Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessment and model systems to tailor preventive strategies?

Cetin, Irene; Huppertz, Berthold; Burton, Graham J.; Cuckle, Howard; Gonen, Ron; Lapaire, Olav; Mandia, L.; Nicolaides, Kypros H.; Redman, C.W.G.; Soothill, Peter; Spencer, Kevin; Thilaganathan, B.; Williams, David; Meiri, Hamutal

doi:10.1016/j.placenta.2010.11.022

Cited by 76 publications

(76 citation statements)

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“…However, it is uncertain whether this may have altered the results of the studies. [30] Differences between studies and only fair diagnostic accuracy may also be explained by differences in the underlying aetiology of pregnancy outcomes and the biology of PP13. The causes of preeclampsia and SGA are heterogeneous and multifactorial and PP13 levels may be affected in some phenotypes and not in others.…”

Section: Discussionmentioning

confidence: 99%

“…The causes of preeclampsia and SGA are heterogeneous and multifactorial and PP13 levels may be affected in some phenotypes and not in others. [30] The frequent variation in PP13 levels between studies emphasizes the need for a gold standard or established normative levels for comparison, so that concentrations from heterogeneous populations can be tested by an independent marker body or be compared to a reference range. [30] Detection of PP13 may also be variable based on amounts bound to carbohydrates and/or Immunoglobulin E (IgE) bound which could limit access of the antibodies in the assay platform to the antigenic site.…”

Section: Discussionmentioning

confidence: 99%

“…[30] The frequent variation in PP13 levels between studies emphasizes the need for a gold standard or established normative levels for comparison, so that concentrations from heterogeneous populations can be tested by an independent marker body or be compared to a reference range. [30] Detection of PP13 may also be variable based on amounts bound to carbohydrates and/or Immunoglobulin E (IgE) bound which could limit access of the antibodies in the assay platform to the antigenic site. Similarly, if the PP13 was shed in syncytiotrophoblast membranes or placental exosomes [31] it may not be as readily measurable as a unbound dimeric protein.…”

Section: Discussionmentioning

confidence: 99%

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First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: In-house study and systematic review

et al. 2012

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Objective: To describe normative levels of PP13 in first-trimester of pregnancy and determine the accuracy of PP13 in predicting preeclampsia and small for gestational age (SGA) infants.Methods: We measured PP13 in archived first trimester serum samples from an unselected maternal cohort of 2,989 women. Associations of PP13 levels and diagnostic accuracy in predicting adverse pregnancy outcomes were assessed using multivariate logistic regression models. Due to inadequate number of cases we then conducted a systematic review involving structured search of electronic databases and subsequent meta-analysis of predictive accuracy using data from similar studies.Results: Overall, 2,678 women were included in the in-house study with 71 (2.7%) preeclampsia cases, 5 (0.2%) early-onset preeclampsia (≤34 weeks) cases; and 191 (7.1%) and 41 (1.5%) infants SGA<10 th and <3 rd centile. Median (IQR) normative level of PP13 in unaffected pregnancies was 53.5 (37.7-71.8) pg/ml. The area under the receiver operating characteristic curve (AUC) for multivariate models was 0.72 (95%CI 0.66-0.78) for preeclampsia; 0.82 (95%CI 0.63-0.99) for early-onset preeclampsia; 0.73 (95%CI 0.69-0.77) for SGA<10 th centile; and 0.83 (95%CI 0.78-0.88) for SGA<3 rd centile. Eight studies were included in the systematic review, normative levels of PP13 was assessed in four studies but these were variable; and meta-analysis was performed on seven studies. Sensitivity rates of PP13 based on 5% fixed false positive rates were 24%, 45% and 26% for preeclampsia, for early-onset preeclampsia and SGA, respectively.Conclusions: First-trimester PP13, in combination with maternal characteristics and other serum biomarkers was inadequate for screening purposes and predicting women at risk.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: In-house study and systematic review

et al. 2012

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“…In addition, we provide evidence that these phenomena are also in play in vivo, as evidenced by the detection of circulating PCDH12 in both serum and urine. We found that seric levels of PCDH12 were up-regulated in preeclampsia (PE), which is a leading cause of maternal and fetal mortality and morbidity that complicates 2-8% of pregnancies (24,25). Altogether, our results indicate that PCDH12 cell surface expression is highly dependent on protease-dependent shedding, a process regulated by cytokines and probably modified in pathological pregnancies.…”

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confidence: 64%

Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein

Bouillot

Tillet

Carmona

et al. 2011

Journal of Biological Chemistry

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Protocadherins are a group of transmembrane proteins with homophilic binding activity, members of the cadherin superfamily. Apart from their role in adhesion, the cellular functions of protocadherins are essentially unknown. Protocadherin (PCDH)12 was previously identified in invasive trophoblasts and endothelial and mesangial cells in the mouse. Invalidation studies revealed that the protein was required for optimal placental development. In this article, we show that its human homolog is abundantly expressed in various trophoblast subtypes of the human placenta and at lower levels in endothelial cells. We demonstrate that PCDH12 is shed at high rates in vitro. The shedding mechanism depends on ADAM10 and results in reduced cellular adhesion in a cell migration assay. PCDH12 is subsequently cleaved by the ␥-secretase complex, and its cytoplasmic domain is rapidly degraded by the proteasome. PCDH12 shedding is regulated by interlinked intracellular pathways, including those involving protein kinase C, PI3K, and cAMP, that either increase or inhibit cleavage. In endothelial cells, VEGF, prostaglandin E 2 , or histamine regulates PCDH12 shedding. The extracellular domain of PCDH12 was also detected in human serum and urine, thus providing evidence of PCDH12 shedding in vivo. Importantly, we observed an increase in circulating PCDH12 in pregnant women who later developed a pre-eclampsia, a frequent pregnancy syndrome and a major cause of maternal and fetal morbidity and mortality. In conclusion, we speculate that, like in mice, PCDH12 may play an important role in human placental development and that proteolytic cleavage in response to external factors, such as cytokines and pathological settings, regulates its activity.The cadherin superfamily is composed of membrane proteins with Ca 2ϩ -dependent cell adhesion properties and homologous sequence repeats located in their extracellular domains (1-3). These repeats are responsible for the homophilic adhesive behavior of members of the cadherin family. Four groups of cadherins have been identified so far: the "classical" type I and type II cadherins; the desmosomal cadherins; and the most recently discovered protocadherin family. Protocadherins were initially discovered by PCR cloning using cadherin homology sequences (4). With genome sequencing, more than 70 different protocadherin genes have been identified altogether. This makes protocadherins the largest subgroup within the cadherin superfamily (5). Most protocadherin genes are clustered in three loci: protocadherin (Pcdh) 3 ␣, ␤, and ␥.

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“…Several authors have studied that combination of markers improves test accuracy in predicting preeclampsia. Because of the complex structure of the PE, a combination of independent biomarkers, each reflecting a different part of the pathophysiology of the disease, should increase the likelihood to derive appropriate predictive methods [74,75]. Screening for Downs's syndrome in the first trimester is a good example where a combination of ultrasound scanning and biochemical markers are used.…”

Section: Discussionmentioning

confidence: 99%

Prediction of the preeclampsia: a view of biochemical markers

Bostancı

Bayram

Cevrioğlu

et al. 2013

RHC

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Preeclampsia is a diverse, multiorgan group of related disease processes that occurs in up to 5%-8% of pregnancies after 20 weeks' gestation and it is one of the leading causes of maternal and fetal morbidity and mortality. Many molecular mechanisms are contributed to the pathogenesis of preeclampsia. Although it is unknown whether the mechanisms act independently or have synergistic effects. This review describes review of primary papers investigating blood based biomarker such as PAP-A, Inhibin A, sFlt1, and PP13 in general and first trimester biochemical markers and combinations of them specifically for preeclampsia.

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Pregenesys pre-eclampsia markers consensus meeting: What do we require from markers, risk assessment and model systems to tailor preventive strategies?

Cited by 76 publications

References 99 publications

First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: In-house study and systematic review

First trimester screening of maternal placental protein 13 for predicting preeclampsia and small for gestational age: In-house study and systematic review

Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein

Prediction of the preeclampsia: a view of biochemical markers

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