A Common Profile of Disordered Angiogenic Factor Production and the Exacerbation of Inflammation in Early Preeclampsia, Late Preeclampsia, and Intrauterine Growth Restriction

Abstract

Preeclampsia and intrauterine growth restriction are two separate disease entities that, according to numerous reports, share the same pathogenesis. In both, angiogenesis disorders and generalized inflammation are the dominant symptoms. In this study, we hypothesized that both diseases demonstrate the same profile in early preeclampsia, late preeclampsia, and intrauterine growth restriction patients, with the only difference being the degree of exacerbation of lesions. One hundred sixty-seven patients were enrolled in the study and divided into four groups: early preeclampsia, late preeclampsia, and intrauterine growth restriction groups, and one control group. Concentrations of the angiogenesis and inflammatory markers soluble fms-like tyrosine kinase receptor 1, placental growth factor, high-sensitivity C-reactive protein, and interleukin-6 were determined, and the behavior of these markers and correlations among them were studied. Higher concentrations of soluble fms-like tyrosine kinase receptor 1, high-sensitivity C-reactive protein, and interleukin-6 and a lower concentration of placental growth factor were observed in the study groups compared with the control group. No differences in concentrations of the studied markers were found among the study groups but significant correlations were observed. The higher values for the angiogenesis and inflammatory markers both in preeclampsia patients and patients with intrauterine growth restriction of placental origin compared with the control group suggest the existence of the same underlying disorders in the development of these pathologies. The observed mutual correlations for disordered angiogenesis and inflammatory markers are suggestive of a mutual relationship between these processes in the development of pathologies evolving secondary to placental ischemia. The same lesion profile was observed for both preeclampsia and 'placental' intrauterine growth restriction patients, which could be used in developing common diagnostic criteria for pregnant patients.

Fig 1. Correlation between high-sensitivity C-reactive protein (hsCRP) and fms-like tyrosine kinase receptor 1 (sFlt-1).

A positive correlation between sFlt-1 and hsCRP was observed in the study population (r = 0.47, p<0,001) using Spearman’s correlation analysis.

Fig 2. Analysis of variance of soluble fms-like tyrosine kinase receptor 1 (sFlt-1) in the study groups.

The difference between sFlt-1 concentrations of the study groups with a 95% confidence interval was p<0.0001 and F = 55.624. Interactions between groups for sFlt-1 usingTukey’s test (examining statistically significant differences) were: intrauterine growth restriction (IUGR)/control (p<0.0001); early/control (p<0.0001); and late/control (p<0.0001). log sFlt-1, log sFlt-1 concentration in plasma; early, early-onset preeclampsia; late, late-onset preeclampsia.

Fig 3. Analysis of variance for the soluble fms-like tyrosine kinase receptor 1 (sFlt-1) and placental growth factor (PlGF) ratio in the study groups.

The difference between the sFlt-1/PlGF ratio in the study groups with a 95% confidence interval was p<0.0001, F = 133.57. Interactions between groups for the sFlt-1/PlGF ratio using Tukey’s test (examining statistically significant differences) were: intrauterine growth restriction (IUGR)/control (p<0.0001); early/control (p<0.0001); late/control (p<0.0001). log sFlt-1/PlGF, log sFlt-1/PlGF ratio; early, early-onset preeclampsia; late, late-onset preeclampsia.

Fig 4. Analysis of variance for high-sensitivity C-reactive protein (hsCRP) in the study groups.

The differences between hsCRP concentrations in the study groups with a 95% confidence interval was p<0.0001, F = 134.29. Interactions between groups for hsCRP using Tukey’s test (examining statistically significant differences) were: intrauterine growth restriction (IUGR)/control (p<0.0001); early/control (p<0.0001); late/control (p<0.0001). log hsCRP, log hsCRP concentration in plasma; early, early-onset preeclampsia; late, late-onset preeclampsia.

Fig 5. Analysis of variance for interleukin (IL)-6 in the study groups.

The difference between IL-6 concentrations in the study groups with a 95% confidence interval was p<0.0001, F = 7.0022. Interactions between groups for IL-6 using Tukey’s test (examining statistically significant differences) were: intrauterine growth restriction (IUGR)/control (not significant); early/control (p<0.0001); late/control (p<0.001). log IL-6, log interleukin 6 concentration in plasma; early, early-onset preeclampsia; late, late-onset preeclampsia.

Fig 6. Analysis of variance for placental growth factor (PlGF) in the study groups.

The difference between PlGF concentrations in the study groups with a 95% confidence interval was p<0.0001, F = 98.339. Interactions between groups for PlGF using Tukey’s test (examining statistically significant differences) were: intrauterine growth restriction (IUGR)/control (p<0.0001); early/control (p<0.0001); late/control (p<0.0001). log PlGF, log PlGF concentration in plasma; early, early-onset preeclampsia; late, late-onset preeclampsia.