The role of urinary soluble endoglin in the diagnosis of pre-eclampsia: comparison with soluble fms-like tyrosine kinase 1 to placental growth factor ratio.

OBJECTIVE: Endoglin, an anti-angiogenic glycoprotein expressed on endothelial cells, has been proposed recently as a biomarker of pre-eclampsia (PE). Given that PE is characterised by an imbalance of angiogenic factors, we sought to determine the clinical utility of urinary soluble endoglin, relative to the soluble fms-like tyrosine kinase 1 to placental growth factor (PlGF) ratio, in the diagnosis of PE during gestation. DESIGN: Prospective observational cohort. SETTING: Tertiary referral university hospital. POPULATION: Two hundred and thirty-four pregnant women were enrolled prospectively in the following groups: healthy controls, n = 63; gestational age (GA), median (interquartile range), 33 weeks (27-39 weeks); chronic hypertension, n = 27; GA, 33 weeks (30-36 weeks); mild PE, n = 38; GA, 37 weeks (34-40 weeks); severe PE, n = 106; GA, 32 weeks (29-37 weeks). METHODS: Free urinary levels of soluble endoglin, soluble fms-like tyrosine kinase 1 and PlGF were measured by sensitive and specific immunoassay. Levels for all urinary analytes were normalised to creatinine. MAIN OUTCOME MEASURES: Urinary soluble endoglin, and the soluble fms-like tyrosine kinase 1 to PlGF ratio. RESULTS: In healthy controls, urinary soluble endoglin levels were increased significantly at term relative to those earlier in gestation. Severe PE was characterised by an increased urinary level of soluble endoglin, soluble fms-like tyrosine kinase 1, protein to creatinine ratio and soluble fms-like tyrosine kinase 1 to PlGF ratio compared with all other groups. There was a direct correlation between urinary soluble endoglin and proteinuria that remained after GA correction (R = 0.382, P < 0.001). Urinary soluble endoglin could not differentiate mild PE from severe preterm PE. Overall, soluble endoglin had the ability to discriminate PE from chronic hypertension and healthy controls only in women who were evaluated at <37 weeks of GA. The sensitivity, specificity and accuracy of urinary soluble endoglin alone in the diagnosis of PE or in the identification of women with PE requiring a mandated delivery before 37 weeks of gestation were 70%, 86% and 76%, respectively. These values were inferior to those of the soluble fms-like tyrosine kinase 1 to PlGF ratio (P < 0.001). The addition of urinary soluble endoglin did not improve the diagnostic accuracy of the soluble fms-like tyrosine kinase 1 to PlGF ratio alone. CONCLUSIONS: We have provided evidence that soluble endoglin is present and elevated in the urine of women who develop preterm PE. Urinary soluble endoglin has only limited ability to determine the severity of PE and to distinguish between PE and chronic hypertension both preterm and at term. Compared with urinary soluble endoglin, the soluble fms-like tyrosine kinase 1 to PlGF ratio remains a better marker of disease presence, severity and outcome.

Fetal inflammatory response in women with proteomic biomarkers characteristic of intra-amniotic inflammation and preterm birth.

OBJECTIVE: To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1 and calgranulins C and A) and fetal inflammatory status at birth. DESIGN: Prospective observational cohort. SETTING: Tertiary referral University hospital. POPULATION: One hundred and thirty-two consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.1] weeks) who had a clinically indicated amniocentesis to rule out infection and their newborns. METHODS: Intra-amniotic inflammation was diagnosed by mass spectrometry surface-enhanced-laser-desorption-ionization time of flight (SELDI-TOF). The AF proteomic fingerprint (mass-restricted [MR] score) ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: 'no' inflammation, MR score 1-2: 'minimal' inflammation and MR score 3-4: 'severe' inflammation. At birth, cord blood was obtained for all women. Severity of histological chorioamnionitis and early-onset neonatal sepsis (EONS) was based on established histological and haematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment. MAIN OUTCOME MEASURES: To relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response. RESULTS: Women with intra-amniotic inflammation delivered at an earlier gestational age (analysis of variance, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with severe intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterised by significantly elevated cord blood IL-6 levels (P<0.001). Of the 39 neonates delivered by mothers with minimal intra-amniotic inflammation, 15 (39%) neonates had umbilical cord blood IL-6 levels above the mean for the group and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001) but not in the amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to-delivery interval, caesarean delivery, status of the membranes, race, MR score and antibiotics and steroid exposure. CONCLUSIONS: We provide evidence that presence of proteomic biomarkers characteristic of inflammation in the AF is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of minimal intra-amniotic inflammation.