The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study

Abstract

Objective Pregnancy is accompanied by dramatic physiologic changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age, and determine biological processes that are perturbed in normal pregnancy. Materials and methods A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age (AGA) without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median=5,) were profiled to measure the abundance of 1,125 proteins using multiplex assays. Linear mixed effects models with polynomial splines were used to model protein abundance as a function of gestational age, and significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having: 1) more than 1.5 fold change between 8 and 40 weeks of gestation; and 2) a false discovery rate (FDR) adjusted p-value <0.1. Gene ontology enrichment analysis was employed to identify biological processes over-represented among the proteins that changed with advancing gestation. Results 1) Ten percent (112/1,125) of the profiled proteins changed in abundance as a function of gestational age; 2) of the 1,125 proteins analyzed Glypican-3, sialic acid-binding immunoglobulin-type lectins (Siglec)-6, placental growth factor (PlGF), C-C motif (CCL)-28, carbonic anhydrase 6, Prolactin (PRL), interleukin-1 receptor 4 (IL-1 R4), dual specificity mitogen-activated protein kinase 4 (MP2K4) and pregnancy-associated plasma protein-A (PAPP-A) had more than 5 fold change in abundance across gestation. These 9 proteins are known to be involved in a wide range of both physiologic and pathologic processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc.; and 3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis and leukocyte migration (FDR=10%). Conclusions The plasma proteome of normal pregnancy demonstrates dramatic changes in both magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy, development of biomarkers to differentiate normal vs. abnormal pregnancy, and determine the response to interventions.

The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4‐vessel sampling

“…However, 5 of the 8 placenta-specific proteins (placental growth factor, urokinase-type plasminogen activator, inhibin b A chain/activin A, MMP-12, and glypican 3) that showed significant changes across gestation in the current study paralleled the gestational changes reported by the previous study, although the latter 2 did not show significant changes after adjusting for multiple testing in our data set. The sixth protein (growth differentiation factor 15) was not part of the SOMAscan platform used by Romero and coworkers (47). For the 26 remaining proteins, the results from the 2 studies were in complete agreement.…”

“…Changes across gestation in the maternal concentrations of a placentaderived protein are not critical for its usefulness as a biomarker or read-out of placental function; however, the pattern of change must be known because prediction models must allow for these changes. Romero and coworkers (47) used the SomaLogics platform to study maternal plasma proteomic profiles across gestation, and documented that there are marked gestational changes in Figure 2. Protein-protein interactions among proteins secreted by the placenta into the maternal circulation, analyzed with NetworkAnalyst.…”

Translational Systems Pharmacology Studies in Pregnant Women

“…As described above, nearly every aspect of maternal physiology is impacted by pregnancy, leading to major changes in expression and function of genes, proteins, and organ systems. In the past, many of these changes have been studied in isolation, based on available technological capabilities . However, advanced technology now enables high‐dimensional study of genes, proteins, and other analytes.…”

“…Romero et al . recently conducted a proteomics study that sampled plasma at 3–6 time points across gestation from 43 women with normal deliveries.…”

“…Many of these proteins are involved in angiogenesis, embryogenesis, and immune regulation. Protein‐protein interaction network mappings and functional analyses identified the proteins with the greatest change across gestation involved in general defense response; defense response to bacteria and fungi; germ cell migration; proteolysis; and leukocyte migration …”