Maternal Second Trimester Serum Tumor Necrosis Factor- -soluble Receptor p55 (sTNFp55) and Subsequent Risk of Preeclampsia

Abstract

Preeclampsia is characterized by diffuse vascular endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha), which plays a key role in the cytokine network responsible for immunoregulation, is also known to contribute to endothelial dysfunction and other metabolic disturbances noted in preeclampsia. Results from cross-sectional studies and one longitudinal study indicate that TNF-alpha (or its soluble receptor, sTNFp55) is increased in the peripheral circulation and amniotic fluid of women with preeclampsia as compared with normotensive women. Between December 1993 and August 1994, prediagnostic sTNFp55 concentrations (a marker of excessive TNF-alpha release) were measured in 35 women with preeclampsia and 222 normotensive women to determine whether elevations precede the clinical manifestation of the disorder. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Mean second trimester (15-22 weeks' gestation) serum sTNFp55 concentrations, measured by enzyme-linked immunosorbent assay, were 14.4% higher in preeclamptic women than in normotensive controls (716.6 pg/ml (standard deviation 193.6) vs. 626.4 pg/ml (standard deviation 158.0); p = 0.003). The relative risk of preeclampsia increased across successively higher quintiles of sTNFp55 (odds ratios were 1.0, 1.3, 2.1, and 3.7, with the lowest quintile used as the referent; p for trend = 0.007). After adjustment for maternal age, adiposity, and parity, the relative risk between extreme quintiles was 3.3 (95% confidence interval 0.8-13.4). These findings indicate that the level of TNF-alpha in maternal circulation is increased prior to the clinical manifestation of the disorder, and they are consistent with the hypothesized role of cytokines in mediating endothelial dysfunction and the pathogenesis of preeclampsia. Further work is needed to identify modifiable risk factors for the excessive synthesis and release of TNF-alpha in pregnancy, and to assess whether lowering of TNF-alpha concentrations in pregnancy alters the incidence and severity of preeclampsia.

Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with subsequent pre-eclampsia

“…TNF-a is, however, also produced in adipose tissue 32 , and therefore it is essential to control for BMI. In a larger well designed study by Williams et al 33 , the circulating level of the TNF-a soluble receptor p55 was significantly increased at around 16 weeks of gestation of pre-eclamptic pregnancies. There was also a doseresponse relationship between plasma P55 and the risk of subsequent pre-eclampsia.…”

Hypertension in pregnancy

“…34 Concentrations of the soluble receptor for TNF␣ (TNF␣ receptor 1; sTNFp55) are also reportedly raised in pre-eclampsia before the clinical onset of the disease. 35,36 However, the frequency of the TNF T2 mutation in the promoter region (the only polymorphism so far studied in this context) is not increased in either pre-eclampsia or HELLP. 37 Another promising candidate gene appears to be the angiotensinogen gene.…”

Serum protein microarray analysis of patients with preeclampsia

“…in preeclampsic patients when compared to normotensive controls (25,26). While certain studies report increased TNF-α or TNF-R1 levels at as early as the first trimester in patients who subsequently develop preeclampsia, others reveal no significant difference between preeclampsic patients and controls (27,28). Leal et al found that maternal serum TNF-R1 levels at 11-13 weeks gestational age was increased in pregnant subjects developing preeclampsia, but the TNF-R1 levels were not associated with the degree of impairment in placental perfusion or the severity of preeclampsia (29).…”