Circulating Angiogenic Factors and Urinary Prolactin as Predictors of Adverse Outcomes in Women With Preeclampsia

Abstract

Preeclampsia is a multisystemic pregnancy-specific disease characterized by endothelial dysfunction.1 This condition develops in 5% to 8% of all pregnant women and remains a major cause of maternal and perinatal morbidity and mortality worldwide. 2,3 Although the cause of this pregnancy-specific syndrome is unclear, accumulating evidence suggests that preeclampsia results from an imbalance between placental proangiogenic and antiangiogenic factors that result in maternal vascular endothelium damage. 4,5 Higher circulating concentrations of soluble vascular endothelial growth factor receptor-1 (also referred as soluble fms-like tyrosine kinase-1 [sFlt-1]) and soluble endoglin (sEng), and lower concentrations of placental growth factor (PlGF), are present at the time of diagnosis of preeclampsia and have been associated with an elevated risk to develop this condition for several weeks before the onset of the clinical manifestations.5-8 On the other hand, prolactin (PRL), which is physiologically elevated during normal pregnancy, has many effects beyond reproduction and lactation, including an eminent role in angiogenesis and antiangiogenesis. 9-11The major circulating PRL isoform is a 23-kDa single-chain polypeptide (monomeric PRL), which comprises up to 90% of total PRL.12 This full-length PRL stimulates angiogenesis. In contrast, 16-and 14-kDa PRL fragments that result from proteolytic cleavage of monomeric PRL have antiangiogenic effects. 9,13 We and others have shown that urinary PRL excretion and its antiangiogenic PRL fragments are elevated in preeclamptic women, increasing with the severity of the disease and the occurrence of adverse outcomes.11,14 Furthermore, the antiangiogenic PRL fragments are also increased in serum, amniotic fluid, and placenta of preeclamptic women.14,15 These data suggest that PRL might contribute to the pathogenesis of preeclampsia and that perturbation of this angiogenesis pathway may have an important impact on the development of clinical manifestations and complications.Despite the establishment of criteria and guidelines for diagnosis of preeclampsia, its severity, and management, these criteria have been unable to predict adverse maternal outcomes.Abstract-Preeclampsia is characterized by an imbalance in angiogenic factors. Urinary prolactin (PRL) levels and its antiangiogenic PRL fragments have been associated with disease severity. In this study, we assessed whether these biomarkers are associated with an increased risk of adverse maternal and perinatal outcomes in preeclamptic women. We studied 501 women with preeclampsia attended at a tertiary care hospital. Serum concentrations of soluble fmslike tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng), as well as urinary PRL levels, were measured by enzymed-linked immunosorbent assay. Antiangiogenic PRL fragments were determined by immunoblotting. The risk for any adverse maternal outcome and for having a small-for-gestational-age infant was higher among women with sFlt-1/PlGF ratios, sEng...

Pravastatin for early‐onset pre‐eclampsia: a randomised, blinded, placebo‐controlled trial

“…Furthermore, women with pre‐eclampsia who received pravastatin had a lower baseline sFlt‐1:PlGF ratio compared with women who received placebo. Others have shown that a high sFlt‐1:PlGF ratio is associated with an increased adverse outcome and shortened time to delivery . Our own exploratory analyses confirmed this association, which could explain the slightly longer pregnancy duration following pravastatin treatment.…”

Diagnosis of preeclampsia with soluble Fms–like tyrosine kinase 1/placental growth factor ratio: an inter–assay comparison

“…10 Contrary to sFlt-1, PlGF is thought to exert a direct proangiogenic function in the maternal circulation, and the levels of PlGF are decreased early in pregnancies later complicated by preeclampsia. 11 The ratio of sFlt-1/PlGF predicts the development of preeclampsia in some, [12][13][14][15] but not all studies. 16 Failure to detect a correlation between an elevated sFlt-1/PlGF ratio and preeclampsia may reflect an imprecise diagnosis of preeclampsia or a separate disease entity; for example, failure of detecting the differential diagnosis of glomerulonephritis.…”

Advanced oxidation protein products enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts: A possible link between oxidative stress and preeclampsia

“…Alterations in the regulation and signaling of angiogenic pathways have been showed to contribute to the inadequate blood supply of the placenta in patients with pre-eclampsia [2,3].…”