Circulating Angiogenic Factors and Risk of Adverse Maternal and Perinatal Outcomes in Twin Pregnancies With Suspected Preeclampsia

Rana, Sarosh; Hacker, Michele R.; Modest, Anna M.; Salahuddin, Saira; Lim, Kee-Hak; Verlohren, Stefan; Perschel, F. H.; Karumanchi, S. Ananth

doi:10.1161/hypertensionaha.112.195065

Cited by 87 publications

(94 citation statements)

References 28 publications

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“…Further, we identified that both urinary PRL levels and the presence of antiangiogenic PRL fragments in urine are superior to circulating concentrations of sFlt-1/PlGF ratio and sEng in predicting the risk of combined adverse maternal outcomes, as well as of all specific adverse outcomes studied. We thus have confirmed and extended previous observations 21,22 as to the association between the circulating sFlt-1/PlGF ratio at the time of initial evaluation and subsequent adverse outcomes in women with singleton or twin pregnancies with suspected preeclampsia; additionally, those studies found an inverse correlation between the sFlt-1/PlGF ratio and the time elapsed between presentation and delivery as we did in the present study. However, we found a greater negative correlation between urinary PRL levels and time elapsed between sampling and delivery when compared with the sFlt-1/PlGF ratio or serum concentrations of sEng.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2013

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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...

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Section: Discussionsupporting

confidence: 92%

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

et al. 2013

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“…The predictive accuracy for preeclampsia-associated complications was best for the sFlt-1/PlGF with an area under the receiver operating characteristics curve of 0.89 and significantly better than other clinical tools such as blood pressure or serum markers for HELLP syndrome such as alanine aspartate transferase. In twins, similar results were shown [82]. …”

Section: Clinical Role In the Diagnosis And Management Of Preeclampsiasupporting

confidence: 84%

Update on the Pathophysiological Implications and Clinical Role of Angiogenic Factors in Pregnancy

2015

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Angiogenic markers are now being incorporated into clinical practice for the screening, diagnosing, and monitoring of preeclampsia. Pregnancy requires both vasculogenesis and angiogenesis in the fetal compartment and angiogenesis in the maternal compartment. Abnormal angiogenesis in the placenta determines impaired remodeling of the maternal spiral arteries and placental underperfusion that may ultimately lead to fetal growth restriction and maternal preeclampsia. The dysregulation of angiogenesis in the placenta and maternal-fetal circulation has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. Abnormal angiogenesis has also been related to other obstetric and fetal conditions such as peripartum cardiomyopathy and fetal cardiac defects. This opens up new challenges for our understanding of angiogenic involvement in maternal cardiovascular function and fetal cardiac development, and it offers new clinical opportunities. This review summarizes the current knowledge of the pathophysiological implications and the clinical role of angiogenic factors in pregnancy.

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“…It is known, however, that multifetal gestations exhibit different patterns of angiogenic factor serum levels with healthy twin pregnancies exhibiting a 3-fold increase in the sFlt-1/PlGF ratio as compared with singleton pregnancies. 16 Therefore, caution must be taken when applying the reference ranges and cutoffs found in this study to multifetal gestations. Furthermore, it is noteworthy that only a small proportion of patients in this European study are of other than white origin.…”

Section: Limitationsmentioning

confidence: 94%

New Gestational Phase–Specific Cutoff Values for the Use of the Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia

Verlohren

Herraı̀z²,

Lapaire³

et al. 2014

Hypertension

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Preeclampsia is a multisystem disorder in pregnancy. With an incidence of 2% to 5% of all pregnancies, it is a frequent pregnancy-related disease and a major cause of maternal and fetal morbidity and mortality.1 Preeclampsia is defined as the newonset of hypertension (≥140/90 mm Hg on 2 separate occasions ≥4 hours apart) and proteinuria (≥300 mg/24 h). 2 The simplicity of this definition contrasts with the complexity of the disease. The pathophysiology of preeclampsia is not conclusively resolved up to now. Early-onset preeclampsia, defined as the onset before 34 weeks of gestation, comprises the mal implantation of the placenta, insufficient spiral-artery remodeling, prevalently resulting in intrauterine growth restriction and an altered expression of placental proteins such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factors (PlGFs).3 In contrast, lateonset preeclampsia, defined as the onset after 34 weeks of gestation, is not necessarily accompanied by placental dysfunction 4 but angiogenic and antiangiogenic factors are also dysregulated, though to a less dramatic extent. 5 We and others have previously shown that the sFlt-1/PlGF ratio is elevated in patients with preeclampsia.6-10 The automated measurement of the sFlt-1/PlGF ratio detects early-onset preeclampsia with a sensitivity of 89% and a specificity of 97% when the single, gestation-wide cutoff of 85 is used. 8 Recently, Rana et al 9 have shown that in patients with signs and symptoms for the disease, an sFlt-1/PlGF ratio ≥85 predicts the occurrence of preeclampsia-related adverse maternal and fetal outcomes, Abstract-To establish gestational phase adapted cutoffs for the use of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio as a diagnostic tool for preeclampsia in the clinical setting, a multicenter case-control study including a total of 1149 patients was performed. We report normal values of sFlt-1, PlGF, and the sFlt-1/PlGF ratio based on the analysis of a total of 877 patients with uneventful pregnancy outcome. A total of 234 patients with preeclampsia and a matched cohort consisting of 468 patients with normal pregnancy outcome were compared, and sFlt-1 and PlGF were measured on an automated platform. Separate cutoffs for the sFlt-1/PlGF ratio were determined for the early (20+0-33+6 weeks) and the late gestational phase (34+0 weeks-delivery). For each of the 2 gestational phases, 2 independent cutoffs framing an equivocal zone were determined: the first cutoff with focus on high sensitivity, and the second focusing on high specificity. Between 20+0 and 33+6 weeks, the cutoffs at ≤33 and ≥85 resulted in a sensitivity/specificity of 95%/94% and 88%/99.5%, respectively. An sFlt-1/PlGF ratio of ≤33 had the lowest likelihood of a negative test (0.05; 95% confidence interval, 0.02-0.13), whereas values ≥85 had the highest likelihood of a positive test (176; 95% confidence interval, 24.88-1245). After 34+0 weeks, the cutoffs at ≤33 and ≥110 yielded a sensitivity/specificity of 89.6%/73.1% ...

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Circulating Angiogenic Factors and Risk of Adverse Maternal and Perinatal Outcomes in Twin Pregnancies With Suspected Preeclampsia

Cited by 87 publications

References 28 publications

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

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

Update on the Pathophysiological Implications and Clinical Role of Angiogenic Factors in Pregnancy

New Gestational Phase–Specific Cutoff Values for the Use of the Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia

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