Performance Of Screening For Pre-eclampsia Research Articles

Maternal vascular indices at 36 weeks’ gestation in the prediction of preeclampsia

Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they wereboth superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

STATIN trial: predictive performance of competing-risks model in screening for pre-eclampsia at 35-37 weeks' gestation.

To examine the predictive performance of a previously reported competing-risks model of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by combinations of maternal risk factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in a validation dataset derived from the screened population of the STATIN study. This was a prospective third-trimester multicenter study of screening for PE in singleton pregnancies by means of a previously reported algorithm that combines maternal risk factors and biomarkers. Women in the high-risk group were invited to participate in a trial of pravastatin vs placebo, but the trial showed no evidence of an effect of pravastatin in the prevention of PE. Patient-specific risks of delivery with PE were calculated using the competing-risks model, and the performance of screening for PE by maternal risk factors alone and by various combinations of risk factors with MAP, UtA-PI, PlGF and sFlt-1 was assessed. The predictive performance of the model was examined by, first, the ability of the model to discriminate between the PE and no-PE groups using the area under the receiver-operating-characteristics curve (AUC) and the detection rate at a fixed false-positive rate of 10%, and, second, calibration by measurements of calibration slope and calibration-in-the-large. The study population of 29 677 pregnancies contained 653 that developed PE. In screening for PE by a combination of maternal risk factors, MAP, PlGF and sFlt-1 (triple test), the detection rate at a 10% false-positive rate was 79% (95% CI, 76-82%) and the results were consistent with the data used for developing the algorithm. Addition of UtA-PI did not improve the prediction provided by the triple test. The AUC for the triple test was 0.923 (95% CI, 0.913-0.932), demonstrating very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 0.875 (95% CI, 0.831-0.919), demonstrating good agreement between the predicted risk and observed incidence of PE. The competing-risks model provides an effective and reproducible method for third-trimester prediction of term PE. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Mortality and Postdischarge Acute Care Utilization for Cardiovascular Conditions at Safety-Net Versus Non–Safety-Net Hospitals

Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear.This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers.Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured.In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function.Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Contingent screening in stratification of pregnancy care based on risk of pre-eclampsia at 19-24 weeks' gestation.

To explore the possibility of carrying out routine screening for pre-eclampsia (PE) with delivery at < 28, < 32, < 36 weeks' gestation by maternal factors, uterine artery pulsatility index (UtA-PI) and mean arterial pressure (MAP) in all pregnancies and reserving measurements of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) for only a subgroup of the population. This was a prospective observational study in two UK maternity hospitals involving women with singleton pregnancy attending for routine assessment at 19-24 weeks' gestation. The improvement in performance of screening for PE, at fixed risk cut-offs, by the addition of serum PlGF and sFlt-1 to screening by maternal factors, UtA-PI and MAP, was estimated. We examined a policy of contingent screening in which biochemical testing was reserved for only a subgroup of the population. The main outcome measures were the additional contribution of PlGF and sFlt-1 to the performance of screening for PE and the proportion of the population requiring measurement of PlGF and sFlt-1 for maximum performance of screening. The study population included 37 886 singleton pregnancies. At each risk cut-off, the highest detection rates for delivery with PE and the lowest screen-positive rates were achieved in screening with maternal factors, UtA-PI, MAP, PlGF and sFlt-1. The maximum performance by such screening was also achieved by contingent screening in which PlGF and sFlt-1 were measured in only about 40% of the population. The performance of screening for PE by a combination of maternal factors, UtA-PI and MAP is improved by measurement of PlGF and sFlt-1 in about 40% of the population. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Stratification of pregnancy care based on risk of pre-eclampsia derived from biophysical and biochemical markers at 19-24 weeks' gestation.

We have proposed previously that all pregnant women should have assessment of risk for pre-eclampsia (PE) at 20 and 36 weeks' gestation and that the 20-week assessment should be used to define subgroups requiring additional monitoring and reassessment at 28 and 32 weeks. The objective of this study was to examine the potential improvement in screening at 19-24 weeks' gestation for PE with delivery at < 28, < 32, < 36 and ≥ 36 weeks' gestation by the addition of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) to the combination of maternal demographic characteristics and medical history, uterine artery pulsatility index (UtA-PI) and mean arterial pressure (MAP). This was a prospective, non-intervention study in women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 36 weeks' gestation were calculated using the competing-risks model to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiples of the median values of UtA-PI, MAP, PlGF and sFlt-1. Different risk cut-offs were used to vary the proportion of the population stratified into each of four risk categories (very high risk, high risk, intermediate risk and low risk) with the intention of detecting about 80%, 85%, 90% and 95% of cases of delivery with PE at < 28, < 32 and < 36 weeks' gestation. The performance of screening was assessed by plotting the detection rate against the screen-positive rate and calculating the areas under these curves, and by the proportion stratified into a given group for fixed detection rates. Model-based estimates of screening performance for these various combinations of markers were also produced. In the study population of 37 886 singleton pregnancies, there were 1130 (3.0%) that subsequently developed PE, including 160 (0.4%) that delivered at < 36 weeks' gestation. In both the modeled and empirical results, there was incremental improvement in the performance of screening with the addition of PlGF and sFlt-1 to the combination of maternal factors, UtA-PI and MAP. If the objective of screening was to identify about 90% of cases of PE with delivery at < 28, < 32 and < 36 weeks and the method of screening was a combination of maternal factors, UtA-PI and MAP, the respective screen-positive rates would be 3.1%, 8.5% and 19.1%. The respective values for screening by maternal factors, UtA-PI, MAP and PlGF were 0.2%, 0.7% and 10.6%, and for screening by maternal factors, UtA-PI, MAP, PlGF and sFlt-1 they were 0.1%, 0.4% and 9.5%. The empirical results were consistent with the modeled results. There was good agreement between the predicted risk and the observed incidence of PE at < 36 weeks' gestation for all three strategies of screening. Prediction of PE at ≥ 36 weeks was poor for all three screening methods, with the detection rate, at a 10% screen-positive rate, ranging from 33.2% to 38.4%. The performance of screening at 19-24 weeks' gestation for PE with delivery at < 28, < 32 and < 36 weeks' gestation achieved by a combination of maternal demographic characteristics and medical history, UtA-PI and MAP is improved by the addition of serum PlGF and sFlt-1. The performance of screening for PE at ≥ 36 weeks' gestation is poor irrespective of the method of screening at 19-24 weeks. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal fraction of cell free DNA in screening for hypertensive disorders at 11–13 weeks

Objective To investigate whether first-trimester maternal plasma fetal fraction is altered in women that subsequently develop preeclampsia (PE) or gestational hypertension (GH) and to examine its potential value in improving the performance of screening for PE and GH by maternal factors and maternal serum pregnancy associated plasma protein-A (PAPP-A), mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI). Methods The study population of 10,131 pregnancies undergoing cell free fetal DNA testing at 11–13 weeks’ gestation included 91 (0.9%) cases with preterm-PE, 222 (2.2%) cases with term-PE, 360 (3.6%) with GH and 9,458 (93.4%) cases unaffected by hypertensive disorders. Maternal plasma fetal fraction levels were expressed as multiples of the median (MoM) after adjustment for maternal factors and crown-rump length. The performance of screening for preterm-PE, term PE and GH by maternal factors and MoM values of fetal fraction, PAPP-A, UtA-PI and MAP was evaluated by receiver operating characteristic (ROC) curves. Results The median fetal fraction MoM was significantly lower in the preterm-PE (0.825; IQR 0.689–1.115 MoM, p < .001), term-PE (0.946; IQR 0.728–1.211 MoM, p = .028) and GH (0.928; IQR 0.711–1.182 MoM, p < .001) groups than in the unaffected group (1.002; IQR 0.785–1.251 MoM). However, the performance of screening for PE or GH by maternal factors alone or by maternal factors and PAPP-A, UtA-PI and MAP was not significantly improved by the addition of fetal fraction. Conclusions First trimester maternal plasma fetal fraction is not useful in screening for hypertensive disorders of pregnancy.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 19-23 weeks' gestation.

To examine the potential value of maternal ophthalmic artery Doppler at 19-23 weeks' gestation on its own and in combination with the established biomarkers of pre-eclampsia (PE), including uterine artery (UtA) pulsatility index (PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. This was a prospective observational study of women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. Waveforms were obtained from the ophthalmic arteries in sequence from the right eye, left eye and again from the right and then left eye. We recorded the average of the four measurements, two from each eye, for the following four indices: first peak of systolic velocity; second peak of systolic velocity; PI; and the ratio of the second to first peak of systolic velocity (PSV ratio). The measurements of the four indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at < 37 and ≥ 37 weeks' gestation and to determine the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR), at a 10% false-positive rate (FPR), in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The modeled performance of screening for PE was also estimated. The study population of 2853 pregnancies contained 76 (2.7%) that developed PE, including 18 (0.6%) that delivered with PE at < 37 weeks' gestation. The ophthalmic artery PSV ratio was significantly increased in PE pregnancies, and the PE effect depended on gestational age at delivery; the deviation from normal was greater for early than late PE. The second peak of systolic velocity was also increased in PE pregnancies, but the effect did not depend on gestational age at delivery. The other two ophthalmic artery indices of first peak of systolic velocity and PI were not significantly affected by PE. The PSV ratio improved the prediction of preterm PE provided by maternal factors alone (from 56.1% to 80.2%), maternal factors, MAP and UtA-PI (80.7% to 87.9%), maternal factors, MAP, UtA-PI and PlGF (85.5% to 90.3%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (84.9% to 89.8%), at a FPR of 10%. The PSV ratio also improved the prediction of term PE provided by maternal factors alone (from 33.8% to 46.0%), maternal factors, MAP and UtA-PI (46.6% to 54.2%), maternal factors, MAP, UtA-PI and PlGF (45.2% to 53.4%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (43.0% to 51.2%), at a FPR of 10%. The empirical results for DR at a 10% FPR were consistent with the modeled results. The second peak of systolic velocity did not improve the prediction of either preterm or term PE provided by maternal factors alone. Ophthalmic artery PSV ratio at 19-23 weeks' gestation, both on its own and in combination with other biomarkers, is potentially useful for prediction of subsequent development of PE, especially preterm PE, but larger studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Mini-combined test compared with NICE guidelines for early risk-assessment for pre-eclampsia: the SPREE diagnostic accuracy study

Background The traditional method of risk assessment for pre-eclampsia recommended by the National Institute for Health and Care Excellence is based on maternal factors and it recommends that high-risk women should be treated with aspirin. An alternative method of screening is based on the competing risk model, which uses Bayes’ theorem to combine maternal factors with mean arterial pressure, the uterine artery pulsatility index, serum placental growth factor and pregnancy-associated plasma protein-A at 11–13 weeks’ gestation. Objective The primary aim was to compare the performance of screening by risks obtained using the competing risk model with risk assessment using the National Institute for Health and Care Excellence guidelines. Design This was a prospective multicentre observational study. Setting The setting was seven NHS maternity hospitals in England. Participants Participants were women with singleton pregnancy attending for a routine hospital visit at 11+0–13+6 weeks’ gestation between April and December 2016. Main outcome measures The performance of screening for pre-eclampsia by the competing risk model was compared with the National Institute for Health and Care Excellence method. Relative reductions in risk with aspirin prophylaxis of 30% and 60% were assumed for all pre-eclampsia and preterm pre-eclampsia, respectively. The primary comparison was the detection rate of the National Institute for Health and Care Excellence method with the detection rate of a mini-combined test (including maternal factors, mean arterial pressure and pregnancy-associated plasma protein-A) in the prediction of all pre-eclampsia for the same screen-positive rate determined by the National Institute for Health and Care Excellence method. Results In 473 (2.8%) of the 16,747 pregnancies there was development of pre-eclampsia, including 142 (0.8%) women with preterm pre-eclampsia. The screen-positive rate by the National Institute for Health and Care Excellence method was 10.3%. For all pre-eclampsia, the false-positive and detection rates by the National Institute for Health and Care Excellence method were 9.7% and 31.6%, respectively. For preterm pre-eclampsia, the false-positive and detection rates were 10.0% and 42.8%, respectively. Compliance with the National Institute for Health and Care Excellence recommendation that high-risk women should be treated with aspirin from the first trimester was 23%. For the same screen-positive rate, the detection rate of the mini-combined test for all pre-eclampsia was 42.8%, which was superior to that of the National Institute for Health and Care Excellence method by 11.2% (95% confidence interval 6.9% to 15.6%). The increase in detection for the same screen-positive rate was accompanied by a reduction in false-positive rate of 0.3%. For the same screen-positive rate as National Institute for Health and Care Excellence, the detection rate for preterm pre-eclampsia by combining maternal factors, mean arterial pressure and placental growth factor was 67.3% compared with 44.1% with the National Institute for Health and Care Excellence method. With the addition of the uterine artery pulsatility index, the detection rate was 78.6%. This was higher than that of the National Institute for Health and Care Excellence method by 35.5% (95% confidence interval 25.2% to 45.8%). Calibration of risks for pre-eclampsia was generally good, with the calibration slope very close to 1.0. The feasibility of incorporating a new biomarker was demonstrated. However, the addition of inhibin A to the full combined test did not improve the detection rates for all pre-eclampsia and preterm pre-eclampsia (61% and 80%, respectively). The same screening model for preterm pre-eclampsia by a combination of maternal factors, mean arterial pressure, the uterine artery pulsatility index and placental growth factor achieved detection rates of 45.8% and 56.3%, respectively, for preterm small for gestational age and early small for gestational age neonates. Limitation The study did not include a health economic assessment. Conclusion The findings suggest that performance of screening for pre-eclampsia provided by a combination of maternal factors and biomarkers is superior to that achieved by current National Institute for Health and Care Excellence guidelines. Future work Future work is required to identify potential biomarkers for further improvement of the competing risk model and to carry out a health economic assessment. Trial registration Current Controlled Trials ISRCTN83611527. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 8. See the NIHR Journals Library website for further project information.

Prediction of Preeclampsia in Nulliparous Women according to First Trimester Maternal Factors and Serum Markers

Objective: To evaluate the performance of maternal risk factors (BMI and mean arterial pressure [MAP]) and first-trimester maternal serum markers in the early prediction of preeclampsia (PE) in nulliparous women. Material and Methods: This was a case-cohort study based on a cohort of 14,207 nulliparous women. A total of 213 cases with term PE (from 37 weeks + 0 days) and 55 cases with preterm PE (before 37 weeks + 0 days) were identified and validated. Randomly, 449 controls were selected. Serum samples previously collected for the double test (pregnancy-associated plasma protein A [PAPP-A] and free β human chorionic gonadotrophin [hCGβ]) as part of the first-trimester screening program were retrieved and analyzed for placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and neutrophil gelatinase-associated lipocalin (NGAL). Concentrations were transformed to multiples of the median (MoM). Multivariate regression analysis was used for prediction models. Receiver-operating characteristics (ROC) curves were used for evaluation of the screening performance. Results: In preterm PE, the PlGF (0.79 MoM), sFlt-1 (0.86 MoM), NGAL (1.15 MoM), and PAPP-A (0.89 MoM) medians were significantly altered. In term PE, PlGF (0.90 MoM) and NT-proBNP (0.86 MoM) medians were significantly reduced. The combination of MAP and PlGF yielded a 39% detection rate of preterm PE for a 10% false-positive rate. The combination of MAP, BMI, and PlGF yielded a 33% detection rate of term PE with a 10% false-positive rate. Conclusion: First-trimester MAP, maternal serum PlGF, and NGAL are markers of preterm PE. Maternal serum sFlt-1 is a significant marker of preterm PE, but only early in the first trimester. First-trimester maternal serum NT-proBNP is not a predictor of PE. Screening performance for PE with these markers individually or in combination is modest.

Validation of competing-risks model in screening for pre-eclampsia in twin pregnancy by maternal factors.

To examine the predictive performance of the competing-risks model in screening for pre-eclampsia (PE) by maternal demographic characteristics and medical history in twin pregnancy, in a training dataset used for development of the model and a validation dataset. The data for this study were derived from two prospective non-intervention multicenter screening studies for PE in twin pregnancies at 11 + 0 to 13 + 6 weeks' gestation. The first study of 2219 women, which was reported previously, was used to develop the competing-risks model for prediction of PE and is therefore considered to be the training set. The validation study comprised 2999 women. Patient-specific risks of delivery with PE at < 34 (early), < 37 (preterm) and < 41 + 3 (all) weeks' gestation were calculated using the competing-risks model and the performance of screening for PE in the training and validation datasets was assessed. We examined the predictive performance of the model by, first, its ability to discriminate between the PE and no-PE groups using the area under the receiver-operating characteristics curve (AUC) and, second, calibration, which assesses agreement between the predicted risk and observed incidence of PE. The incidence of early PE, preterm PE and all PE in the training and validation datasets was similar (1.8% vs 1.4%, 5.6% vs 5.6% and 7.7% vs 7.2%, respectively) and this was substantially higher than in our previous studies in singleton pregnancies. The training and validation datasets had similar AUCs for early PE (0.670 (95% CI, 0.593-0.747) vs 0.677 (95% CI, 0.594-0.760)), preterm PE (0.666 (95% CI, (0.617-0.715) vs 0.652 (95% CI, 0.609-0.694)) and all PE (0.656 (95% CI, 0.615-0.697) vs 0.644 (95% CI, 0.606-0.682)). Calibration plots of the predictive performance of the competing-risks model demonstrated that, in both the training and validation datasets, the observed incidence of PE was lower than the predicted one and such overestimation of risk was particularly marked for early PE. Discrimination and calibration of the competing-risks model for PE in a validation dataset are consistent with those in the training dataset. However, the model needs to be adjusted to correct the observed overestimation of risk for early PE. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Predictive performance of the competing risk model in screening for preeclampsia

The established method of screening for preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. The objective of the study was to examine the predictive performance of the competing risks model in screening for preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies. The data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for preeclampsia in singleton pregnancies at 11+0 to 13+6 weeks' gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with preeclampsia at <34, <37, and <41+3 weeks' gestation were calculated using the competing risks model and the performance of screening for preeclampsia by maternal factors alone and the triple test in each of the 3 data sets was assessed. We examined the predictive performance of the model by first, the ability of the model to discriminate between the preeclampsia and no-preeclampsia groups using the area under the receiver operating characteristic curve and the detection rate at fixed screen-positive rate of 10%, and second, calibration by measurements of calibration slope and calibration in the large. The detection rate at the screen-positive rate of 10% of early-preeclampsia, preterm-preeclampsia, and all-preeclampsia was about 90%, 75%, and 50%, respectively, and the results were consistent between the training and 2 validation data sets. The area under the receiver operating characteristic curve was >0.95, >0.90, and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0, demonstrating a good agreement between the predicted risks and observed incidence of preeclampsia. In the prediction of early-preeclampsia and preterm-preeclampsia, the observed incidence in the training set and 1 of the validation data sets was consistent with the predicted one. In the other validation data set, which was specifically designed for evaluation of the model, the incidence was higher than predicted, presumably because of better ascertainment of outcome. The incidence of all-preeclampsia was lower than predicted in all 3 data sets because at term many pregnancies deliver for reasons other than preeclampsia, and therefore, pregnancies considered to be at high risk for preeclampsia that deliver for other reasons before they develop preeclampsia can be wrongly considered to be false positives. The competing risks model provides an effective and reproducible method for first-trimester prediction of early preeclampsia and preterm preeclampsia as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.

234. Maternal cardiovascular function at 35–37 weeks’ gestation: Normal vs hypertensive disorders of pregnancy

Objective To examine the effects of maternal characteristics and obstetric and medical history on maternal cardiovascular parameters (MCPs) at 35–37 weeks’ gestation using bioreactance (NICOM). To investigate the potential value of combining maternal factors with multiples of the normal median values of MCPs at 35–37 weeks’ gestation in the prediction of pre-eclampsia (PE) and gestational hypertension (GH). Methods In 3013 singleton pregnancies maternal characteristics and medical history were recorded;uterine artery pulsatility index (UtA”PI), mean arterial pressure (MAP) and MCPs were measured. In those who remained normotensive, multivariable regression analysis was used to determine significant predictors of the MCPs among gestational age (GA), maternal characteristics and medical history. Multivariable logistic regression analysis was then used to determine if the maternal factors and MCPs made a significant contribution to predicting PE and GH. The performance of screening was determined by the area under ROC curves. Results Multivariable regression analysis demonstrated that significant independent prediction of MCPs including cardiac output, cardiac index, total peripheral resistance, stroke volume, MAP and heart rate, significant prediction was provided by GA, maternal characteristics and medical history. In pregnancies that subsequently delivered with PE or GH, total peripheral resistance and MAP were higher and maternal cardiac output was lower. The increases in total peripheral resistance and MAP were inversely related to gestational age at delivery. The performance of screening for PE and GH achieved by maternal characteristics and medical history was improved by the inclusion of MAP, but not by UtA”PI or MCPs. Conclusion MCPs are affected by maternal characteristics and medical and obstetric history, and they should therefore be converted into multiples of the normal median adjusted for significant independent predictors before their inclusion in combined screening for PE. In women developing term PE total peripheral resistance and MAP are increased and maternal cardiac output is reduced. However, assessment of MCPs at 35–37 weeks’ gestation is unlikely to improve the performance of screening for PE provided by maternal factors and MAP alone.

Screening for pre-eclampsia at 35-37 weeks' gestation.

To examine the performance of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). This was a prospective observational study in women with singleton pregnancy attending for an ultrasound scan at 35 + 0 to 36 + 6 weeks as part of routine pregnancy care. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with various combinations of biomarker multiples of the median (MoM) values to derive the patient-specific risks of delivery with PE. The performance of such screening was estimated. The study population of 13 350 pregnancies included 272 (2.0%) that subsequently developed PE. In pregnancies that developed PE, the MoM values of MAP, UtA-PI and sFlt-1 were increased and PlGF MoM was decreased. At a risk cut-off of 1 in 20, the proportion of the population stratified into high risk was about 10% of the total, and the proportion of cases of PE contained within this high-risk group was 28% with screening by maternal factors alone; the detection rate increased to 53% with the addition of MAP, 67% with the addition of MAP and PlGF and 70% with the addition of MAP, PlGF and sFlt-1. The performance of screening was not improved by the addition of UtA-PI. The performance of screening depended on the racial origin of the women; in screening by a combination of maternal factors, MAP, PlGF and sFlt-1 and use of the risk cut-off of 1 in 20, the detection rate and screen-positive rate were 66% and 9.5%, respectively, for Caucasian women and 88% and 18% for those of Afro-Caribbean racial origin. Screening by maternal factors and biomarkers at 35-37 weeks' gestation can identify a high proportion of pregnancies that develop late PE. The performance of screening depends on the racial origin of the women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of diagnostic accuracy of early screening for pre‐eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE

To test the hypothesis that the performance of first-trimester screening for pre-eclampsia (PE) by a method that uses Bayes' theorem to combine maternal factors with biomarkers is superior to that defined by current National Institute for Health and Care Excellence (NICE) guidelines. This was a prospective multicenter study (screening program for pre-eclampsia (SPREE)) in seven National Health Service maternity hospitals in England, of women recruited between April and December 2016. Singleton pregnancies at 11-13 weeks' gestation had recording of maternal characteristics and medical history and measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). The performance of screening for PE by the Bayes' theorem-based method was compared with that of the NICE method. Primary comparison was detection rate (DR) using NICE method vs mini-combined test (maternal factors, MAP and PAPP-A) in the prediction of PE at any gestational age (all-PE) for the same screen-positive rate determined by the NICE method. Key secondary comparisons were DR of screening recommended by the NICE guidelines vs three Bayes' theorem-based methods (maternal factors, MAP and PAPP-A; maternal factors, MAP and PlGF; and maternal factors, MAP, UtA-PI and PlGF) in the prediction of preterm PE, defined as that requiring delivery < 37 weeks. All-PE developed in 473 (2.8%) of the 16 747 pregnancies and preterm PE developed in 142 (0.8%). The screen-positive rate by the NICE method was 10.3% and the DR for all-PE was 30.4% and for preterm PE it was 40.8%. Compliance with the NICE recommendation that women at high risk for PE should be treated with aspirin from the first trimester to the end of pregnancy was only 23%. The DR of the mini-combined test for all-PE was 42.5%, which was superior to that of the NICE method by 12.1% (95% CI, 7.9-16.2%). In screening for preterm PE by a combination of maternal factors, MAP and PlGF, the DR was 69.0%, which was superior to that of the NICE method by 28.2% (95% CI, 19.4-37.0%) and with the addition of UtA-PI the DR was 82.4%, which was higher than that of the NICE method by 41.6% (95% CI, 33.2-49.9%). The performance of screening for PE as currently recommended by NICE guidelines is poor and compliance with these guidelines is low. The performance of screening is substantially improved by a method combining maternal factors with biomarkers. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.

Repeat measurements of uterine artery pulsatility index, mean arterial pressure and serum placental growth factor at 12, 22 and 32 weeks in prediction of pre‐eclampsia

To investigate the potential value of repeat measurements of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum placental growth factor (PlGF) at 12, 22 and 32 weeks' gestation in the prediction of pre-eclampsia (PE) developing after 32 weeks. Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13, 19-24 and/or 30-34 weeks' gestation in two maternity hospitals in England. UtA-PI, MAP and PlGF were measured. Bayes' theorem was used to combine the a-priori risk from maternal factors with UtA-PI, MAP and PlGF multiples of the median values. The performance of screening for PE developing after the 30-34-week visit by UtA-PI, MAP and PlGF measured at 11-13, 19-24 and 30-34 weeks and their combinations was examined. Screening at 30-34 weeks by UtA-PI, MAP and PlGF detected, at a 10% false-positive rate, 79%, 86% and 92% of preterm PE and 42%, 50% and 56% of term PE. The addition of biomarker values at 11-13 and/or 19-24 weeks was not associated with any improvement in the detection rate of preterm PE; in the case of term PE, there was a marginal (< 2%) improvement in detection for UtA-PI and MAP and a modest improvement of about 5% for PlGF. Measurements of UtA-PI, MAP and PlGF in the first and/or second trimester have a small or no effect on improving the prediction of PE provided by screening in the early third trimester. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

P 35 First trimester maternal serum neutrophil gelatinase-associated lipocalin (NGAL) in prediction of preeclampsia in nulliparous women

Introduction Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDA glycoprotein and a marker of endothelial damage. Pregnancies complicated by preeclampsia (PE) are characterized by placental insufficiency and endothelial dysfunction. Its speculated that NGAL is elevated in pregnancies with PE. Objectives To establish first trimester maternal serum NGAL concentration in normal pregnancies and in pregnancies complicated by PE. Furthermore, to evaluate the screening performance for PE. Material and methods Case-cohort study based on a cohort of nulliparous women consecutively enrolled into the first trimester combined screening programme for trisomy 21. The NGAL concentration was measured in cases with late-onset (GA ⩾ 37 weeks + 0 days) PE (n = 213), early-onset (GA Results Serum samples were drawn at a median gestational age of 11 weeks + 0 days (range 8 weeks + 1 day – 13 weeks + 5 days). The NGAL concentration was not correlated with gestational age (r = 0.07, p = 0.14), but correlated very weakly with maternal weight (r = 0.12, p = 0.01). The median NGAL concentration in controls was 68.0 ng/mL (IQR 38.5 ng/mL). The NGAL concentration was significantly elevated in cases with early-onset PE (median 78.0 ng/mL, IQR 50 ng/mL, p = 0.04). In contrast, no significant change was found in cases with late-onset PE (median 69.0 ng/mL, IQR 49.5 ng/mL, p = 0.07). The detection rate was 15% for a 10% false positive rate in screening for early-onset PE. The area under the ROC curve was 0.59. Conclusion First trimester maternal serum NGAL is not correlated with gestational age. NGAL is significantly elevated in pregnancies that develop early-onset PE. In contrast, NGAL is unchanged in cases with late-onset PE. Screening performance for early-onset PE is poor.

Maternal cardiac function at 35-37 weeks' gestation: prediction of pre-eclampsia and gestational hypertension.

To investigate the potential value of combining maternal factors with multiples of the normal median values of maternal cardiovascular parameters at 35-37 weeks' gestation in the prediction of pre-eclampsia (PE) and gestational hypertension (GH). In 2764 singleton pregnancies maternal characteristics and medical history were recorded; uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and maternal cardiovascular parameters were measured. Multivariable logistic regression analysis was then used to determine if the maternal factors and maternal cardiovascular parameters made a significant contribution to predicting PE and GH. The performance of screening was determined by the area under receiver-operating characteristics curves. In pregnancies that subsequently delivered with PE or GH, total peripheral resistance and MAP were higher and maternal cardiac output was lower, mainly owing to a decrease in heart rate in PE and a decrease in stroke volume in GH. The increases in total peripheral resistance and MAP were inversely related to gestational age at delivery. The performance of screening for PE and GH achieved by maternal characteristics and medical history was improved by the inclusion of MAP, but not by UtA-PI or maternal cardiovascular parameters. In women developing term PE total peripheral resistance and MAP are increased and maternal cardiac output is reduced. However, assessment of maternal cardiac function at 35-37 weeks' gestation is unlikely to improve the performance of screening for PE provided by maternal factors and MAP alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal serum soluble fms-like tyrosine kinase-1 at 22 and 32 weeks in the prediction of pre-eclampsia.

To investigate the potential value of repeat measurements of maternal serum concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) at 22 and 32 weeks' gestation in the prediction of pre-eclampsia (PE) in women delivering after 32 weeks. The data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 and/or 30-34 weeks' gestation in one of two maternity hospitals in England. Serum sFlt-1 was measured in 7565 and 8264 singleton pregnancies at 19-24 and 30-34 weeks, respectively. Bayes' theorem was used to combine the a-priori risk from maternal factors with sFlt-1 multiples of the median (MoM) values. The performance of screening for PE developing after the 30-34-week visit by sFlt-1, measured at 19-24, 30-34 and at both 19-24 and 30-34 weeks was examined. In pregnancies with PE, sFlt-1 in both the second and third trimesters was increased and the deviation from normal was inversely related to the gestational age at which delivery became necessary for maternal or fetal indications. Serum sFlt-1 at 19-24 weeks was not useful in predicting PE beyond the 30-34-week visit, but the addition of sFlt-1 at 19-24 weeks improved the prediction of PE provided by sFlt-1 at 30-34 weeks. Screening by maternal factors and sFlt-1 at 30-34 weeks predicted 94% of preterm PE and 54% of term PE, at a false-positive rate of 10%; this was improved to 99% and 64%, respectively, by the additional measurement of sFlt-1 at 19-24 weeks. Measurement of sFlt-1 in the second trimester improves the prediction of PE provided by screening in the early third-trimester. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 35-37 weeks' gestation

To develop a model for prediction of term pre-eclampsia (PE) based on a combination of maternal factors and late third-trimester biomarkers. Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 35-37 weeks' gestation in two maternity hospitals in the UK. Uterine artery pulsatility index (UtA-PI) was measured in 5362 pregnancies, mean arterial pressure (MAP) in 5386 and serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in 3920. Bayes' theorem was used to combine the a-priori risk of PE from maternal factors with various combinations of biomarkers, expressed as multiples of the median (MoM). Five-fold cross-validation was used to estimate the performance of screening for PE, requiring delivery at some stage after assessment. The empirical performance of screening was compared to model predictions. In pregnancies that developed PE, the values of MAP, UtA-PI and sFlt-1 were increased and PlGF was decreased compared to unaffected pregnancies. For all biomarkers evaluated, the deviation from normal was inversely related to the gestational age at which delivery became necessary for maternal or fetal indications. Screening by maternal factors and by a combination of maternal factors with all biomarkers predicted 35% and 84% of PE, respectively, at a 10% false-positive rate. A combination of maternal factors and biomarkers at 35-37 weeks' gestation can provide effective screening for term PE. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.