Midpregnancy levels of angiogenic markers in relation to maternal characteristics

Published:December 13, 2010DOI:


      The purpose of this study was to describe relations among maternal demographic and lifestyle characteristics and midpregnancy levels of angiogenic markers (soluble Fms-like tyrosine kinase-1, placental growth factor, soluble endoglin).

      Study Design

      In a large pregnancy cohort, linear models were used to evaluate relations among maternal characteristics and midpregnancy angiogenic markers with and without covariate adjustment. Associations were examined in a subcohort that included term and preterm deliveries (n = 1302) and among “normal” term pregnancies (n = 668).


      Concentrations of all factors declined with increasing maternal body mass index. Multiparous women had lower soluble Fms-like tyrosine kinase-1 levels than primiparous women. Higher placental growth factor and slightly lower soluble endoglin levels were observed among women who smoked at enrollment, but not among those women who quit before enrollment. African American women had higher levels of all markers.


      Understanding relations among maternal characteristics and levels of angiogenic factors may improve studies that use these markers to examine etiology and/or to predict adverse pregnancy outcome.

      Key words

      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


        • Romero R.
        • Nien J.K.
        • Espinoza J.
        • et al.
        A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
        J Matern Fetal Neonatal Med. 2008; 21: 9-23
        • Wang A.
        • Rana S.
        • Karumanchi S.A.
        Preeclampsia: the role of angiogenic factors in its pathogenesis.
        Physiology (Bethesda). 2009; 24: 147-158
        • Signore C.
        • Mills J.L.
        • Qian C.
        • et al.
        Circulating soluble endoglin and placental abruption.
        Prenat Diagn. 2008; 28: 852-858
        • Ananth C.V.
        • Vintzileos A.M.
        Medically indicated preterm birth: recognizing the importance of the problem.
        Clin Perinatol. 2008; 35: 53-67
        • 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
        • Levine R.J.
        • Lam C.
        • Qian C.
        • et al.
        Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
        N Engl J Med. 2006; 355: 992-1005
        • Smith G.C.S.
        • Crossley J.A.
        • Aitken D.A.
        • et al.
        Circulating angiogenic factors in early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth and stillbirth.
        Obstet Gynecol. 2007; 109: 1316-1324
        • Chaiworapongsa T.
        • Romero R.
        • Tarca A.
        • et al.
        A subset of patients destined to develop spontaneous preterm labor has an abnormal angiogenic/anti-angiogenic profile in maternal plasma: evidence in support of pathophysiologic heterogeneity of preterm labor derived from a longitudinal study.
        J Matern Fetal Neonatal Med. 2009; 22: 1122-1139
        • Holston A.M.
        • Qian C.
        • Yu K.F.
        • Epstein F.H.
        • Karumanchi A.
        • Levine R.J.
        Circulating angiogenic factors in gestational proteinuria without hypertension.
        Am J Obstet Gynecol. 2009; 200: 10
        • Espinoza J.
        • Chaiworapongsa T.
        • Romero R.
        • et al.
        Unexplained fetal death: another anti-angiogenic state.
        J Matern Fetal Neonatal Med. 2007; 20: 495-507
        • Autiero M.
        • Luttun A.
        • Tjwa M.
        • Carmeliet P.
        Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders.
        J Thromb Haemost. 2003; 1: 1356-1370
        • Lockwood C.J.
        • Toti P.
        • Arcuri F.
        • et al.
        Thrombin regulates soluble Fms-like tyrosine kinase-1 (sflt-1) expression in first trimester decidua.
        Am J Pathol. 2007; 170: 1398-1405
        • Rajakumar A.
        • Michael H.M.
        • Rajakumar P.A.
        • et al.
        Extra-placental expression of vascular endothelial growth factor receptor-1, (flt-1) and soluble flt-1 (sfit-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women.
        Placenta. 2005; 26: 563-573
        • Demir R.
        • Seval Y.
        • Huppertz B.
        Vasculogenesis and angiogenesis in the early human placenta.
        Acta Histochemica. 2007; 109: 257-265
        • Espinoza J.
        • Uckele J.E.
        • Starr R.A.
        • Seubert D.E.
        • Espinoza A.F.
        • Berry S.M.
        Angiogenic imbalances: the obstetric perspective.
        Am J Obstet Gynecol. 2010; 203: 17.e1-17.e8
        • Thadhani R.
        • Mutter W.P.
        • Wolf M.
        • et al.
        First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.
        J Clin Endocrinol Metab. 2004; 89: 770-775
        • Venkatesha S.
        • Toporsian M.
        • Lam C.
        • et al.
        Soluble endoglin contributes to the pathogenesis of preeclampsia.
        Nat Med. 2006; 12: 642-649
        • Vatten L.J.
        • Eskild A.
        • Nilsen T.I.L.
        • Jeansson S.
        • Jenum P.A.
        • Staff A.C.
        Changes in circulating level of angiogenic factors from the first to second trimester as predictors of preeclampsia.
        Am J Obstet Gynecol. 2007; 196: 239.e1-239.e6
        • Lindheimer M.D.
        • Romero R.
        Emerging roles of antiangiogenic and angiogenic proteins in pathogenesis and prediction of preeclampsia.
        Hypertension. 2007; 50: 35-36
        • Staff A.C.
        • Harsem N.K.
        • Braekke K.
        • Hyer M.
        • Hoover R.N.
        • Troisi R.
        Maternal, gestational and neonatal characteristics and maternal angiogenic factors in normotensive pregnancies.
        Eur J Obstet Gynecol Reprod Biol. 2009; 143: 29-33
        • Poon L.C.Y.
        • Kametas N.A.
        • Maiz N.
        • Akolekar R.
        • Nicolaides K.H.
        First-trimester prediction of hypertensive disorders in pregnancy.
        Hypertension. 2009; 53: 812-818
        • Powers R.W.
        • Roberts J.M.
        • Cooper K.M.
        • et al.
        Maternal serum soluble Fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia.
        Am J Obstet Gynecol. 2005; 193: 185-191
        • Maynard S.E.
        • Min J.Y.
        • Merchan J.
        • 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
        • Wolf M.
        • Shah A.
        • Lam C.
        • et al.
        Circulating levels of the antiangiogenic marker sflt-1 are increased in first versus second pregnancies.
        Am J Obstet Gynecol. 2005; 193: 16-22
        • Jeyabalan A.
        • McGonigal S.
        • Gilmour C.
        • Hubel C.A.
        • Rajakumar A.
        Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia.
        Placenta. 2008; 29: 555-563
        • Akolekar R.
        • Zaragoza E.
        • Poon L.C.Y.
        • Pepes S.
        • Nicolaides K.H.
        Maternal serum placental growth factor at 11+0 to 13+6 weeks of gestation in the prediction of preeclampsia.
        Ultrasound Obstet Gynecol. 2008; 32: 732-739
        • Kusanovic J.P.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.
        J Matern Fetal Neonatal Med. 2009; 22: 1021-1038
        • Vogel I.
        • Thorsen P.
        • Curry A.
        • Sandager P.
        • Uldbjerg N.
        Biomarkers for the prediction of preterm delivery.
        Acta Obstet Gynecol Scand. 2005; 84: 516-525
        • Hamilton M.P.R.
        • Abdalla H.I.
        • Whitfield C.R.
        Significance of raised maternal serum alpha-fetoprotein in singleton pregnancies with normally formed fetuses.
        Obstet Gynecol. 1985; 65: 465-470
        • Xu J.
        • Holzman C.
        • Arvidson C.
        • Chung H.
        • Goepfert A.
        Midpregnancy vaginal fluid defensins, bacterial vaginosis and risk of preterm delivery.
        Obstet Gynecol. 2008; 112: 524-531
        • Alexander G.R.
        • Himes J.H.
        • Kaufman R.B.
        • Mor J.
        • Kogan M.
        A United States national reference for fetal growth.
        Obstet Gynecol. 1996; 87: 163-168
        • Division of Nutrition, Physical Activity and Obesity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention
        About BMI for Adults, 2009 (vol 2010).
        (Accessed June 7, 2010)
        • Sibai B.
        • Dekker G.
        • Kupferminc M.
        Lancet. 2005; 365: 785-799
        • Widmer M.
        • Villar J.
        • Benigni A.
        • Conde-Agudelo A.
        • Karumanchi S.A.
        • Lindheimer M.
        Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review.
        Obstet Gynecol. 2007; 109: 168-180
        • Wa Law L.
        • Sahota D.S.
        • Wai Chan L.
        • Chen M.
        • Kin Lau T.
        • Leung T.Y.
        Effect of long-term storage on placental growth factor and Fms-like tyrosine kinase 1 measurements in samples from pregnant women.
        J Matern Fetal Neonatal Med. 2010; 23: 1475-1480
        • Kim Waller D.
        • Lustig L.S.
        • Cunningham G.C.
        • Feuchtbaum L.B.
        • Hook E.B.
        The association between maternal serum alpha-fetoprotein and preterm birth, small for gestational age infants, preeclampsia, and placental complications.
        Obstet Gynecol. 1996; 88: 816-822
        • Louis M.N.
        • Glenn E.P.
        • David A.L.
        • George J.K.
        • James E.H.
        Refinements in managing maternal weight adjustment for interpreting prenatal screening results.
        Prenat Diagn. 1996; 16: 1115-1119
        • Chen Y.
        • Holzman C.
        • Chung H.
        • Senagore P.
        • Talge N.M.
        • Siler-Khodr T.
        Levels of maternal serum corticotrophin-releasing hormone (CRH) at midpregnancy in relation to maternal characteristics.
        Psychoneuroendocrinology. 2010; 35: 820-832
        • Faupel-Badger J.M.
        • Hsieh C.-C.
        • Troisi R.
        • Lagiou P.
        • Potischman N.
        Plasma volume expansion in pregnancy: implications for biomarkers in population studies.
        Cancer Epidemiol Biomarkers Prev. 2007; 16: 1720-1723
        • Salas S.P.
        • Marshall G.
        • Gutierrez B.
        • Rosso P.
        Time course of maternal plasma volume and hormonal changes in women with preeclampsia or fetal growth restriction.
        Hypertension. 2006; 47: 203-208
        • Ness R.B.
        • Sibai B.M.
        Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia.
        Am J Obstet Gynecol. 2006; 195: 40-49
        • Ness R.B.
        • Zhang J.
        • Bass D.
        • Klebanoff M.A.
        Interactions between smoking and weight in pregnancies complicated by preeclampsia and small-for-gestational-age birth.
        Am J Epidemiol. 2008; 168: 427-433
        • Conde-Agudelo A.
        • Althabe F.
        • Belizan J.M.
        • Kafury-Goeta A.C.
        Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review.
        Am J Obstet Gynecol. 1999; 181: 1026-1035
        • Jeyabalan A.
        • Powers R.W.
        • Durica A.R.
        • Harger G.F.
        • Roberts J.M.
        • Ness R.B.
        Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia.
        Am J Hypertens. 2008; 21: 943-947
        • Levine R.
        • Qian C.
        • Yu K.
        • Sibai B.
        • Karumanchi A.
        Circulating angiogenic factors in smokers and non-smokers during normotensive pregnancy.
        Am J Obstet Gynecol. 2006; 195: S37
        • Levine R.J.
        • Qian C.
        • Maynard S.E.
        • Yu K.F.
        • Epstein F.H.
        • Karumanchi S.A.
        Serum sflt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women.
        Am J Obstet Gynecol. 2006; 194: 1034-1041
        • Karumanchi S.A.
        • Levine R.J.
        How does smoking reduce the risk of preeclampsia?.
        Hypertension. 2010; 55: 1100-1101
        • England L.J.
        • Grauman A.
        • Qian C.
        • et al.
        Misclassification of maternal smoking status and its effects on an epidemiologic study of pregnancy outcomes.
        Nicotine Tob Res. 2007; 9: 1005-1013
        • Wikstrom A.-K.
        • Stephansson O.
        • Cnattingius S.
        Tobacco use during pregnancy and preeclampsia risk: effects of cigarette smoking and snuff.
        Hypertension. 2010; 55: 1254-1259
        • Eskenazi B.
        • Fenster L.
        • Sidney S.
        A multivariate analysis of risk factors for preeclampsia.
        JAMA. 1991; 266: 237-241
        • Rana S.
        • Karumanchi S.A.
        • Levine R.J.
        • et al.
        Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia.
        Hypertension. 2007; 50: 137-142
        • Erez O.
        • Romero R.
        • Espinoza J.
        • et al.
        The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.
        J Matern Fetal Neonatal Med. 2008; 21: 279-287

      Linked Article