Evaluation of leucine-rich alpha-2 glycoprotein as a biomarker of fetal infection

PLoS One. 2020 Nov 19;15(11):e0242076. doi: 10.1371/journal.pone.0242076. eCollection 2020.


This study aimed to determine the association between umbilical cord leucine-rich alpha-2 glycoprotein (LRG) and fetal infection and investigate the underlying mechanism of LRG elevation in fetuses. We retrospectively reviewed the medical records of patients who delivered at Osaka University Hospital between 2012 and 2017 and selected those with histologically confirmed chorioamnionitis (CAM), which is a common pregnancy complication that may cause neonatal infection. The participants were divided into two groups: CAM with fetal infection (CAM-f[+] group, n = 14) and CAM without fetal infection (CAM-f[-] group, n = 31). Fetal infection was defined by the histological evidence of funisitis. We also selected 50 cases without clinical signs of CAM to serve as the control. LRG concentrations in sera obtained from the umbilical cord were unaffected by gestational age at delivery, neonatal birth weight, nor the presence of noninfectious obstetric complications (all, p > 0.05). Meanwhile, the LRG levels (median, Interquartile range [IQR]) were significantly higher in the CAM-f(+) group (10.37 [5.21-13.7] μg/ml) than in the CAM-f(-) (3.61 [2.71-4.65] μg/ml) or control group (3.39 [2.81-3.93] μg/ml; p < 0.01). The area under the receiver operating characteristic (ROC) curve of LRG for recognizing fetal infection was 0.92 (optimal cutoff, 5.08 μg/ml; sensitivity, 86%; specificity, 88%). In a mouse CAM model established by lipopolysaccharide administration, the fetal LRG protein in sera and LRG mRNA in the liver were significantly higher than those in phosphate-buffered saline (PBS)-administered control mice (p < 0.01). In vitro experiments using a fetal liver-derived cell line (WRL68) showed that the expression of LRG mRNA was significantly increased after interleukin (IL)-6, IL-1β, and tumor necrosis factor- alpha (TNF-α) stimulation (p < 0.01); the induction was considerably stronger following IL-6 and TNF-α stimulation (p < 0.01). In conclusion, LRG is an effective biomarker of fetal infection, and fetal hepatocytes stimulated with inflammatory cytokines may be the primary source of LRG production in utero.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood*
  • Case-Control Studies
  • Cell Line
  • Chorioamnionitis / blood*
  • Chorioamnionitis / chemically induced
  • Chorioamnionitis / genetics
  • Disease Models, Animal
  • Female
  • Fetal Blood / chemistry
  • Glycoproteins / blood*
  • Glycoproteins / genetics*
  • Humans
  • Lipopolysaccharides / adverse effects
  • Liver / metabolism
  • Mice
  • Pregnancy
  • ROC Curve
  • Retrospective Studies
  • Up-Regulation


  • Biomarkers
  • Glycoproteins
  • LRG1 protein, human
  • LRG1 protein, mouse
  • Lipopolysaccharides

Grants and funding

This study was supported by JSPS KAKENHI Grant Numbers JP19K08371 (to Mi.F), JP18K09228 (to M.E.) and JP17H04215 (to T.N.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.