Background We aimed to evaluate the value of inhibin A and PAPP‐A2 (pregnancy‐associated plasma protein‐A2) as novel biomarkers in the prediction of preeclampsia‐related complications and how they compare with angiogenic biomarkers. Methods and Results Making use of a secondary analysis of a prospective, multicenter, observational study, intended to evaluate the usefulness of sFlt‐1 (soluble Fms‐like tyrosine kinase‐1)/PlGF (placental growth factor) ratio, we measured inhibin A and PAPP‐A2 levels in 524 women with suspected/confirmed preeclampsia. Women had a median gestational age of 35 weeks (range, 20–41 weeks) while preeclampsia occurred in 170 (32%) women. Levels of inhibin A and PAPP‐A2 were significantly increased in women with preeclampsia and in maternal perfusate of preeclamptic placentas. Inhibin A and PAPP‐A2 (C‐index = 0.73 and 0.75) significantly improved the prediction of maternal complications when added on top of the traditional criteria; gestational age, parity, proteinuria, and diastolic blood pressure (C‐index = 0.60). PAPP‐A2 was able to improve the C‐index from 0.75 to 0.77 when added on top of the sFlt‐1/PlGF ratio for the prediction of maternal complications. To discriminate fetal/neonatal complications on top of traditional criteria, inhibin A and PAPP‐A2 showed additive value (C‐index = 0.79 to 0.80 and 0.82, respectively) but their discriminative ability remained inferior to that of sFlt‐1/PlGF ratio or PlGF. Interestingly, the PAPP‐A2/PlGF ratio alone showed remarkable value to predict pregnancy complications, being superior to sFlt‐1/PlGF ratio in the case of maternal complications. Conclusions Inhibin A and PAPP‐A2 show significant potential to predict preeclampsia‐related pregnancy complications and might prove beneficial on top of the angiogenic markers.

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.