Advertisement

Placenta accreta spectrum: biomarker discovery using plasma proteomics

Published:March 18, 2020DOI:https://doi.org/10.1016/j.ajog.2020.03.019

      Background

      Many cases of placenta accreta spectrum are not diagnosed antenatally, despite identified risk factors and improved imaging methods. Identification of plasma protein biomarkers could further improve the antenatal diagnosis of placenta accreta spectrum .

      Objective

      The purpose of this study was to determine if women with placenta accreta spectrum have a distinct plasma protein profile compared with control subjects.

      Study Design

      We obtained plasma samples before delivery from 16 participants with placenta accreta spectrum and 10 control subjects with similar gestational ages (35.1 vs 35.5 weeks gestation, respectively). We analyzed plasma samples with an aptamer-based proteomics platform for alterations in 1305 unique proteins. Heat maps of the most differentially expressed proteins (T test, P<.01) were generated with matrix visualization and analysis software. Principal component analysis was performed with the use of all 1305 proteins and the top 21 dysregulated proteins. We then confirmed dysregulated proteins using enzyme-linked immunosorbent assay and report significant differences between placenta accreta spectrum and control cases (Wilcoxon-rank sum test, P<.05).

      Results

      Many of the top 50 proteins that significantly dysregulated in participants with placenta accreta spectrum were inflammatory cytokines, factors that regulate vascular remodeling, and extracellular matrix proteins that regulate invasion. Placenta accreta spectrum, with the use of the top 21 proteins, distinctly separated the placenta accreta spectrum cases from control cases (P<.01). Using enzyme-linked immunosorbent assay, we confirmed 4 proteins that were dysregulated in placenta accreta spectrum compared with control cases: median antithrombin III concentrations (240.4 vs 150.3 mg/mL; P=.002), median plasminogen activator inhibitor 1 concentrations (4.1 vs 7.1 ng/mL; P<.001), soluble Tie2 (13.5 vs 10.4 ng/mL; P=.02), soluble vascular endothelial growth factor receptor 2 (9.0 vs 5.9 ng/mL; P=.003).

      Conclusion

      Participants with placenta accreta spectrum had a unique and distinct plasma protein signature.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      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:

      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

      References

        • Jauniaux E.
        • Ayres-de-Campos D.
        • Langhoff-Roos J.
        • et al.
        FIGO classification for the clinical diagnosis of placenta accreta spectrum disorders.
        Int J Gynaecol Obstet. 2019; 146: 20-24
        • Jauniaux E.
        • Collins S.L.
        • Jurkovic D.
        • Burton G.J.
        Accreta placentation: a systematic review of prenatal ultrasound imaging and grading of villous invasiveness.
        Am J Obstet Gynecol. 2016; 215: 712-721
        • Jauniaux E.
        • Collins S.
        • Burton G.J.
        Placenta accreta spectrum: pathophysiology and evidence-based anatomy for prenatal ultrasound imaging.
        Am J Obstet Gynecol. 2018; 218: 75-87
        • Shainker S.
        • Shamshirsaz A.
        • Haviland M.
        • et al.
        Utilization and outcomes of massive transfusion protocols in women with and without invasive placentation.
        J Matern Fetal Neonatal Med. 2019; : 1-5
        • Silver R.M.
        • Landon M.B.
        • Rouse D.J.
        • et al.
        Maternal morbidity associated with multiple repeat cesarean deliveries.
        Obstet Gynecol. 2006; 107: 1226-1232
        • Jauniaux E.
        • Bunce C.
        • Gronbeck L.
        • Langhoff-Roos J.
        Prevalence and main outcomes of placenta accreta spectrum: a systematic review and meta-analysis.
        Am J Obstet Gynecol. 2019; 221: 208-218
        • Collins S.L.
        • Alemdar B.
        • van Beekhuizen H.J.
        • et al.
        Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta.
        Am J Obstet Gynecol. 2019; 220: 511-526
        • Silver R.M.
        • Fox K.A.
        • Barton J.R.
        • et al.
        Center of excellence for placenta accreta.
        Am J Obstet Gynecol. 2015; 212: 561-568
        • Erfani H.
        • Fox K.A.
        • Clark S.L.
        • et al.
        Maternal outcomes in unexpected placenta accreta spectrum disorders: single-center experience with a multidisciplinary team.
        Am J Obstet Gynecol. 2019; 221: 337.e1-337.e5
        • Zuckerwise L.C.
        • Craig A.M.
        • Newton J.M.
        • Zhao S.
        • Bennett K.A.
        • Crispens M.A.
        Outcomes following a clinical algorithm allowing for delayed hysterectomy in the management of severe placenta accreta spectrum.
        Am J Obstet Gynecol. 2020; 222: 179.e1-179.e9
        • D’Antonio F.
        • Iacovella C.
        • Bhide A.
        Prenatal identification of invasive placentation using ultrasound: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2013; 42: 509-517
        • Bailit J.L.
        • Grobman W.A.
        • Rice M.M.
        • et al.
        Morbidly adherent placenta treatments and outcomes.
        Obstet Gynecol. 2015; 125: 683-689
        • Fitzpatrick K.E.
        • Sellers S.
        • Spark P.
        • Kurinczuk J.J.
        • Brocklehurst P.
        • Knight M.
        The management and outcomes of placenta accreta, increta, and percreta in the UK: a population-based descriptive study.
        BJOG. 2014; 121: 62-71
        • Berezowsky A.
        • Pardo J.
        • Ben-Zion M.
        • Wiznitzer A.
        • Aviram A.
        Second trimester biochemical markers as possible predictors of pathological placentation: a retrospective case-control study.
        Fetal Diagn Ther. 2019; 46: 187-192
        • Biberoglu E.
        • Kirbas A.
        • Daglar K.
        • et al.
        Serum angiogenic profile in abnormal placentation.
        J Matern Fetal Neonatal Med. 2016; 29: 3193-3197
        • Buke B.
        • Akkaya H.
        • Demir S.
        • et al.
        Relationship between first trimester aneuploidy screening test serum analytes and placenta accreta.
        J Matern Fetal Neonatal Med. 2018; 31: 59-62
        • Samuel A.
        • Bonanno C.
        • Oliphant A.
        • Batey A.
        • Wright J.D.
        Fraction of cell-free fetal DNA in the maternal serum as a predictor of abnormal placental invasion-a pilot study.
        Prenat Diagn. 2013; 33: 1050-1053
        • Ganz P.
        • Heidecker B.
        • Hveem K.
        • et al.
        Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease.
        JAMA. 2016; 315: 2532-2541
        • Gold L.
        • Walker J.J.
        • Wilcox S.K.
        • Williams S.
        Advances in human proteomics at high scale with the SOMAscan proteomics platform.
        N Biotechnol. 2012; 29: 543-549
        • Ciampa E.
        • Li Y.
        • Dillon S.
        • et al.
        cerebrospinal fluid protein changes in preeclampsia.
        Hypertension. 2018; 72: 219-226
        • Tarca A.L.
        • Romero R.
        • Benshalom-Tirosh N.
        • et al.
        The prediction of early preeclampsia: Results from a longitudinal proteomics study.
        PLoS One. 2019; 14e0217273
        • Einerson B.D.
        • Straubhar A.
        • Soisson S.
        • et al.
        Hyperglycosylated hCG and placenta accreta spectrum.
        Am J Perinatol. 2019; 36: 22-26
        • Gold L.
        • Ayers D.
        • Bertino J.
        • et al.
        Aptamer-based multiplexed proteomic technology for biomarker discovery.
        PLoS One. 2010; 5e15004
        • Mehan M.R.
        • Ostroff R.
        • Wilcox S.K.
        • et al.
        Highly multiplexed proteomic platform for biomarker discovery, diagnostics, and therapeutics.
        Adv Exp Med Biol. 2013; 735: 283-300
        • Phipson B.
        • Lee S.
        • Majewski I.J.
        • Alexander W.S.
        • Smyth G.K.
        Robust hyperparameter estimation protects against hypervariable genes and improves power to detect differential expression.
        Ann Appl Stat. 2016; 10: 946-963
        • Umemura K.
        • Ishioka S.
        • Endo T.
        • Ezaka Y.
        • Takahashi M.
        • Saito T.
        Roles of microRNA-34a in the pathogenesis of placenta accreta.
        J Obstet Gynaecol Res. 2013; 39: 67-74
        • Duzyj C.M.
        • Buhimschi I.A.
        • Motawea H.
        • et al.
        The invasive phenotype of placenta accreta extravillous trophoblasts associates with loss of E-cadherin.
        Placenta. 2015; 36: 645-651
        • Bartels H.C.
        • Postle J.D.
        • Downey P.
        • Brennan D.J.
        Placenta accreta spectrum: a review of pathology, molecular biology, and biomarkers.
        Dis Markers. 2018; 2018: 1507674
        • Tseng J.J.
        • Chou M.M.
        Differential expression of growth-, angiogenesis- and invasion-related factors in the development of placenta accreta.
        Taiwan J Obstet Gynecol. 2006; 45: 100-106
        • Zhou J.
        • Li J.
        • Yan P.
        • et al.
        Maternal plasma levels of cell-free beta-HCG mRNA as a prenatal diagnostic indicator of placenta accrete.
        Placenta. 2014; 35: 691-695
        • Desai N.
        • Krantz D.
        • Roman A.
        • Fleischer A.
        • Boulis S.
        • Rochelson B.
        Elevated first trimester PAPP: a is associated with increased risk of placenta accreta.
        Prenat Diagn. 2014; 34: 159-162
        • Cartwright J.E.
        • Fraser R.
        • Leslie K.
        • Wallace A.E.
        • James J.L.
        Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders.
        Reproduction. 2010; 140: 803-813
        • Kokkinos M.I.
        • Murthi P.
        • Wafai R.
        • Thompson E.W.
        • Newgreen D.F.
        Cadherins in the human placenta–epithelial-mesenchymal transition (EMT) and placental development.
        Placenta. 2010; 31: 747-755
        • Wehrum M.J.
        • Buhimschi I.A.
        • Salafia C.
        • et al.
        Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.
        Am J Obstet Gynecol. 2011; 204: 411.e1-411.e11
        • Duzyj C.M.
        • Buhimschi I.A.
        • Laky C.A.
        • et al.
        Extravillous trophoblast invasion in placenta accreta is associated with differential local expression of angiogenic and growth factors: a cross-sectional study.
        BJOG. 2018; 125: 1441-1448
        • Dumont D.J.
        • Gradwohl G.
        • Fong G.H.
        • et al.
        Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo.
        Genes Dev. 1994; 8: 1897-1909
        • Augustin H.G.
        • Koh G.Y.
        • Thurston G.
        • Alitalo K.
        Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system.
        Nat Rev Mol Cell Biol. 2009; 10: 165-177
        • Voskas D.
        • Jones N.
        • Van Slyke P.
        • et al.
        A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice.
        Am J Pathol. 2005; 166: 843-855
        • Vikkula M.
        • Boon L.M.
        • Carraway 3rd, K.L.
        • et al.
        Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.
        Cell. 1996; 87: 1181-1190
        • Antfolk D.
        • Sjoqvist M.
        • Cheng F.
        • et al.
        Selective regulation of Notch ligands during angiogenesis is mediated by vimentin.
        Proc Natl Acad Sci U S A. 2017; 114: E4574-E4581
        • Limbourg F.P.
        • Takeshita K.
        • Radtke F.
        • Bronson R.T.
        • Chin M.T.
        • Liao J.K.
        Essential role of endothelial Notch1 in angiogenesis.
        Circulation. 2005; 111: 1826-1832
        • Das A.M.
        • Seynhaeve A.L.
        • Rens J.A.
        • et al.
        Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration.
        Angiogenesis. 2014; 17: 163-177
        • Adissu H.A.
        • McKerlie C.
        • Di Grappa M.
        • et al.
        Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer.
        Prostate. 2015; 75: 1831-1843
        • Vazquez F.
        • Hastings G.
        • Ortega M.A.
        • et al.
        METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity.
        J Biol Chem. 1999; 274: 23349-23357
        • McCann J.V.
        • Xiao L.
        • Kim D.J.
        • et al.
        Endothelial miR-30c suppresses tumor growth via inhibition of TGF-beta-induced Serpine1.
        J Clin Invest. 2019; 130: 1654-1670
        • McMahon K.
        • Karumanchi S.A.
        • Stillman I.E.
        • Cummings P.
        • Patton D.
        • Easterling T.
        Does soluble fms-like tyrosine kinase-1 regulate placental invasion? Insight from the invasive placenta.
        Am J Obstet Gynecol. 2014; 210: 68.e1-68.e4
        • Shainker S.A.
        • Dannheim K.
        • Gerson K.D.
        • et al.
        Down-regulation of soluble fms-like tyrosine kinase 1 expression in invasive placentation.
        Arch Gynecol Obstet. 2017; 296: 257-262
        • Wang F.
        • Zhang G.
        • Lu Z.
        • et al.
        Antithrombin III/serpinC1 insufficiency exacerbates renal ischemia/reperfusion injury.
        Kidney Int. 2015; 88: 796-803
        • Korner A.
        • Schlegel M.
        • Kaussen T.
        • et al.
        Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A.
        Nat Commun. 2019; 10: 633
        • Vandercappellen J.
        • Van Damme J.
        • Struyf S.
        The role of the CXC chemokines platelet factor-4 (CXCL4/PF-4) and its variant (CXCL4L1/PF-4var) in inflammation, angiogenesis and cancer.
        Cytokine Growth Factor Rev. 2011; 22: 1-18
        • Silver R.M.
        • Branch D.W.
        Placenta accreta spectrum.
        N Engl J Med. 2018; 378: 1529-1536