Angiogenic imbalance in pre-eclampsia and fetal growth restriction: enhanced soluble fms-like tyrosine kinase-1 binding or diminished production of placental growth factor?

OBJECTIVES: To assess levels of total placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and free PlGF in women with pre-eclampsia (PE) with or without a small-for-gestational-age (SGA) neonate in order to establish whether low free PlGF levels associated with PE and SGA are due to enhanced sFlt-1 binding or decreased PlGF production. METHODS: This was a secondary analysis of a prospective multicenter cohort study involving 407 pregnancies with suspected or confirmed PE, in which total PlGF levels were calculated from measured sFlt-1 and free PlGF levels. The control group included women who were suspected to have PE at a certain point in pregnancy but did not develop PE. The analysis was stratified according to whether PE was early- or late-onset (gestational age < 34 weeks vs ≥ 34 weeks) and according to the presence of SGA at birth, which was used as a proxy of fetal growth restriction in the absence of Doppler ultrasound and biometric data. RESULTS: In early-onset PE, both women with and those without SGA had lower free (19 and 45 pg/mL) and total (44 and 100 pg/mL) PlGF levels compared with women without PE (free and total PlGF, 300 and 381 pg/mL, respectively). SGA alone did not affect free and total PlGF in this condition (free and total PlGF, 264 and 352 pg/mL, respectively). Observations in women with late-onset PE were similar, although the changes were more modest. Both SGA (gestational age < 34 weeks) and PE were individually associated with increased sFlt-1 and, in women with both PE and SGA, the upregulation of sFlt-1 occurred in a synergistic manner, thus resulting in the highest sFlt-1/free PlGF ratio in this group. This occurred in both early- and late-onset PE. CONCLUSIONS: Particularly in pregnancies with early-onset PE and SGA, diminished PlGF production is an important cause of low free PlGF levels. Under such conditions, sFlt-1 lowering is unlikely to restore the angiogenic balance. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of pre-eclampsia-related complications in women with suspected or confirmed pre-eclampsia: development and internal validation of clinical prediction model.

OBJECTIVE: A model that can predict reliably the risk of pre-eclampsia (PE)-related pregnancy complications does not exist. The aim of this study was to develop and validate internally a clinical prediction model to predict the risk of a composite outcome of PE-related maternal and fetal complications within 7, 14 and 30 days of testing in women with suspected or confirmed PE. METHODS: The data for this study were derived from a prospective, multicenter, observational cohort study on women with a singleton pregnancy and suspected or confirmed PE at 20 to < 37 weeks' gestation. For the development of the prediction model, the possible contribution of clinical and standard laboratory variables, as well as the biomarkers soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and their ratio, in the prediction of a composite outcome of PE-related complications, consisting of maternal and fetal adverse events within 7, 14 and 30 days, was explored using multivariable competing-risks regression analysis. The discriminative ability of the model was assessed using the concordance (c-) statistic. A bootstrap validation procedure with 500 replications was used to correct the estimate of the prediction model performance for optimism and to compute a shrinkage factor for the regression coefficients to correct for overfitting. RESULTS: Among 384 women with suspected or confirmed PE, 96 (25%) had an adverse PE-related outcome at any time after hospital admission. Important predictors of adverse PE-related outcome included sFlt-1/PlGF ratio, gestational age at the time of biomarker measurement and protein-to-creatinine ratio as continuous variables. The c-statistics (corrected for optimism) for developing a PE-related complication within 7, 14 and 30 days were 0.89, 0.88 and 0.87, respectively. There was limited overfitting, as indicated by a shrinkage factor of 0.91. CONCLUSIONS: We propose a simple clinical prediction model with good discriminative performance to predict PE-related complications. Determination of its usefulness in clinical practice awaits further investigation and external validation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Copeptin and mid-regional pro-atrial natriuretic peptide in women with suspected or confirmed pre-eclampsia: comparison with sFlt-1/PlGF ratio.

OBJECTIVES: Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) may contribute to the pathogenesis of pre-eclampsia (PE), but their role remains to be elucidated. Our aims were to evaluate the surrogates of AVP and ANP, C-terminal pro-AVP (copeptin) and mid-regional pro-ANP (MR-proANP), as biomarkers for the prediction of PE-related pregnancy complications and whether they are associated with angiogenic markers and/or clinical manifestations of PE. METHODS: This was a retrospective analysis of a prospective cohort study that enrolled pregnant women with suspected or confirmed PE, between December 2013 and April 2016. From each patient, a blood sample was obtained at study entry and serum levels of copeptin, MR-proANP, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. We evaluated the ability of sFlt-1, PlGF, sFlt-1/PlGF ratio, copeptin and MR-proANP, assessed either alone or combined with traditional predictors (gestational age, parity, diastolic blood pressure and proteinuria), to predict maternal complications and fetal/neonatal complications. Models were compared using concordance statistic (C-index). RESULTS: A total of 526 women were evaluated in the study. Women with confirmed PE displayed elevated serum copeptin and MR-proANP levels in comparison to those with suspected PE but no hypertensive disease of pregnancy. When combined with traditional predictors, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP (0.76, 0.63 and 0.67, respectively, vs 0.60 for the traditional predictors alone) for the prediction of maternal complications. Similarly, for the prediction of fetal/neonatal complications, the sFlt-1/PlGF ratio displayed a higher C-index than copeptin and MR-proANP when added to the traditional model (0.83, 0.79 and 0.80, respectively, vs 0.79 for the traditional predictors alone). When subdividing women according to sFlt-1/PlGF ratio (≥ 85 vs < 85), no differences in copeptin levels were observed, while MR-proANP level was elevated in women with sFlt-1/PlGF ratio ≥ 85. Multiple regression analysis revealed that copeptin and MR-proANP were independent determinants of proteinuria. CONCLUSIONS: Copeptin and MR-proANP have limited value in predicting PE-related complications when compared with the sFlt-1/PlGF ratio. However, both copeptin and MR-proANP were associated with proteinuria, with copeptin exerting this effect independently of the sFlt-1/PlGF ratio. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.