The molecular architecture of human labor at term during the execution phase: changes across cervical dilatation

Human parturition includes a preparatory phase that precedes the clinical onset of labor and an execution phase represented by clinically established labor. We sought to define the molecular architecture of the execution phase by characterizing the changes in the amniotic fluid proteome associated with increasing cervical dilatation during human labor at term.

This retrospective cross-sectional study included 98 women who delivered at term by cesarean delivery with intact membranes. Amniotic fluid was obtained from 61 women not in labor and 37 women in spontaneous labor, who were classified according to cervical dilatation: less than 1 cm, 1-3 cm, 4-6 cm, and 7-10 cm. The abundance of 7,288 proteins was measured using an aptamer-based platform. Differential protein abundance was assessed between women in labor and those not in labor and in relation to cervical dilatation. Functional enrichment analyses were performed to identify the biological processes represented by these changes.

The principal findings were: 1) established labor was associated with extensive molecular changes in amniotic fluid; 656 of 7,288 proteins differed between women in labor and those not in labor, including 214 with increased abundance and 442 with decreased abundance; 2) at 1-3 centimeters of cervical dilatation, aldo-keto reductase family 1 member B1 (AKR1B1) and L-plastin (LCP1) were selectively increased; the former has prostaglandin F synthase activity, whereas the latter is an actin-bundling protein, findings consistent with prostaglandin-related biology and actin-cytoskeletal organization at this stage of clinically established labor; 3) the molecular differences expanded markedly with increasing cervical dilatation, with 359 proteins differing at 4-6 centimeters and 3,050 at 7-10 centimeters compared with women not in labor; 4) among women in labor, 580 proteins were associated with cervical dilatation; 573 increased and 7 decreased with greater cervical dilatation, and nearly all increased as cervical dilatation advanced; these included interleukin-6, interleukin-8, granulocyte colony-stimulating factor, interferon gamma-inducible protein 16, neutrophil cytosol factor 1, and inducible T-cell costimulator ligand; 5) functional enrichment analysis identified biological processes related to cell-to-cell communication, cell-junction organization, tissue organization, tissue morphogenesis, cell adhesion, extracellular-matrix organization, innate immune activation, myeloid-cell and neutrophil activation, neutrophil degranulation, cytokine signaling, and ribonucleic acid processing; and 6) most proteins associated with labor had not previously been implicated in human parturition, thereby substantially expanding the known molecular landscape of labor.

The execution phase of human parturition is characterized by selective differences involving prostaglandin-related biology and actin-cytoskeletal organization at 1-3 cm of cervical dilatation, whereas greater cervical dilatation is associated with extensive differences involving immune, inflammatory, and tissue-organization-related biological processes. These findings define the molecular architecture of established labor but do not identify the molecular events that prepare for or initiate labor.