First trimester screening of serum soluble fms-like tyrosine kinase-1 and placental growth factor predicting hypertensive disorders of pregnancy

AbstractObjectiveTo assess the accuracy of first trimester soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in predicting pregnancy hypertension and pre-eclampsia; and compare with the accuracy of routinely collected maternal and clinical risk factors.Study designIn this population-based cohort study, serum sFlt-1 and PlGF levels were measured in first trimester in 2,681 women with singleton pregnancies in New South Wales, Australia.Main outcome measuresPrediction of pregnancy hypertension and pre-eclampsia.ResultsThere were 213 (7.9%) women with pregnancy hypertension, including 68 (2.5%) with pre-eclampsia. The area under the curve (AUC) for both sFlt-1 and PlGF was not different from chance, but combined was 0.55 (P=0.005). Parity and previous diagnosed hypertension had better predictive accuracy than serum biomarkers (AUC=0.64, P<0.001) and the predictive accuracy for all maternal and clinical information was fair (AUC=0.70, P<0.001 for pregnancy hypertension and AUC=0.74, P<0.001 for pre-eclampsia). Adding sFlt-1 and PlGF to maternal risk factors did not improve the ability of the models to predict pregnancy hypertension or pre-eclampsia.ConclusionsMaternal first trimester serum concentrations of sFlt-1 and PlGF do not predict hypertensive disorders in pregnancy any better than routinely collected clinical and maternal risk factor information. Screening for sFlt-1 and PlGF levels in early pregnancy would not identify those pregnancies at-risk

First trimester screening of serum soluble fms-like tyrosine kinase-1 and placental growth factor predicting hypertensive disorders of pregnancy

AbstractObjectiveTo assess the accuracy of first trimester soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in predicting pregnancy hypertension and pre-eclampsia; and compare with the accuracy of routinely collected maternal and clinical risk factors.Study designIn this population-based cohort study, serum sFlt-1 and PlGF levels were measured in first trimester in 2,681 women with singleton pregnancies in New South Wales, Australia.Main outcome measuresPrediction of pregnancy hypertension and pre-eclampsia.ResultsThere were 213 (7.9%) women with pregnancy hypertension, including 68 (2.5%) with pre-eclampsia. The area under the curve (AUC) for both sFlt-1 and PlGF was not different from chance, but combined was 0.55 (P=0.005). Parity and previous diagnosed hypertension had better predictive accuracy than serum biomarkers (AUC=0.64, P<0.001) and the predictive accuracy for all maternal and clinical information was fair (AUC=0.70, P<0.001 for pregnancy hypertension and AUC=0.74, P<0.001 for pre-eclampsia). Adding sFlt-1 and PlGF to maternal risk factors did not improve the ability of the models to predict pregnancy hypertension or pre-eclampsia.ConclusionsMaternal first trimester serum concentrations of sFlt-1 and PlGF do not predict hypertensive disorders in pregnancy any better than routinely collected clinical and maternal risk factor information. Screening for sFlt-1 and PlGF levels in early pregnancy would not identify those pregnancies at-risk

Angiopoietin 1 and 2 serum concentrations in first trimester of pregnancy as biomarkers of adverse pregnancy outcomes

Objective: To assess Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels in the first trimester of pregnancy, their association with adverse pregnancy outcomes; and their predictive accuracy. Study Design: This cohort study measured serum Ang-1 and Ang-2 levels in 4,785 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum biomarkers with subsequent adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, miscarriage >10 weeks and stillbirth). Results: Median (interquartile range) levels for Ang-1, Ang-2 and the Ang-1/Ang-2 ratio for the total population were 19.6 ng/ml (13.6-26.4), 15.5 ng/ml (10.3-22.7) and 1.21 (0.83-1.73), respectively. Maternal age, weight, country of birth and socio-economic status significantly affected Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels. After adjusting for maternal and clinical risk factors, women with low Ang-2 levels (90th centile) had increased risk of developing most adverse pregnancy outcomes. Compared to the Ang-1/Ang-2 ratio alone, maternal and clinical risk factors had better predictive accuracy for most adverse pregnancy outcomes. The exception was miscarriage [Ang-1/Ang-2 ratio area under ROC curve (AUC) =0.70; maternal risk factors AUC =0.58]. Overall, adding the Ang-1/Ang-2 ratio to maternal risk factors did not improve the ability of the models to predict adverse pregnancy outcomes. Conclusions: Our findings suggest that the Ang-1/Ang-2 ratio in first trimester is associated with most adverse pregnancy outcomes, but do not predict outcomes any better than clinical and maternal risk factor information.Australian National Health and Medical Research Council (NHMRC) Project Grant (#632653)

Angiopoietin 1 and 2 serum concentrations in first trimester of pregnancy as biomarkers of adverse pregnancy outcomes

Objective: To assess Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels in the first trimester of pregnancy, their association with adverse pregnancy outcomes; and their predictive accuracy. Study Design: This cohort study measured serum Ang-1 and Ang-2 levels in 4,785 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum biomarkers with subsequent adverse pregnancy outcomes (small for gestational age, preterm birth, preeclampsia, miscarriage >10 weeks and stillbirth). Results: Median (interquartile range) levels for Ang-1, Ang-2 and the Ang-1/Ang-2 ratio for the total population were 19.6 ng/ml (13.6-26.4), 15.5 ng/ml (10.3-22.7) and 1.21 (0.83-1.73), respectively. Maternal age, weight, country of birth and socio-economic status significantly affected Ang-1, Ang-2 and the Ang-1/Ang-2 ratio levels. After adjusting for maternal and clinical risk factors, women with low Ang-2 levels (90th centile) had increased risk of developing most adverse pregnancy outcomes. Compared to the Ang-1/Ang-2 ratio alone, maternal and clinical risk factors had better predictive accuracy for most adverse pregnancy outcomes. The exception was miscarriage [Ang-1/Ang-2 ratio area under ROC curve (AUC) =0.70; maternal risk factors AUC =0.58]. Overall, adding the Ang-1/Ang-2 ratio to maternal risk factors did not improve the ability of the models to predict adverse pregnancy outcomes. Conclusions: Our findings suggest that the Ang-1/Ang-2 ratio in first trimester is associated with most adverse pregnancy outcomes, but do not predict outcomes any better than clinical and maternal risk factor information.Australian National Health and Medical Research Council (NHMRC) Project Grant (#632653)

Evaluation of first trimester serum soluble endothelial cell-specific tyrosine kinase receptor in normal and affected pregnancies

Aims: To assess soluble endothelial cell-specific tyrosine kinase receptor (sTie-2) levels in the first trimester of pregnancy and its association with adverse pregnancy outcomes; and examine the predictive accuracy. Study Design: In this nested case-control study, serum sTie-2 levels were measured in 2,616 women with singleton pregnancies attending first trimester screening in New South Wales, Australia. Multivariate logistic regression models were used to assess the association and predictive accuracy of serum sTie-2 with subsequent adverse pregnancy outcomes. Results: Median (interquartile range) sTie-2 for the total population was 19.6 ng/ml (13.6-26.4). Maternal age, weight, and smoking status significantly affected sTie-2 levels. There was no difference in serum sTie-2 between unaffected and women with adverse pregnancy outcomes. After adjusting maternal and clinical risk factors, low sTie-2 (<25th centile) was associated with preeclampsia (Adjusted odds ratio: 1.61; 95%CI: 1.01-2.57), however, the accuracy of sTie-2 in predicting preeclampsia was not different from chance (AUC=0.54; P=0.08) and does not add valuable predictive information to maternal and clinical risk factors. Conclusions: Our findings suggest that low sTie-2 levels are associated with preeclampsia, however, it does not add valuable information to clinical and maternal risk factor information in predicting preeclampsia or any other adverse pregnancy outcomes.NHMR

Response to Antenatal Cholecalciferol Supplementation Is Associated With Common Vitamin D-Related Genetic Variants.

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation. Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation. Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation. Setting: Hospital antenatal clinics. Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped. Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery. Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]. Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not. Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity

Preeclampsia and Blood Pressure Trajectory during Pregnancy in Relation to Vitamin D Status

Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (β = 0.03, p = 0.022) and T1 diastolic blood pressure (β = 0.02, p = 0.016), and to systolic (β = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension