PAPP‐A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia

Neuman, Rugina I.; Meer, Maaike M. Alblas van der; Nieboer, Daan; Saleh, Langeza; Verdonk, Koen; Kalra, Bhanu; Kumar, Ajay; Alpadi, Kannan; Meiracker, Anton H. van den; Visser, Willy; Danser, A.H. Jan

doi:10.1161/jaha.120.018219

Cited by 24 publications

(27 citation statements)

References 24 publications

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“…Similarly, the expression of SDC1, NPPB (natriuretic peptide B), GDF15 (growth differentiation factor 15), and ADAMTS6 (ADAM metallopeptidase with thrombospondin type 1 motif 6) all had a lower expression in our experimental exposures, and all are lower in preeclampsia ( Junus et al, 2014 ; Chen et al, 2016 ; Gandley et al, 2016 ; Jiang et al, 2020 ). In contrast, our data are inconsistent with respect to the expression of PAPPA2, a regulator of trophoblast invasion and migration, or MNDA (myeloid cell nuclear differentiation antigen), which exhibited a lower expression level in our paradigms but is elevated in placentas from women with preeclampsia ( Wagner et al, 2011 ; Kolialexi et al, 2017 ; Neuman et al, 2020 ).…”

Section: Discussioncontrasting

confidence: 97%

RNA Network Interactions During Differentiation of Human Trophoblasts

Chu

Mouillet

Cao

et al. 2021

Front. Cell Dev. Biol.

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In the human placenta, two trophoblast cell layers separate the maternal blood from the villous basement membrane and fetal capillary endothelial cells. The inner layer, which is complete early in pregnancy and later becomes discontinuous, comprises the proliferative mononuclear cytotrophoblasts, which fuse together and differentiate to form the outer layer of multinucleated syncytiotrophoblasts. Because the syncytiotrophoblasts are responsible for key maternal-fetal exchange functions, tight regulation of this differentiation process is critical for the proper development and the functional role of the placenta. The molecular mechanisms regulating the fusion and differentiation of trophoblasts during human pregnancy remain poorly understood. To decipher the interactions of non-coding RNAs (ncRNAs) in this process, we exposed cultured primary human trophoblasts to standard in vitro differentiation conditions or to conditions known to hinder this differentiation process, namely exposure to hypoxia (O2 < 1%) or to the addition of dimethyl sulfoxide (DMSO, 1.5%) to the culture medium. Using next generation sequencing technology, we analyzed the differential expression of trophoblastic lncRNAs, miRNAs, and mRNAs that are concordantly modulated by both hypoxia and DMSO. Additionally, we developed a model to construct a lncRNA-miRNA-mRNA co-expression network and inferred the functions of lncRNAs and miRNAs via indirect gene ontology analysis. This study improves our knowledge of the interactions between ncRNAs and mRNAs during trophoblast differentiation and identifies key biological processes that may be impaired in common gestational diseases, such as fetal growth restriction or preeclampsia.

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Section: Discussioncontrasting

confidence: 97%

RNA Network Interactions During Differentiation of Human Trophoblasts

Chu

Mouillet

Cao

et al. 2021

Front. Cell Dev. Biol.

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“…The high correlation was found for increased Inhibin-A and sflt-1 / PlGF ratio for PE and PE+FGR, but not for FGR alone, whereas the decrease of PlGF yielded high correlations with each of the three complications. Hence, we are expanding the conclusions of Neuman et al [42].…”

Section: Interpretation Of Results and Comparison With Findings Of Prmentioning

confidence: 59%

“…Inhibin-A is a glycoprotein hormone that is abundantly expressed in the placenta and its levels in both the placental and circulating maternal levels are increased in cases of PE, and the increase is apparent from the second trimester of pregnancy [23,26,27]. Inhibin-A was initially identified as a second trimester marker of chromosomal abnormalities [37] and was subsequently reported as a second and third trimester marker of PE [37][38][39][40][41][42]. We found that Inhibin-A level is considerably higher in early than late PE the magnitude of increase was greater in PE alone rather than PE+FGR or FGR alone.…”

Section: Interpretation Of Results and Comparison With Findings Of Prmentioning

confidence: 99%

“…We added to the above the finding and quantification of the added value of Inhibin-A on top of the angiogenic markers and showed its value mainly in augmenting the accuracy of predicting PE. Neuman et al [42] were the first to examine the added value of Inhibin-A to that of angiogenic markers and reported that this was beneficial mainly for early rather than late PE. We found that Inhibin-A had an additive value to both PlGF and the sFlt-1 / PlGF ratio in the prediction of both early and late PE and to a lesser extent of PE+FGR.…”

Section: Interpretation Of Results and Comparison With Findings Of Prmentioning

confidence: 99%

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Inhibin-A Augments Plgf and the Sflt-1 / Plgf Ratio in the Prediction of Preeclampsia and / or Fgr near Delivery

Sharabi-Nov¹,

Sršen²,

Kumar³

et al. 2020

Preprint

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Objective: We previously provided evidence to confirm that soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio, are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this study we examine the potential additive value of Inhibin-A, a hormone marker of the transforming growth factor family. Methods: We used a cohort of 125 pregnant women enrolled near delivery at clinics of the University Medical Center of Ljubljana, Slovenia. There were 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 iatrogenic preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 13 of PE, 12 of FGR, 22 of PE+FGR, and 6 of PTD. We recorded demographic characteristics and medical history and the levels of PlGF, sFlt-1 and Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations was estimated from areas under the curve (AUC) of Receiver Operating Characteristics (ROC) curves. We estimated accuracy by the continuous marker model and a cut-off model. Results: Combining Inhibin-A with PlGF or with the sFlt-1 / PlGF ratio showed a 10-20% increase in AUCs and 5-15% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR but not for FGR alone. The use of a cut-off model was adequate, although a bit higher accuracy was obtained from the continuous model. Highest correlation was found for PlGF with all three complications. Conclusion: Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by the angiogenic markers alone, bringing the results to a diagnostic level, thus assisting in directing clinical management. Inhibin-A had no added value for the accuracy of predicting FGR alone.

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“…Inhibin-A is a glycoprotein hormone that is abundantly expressed in the placenta, and its levels in both the placental and circulating maternal levels are increased in cases of PE, and the increase is apparent from the second trimester of pregnancy [23,26,27]. Inhibin-A was initially identified as a second trimester marker of chromosomal abnormalities [37] and was subsequently reported as a second and third trimester marker of PE [37][38][39][40][41][42]. We found that the Inhibin-A level is considerably higher in early than late PE; the magnitude of increase was greater in PE alone rather than PE+FGR or FGR alone.…”

Section: Interpretation Of Results and Comparison With Findings Of Previous Studiesmentioning

confidence: 99%

Maternal Serum Inhibin-A Augments the Value of Maternal Serum PlGF and of sFlt-1/PlGF Ratio in the Prediction of Preeclampsia and/or FGR Near Delivery—A Secondary Analysis

et al. 2021

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Objective: We previously provided evidence to confirm that maternal serum levels of soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this secondary analysis, we further examine the potential additive value of maternal serum Inhibin-A, which is a hormone marker of the transforming growth factor family, to the accuracy provided by maternal serum PlGF and sFlt-1. Methods: We conducted a secondary analysis where we extracted the data of a cohort of 125 pregnant women enrolled near delivery at the clinics of the University Medical Center of Ljubljana, Slovenia. The dataset included 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 10 of PE, 12 of FGR, 28 of PE+FGR, and 6 of PTD. In addition to the recorded demographic characteristics and medical history and the maternal serum levels of PlGF and sFlt-1/PlGF ratio, which were previously published, we evaluated the added value of maternal serum Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations were estimated from areas under the curve (AUC) of receiver operating characteristics (ROC) curves, Box and Whisker plots, and by multiple regression. We estimated accuracy by the continuous marker model and a cutoff model. Results: In this study, we combined Inhibin-A with PlGF or with the sFlt-1/PlGF ratio and showed a 10–20% increase in AUCs and 15–45% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR and FGR in all cases but not for FGR in early cases delivered < 34 weeks. The use of a cutoff model was adequate, although a bit higher accuracy was obtained from the continuous model. The highest correlation was found for PlGF with all three complications. Conclusion: In this secondary analysis, we have found that maternal serum Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by maternal serum angiogenic markers alone, bringing the results to a diagnostic level; thus, it could be considered for directing clinical management. Inhibin-A had smaller or no added value for the accuracy of predicting FGR alone, mainly of early cases delivered <34 weeks.

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PAPP‐A2 and Inhibin A as Novel Predictors for Pregnancy Complications in Women With Suspected or Confirmed Preeclampsia

Cited by 24 publications

References 24 publications

RNA Network Interactions During Differentiation of Human Trophoblasts

RNA Network Interactions During Differentiation of Human Trophoblasts

Inhibin-A Augments Plgf and the Sflt-1 / Plgf Ratio in the Prediction of Preeclampsia and / or Fgr near Delivery

Maternal Serum Inhibin-A Augments the Value of Maternal Serum PlGF and of sFlt-1/PlGF Ratio in the Prediction of Preeclampsia and/or FGR Near Delivery—A Secondary Analysis

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