008; 198: 7-22
        • Powis K.M.
        • McElrath T.F.
        • Hughes M.D.
        • et al.
        High viral load and elevated angiogenic markers associated with increased risk of preeclampsia among women initiating highly active antiretroviral therapy in pregnancy in the Mma Bana Study, Botswana.
        J Acquir Immune Defic Syndr. 2013; 62: 517-524
        • Haggerty C.L.
        • Klebanoff M.A.
        • Panum I.
        • et al.
        Prenatal Chlamydia trachomatis infection increases the risk of preeclampsia.
        Pregnancy Hypertens. 2013; 3: 151-154
        • Smaill F.
        • Vazquez J.C.
        Antibiotics for asymptomatic bacteriuria in pregnancy.
        Cochrane Database Syst Rev. 2015; 8: CD000490
        • Bryant R.E.
        • Windom R.E.
        • Vineyard J.P.
        • Sanford J.P.
        Asymptomatic bacteriuria in pregnancy and its association with prematurity.
        J Lab Clin Med. 1964; 63: 224-231
        • Low J.A.
        • Johnston E.E.
        • McBride R.L.
        • Tuffnell P.G.
        The significance of asymptomatic bacteriuria in the normal obstetric patient.
        Am J Obstet Gynecol. 1964; 90: 897-906
        • Little P.J.
        The incidence of urinary infection in 5000 pregnant women.
        Lancet. 1966; 2: 925-928
        • Brumfitt W.
        The effects of bacteriuria in pregnancy on maternal and fetal health.
        Kidney Int. 1975; 4: S113-S119
        • Qureshi R.N.
        • Khan K.S.
        • Darr O.
        • Khattak N.
        • Farooqui B.J.
        • Rizvi J.H.
        Bacteriuria and pregnancy outcome: a prospective hospital-based study in Pakistani women.
        J Pak Med Assoc. 1994; 44: 12-13
        • McElrath T.F.
        • Lim K.H.
        • Pare E.
        • et al.
        Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy.
        Am J Obstet Gynecol. 2012; 207: 407.e1-407.e7
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Maynard S.E.
        • Min J.Y.
        • Lim K.H.
        • et al.
        Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
        J Clin Invest. 2003; 111: 649-658
        • Minassian C.
        • Thomas S.L.
        • Williams D.J.
        • Campbell O.
        • Smeeth L.
        Acute maternal infection and risk of pre-eclampsia: a population-based case-control study.
        PLoS One. 2013; 8: e73047
        • Karmon A.
        • Sheiner E.
        The relationship between urinary tract infection during pregnancy and preeclampsia: causal, confounded or spurious?.
        Arch Gynecol Obstet. 2008; 277: 479-481
        • Mittendorf R.
        • Lain K.Y.
        • Williams M.A.
        • Walker C.K.
        Pre-eclampsia: a nested, case-control study of risk factors and their interactions.
        J Reprod Med. 1996; 41: 491-496
        • Hsu C.D.
        • Witter F.R.
        Urogenital infection in preeclampsia.
        Int J Gynaecol Obstet. 1995; 49: 271-275
        • Chaiworapongsa T.
        • Romero R.
        • Gotsch F.
        • et al.
        Acute pyelonephritis during pregnancy changes the balance of angiogenic and anti-angiogenic factors in maternal plasma.
        J Matern Fetal Neonatal Med. 2010; 23: 167-178
        • Silver K.L.
        • Conroy A.L.
        • Leke R.G.
        • et al.
        Circulating soluble endoglin levels in pregnant women in Cameroon and Malawi and associations with placental malaria and fetal growth restriction.
        PLoS One. 2011; 6: e24985
        • Stephan H.
        • Faber R.
        Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops.
        N Engl J Med. 2006; 354: 1857-1858
        • Rana S.
        • Venkatesha S.
        • DePaepe M.
        • Chien E.K.
        • Paglia M.
        • Karumanchi S.A.
        Cytomegalovirus-induced mirror syndrome associated with elevated levels of circulating antiangiogenic factors.
        Obstet Gynecol. 2007; 109: 549-552
        • Goebel S.
        • Huang M.
        • Davis W.C.
        • et al.
        VEGF-A stimulation of leukocyte adhesion to colonic microvascular endothelium: implications for inflammatory bowel disease.
        Am J Physiol Gastrointest Liver Physiol. 2006; 290: G648-G654
        • Joussen A.M.
        • Poulaki V.
        • Le M.L.
        • et al.
        A central role for inflammation in the pathogenesis of diabetic retinopathy.
        FASEB J. 2004; 18: 1450-1452
        • Rana S.
        • Schnettler W.T.
        • Powe C.
        • et al.
        Clinical characterization and outcomes of preeclampsia with normal angiogenic profile.
        Hypertens Pregnancy. 2013; 32: 189-201
        • Powers R.W.
        • Roberts J.M.
        • Plymire D.A.
        • et al.
        Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia?.
        Hypertension. 2012; 60: 239-246
        • Bent S.
        • Nallamothu B.K.
        • Simel D.L.
        • Fihn S.D.
        • Saint S.
        Does this woman have an acute uncomplicated urinary tract infection?.
        JAMA. 2002; 287: 2701-2710
        • Grigoryan L.
        • Trautner B.W.
        • Gupta K.
        Diagnosis and management of urinary tract infections in the outpatient setting: a review.
        JAMA. 2014; 312: 1677-1684
        • Hurlbut T.
        • Littenberg B.
        The diagnostic accuracy of rapid dipstick tests to predict urinary tract infection.
        Am J Clin Pathol. 1991; 96: 582-588