title: Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies.
  
  
  METHODS
  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).
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Biostatistics, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Mimi Y
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, New York University School of Medicine, New York, NY.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
authors.affiliation: Research Division, Hospital for Special Surgery, New York, NY.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Guerra
authors.affiliation: Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Sarosh
authors.initials: S
authors.lastname: Rana
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Laskin
authors.affiliation: Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.affiliation: Division of Rheumatology, Hospital for Special Surgery, New York, NY; Weill Cornell Medical College, New York, NY.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lockshin
authors.affiliation: Division of Rheumatology, Hospital for Special Surgery, New York, NY; Weill Cornell Medical College, New York, NY.
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Sammaritano
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
authors.forename: D Ware
authors.initials: DW
authors.lastname: Branch
authors.affiliation: Department of Obstetrics and Gynecology, University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, UT.
authors.forename: T Flint
authors.initials: TF
authors.lastname: Porter
authors.affiliation: Clinical Pharmacology, Oklahoma Medical Research Foundation and the University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Section of Reproductive Endocrinology and Infertility, University of Chicago, Chicago, IL.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Stephenson
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.affiliation: Division of Rheumatology, Hospital for Special Surgery, New York, NY; Weill Cornell Medical College, New York, NY. Electronic address: salmonj@hss.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D017152:Antibodies, Antiphospholipid / Q000097:blood; D000925:Anticoagulants / Q000627:therapeutic use; D015703:Antigens, CD / Q000097:blood*; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000188:drug therapy; D001241:Aspirin / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D000071063:Endoglin; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood*; D005865:Gestational Age; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood*; D011237:Predictive Value of Tests; D011247:Pregnancy; D011256:Pregnancy Outcome; D011257:Pregnancy Proteins / Q000097:blood*; D011261:Pregnancy Trimester, First / Q000097:blood; D011262:Pregnancy Trimester, Second / Q000097:blood; D018566:Pregnancy, High-Risk; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000097:blood*; D012720:Severity of Illness Index; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017152:Antibodies, Antiphospholipid; D000925:Anticoagulants; D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D000072483:Placenta Growth Factor; D006493:Heparin; D040281:Vascular Endothelial Growth Factor Receptor-1; D001241:Aspirin
keywords: angiogenic factors; antiphospholipid antibodies; placental insufficiency; preeclampsia; systemic lupus erythematosus