Maternal Serum Meteorin Levels and the Risk of Preeclampsia

Abstract

Background: Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker.

Methods and findings: Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included.

Conclusions: The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia.

Fig 1. METRN immunohistochemisty in human placenta.

Human placenta in the first trimester of pregnancy (spontaneous abortion) in which immature mesenchymal villi of first trimester decidua are illustrated. Moderate cytoplasmic immunoreactivity for METRN was observed in cytotrophoblast cells, syncytiotrophoblast cells and decidual cells (20x). A non-specific rabbit IgG was used as negative control in place of the primary polyclonal rabbit anti-METRN antibody in each immunohistochemistry placental specimen.

Fig 2. Serum METRN levels in the three trimesters of pregnancy and in a group of eumenorrheic woman.

The highest levels of METRN are observed in early pregnancy (EP) and then decline with advancing gestation in the subsequent periods, in middle pregnancy (MP), and late pregnancy (LP), with this reduction in serum METRN being statistically significant (p <0.01). Moreover, significant differences were observed when comparing serum METRN in the groups of eumenorrheic women (EW) and EP (p <0.001).

Fig 3. Serum METRN levels in healthy and preeclamptic women during pregnancy.

A significant decrease in serum METRN in the group of mild preeclamptic pregnant women is observed when compared with the group of healthy pregnant women at the onset of pregnancy (EP) (p <0.001). The other periods analyzed did not show significant variations in serum METRN levels.

Fig 4. Classifier model based on decision trees.

Decision nodes are represented by circles. Decision nodes show the significant variables used to perform the classification: EP-METRN (METRN levels in early pregnancy), MP-SBP (systolic blood pressure in middle pregnancy), MP-Weight (weight in middle pregnancy), ∆Weight (delta of weight between middle and early pregnancy: ∆Weight = MP.weight–EP.weight) and ∆SBP (Delta of Systolic Blood Pressure between middle and early pregnancy: ∆SBP = MP.SBP–EP.SBP). Each branch represents a test given to the decision node. Leaf nodes are represented by squares. Leaf nodes show the class in which a patient is classified (normal or preeclampsia). Leaf nodes also show the total of women from the cohort that were properly classified / total of women from the cohort misclassified.