Please cite this paper as: Brou L, Almli L, Pearce B, Bhat G, Drobek C, Fortunato S, Menon R. Dysregulated biomarkers induce distinct pathways in preterm birth. BJOG 2012;119:458–473. Objective  To document racial disparity in biomarker concentrations in maternal/fetal plasma and amniotic fluid between African Americans and European Americans with spontaneous preterm birth (PTB; cases) and normal term birth (controls), and their contribution to distinct pathophysiological pathways of PTB. Design  Nested case–control study. Setting  The Perinatal Research Center, Nashville, Tennessee, USA. Sample  Maternal and fetal plasma and amniotic fluid samples were collected from 105 cases (59 African American and 46 European American) and 86 controls (40 African American and 46 European American). Methods  Thirty‐six biomarkers were analysed using the protein microarray approach. Main outcome measures  Differences in biomarker concentrations between cases and controls of different races in maternal, fetal and intra‐amniotic compartments, and the risk of PTB. Dysregulated biomarker‐induced PTB pathways associated with PTB in each race were determined using ingenuity pathway analysis (IPA). Results  Racial disparity was observed in biomarker concentrations in each compartment between cases and controls: amniotic fluid, IL8 and MIP1α differed between case and controls in European Americans, whereas ANGPT2, Eotaxin, ICAM‐1, IL‐1β, IL1RA, RANTES and TNFα differed between case and controls in African Americans. In both races the FAS ligand, MCP‐3 and TNFR‐I differed between cases and controls. For fetal plasma, ANGPT2, Eotaxin, FGF basic, ICAM‐1, IGF‐I, IL10, IL‐1β, IL2, IP10 KGF, MCP‐3, MIP1α, PDGF‐BB, TGFα, TGFβ1, TIMP1, TNFα, TNFR‐I, TNFR‐II and VEGF differed between cases and controls in European Americans, whereas only MMP7 differed between cases and controls in African Americans. IL‐8 differed between cases and controls in both races. For maternal plasma, IL1RA, MMP7 and VEGF differed between cases and controls in European Americans, whereas ANGPT2, FGF basic, IL‐1β, IL5, IL6R, KGF, MCP‐3, MIP1α, TIMP1 and TNFα differed between cases and controls in African Americans. ANG, IL8 and TNFR‐I differed between cases and controls in both races. Conclusions  We conclude that: (1) biomarker concentrations in maternal, fetal and intra‐amniotic compartments differ between cases and controls; (2) there is racial disparity in the biomarker profile in each of the compartments; (3) substantial numbers of dysregulated fetal plasma biomarkers contribute to PTB in European Americans, whereas maternal plasma biomarkers contribute to PTB in African Americans; and (4) both inflammation and haematological functions are associated with PTB in European Americans, but maternal proinflammatory changes dominate PTB in African Americans. Biomarker analyses document racial disparity and the distinct pathophysiological contributions from different compartments that can determine pregnancy outcome.

Multivariate adaptive regression splines models multiple biomarkers associated with preterm birth and demonstrated racial disparity.

Problem Preterm premature rupture of fetal membranes (pPROM) occurs in 30–40% of spontaneous preterm births (PTB) and is associated with intra-amniotic infection and inflammation. The membranes may sense and respond to microbes via Toll-like receptors (TLRs), however, little is known about their expression and regulation in this tissue. The objective of this study was to evaluate the expression of TLR1-10 in fetal membranes after exposure to pathogens associated with intra-amniotic infection and PTB. Method of study Normal human term fetal membrane explants were exposed to various bacteria. After 24hrs RNA was extracted and quantitative RT-PCR performed for TLRs 1–10. Results Treatment of fetal membranes with Mycoplasma hominis increased expression of TLR4, TLR6, and TLR8 mRNA. Ureaplasma parvum upregulated TLR8 mRNA, and Porphyromonas gingivalis significantly increased fetal membrane TLR7 expression. In contrast, treatment with Gram-negative Escherichia. coli (and its cell wall component LPS) downregulated TLR10 mRNA. No effect was detected for Ureaplasma urealyticum, Gardnerella vaginalis, or Group B Streptococcus. Conclusions These findings demonstrate that different types of bacteria have distinct effects on fetal membrane TLR expression patterns. Moreover, these findings highlight the disparity of fetal membrane responses to infection and thus, suggest heterogeneity in the mechanisms by which infection-associated pregnancy complications, such as pPROM and PTB, arise.

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