Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study

Published:September 28, 2015DOI:


      Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction.


      We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies.

      Study Design

      We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE ≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE).


      Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval [CI], 3.5–84.8; positive predictive value [PPV], 61%; negative predictive value [NPV], 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0–121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high-risk subgroup was 94% (95% CI, 70–99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1–8.6%).


      Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources.

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        • Petri M.
        • Allbritton J.
        Fetal outcome of lupus pregnancy: a retrospective case-control study of the Hopkins Lupus Cohort.
        J Rheumatol. 1993; 20: 650-656
        • Georgiou P.E.
        • Politi E.N.
        • Katsimbri P.
        • Sakka V.
        • Drosos A.A.
        Outcome of lupus pregnancy: a controlled study.
        Rheumatology (Oxford). 2000; 39: 1014-1019
        • Clowse M.E.
        • Jamison M.
        • Myers E.
        • James A.H.
        A national study of the complications of lupus in pregnancy.
        Am J Obstet Gynecol. 2008; 199: 127.e1-127.e6
        • Buyon J.P.
        • Kim M.Y.
        • Guerra M.M.
        • et al.
        Predictors of pregnancy outcome in a prospective, multiethnic cohort of lupus patients: a cohort study.
        Ann Intern Med. 2015; 163 (163-63)
        • Pijnenborg R.
        • Vercruysse L.
        • Hanssens M.
        The uterine spiral arteries in human pregnancy: facts and controversies.
        Placenta. 2006; 27: 939-958
        • Roberts J.M.
        • Hubel C.A.
        The two stage model of preeclampsia: variations on the theme.
        Placenta. 2009; 30: S32-S37
        • Burton G.J.
        • Woods A.W.
        • Jauniaux E.
        • Kingdom J.C.
        Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
        Placenta. 2009; 30: 473-482
        • Young B.C.
        • Levine R.J.
        • Karumanchi S.A.
        Pathogenesis of preeclampsia.
        Annu Rev Pathol. 2010; 5: 173-192
        • Zhou Y.
        • Damsky C.H.
        • Fisher S.J.
        Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome?.
        J Clin Invest. 1997; 99: 2152-2164
        • 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
        • 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
        • Maharaj A.S.
        • Walshe T.E.
        • Saint-Geniez M.
        • et al.
        VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma.
        J Exp Med. 2008; 205: 491-501
        • Lu F.
        • Longo M.
        • Tamayo E.
        • et al.
        The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice.
        Am J Obstet Gynecol. 2007; 196: 396.e1-396.e7
        • 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
        • 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
        • Noori M.
        • Donald A.E.
        • Angelakopoulou A.
        • Hingorani A.D.
        • Williams D.J.
        Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
        Circulation. 2010; 122: 478-487
        • Herraiz I.
        • Droge L.A.
        • Gomez-Montes E.
        • Henrich W.
        • Galindo A.
        • Verlohren S.
        Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction.
        Obstet Gynecol. 2014; 124: 265-273
        • Asvold B.O.
        • Vatten L.J.
        • Romundstad P.R.
        • Jenum P.A.
        • Karumanchi S.A.
        • Eskild A.
        Angiogenic factors in maternal circulation and the risk of severe fetal growth restriction.
        Am J Epidemiol. 2011; 173: 630-639
        • Romero R.
        • Chaiworapongsa T.
        • Erez O.
        • et al.
        An imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study.
        J Matern Fetal Neonatal Med. 2010; 23: 1384-1399
        • Whitten A.E.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
        Am J Obstet Gynecol. 2013; 208: 310.e1-310.e11
        • Chaiworapongsa T.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia.
        Am J Obstet Gynecol. 2013; 208: 287.e1-287.e15
        • Hochberg M.C.
        Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
        Arthritis Rheum. 1997; 40: 1725
        • Lockshin M.D.
        • Kim M.
        • Laskin C.A.
        • et al.
        Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies.
        Arthritis Rheum. 2012; 64: 2311-2318
        • Miyakis S.
        • Lockshin M.D.
        • Atsumi T.
        • et al.
        International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
        J Thromb Haemost. 2006; 4: 295-306
        • ACOG Committee on Practice Bulletins–Obstetrics
        Diagnosis and management of preeclampsia and eclampsia. ACOG Practice bulletin no. 33, January 2002.
        Obstet Gynecol. 2002; 99: 159-167
        • 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
        • Fleiss J.
        • Levin B.
        • Paik M.
        Statistical methods for rates and proportions.
        3rd ed. John Wiley and Sons Inc, Hoboken (NJ)2003
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Moons K.G.
        • Altman D.G.
        • Reitsma J.B.
        • et al.
        Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): explanation and elaboration.
        Ann Intern Med. 2015; 162: W1-73
        • Vickers A.J.
        • Cronin A.M.
        • Begg C.B.
        One statistical test is sufficient for assessing new predictive markers.
        BMC Med Res Methodol. 2011; 11: 13
        • de Jesus G.R.
        • Rodrigues G.
        • de Jesus N.R.
        • Levy R.A.
        Pregnancy morbidity in antiphospholipid syndrome: what is the impact of treatment?.
        Curr Rheumatol Rep. 2014; 16: 403
        • Hagmann H.
        • Bossung V.
        • Belaidi A.A.
        • et al.
        Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination.
        PLoS One. 2014; 9: e85258
        • Searle J.
        • Mockel M.
        • Gwosc S.
        • et al.
        Heparin strongly induces soluble fms-like tyrosine kinase 1 release in vivo and in vitro–brief report.
        Arterioscler Thromb Vasc Biol. 2011; 31: 2972-2974
        • Li C.
        • Raikwar N.S.
        • Santillan M.K.
        • Santillan D.A.
        • Thomas C.P.
        Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclo-oxygenase 1.
        Placenta. 2015; 36: 446-453
        • Qazi U.
        • Lam C.
        • Karumanchi S.A.
        • Petri M.
        Soluble Fms-like tyrosine kinase associated with preeclampsia in pregnancy in systemic lupus erythematosus.
        J Rheumatol. 2008; 35: 631-634
        • Rodger M.A.
        • Carrier M.
        • Le Gal G.
        • et al.
        Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications.
        Blood. 2014; 123: 822-828
        • LeFevre M.L.
        US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: US Preventive Services Task Force recommendation statement.
        Ann Intern Med. 2014; 161: 819-826
        • Schramm A.M.
        • Clowse M.E.
        Aspirin for prevention of preeclampsia in lupus pregnancy.
        Autoimmune Dis. 2014; 2014: 920467
        • Girardi G.
        • Berman J.
        • Redecha P.
        • et al.
        Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.
        J Clin Invest. 2003; 112: 1644-1654
        • Girardi G.
        • Yarilin D.
        • Thurman J.M.
        • Holers V.M.
        • Salmon J.E.
        Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction.
        J Exp Med. 2006; 203: 2165-2175
        • Berman J.
        • Girardi G.
        • Salmon J.E.
        TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss.
        J Immunol. 2005; 174: 485-490
        • Andrade D.
        • Kim M.
        • Blanco L.P.
        • et al.
        Interferon-alpha and angiogenic dysregulation in pregnant lupus patients who develop preeclampsia.
        Arthritis Rheumatol. 2015; 67: 977-987
        • Thacker S.G.
        • Berthier C.C.
        • Mattinzoli D.
        • Rastaldi M.P.
        • Kretzler M.
        • Kaplan M.J.
        The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction.
        J Immunol. 2010; 185: 4457-4469
        • Gelber S.E.
        • Brent E.
        • Redecha P.
        • et al.
        Prevention of defective placentation and pregnancy loss by blocking innate immune pathways in a syngeneic model of placental insufficiency.
        J Immunol. 2015; 195: 1129-1138