Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms


      We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators’ ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB.

      Study Design

      We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34.0 weeks’ gestation. Each woman was assessed for the presence of underlying SPTB causes. A hierarchic cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis with the use of VEGAS software.


      One thousand twenty-eight women with SPTB were assigned phenotypes. Hierarchic clustering of the phenotypes revealed 5 major clusters. Cluster 1 (n = 445) was characterized by maternal stress; cluster 2 (n = 294) was characterized by premature membrane rupture; cluster 3 (n = 120) was characterized by familial factors, and cluster 4 (n = 63) was characterized by maternal comorbidities. Cluster 5 (n = 106) was multifactorial and characterized by infection (INF), decidual hemorrhage (DH), and placental dysfunction (PD). These 3 phenotypes were correlated highly by χ2 analysis (PD and DH, P < 2.2e-6; PD and INF, P = 6.2e-10; INF and DH, (P = .0036). Gene-based testing identified the INS (insulin) gene as significantly associated with cluster 3 of SPTB.


      We identified 5 major clusters of SPTB based on a phenotype tool and hierarch clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors that were underlying SPTB.

      Key words

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        • Muglia L.J.
        • Katz M.
        The enigma of spontaneous preterm birth.
        N Engl J Med. 2010; 362: 529-535
      1. Preterm birth: crisis and opportunity.
        Lancet. 2006; 368: 339
        • Esplin M.S.
        Overview of spontaneous preterm birth: a complex and multifactorial phenotype.
        Clin Obstet Gynecol. 2014; 57: 518-530
        • Goldenberg R.L.
        • Culhane J.F.
        • Iams J.D.
        • Romero R.
        Epidemiology and causes of preterm birth.
        Lancet. 2008; 371: 75-84
        • Moutquin J.M.
        Classification and heterogeneity of preterm birth.
        BJOG. 2003; 110: 30-33
        • Lockwood C.J.
        • Kuczynski E.
        Risk stratification and pathological mechanisms in preterm delivery.
        Paediatr Perinat Epidemiol. 2001; 15: 78-89
        • York T.P.
        • Strauss 3rd, J.F.
        • Neale M.C.
        • Eaves L.J.
        Racial differences in genetic and environmental risk to preterm birth.
        PloS One. 2010; 5: e12391
        • Esplin M.S.
        • O’Brien E.
        • Fraser A.
        • et al.
        Estimating recurrence of spontaneous preterm delivery.
        Obstet Gynecol. 2008; 112: 516-523
        • Simonsen S.E.
        • Lyon J.L.
        • Stanford J.B.
        • Porucznik C.A.
        • Esplin M.S.
        • Varner M.W.
        Risk factors for recurrent preterm birth in multiparous Utah women: a historical cohort study.
        BJOG. 2013; 120: 863-872
        • Porter T.F.
        • Fraser A.M.
        • Hunter C.Y.
        • Ward R.H.
        • Varner M.W.
        The risk of preterm birth across generations.
        Obstet Gynecol. 1997; 90: 63-67
        • Clausson B.
        • Lichtenstein P.
        • Cnattingius S.
        Genetic influence on birthweight and gestational length determined by studies in offspring of twins.
        BJOG. 2000; 107: 375-381
        • Zhang H.
        • Baldwin D.A.
        • Bukowski R.K.
        • et al.
        A genome-wide association study of early spontaneous preterm delivery.
        Genet Epidemiol. 2015; 39: 217-226
        • Dolan S.M.
        • Hollegaard M.V.
        • Merialdi M.
        • et al.
        Synopsis of preterm birth genetic association studies: the preterm birth genetics knowledge base (PTBGene).
        Public Health Genomics. 2010; 13: 514-523
        • Manuck T.A.
        • Esplin M.S.
        • Biggio J.
        • et al.
        The phenotype of spontaneous preterm birth: application of a clinical phenotyping tool.
        Am J Obstet Gynecol. 2015; 212: 487.e1-487.e11
        • Gower J.C.
        A general coefficient of similarity and some of its properties.
        Biometrics. 1971; 27: 857-874
        • Kaufman L.
        • Rousseeuw P.J.
        Finding groups in data: an introduction to cluster analysis.
        99th ed. Wiley, New York1990
        • Liu J.Z.
        • McRae A.F.
        • Nyholt D.R.
        • et al.
        A versatile gene-based test for genome-wide association studies.
        Am J Hum Genet. 2010; 87: 139-145
        • Loza M.J.
        • McCall C.E.
        • Li L.
        • Isaacs W.B.
        • Xu J.
        • Chang B.L.
        Assembly of inflammation-related genes for pathway-focused genetic analysis.
        PloS One. 2007; 2: e1035
        • Velez D.R.
        • Fortunato S.J.
        • Thorsen P.
        • Lombardi S.J.
        • Williams S.M.
        • Menon R.
        Preterm birth in Caucasians is associated with coagulation and inflammation pathway gene variants.
        PloS One. 2008; 3: e3283
        • Goldenberg R.L.
        • Andrews W.W.
        • Faye-Petersen O.
        • Cliver S.
        • Goepfert A.R.
        • Hauth J.C.
        The Alabama Preterm Birth Project: placental histology in recurrent spontaneous and indicated preterm birth.
        Am J Obstet Gynecol. 2006; 195: 792-796
        • Hackney D.N.
        • Tirumala R.
        • Salamone L.J.
        • Miller R.K.
        • Katzman P.J.
        Do placental histologic findings of chorion-decidual hemorrhage or inflammation in spontaneous preterm birth influence outcomes in the subsequent pregnancy?.
        Placenta. 2014; 35: 58-63
        • Goldenberg R.L.
        • Gravett M.G.
        • Iams J.
        • et al.
        The preterm birth syndrome: issues to consider in creating a classification system.
        Am J Obstet Gynecol. 2012; 206: 113-118
        • Villar J.
        • Papageorghiou A.T.
        • Knight H.E.
        • et al.
        The preterm birth syndrome: a prototype phenotypic classification.
        Am J Obstet Gynecol. 2012; 206: 119-123
        • Laughon S.K.
        • Albert P.S.
        • Leishear K.
        • Mendola P.
        The NICHD Consecutive Pregnancies Study: recurrent preterm delivery by subtype.
        Am J Obstet Gynecol. 2014; 210: 131.e1-131.e8
        • Manuck T.A.
        • Major H.D.
        • Varner M.W.
        • Chettier R.
        • Nelson L.
        • Esplin M.S.
        Progesterone receptor genotype, family history, and spontaneous preterm birth.
        Obstet Gynecol. 2010; 115: 765-770
        • Uzun A.
        • Dewan A.T.
        • Istrail S.
        • Padbury J.F.
        Pathway-based genetic analysis of preterm birth.
        Genomics. 2013; 101: 163-170
        • Menon R.
        • Fortunato S.J.
        • Thorsen P.
        • Williams S.
        Genetic associations in preterm birth: a primer of marker selection, study design, and data analysis.
        J Soc Gynecol Investig. 2006; 13: 531-541
        • Hillier S.L.
        • Martius J.
        • Krohn M.
        • Kiviat N.
        • Holmes K.K.
        • Eschenbach D.A.
        A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.
        N Engl J Med. 1988; 319: 972-978