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M14.6 HtrA3 is up-regulated with placental hypoxia and in serum of preeclamptic women during early gestation
State of the Art Lectures, Plenary Presentations and Oral Communications / Pregnancy Hypertension 1, Supplement 1 (2010) S1–S41
S13
M14.6
M15.2
HtrA3 is up-regulated with placental hypoxia and in serum of preeclamptic women during early gestation
Change in plasma angiogenic/antiangiogenic proteins between first and second trimester for prediction of preeclampsia in a low risk nulliparous population
Guiying Nie. Prince Henry’s Institute of Medical Research, Australia The pathogenic origin of preeclampsia is defective placental development (placentation) during early pregnancy. Owing to the lack of reliable early detection biomarkers, preeclampsia is not diagnosed until later in pregnancy and delivery remains the sole effective therapy. HtrA3 is a recently cloned gene with high expression during placentation in the mouse, rhesus monkey and human. We established that in women, placental HtrA3 protein was maximally produced in the 1st trimester, then dramatically down-regulated, especially in the syncytiotrophoblasts. HtrA3 was secreted into the maternal circulation with a serum profile reflecting placental production. Oxygen tension, which is dynamic during placentation, regulated HtrA3; hypoxia enhanced, while hypoxia-normoxia transition decreased, HtrA3 protein production and secretion specifically in syncytiotrophoblast, reflecting placental HtrA3 production. Importantly, maternal serum HtrA3 levels around the time of placental oxygen switch (∼13-14 weeks) significantly differed between women who subsequently experienced normal or preeclamptic pregnancies, being much higher in women destined to develop preeclampsia. This delay in HtrA3 down-regulation, likely reflects prolonged placental hypoxic exposure due to abnormalities in vessel remodeling (the root cause of preeclampsia). We thus provide experimental evidence and a molecular rationale suggesting abnormal maternal serum HtrA3 levels during early pregnancy are associated with development of preeclampsia.
M15.1 Low first trimester PAPP-A and PlGF are independently predictive of early onset severe pre-eclampsia
Leslie Myatt. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network, Bethesda Maryland, USA Background: Preeclampsia may present as either mild or severe and as early (<34 weeks’ gestation) or late (≥34 weeks) onset disease that may represent differing disease phenotypes. Objective: To examine the utility of PlGF, sFlt and endoglin changes between first and second trimesters for prediction of differing phenotypes of preeclampsia. Methods: Nulliparous singleton women were enrolled in a multicenter randomized trial of antioxidants to prevent preeclampsia. Plasma was drawn at 9-12, 15-18 and 23-26 weeks’ gestation and subsequently measured for PlGF, sFlt and endoglin by luminex assay. Slope was defined as the difference in the concentrations between first and early or late second trimester divided by the number of weeks between measurements. The area under the ROC curve (AUC) and sensitivity were used to assess predictive performance. Results: Between the first and early second trimester, the slopes of endoglin and PlGF were significantly different in women who developed overall, severe or early onset preeclampsia compared with normotensive women. Between the first and late second trimester, the slope of sFlt was significant for overall and severe preeclampsia and the slope of PlGF was significant for all preeclampsia phenotypes (Table 1). The PlGF slope from first and late second trimester had the highest AUCs (0.70 severe, 0.76 early onset) and the highest sensitivities for a 20% false positive rate (51.7% severe, 59.5% early onset).
Gordon Smith 1 , Jennifer Crossley 2 , David Aitken 2 , Nicola Jenkins 2 , Fiona Lyall 2 , Alan Cameron 3 , Michael Connor 2 . 1 Department of Obstetrics & Gynaecology, University of Cambridge, UK; 2 Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK; 3 Department of Fetal Medicine, Queen Mother’s Hospital, Glasgow, UK
Table 1. Change in biomarkers between first and late second trimester and phenotypes of preeclampsia
Background: First trimester levels of both PAPP-A and PlGF have been associated with the risk of pre-eclampsia. Aims: We sought to determine the ability of combinations of first trimester maternal serum levels of PAPP-A, PlGF and maternal characteristics in predicting preterm and term pre-eclampsia. Methods: We performed secondary analysis of a previously described nested case control study (Obstet Gynecol 2007;109:1316–24). Two outcomes were assessed: pre-eclampsia with medically-indicated delivery <37 weeks (preterm pre-eclampsia, n=58) and pre-eclampsia associated with delivery by any means at term (term pre-eclampsia, n=241). Controls were women delivered at term without a diagnosis of pre-eclampsia (n=937). Analytes were measured 10-14 weeks and quantified as multiples of the median (MoM) for gestational age. Logistic regression was employed and associations expressed as odds ratios (95% CI) for a decrease in MoM values from the 95th to the 5th percentile. Prediction was assessed out of sample using cross validation and quantified by area under the receiver operating characteristic curve (AUROCC). Results: Term pre-eclampsia was associated with lower PAPP-A (OR 1.63, [1.14-2.33], P=0.007) but not significantly associated with lower PlGF (OR 1.13 [0.70-1.80], P=0.62). The association with PAPP-A was virtually identical when adjusted for PlGF and maternal characteristics. Preterm pre-eclampsia was associated with both lower PAPP-A (2.59 [1.51-4.45], P=0.001) and PlGF (3.52 [1.52-8.20], P=0.003). Associations remained highly significant when adjusted for each other and maternal characteristics. Comparing models containing maternal characteristics and PAPP-A/PlGF with models only containing maternal characteristics, there was no difference in the prediction of term pre-eclampsia (AUROCC 66.4% vs 66.2%, respectively P=0.76), but better prediction of preterm pre-eclampsia (AUROCC 62.6% vs 56.6%, respectively P=0.003). Conclusions: Low first trimester levels of PAPP-A and PlGF were both associated with preterm pre-eclampsia and improved prediction compared with maternal characteristics alone.
sFlt slope* Endoglin slope# PlGF slope*
Normotensive (N=398)
Preeclampsia (N=144)
Severe Preeclampsia (N=58)
Early Onset Preeclampsia (N=37)
15.7 –0.007 25.7
23.7 –0.004 16.8
36.5 0.029 14.4
13.3 –0.008 10.8
*pg/ml/week, # ng/ml/week.
Conclusion: Change in PlGF concentration between first and early or late second trimester is associated with subsequent development of preeclampsia, especially early onset or severe.
M15.3 Maternal NT-proBNP as a risk factor for superimposed preeclampsia in chronic hypertensive pregnancies Stefano Cecchi, Stefano Raffaele Giannubilo, Valeria Bezzeccheri, Andrea Luigi Tranquilli. Dipartimento Scienze Cliniche Specialistiche UNIVPM, Italy Introduction Serum concentrations of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be used to monitor cardiac function during pregnancy; his concentrations are significantly higher in preeclamptic women compared to chronic hypertensive and normotensive pregnancies. The purpose of this study was to assess the performance of NT-proBNP concentrations in chronic hypertensive pregnancies, and its possible role, also in combination with 24-h BP monitoring and doppler of uterine arteries, in predicting the onset of superimposed preeclampsia. Methods We investigated proBNP (in his trend and expressed as proBNP/week [BNPw]) from 16w to delivery of 21 pregnant women with chronic hypertension. Twenty-four-hour BP monitoring and doppler assessment of uterine arteries were performed at first check and later at 24w. Results: Pro-BNP concentrations in chronic hypertensive pregnancies are consistently above the 75th percentile for gestational age in all chronic hypertensive pregnancies and they don’t follow the decrease observed in physiological pregnancies. We found an incidence of superimposed preeclampsia of 28.6%. Women with a BNPw >11 pg/ml had a higher risk of developing superimposed preeclamspia (OR 2.68, I.C. 1.89-3.57). This data assumes greater importance when combined with an altered 24-h BP monitoring (OR 3.44, I.C. 2.95-5.61), with an abnormal uterine artery doppler (OR 4.14, I.C. 3.54-6.79) or with both these findings (OR 7.82, I.C. 6.11-9.37).
S13
M14.6
M15.2
HtrA3 is up-regulated with placental hypoxia and in serum of preeclamptic women during early gestation
Change in plasma angiogenic/antiangiogenic proteins between first and second trimester for prediction of preeclampsia in a low risk nulliparous population
Guiying Nie. Prince Henry’s Institute of Medical Research, Australia The pathogenic origin of preeclampsia is defective placental development (placentation) during early pregnancy. Owing to the lack of reliable early detection biomarkers, preeclampsia is not diagnosed until later in pregnancy and delivery remains the sole effective therapy. HtrA3 is a recently cloned gene with high expression during placentation in the mouse, rhesus monkey and human. We established that in women, placental HtrA3 protein was maximally produced in the 1st trimester, then dramatically down-regulated, especially in the syncytiotrophoblasts. HtrA3 was secreted into the maternal circulation with a serum profile reflecting placental production. Oxygen tension, which is dynamic during placentation, regulated HtrA3; hypoxia enhanced, while hypoxia-normoxia transition decreased, HtrA3 protein production and secretion specifically in syncytiotrophoblast, reflecting placental HtrA3 production. Importantly, maternal serum HtrA3 levels around the time of placental oxygen switch (∼13-14 weeks) significantly differed between women who subsequently experienced normal or preeclamptic pregnancies, being much higher in women destined to develop preeclampsia. This delay in HtrA3 down-regulation, likely reflects prolonged placental hypoxic exposure due to abnormalities in vessel remodeling (the root cause of preeclampsia). We thus provide experimental evidence and a molecular rationale suggesting abnormal maternal serum HtrA3 levels during early pregnancy are associated with development of preeclampsia.
M15.1 Low first trimester PAPP-A and PlGF are independently predictive of early onset severe pre-eclampsia
Leslie Myatt. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network, Bethesda Maryland, USA Background: Preeclampsia may present as either mild or severe and as early (<34 weeks’ gestation) or late (≥34 weeks) onset disease that may represent differing disease phenotypes. Objective: To examine the utility of PlGF, sFlt and endoglin changes between first and second trimesters for prediction of differing phenotypes of preeclampsia. Methods: Nulliparous singleton women were enrolled in a multicenter randomized trial of antioxidants to prevent preeclampsia. Plasma was drawn at 9-12, 15-18 and 23-26 weeks’ gestation and subsequently measured for PlGF, sFlt and endoglin by luminex assay. Slope was defined as the difference in the concentrations between first and early or late second trimester divided by the number of weeks between measurements. The area under the ROC curve (AUC) and sensitivity were used to assess predictive performance. Results: Between the first and early second trimester, the slopes of endoglin and PlGF were significantly different in women who developed overall, severe or early onset preeclampsia compared with normotensive women. Between the first and late second trimester, the slope of sFlt was significant for overall and severe preeclampsia and the slope of PlGF was significant for all preeclampsia phenotypes (Table 1). The PlGF slope from first and late second trimester had the highest AUCs (0.70 severe, 0.76 early onset) and the highest sensitivities for a 20% false positive rate (51.7% severe, 59.5% early onset).
Gordon Smith 1 , Jennifer Crossley 2 , David Aitken 2 , Nicola Jenkins 2 , Fiona Lyall 2 , Alan Cameron 3 , Michael Connor 2 . 1 Department of Obstetrics & Gynaecology, University of Cambridge, UK; 2 Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, UK; 3 Department of Fetal Medicine, Queen Mother’s Hospital, Glasgow, UK
Table 1. Change in biomarkers between first and late second trimester and phenotypes of preeclampsia
Background: First trimester levels of both PAPP-A and PlGF have been associated with the risk of pre-eclampsia. Aims: We sought to determine the ability of combinations of first trimester maternal serum levels of PAPP-A, PlGF and maternal characteristics in predicting preterm and term pre-eclampsia. Methods: We performed secondary analysis of a previously described nested case control study (Obstet Gynecol 2007;109:1316–24). Two outcomes were assessed: pre-eclampsia with medically-indicated delivery <37 weeks (preterm pre-eclampsia, n=58) and pre-eclampsia associated with delivery by any means at term (term pre-eclampsia, n=241). Controls were women delivered at term without a diagnosis of pre-eclampsia (n=937). Analytes were measured 10-14 weeks and quantified as multiples of the median (MoM) for gestational age. Logistic regression was employed and associations expressed as odds ratios (95% CI) for a decrease in MoM values from the 95th to the 5th percentile. Prediction was assessed out of sample using cross validation and quantified by area under the receiver operating characteristic curve (AUROCC). Results: Term pre-eclampsia was associated with lower PAPP-A (OR 1.63, [1.14-2.33], P=0.007) but not significantly associated with lower PlGF (OR 1.13 [0.70-1.80], P=0.62). The association with PAPP-A was virtually identical when adjusted for PlGF and maternal characteristics. Preterm pre-eclampsia was associated with both lower PAPP-A (2.59 [1.51-4.45], P=0.001) and PlGF (3.52 [1.52-8.20], P=0.003). Associations remained highly significant when adjusted for each other and maternal characteristics. Comparing models containing maternal characteristics and PAPP-A/PlGF with models only containing maternal characteristics, there was no difference in the prediction of term pre-eclampsia (AUROCC 66.4% vs 66.2%, respectively P=0.76), but better prediction of preterm pre-eclampsia (AUROCC 62.6% vs 56.6%, respectively P=0.003). Conclusions: Low first trimester levels of PAPP-A and PlGF were both associated with preterm pre-eclampsia and improved prediction compared with maternal characteristics alone.
sFlt slope* Endoglin slope# PlGF slope*
Normotensive (N=398)
Preeclampsia (N=144)
Severe Preeclampsia (N=58)
Early Onset Preeclampsia (N=37)
15.7 –0.007 25.7
23.7 –0.004 16.8
36.5 0.029 14.4
13.3 –0.008 10.8
*pg/ml/week, # ng/ml/week.
Conclusion: Change in PlGF concentration between first and early or late second trimester is associated with subsequent development of preeclampsia, especially early onset or severe.
M15.3 Maternal NT-proBNP as a risk factor for superimposed preeclampsia in chronic hypertensive pregnancies Stefano Cecchi, Stefano Raffaele Giannubilo, Valeria Bezzeccheri, Andrea Luigi Tranquilli. Dipartimento Scienze Cliniche Specialistiche UNIVPM, Italy Introduction Serum concentrations of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be used to monitor cardiac function during pregnancy; his concentrations are significantly higher in preeclamptic women compared to chronic hypertensive and normotensive pregnancies. The purpose of this study was to assess the performance of NT-proBNP concentrations in chronic hypertensive pregnancies, and its possible role, also in combination with 24-h BP monitoring and doppler of uterine arteries, in predicting the onset of superimposed preeclampsia. Methods We investigated proBNP (in his trend and expressed as proBNP/week [BNPw]) from 16w to delivery of 21 pregnant women with chronic hypertension. Twenty-four-hour BP monitoring and doppler assessment of uterine arteries were performed at first check and later at 24w. Results: Pro-BNP concentrations in chronic hypertensive pregnancies are consistently above the 75th percentile for gestational age in all chronic hypertensive pregnancies and they don’t follow the decrease observed in physiological pregnancies. We found an incidence of superimposed preeclampsia of 28.6%. Women with a BNPw >11 pg/ml had a higher risk of developing superimposed preeclamspia (OR 2.68, I.C. 1.89-3.57). This data assumes greater importance when combined with an altered 24-h BP monitoring (OR 3.44, I.C. 2.95-5.61), with an abnormal uterine artery doppler (OR 4.14, I.C. 3.54-6.79) or with both these findings (OR 7.82, I.C. 6.11-9.37).