Serum PlGF compared with PAPP-A in first trimester screening for preterm pre-eclampsia: Adjusting for the effect of aspirin treatment.

OBJECTIVE: To compare the predictive performance for preterm-pre-eclampsia (PE) in first-trimester screening by serum placental growth factor (PlGF) versus pregnancy associated plasma protein-A (PAPP-A), in combination with maternal risk factors, mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI), after adjustment for the effect of aspirin in women receiving this treatment. DESIGN: Non-intervention multicentre screening studies for PE in singleton pregnancies. SETTING: Maternity hospitals. POPULATION: Two independent prospective studies of 8775 and 16 451 women with singleton pregnancies attending for routine assessment at 11+0 -13+6 weeks' gestation. METHODS: The competing risks model was used to estimate patient-specific risks of delivery with PE at <37 weeks' gestation based on maternal risk factors and combinations with MAP, UtA-PI and either PlGF or PAPP-A. McNemar's test was used to compare the detection rate (DR) of preterm-PE of screening utilising PlGF versus PAPP-A, after adjustments for the effects of aspirin. MAIN OUTCOME MEASURE: Predictive performance for preterm-PE. RESULTS: In the combined data of 25 226 women, including 678 (2.7%) who developed PE, there were 194(0.8%) with preterm-PE. Addition of PlGF improved the DR of preterm-PE, at 10% screen positive rate, by 18.4% (95% CI 12.2-24.6) in screening by maternal risk factors, by 19.9% (95% CI 13.6-26.2) in screening by maternal factors and MAP, and by 7.0% (95% CI 2.3-11.6) in screening by maternal factors, MAP and UtA-PI. PAPP-A did not significantly improve the DR provided by any combination of biomarkers. CONCLUSION: The predictive performance of first trimester PlGF for preterm-PE is superior to that of PAPP-A.

Development and validation of model for prediction of placental dysfunction-related stillbirth from maternal factors, fetal weight and uterine artery Doppler at mid-gestation.

OBJECTIVE: To examine the performance of a model combining maternal risk factors, uterine artery pulsatility index (UtA-PI) and estimated fetal weight (EFW) at 19-24 weeks' gestation, for predicting all antepartum stillbirths and those due to impaired placentation, in a training dataset used for development of the model and in a validation dataset. METHODS: The data for this study were derived from prospective screening for adverse obstetric outcome in women with singleton pregnancy attending for routine pregnancy care at 19 + 0 to 24 + 6 weeks' gestation. The study population was divided into a training dataset used to develop prediction models for placental dysfunction-related antepartum stillbirth and a validation dataset to which the models were then applied. Multivariable logistic regression analysis was used to develop a model based on a combination of maternal risk factors, EFW Z-score and UtA-PI multiples of the normal median. We examined the predictive performance of the model by, first, the ability of the model to discriminate between the stillbirth and live-birth groups, using the area under the receiver-operating-characteristics curve (AUC) and the detection rate (DR) at a fixed false-positive rate (FPR) of 10%, and, second, calibration by measurements of calibration slope and intercept. RESULTS: The study population of 131 514 pregnancies included 131 037 live births and 477 (0.36%) stillbirths. There are four main findings of this study. First, 92.5% (441/477) of stillbirths were antepartum and 7.5% (36/477) were intrapartum, and 59.2% (261/441) of antepartum stillbirths were observed in association with placental dysfunction and 40.8% (180/441) were unexplained or due to other causes. Second, placental dysfunction accounted for 80.1% (161/201) of antepartum stillbirths at < 32 weeks' gestation, 54.2% (52/96) at 32 + 0 to 36 + 6 weeks and 33.3% (48/144) at ≥ 37 weeks. Third, the risk of placental dysfunction-related antepartum stillbirth increased with increasing maternal weight and decreasing maternal height, was 3-fold higher in black than in white women, was 5.5-fold higher in parous women with previous stillbirth than in those with previous live birth, and was increased in smokers, in women with chronic hypertension and in parous women with a previous pregnancy complicated by pre-eclampsia and/or birth of a small-for-gestational-age baby. Fourth, in screening for placental dysfunction-related antepartum stillbirth by a combination of maternal risk factors, EFW and UtA-PI in the validation dataset, the DR at a 10% FPR was 62.3% (95% CI, 57.2-67.4%) and the AUC was 0.838 (95% CI, 0.799-0.878); these results were consistent with those in the dataset used for developing the algorithm and demonstrate high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 1.029 and the intercept was -0.009, demonstrating good agreement between the predicted risk and observed incidence of placental dysfunction-related antepartum stillbirth. The performance of screening was better for placental dysfunction-related antepartum stillbirth at < 37 weeks' gestation compared to at term (DR at a 10% FPR, 69.8% vs 29.2%). CONCLUSIONS: Screening at mid-gestation by a combination of maternal risk factors, EFW and UtA-PI can predict a high proportion of placental dysfunction-related stillbirths and, in particular, those that occur preterm. Such screening provides poor prediction of unexplained stillbirth or stillbirth due to other causes. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Screening for pre-eclampsia at 11-13 weeks' gestation: use of pregnancy-associated plasma protein-A, placental growth factor or both.

OBJECTIVE: First-trimester screening for pre-eclampsia (PE) is useful because treatment of the high-risk group with aspirin reduces the rate of early PE with delivery at < 34 weeks' gestation by about 80% and that of preterm PE with delivery at < 37 weeks by 60%. In previous studies, we reported that the best way of identifying the high-risk group is by a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). An alternative biochemical marker is pregnancy-associated plasma protein-A (PAPP-A), which is used widely as part of early screening for trisomy. The objective of this study was to examine the additive value of PlGF and PAPP-A in first-trimester screening for preterm PE by maternal factors, MAP and UtA-PI and define the risk cut-off and screen-positive rate to achieve a desired detection rate of PE if PAPP-A rather than PlGF was to be used for first-trimester screening. METHODS: This was a non-intervention screening study. The data were derived from prospective screening for adverse obstetric outcomes in women with singleton pregnancy attending for a routine first-trimester hospital visit. Patient-specific risks of delivery with PE at < 37 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 (MoM) values of MAP, UtA-PI, PlGF and PAPP-A. The performance of screening in the total population and in subgroups of women of white and black racial origin was estimated. McNemar's test was used to compare the detection rate, for a fixed screen-positive rate, of screening with and without PlGF and PAPP-A. Risk cut-offs and screen-positive rates to achieve desired detection rates of preterm PE were determined in screening with and without PlGF and PAPP-A. RESULTS: The study population was composed of 60 875 singleton pregnancies, including 1736 (2.9%) that developed PE. There are three main findings of this study. First, the performance of first-trimester screening for PE by a combination of maternal factors, MAP, UtA-PI and PlGF is superior to that of screening by maternal factors, MAP, UtA-PI and PAPP-A; for example, in screening by maternal factors, MAP, UtA-PI and PlGF, at a screen-positive rate of 10%, the detection rate of PE with delivery at < 37 weeks' gestation was 74.1%, which was 7.1% (95% CI, 3.8-10.6%) higher than in screening by maternal factors, MAP, UtA-PI and PAPP-A. Second, addition of serum PAPP-A does not improve the prediction of PE provided by maternal factors, MAP, UtA-PI and PlGF. Third, the risk cut-off and screen-positive rate to achieve a given fixed detection rate of preterm PE vary according to the racial composition of the study population and whether the biomarkers used for screening are MAP, UtA-PI and PlGF or MAP, UtA-PI and PAPP-A. For example, in screening by a combination of maternal factors, MAP, UtA-PI and PlGF in white women, if the desired detection rate of preterm PE was 75%, the risk cut-off should be 1 in 136 and the screen-positive rate would be 14.1%; in black women, to achieve a detection rate of 75%, the risk cut-off should be 1 in 29 and the screen-positive rate would be 12.5%. In screening by a combination of maternal factors, MAP, UtA-PI and PAPP-A in white women, if the desired detection rate of preterm PE was 75%, the risk cut-off should be 1 in 140 and the screen-positive rate would be 16.9%; in black women, to achieve a detection rate of 75%, the risk cut-off should be 1 in 44 and the screen-positive rate would be 19.3%. CONCLUSION: In first-trimester screening for PE, the preferred biochemical marker is PlGF rather than PAPP-A. However, if PAPP-A was to be used rather than PlGF, the same detection rate can be achieved but at a higher screen-positive rate. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Aspirin delays the development of preeclampsia.

BACKGROUND: In the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial, risks of preterm preeclampsia were obtained from the competing risk model. Consenting women with risks of greater than 1 in 100 were randomized to treatment with aspirin or placebo. The trial showed strong evidence of an effect (odds ratio, 0.38, 95% confidence interval, 0.20-0.74) on the incidence of preterm preeclampsia, which was the primary outcome of Aspirin for Evidence-Based Preeclampsia Prevention. There was a small and insignificant effect on the incidence of term preeclampsia, which was a secondary outcomes (odds ratio, 0.95, 95% confidence interval, 0.64-1.39). These differential effects on term and preterm preeclampsia could reflect a mechanism in which the action of aspirin is to delay the delivery with preeclampsia, thereby converting what would be, without treatment, preterm preeclampsia to term preeclampsia. OBJECTIVE: The objective of the study was to examine the hypothesis that the effect of aspirin is to delay the time of delivery in women who have preeclampsia. STUDY DESIGN: This was an unplanned exploratory analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. The delay hypothesis predicts that in groups for which preterm preeclampsia, without aspirin, were infrequent relative to term preeclampsia, a reduction in term preeclampsia would be expected because few cases of preterm preeclampsia would be converted to term preeclampsia. In contrast, in groups for which preterm preeclampsia were frequent relative to term preeclampsia, the conversion of preterm preeclampsia to term preeclampsia by aspirin would reduce or even reverse any effect on the incidence term preeclampsia. This is examined using the Aspirin for Evidence-Based Preeclampsia Prevention trial data by analysis of the effect of aspirin on the incidence of term preeclampsia stratified according to the risk of preterm preeclampsia at randomization. Given that women were included in Aspirin for Evidence-Based Preeclampsia Prevention with risks of preterm preeclampsia >1 in 100, a risk cutoff if 1 in 50 was used to define higher risk and lower risk strata. A statistical model in which the effect of aspirin is to delay the gestational age at delivery was fitted to the Aspirin for Evidence-Based Preeclampsia Prevention trial data and the consistency of the predictions from this model with the observed incidence was demonstrated. RESULTS: In the lower-risk group (<1 in 50), there was a reduction in the incidence of term preeclampsia (odds ratio, 0.62, 95% confidence interval, 0.29-1.30). In contrast, in the higher risk group (≥1 in 50) there was a small increase in the incidence of term- preeclampsia (odds ratio 1.11, 95% confidence interval, 0.71- .75). Although these effects fail to achieve significance, they are consistent with the delay hypothesis. Within the framework of the aspirin-related delay hypothesis, the effect of aspirin was to delay the gestational age at delivery with preeclampsia by an estimated 4.4 weeks (95% confidence interval, 1.4-7.1 weeks) for those that in the placebo group would be delivered at 24 weeks and the effect decreased by an estimated 0.23 weeks (95% confidence interval, 0.021-0.40 weeks) for each week of gestation so that at 40+0 weeks, the estimated delay was by 0.8 weeks (95% confidence interval, -0.03 to 1.7 weeks). CONCLUSION: The Aspirin for Evidence-Based Preeclampsia Prevention trial data are consistent with the hypothesis that aspirin delays the gestational age at delivery with preeclampsia.

Prediction of large-for-gestational-age neonate by routine third-trimester ultrasound.

OBJECTIVES: First, to evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31 + 0 to 33 + 6 and 35 + 0 to 36 + 6 weeks' gestation in the prediction of a large-for-gestational-age (LGA) neonate born at ≥ 37 weeks' gestation. Second, to assess the additive value of fetal growth velocity between 32 and 36 weeks' gestation to the performance of EFW at 35 + 0 to 36 + 6 weeks' gestation for prediction of a LGA neonate. Third, to define the predictive performance for a LGA neonate of different EFW cut-offs on routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. Fourth, to propose a two-stage strategy for identifying pregnancies with a LGA fetus that may benefit from iatrogenic delivery during the 38th gestational week. METHODS: This was a retrospective study. First, data from 21 989 singleton pregnancies that had undergone routine ultrasound examination at 31 + 0 to 33 + 6 weeks' gestation and 45 847 that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks were used to compare the predictive performance of EFW and AC for a LGA neonate with birth weight > 90th and > 97th percentiles born at ≥ 37 weeks' gestation. Second, data from 14 497 singleton pregnancies that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation and had a previous scan at 30 + 0 to 34 + 6 weeks were used to determine, through multivariable logistic regression analysis, whether addition of growth velocity, defined as the difference in EFW Z-score or AC Z-score between the early and late third-trimester scans divided by the time interval between the scans, improved the performance of EFW at 35 + 0 to 36 + 6 weeks in the prediction of delivery of a LGA neonate at ≥ 37 weeks' gestation. Third, in the database of the 45 847 pregnancies that had undergone routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation, the screen-positive and detection rates for a LGA neonate born at ≥ 37 weeks' gestation and ≤ 10 days after the initial scan were calculated for different EFW percentile cut-offs between the 50th and 90th percentiles. RESULTS: First, the areas under the receiver-operating characteristics curves (AUC) of screening for a LGA neonate were significantly higher using EFW Z-score than AC Z-score and at 35 + 0 to 36 + 6 than at 31 + 0 to 33 + 6 weeks' gestation (P < 0.001 for all). Second, the performance of screening for a LGA neonate achieved by EFW Z-score at 35 + 0 to 36 + 6 weeks was not significantly improved by addition of EFW growth velocity or AC growth velocity. Third, in screening by EFW > 90th percentile at 35 + 0 to 36 + 6 weeks' gestation, the predictive performance for a LGA neonate born at ≥ 37 weeks' gestation was modest (65% and 46% for neonates with birth weight > 97th and > 90th percentiles, respectively, at a screen-positive rate of 10%), but the performance was better for prediction of a LGA neonate born ≤ 10 days after the scan (84% and 71% for neonates with birth weight > 97th and > 90th percentiles, respectively, at a screen-positive rate of 11%). Fourth, screening by EFW > 70th percentile at 35 + 0 to 36 + 6 weeks' gestation predicted 91% and 82% of LGA neonates with birth weight > 97th and > 90th percentiles, respectively, born at ≥ 37 weeks' gestation, at a screen-positive rate of 32%, and the respective values of screening by EFW > 85th percentile for prediction of a LGA neonate born ≤ 10 days after the scan were 88%, 81% and 15%. On the basis of these results, it was proposed that routine fetal biometry at 36 weeks' gestation is a screening rather than diagnostic test for fetal macrosomia and that EFW > 70th percentile should be used to identify pregnancies in need of another scan at 38 weeks, at which those with EFW > 85th percentile should be considered for iatrogenic delivery during the 38th week. CONCLUSIONS: First, the predictive performance for a LGA neonate by routine ultrasonographic examination during the third trimester is higher if the scan is carried out at 36 than at 32 weeks, the method of screening is EFW than fetal AC, the outcome measure is birth weight > 97th than > 90th percentile and if delivery occurs within 10 days than at any stage after assessment. Second, prediction of a LGA neonate by EFW > 90th percentile is modest and this study presents a two-stage strategy for maximizing the prenatal prediction of a LGA neonate. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of small-for-gestational-age neonates at 35-37 weeks' gestation: contribution of maternal factors and growth velocity between 20 and 36 weeks.

OBJECTIVES: To evaluate the performance of ultrasonographic estimated fetal weight (EFW) at 35 + 0 to 36 + 6 weeks' gestation in the prediction of delivery of a small-for-gestational-age (SGA) neonate and assess the additive value of, first, maternal risk factors and, second, fetal growth velocity between 20 and 36 weeks' gestation in improving such prediction. METHODS: This was a prospective study of 44 043 singleton pregnancies undergoing routine ultrasound examination at 19 + 0 to 23 + 6 and at 35 + 0 to 36 + 6 weeks' gestation. Multivariable logistic regression analysis was used to determine whether addition of maternal risk factors and growth velocity, the latter defined as the difference in EFW Z-score or fetal abdominal circumference (AC) Z-score between the third- and second-trimester scans divided by the time interval between the scans, improved the performance of EFW Z-score at 35 + 0 to 36 + 6 weeks in the prediction of delivery of a SGA neonate with birth weight < 10th and < 3rd percentiles within 2 weeks and at any stage after assessment. RESULTS: Screening by EFW Z-score at 35 + 0 to 36 + 6 weeks' gestation predicted 63.4% (95% CI, 62.0-64.7%) of neonates with birth weight < 10th percentile and 74.2% (95% CI, 72.2-76.1%) of neonates with birth weight < 3rd percentile born at any stage after assessment, at a screen-positive rate of 10%. The respective values for SGA neonates born within 2 weeks after assessment were 76.8% (95% CI, 74.4-79.0%) and 81.3% (95% CI, 78.2-84.0%). For a desired 90% detection rate of SGA neonate delivered at any stage after assessment, the necessary screen-positive rate would be 33.7% for SGA < 10th percentile and 24.4% for SGA < 3rd percentile. Multivariable logistic regression analysis demonstrated that, in the prediction of a SGA neonate with birth weight < 10th and < 3rd percentiles, there was a significant contribution from EFW Z-score at 35 + 0 to 36 + 6 weeks' gestation, maternal risk factors and AC growth velocity, but not EFW growth velocity. However, the area under the receiver-operating characteristics curve for prediction of delivery of a SGA neonate by screening with maternal risk factors and EFW Z-score was not improved by addition of AC growth velocity. CONCLUSION: Screening for SGA neonates by EFW at 35 + 0 to 36 + 6 weeks' gestation and use of the 10th percentile as the cut-off predicts 63% of affected neonates. Prediction of 90% of SGA neonates necessitates classification of about 35% of the population as being screen positive. The predictive performance of EFW is not improved by addition of estimated growth velocity between the second and third trimesters of pregnancy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Routine ultrasound at 32 vs 36 weeks' gestation: prediction of small-for-gestational-age neonates.

OBJECTIVE: To evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31 + 0 to 33 + 6 and 35 + 0 to 36 + 6 weeks' gestation in the prediction of a small-for-gestational-age (SGA) neonate. METHODS: This was a prospective study of 21 989 singleton pregnancies undergoing routine ultrasound examination at 31 + 0 to 33 + 6 weeks' gestation and 45 847 undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. In each case, the estimated fetal weight (EFW) from measurements of fetal head circumference, AC and femur length was calculated using the Hadlock formula and expressed as a percentile according to The Fetal Medicine Foundation fetal and neonatal population weight charts. The same charts were used for defining a SGA neonate with birth weight < 10th and < 3rd percentiles. For each gestational-age window, the screen-positive and detection rates, at different EFW percentile cut-offs between the 10th and 50th percentiles, were calculated for prediction of delivery of a SGA neonate with birth weight < 10th and < 3rd percentiles within 2 weeks and at any stage after assessment. The areas under the receiver-operating characteristics curves (AUC) in screening for a SGA neonate by EFW and AC at 31 + 0 to 33 + 6 and at 35 + 0 to 36 + 6 weeks' gestation were compared. RESULTS: First, the AUCs in screening by EFW for a SGA neonate with birth weight < 10th and < 3rd percentiles delivered within 2 weeks and at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation were significantly higher than those at 31 + 0 to 33 + 6 weeks (P < 0.001). Second, at both 35 + 0 to 36 + 6 and 31 + 0 to 33 + 6 weeks' gestation, the predictive performance for a SGA neonate with birth weight < 10th and < 3rd percentiles born at any stage after screening was significantly higher using EFW Z-score than AC Z-score. Similarly, at 35 + 0 to 36 + 6 weeks, but not at 31 + 0 to 33 + 6 weeks, the predictive performance for a SGA neonate with birth weight < 10th and < 3rd percentiles born within 2 weeks after screening was significantly higher using EFW Z-score than AC Z-score. Third, screening by EFW < 10th percentile at 35 + 0 to 36 + 6 weeks' gestation predicted 70% and 84% of neonates with birth weight < 10th and < 3rd percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 46% and 65%. Fourth, prediction of > 85% of SGA neonates with birth weight < 10th percentile born at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation requires use of EFW < 40th percentile. Screening at this percentile cut-off predicted 95% and 99% of neonates with birth weight < 10th and < 3rd percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 87% and 94%. CONCLUSIONS: The predictive performance for a SGA neonate of routine ultrasonographic examination during the third trimester is higher if, first, the scan is carried out at 35 + 0 to 36 + 6 weeks' gestation than at 31 + 0 to 33 + 6 weeks, second, the method of screening is EFW than fetal AC, third, the outcome measure is birth weight < 3rd than < 10th percentile, and, fourth, if delivery occurs within 2 weeks than at any stage after assessment. Prediction of a SGA neonate by EFW < 10th percentile is modest and prediction of > 85% of cases at 35 + 0 to 36 + 6 weeks' gestation necessitates use of EFW < 40th percentile. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To examine the performance of screening for early, preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery (UtA) pulsatility index (PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). METHODS: The data for this study were derived from three previously reported prospective non-intervention screening studies at 11 + 0 to 13 + 6 weeks' gestation in a combined total of 61 174 singleton pregnancies, including 1770 (2.9%) that developed PE. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiples of the median (MoM) values to derive patient-specific risks of delivery with PE at < 37 weeks' gestation. The performance of such screening was estimated. RESULTS: In pregnancies that developed PE, compared to those without PE, the MoM values of UtA-PI and MAP were increased and those of PAPP-A and PlGF were decreased, and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PlGF predicted 90% of early PE, 75% of preterm PE and 41% of term PE, at a screen-positive rate of 10%; inclusion of PAPP-A did not improve the performance of screening. The performance of screening depended on the racial origin of the women; on screening by a combination of maternal factors, MAP, UtA-PI and PlGF and using a risk cut-off of 1 in 100 for PE at < 37 weeks in Caucasian women, the screen-positive rate was 10% and detection rates for early, preterm and term PE were 88%, 69% and 40%, respectively. With the same method of screening and risk cut-off in women of Afro-Caribbean racial origin, the screen-positive rate was 34% and detection rates for early, preterm and term PE were 100%, 92% and 75%, respectively. CONCLUSION: Screening by maternal factors and biomarkers at 11-13 weeks' gestation can identify a high proportion of pregnancies that develop early and preterm PE. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.

Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia.

BACKGROUND: The Aspirin for Evidence-Based Preeclampsia Prevention trial was a multicenter study in women with singleton pregnancies. Screening was carried out at 11-13 weeks' gestation with an algorithm that combines maternal factors and biomarkers (mean arterial pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein A and placental growth factor). Those with an estimated risk for preterm preeclampsia of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/d) vs placebo from 11-14 until 36 weeks' gestation. Preterm preeclampsia with delivery at <37 weeks' gestation, which was the primary outcome, occurred in 1.6% (13/798) participants in the aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74). OBJECTIVE: We sought to examine the influence of compliance on the beneficial effect of aspirin in prevention of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial. STUDY DESIGN: This was a secondary analysis of data from the trial. The proportion of prescribed tablets taken was used as an overall measure of compliance. Logistic regression analysis was used to estimate the effect of aspirin on the incidence of preterm preeclampsia according to compliance of <90% and ≥90%, after adjustment for the estimated risk of preterm preeclampsia at screening and the participating center. The choice of cut-off of 90% was based on an exploratory analysis of the treatment effect. Logistic regression analysis was used to investigate predictors of compliance ≥90% among maternal characteristics and medical history. RESULTS: Preterm preeclampsia occurred in 5/555 (0.9%) participants in the aspirin group with compliance ≥90%, in 8/243 (3.3%) of participants in the aspirin group with compliance <90%, in 22/588 (3.7%) of participants in the placebo group with compliance ≥90%, and in 13/234 (5.6%) of participants in the placebo group with compliance <90%. The odds ratio in the aspirin group for preterm preeclampsia was 0.24 (95% confidence interval, 0.09-0.65) for compliance ≥90% and 0.59 (95% confidence interval, 0.23-1.53) for compliance <90%. Compliance was positively associated with family history of preeclampsia and negatively associated with smoking, maternal age <25 years, Afro-Caribbean and South Asian racial origin, and history of preeclampsia in a previous pregnancy. CONCLUSION: The beneficial effect of aspirin in the prevention of preterm preeclampsia appears to depend on compliance.

Hidden high rate of pre-eclampsia in twin compared with singleton pregnancy.

OBJECTIVES: To examine the gestational age at delivery in dichorionic (DC) and monochorionic (MC) twin pregnancies, with and without pre-eclampsia (PE), and to determine the relative risk of total and preterm PE compared with that in singleton pregnancies. METHODS: This was a screening study for PE in twin pregnancies undergoing first-trimester combined screening for aneuploidy and subsequently delivering two phenotypically normal live or stillborn babies at ≥ 24 weeks' gestation. The distribution of gestational age at delivery in DC and MC twins was determined and compared with that in singleton pregnancies from the same population. The relative risk for total and preterm PE in twins compared with singleton pregnancies was determined. Kaplan-Meier estimates of the cumulative incidence of PE in twin and singleton pregnancies, assuming no other cause for delivery, were determined and hazard ratios for twins relative to singletons were obtained from a Cox proportional hazards regression model. RESULTS: The incidence of PE in singletons was 2.3% (2162/93 297), in DC twin pregnancies was 8.1% (145/1789) and in MC twin pregnancies was 6.0% (26/430). Compared with singletons, the relative risk of total PE was 3.5 for DC twins and 2.6 for MC twins. Delivery < 37 weeks' gestation occurred in 5.5% of singletons, 46.5% of DC twins and 91.4% of MC twins. The incidence of preterm PE was 0.6%, 5.5% and 5.8% for singletons, DC twins and MC twins, respectively. Compared with singletons, the relative risk of preterm PE was 8.7 for DC twins and 9.1 for MC twins. In the Cox proportional hazards regression model, the hazard ratios for DC and MC twin pregnancies relative to singleton pregnancies were 14 and 23, respectively. CONCLUSIONS: The relative risk of preterm PE in DC and MC twins is similar and substantially higher than in singleton pregnancies. In ongoing twin pregnancies, the high relative risk of PE may merit a higher intensity of monitoring than is routine for singleton pregnancies. © 2017 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model in screening for pre-eclampsia in twin pregnancy by maternal characteristics and medical history.

OBJECTIVE: A survival-time regression model for gestational age at delivery with pre-eclampsia (PE) in singleton pregnancy, using maternal demographic characteristics and medical history, was reported previously. The objective of this study was to extend this model to dichorionic (DC) and monochorionic (MC) twin pregnancy. METHODS: The study population included 1789 DC and 430 MC twin pregnancies and 93 297 singleton pregnancies. A survival-time model for gestational age at delivery with PE was developed from variables of maternal characteristics and medical history. The risk of PE with delivery < 37 weeks and < 42 weeks in twin pregnancies was determined and compared with that in singleton pregnancies. RESULTS: In singleton pregnancies comprising women of Caucasian racial origin, mean weight of 69 kg at 12 weeks' gestation, mean height of 164 cm, nulliparous, with spontaneous conception, no family history of PE and no history of diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, the mean of the Gaussian distribution of gestational age at delivery with PE was 55 weeks. In DC twins with PE, mean gestational age at delivery was shifted to the left by 8.2 (95% CI, 7.2-9.1) weeks and in MC twins it was shifted to the left by 10.0 (95% CI, 8.5-11.4) weeks. The risk of delivery with PE occurring at, or before, a specified gestational age is given by the area under the fitted distribution curve. For a reference population with the above characteristics, the estimated risk of PE < 37 weeks' gestation, assuming no other cause of delivery, was 0.6% for singletons, 9.0% for DC twins and 14.2% for MC twins; the respective values for PE < 42 weeks were 3.6%, 27.0% and 36.5%. CONCLUSIONS: A model based on maternal characteristics and medical history has been developed for estimation of patient-specific risks for PE in DC and MC twin pregnancy. Such estimation of the a-priori risk for PE is an essential first step in the use of Bayes' theorem to combine maternal factors with biomarkers for the continuing development of more effective methods of screening for the disease. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations.

OBJECTIVE: To compare the performance of screening for pre-eclampsia (PE) based on risk factors from medical history, as recommended by NICE and ACOG, with the method proposed by The Fetal Medicine Foundation (FMF), which uses Bayes' theorem to combine the a-priori risk from maternal factors, derived by a multivariable logistic model, with the results of various combinations of biophysical and biochemical measurements. METHODS: This was a prospective multicenter study of screening for PE in 8775 singleton pregnancies at 11-13 weeks' gestation. A previously published FMF algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those derived from application of NICE guidelines and ACOG recommendations. According to NICE, all high-risk pregnancies should be offered low-dose aspirin. According to ACOG, use of aspirin should be reserved for women with a history of PE in at least two previous pregnancies or PE requiring delivery < 34 weeks' gestation. RESULTS: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. Screening with use of the FMF algorithm based on a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) detected 100% (95% CI, 80-100%) of PE < 32 weeks, 75% (95% CI, 62-85%) of PE < 37 weeks and 43% (95% CI, 35-50%) of PE ≥ 37 weeks, at a 10.0% FPR. Screening with use of NICE guidelines detected 41% (95% CI, 18-67%) of PE < 32 weeks, 39% (95% CI, 27-53%) of PE < 37 weeks and 34% (95% CI, 27-41%) of PE ≥ 37 weeks, at 10.2% FPR. Screening with use of ACOG recommendations detected 94% (95% CI, 71-100%) of PE < 32 weeks, 90% (95% CI, 79-96%) of PE < 37 weeks and 89% (95% CI, 84-94%) of PE ≥ 37 weeks, at 64.2% FPR. Screening based on the ACOG recommendations for use of aspirin detected 6% (95% CI, 1-27%) of PE < 32 weeks, 5% (95% CI, 2-14%) of PE < 37 weeks and 2% (95% CI, 0.3-5%) of PE ≥ 37 weeks, at 0.2% FPR. CONCLUSION: Performance of screening for PE at 11-13 weeks' gestation by the FMF algorithm using a combination of maternal factors, MAP, UtA-PI and PlGF, is by far superior to the methods recommended by NICE and ACOG. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Competing-risks model in screening for pre-eclampsia in twin pregnancy according to maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To develop a model for screening for pre-eclampsia (PE) in twin pregnancies based on maternal demographic characteristics and medical history and biomarkers at 11-13 weeks' gestation. METHODS: This was a screening study in twin pregnancies at 11-13 weeks' gestation. Bayes theorem was used to combine the a-priori risk from maternal factors with various combinations of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) multiples of the median (MoM) values. The performance of screening for PE requiring delivery at < 32, < 37 and < 42 weeks' gestation was estimated in 1100 twin pregnancies and 35 948 singleton pregnancies with complete data on UtA-PI, MAP, PlGF and PAPP-A. RESULTS: In twin pregnancies that developed PE, the values of MAP and UtA-PI were increased and the values of PlGF and PAPP-A were decreased. The distributions of log10 MoM values of biomarkers with gestational age at delivery were similar to those that were previously reported in singleton pregnancies and it was therefore assumed that the same model could be used for both singleton and twin pregnancies. The performance of screening for PE by maternal factors was improved by the addition of MAP, UtA-PI and PlGF; there was no further improvement with the addition of PAPP-A. In a mixed population of singleton and twin pregnancies, combined screening by maternal factors, MAP, UtA-PI and PlGF and risk cut-off of 1 in 75 for PE at < 37 weeks, the detection rate of PE at < 32, < 37 and < 42 weeks in singleton pregnancies was 91%, 77% and 57%, respectively, at a screen-positive rate (SPR) of 13%; the respective rates for twin pregnancies were 100%, 99% and 97%, at a SPR of 75%. CONCLUSION: First-trimester combined screening for PE in singleton pregnancies can be adapted for screening in twins, leading to detection of nearly all affected cases but at a high SPR. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To examine the diagnostic accuracy of a previously developed model for prediction of pre-eclampsia (PE) by a combination of maternal factors and biomarkers at 11-13 weeks' gestation. METHODS: This was a prospective first-trimester multicenter study of screening for PE in 8775 singleton pregnancies. A previously published algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those for the dataset used for development of the algorithm. RESULTS: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. With combined screening by maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor, the DR was 100% (95% CI, 80-100%) for PE < 32 weeks, 75% (95% CI, 62-85%) for PE < 37 weeks and 43% (95% CI, 35-50%) for PE ≥ 37 weeks, at a 10% FPR. These DRs were similar to the estimated rates for the dataset used for development of the model: 89% (95% CI, 79-96%) for PE < 32 weeks, 75% (95% CI, 70-80%) for PE < 37 weeks and 47% (95% CI, 44-51%) for PE ≥ 37 weeks. CONCLUSION: Assessment of a combination of maternal factors and biomarkers at 11-13 weeks provides effective first-trimester screening for preterm PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

ASPRE trial: performance of screening for preterm pre-eclampsia.

OBJECTIVE: To examine the performance of screening for preterm and term pre-eclampsia (PE) in the study population participating in the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) trial. METHODS: This was a prospective first-trimester multicenter study on screening for preterm PE in 26 941 singleton pregnancies by means of an algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index and maternal serum pregnancy-associated plasma protein-A and placental growth factor at 11-13 weeks' gestation. Eligible women with an estimated risk for preterm PE of > 1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg per day) vs placebo from 11-14 until 36 weeks' gestation, which showed that, in the aspirin group, the incidence of preterm PE was reduced by 62%. In the screened population, the detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 37 and ≥ 37 weeks were estimated after adjustment for the effect of aspirin in those receiving this treatment. We excluded 1144 (4.2%) pregnancies because of loss to follow-up or study withdrawal (n = 716), miscarriage (n = 243) or termination (n = 185). RESULTS: The study population of 25 797 pregnancies included 180 (0.7%) cases of preterm PE, 450 (1.7%) of term PE and 25 167 (97.6%) without PE. In combined first-trimester screening for preterm PE with a risk cut-off of 1 in 100, the DR was 76.7% (138/180) for preterm PE and 43.1% (194/450) for term PE, at screen-positive rate of 10.5% (2707/25 797) and FPR of 9.2% (2375/25 797). CONCLUSION: The performance of screening in the ASPRE study was comparable with that of a study of approximately 60 000 singleton pregnancies used for development of the algorithm; in that study, combined screening detected 76.6% of cases of preterm PE and 38.3% of term PE at a FPR of 10%. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19-24 weeks' gestation.

BACKGROUND: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. The traditional approach to screening for PE is to use a risk-scoring system based on maternal demographic characteristics and medical history (maternal factors), but the performance of such an approach is very poor. OBJECTIVE: To develop a model for PE based on a combination of maternal factors with second-trimester biomarkers. STUDY DESIGN: The data for this study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 weeks' gestation in 3 maternity hospitals in England between January 2006 and July 2014. We had data from maternal factors, uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), serum placental growth factor (PLGF), and serum soluble fms-like tyrosine kinase-1 (SFLT) from 123,406, 67,605, 31,120, 10,828, and 8079 pregnancies, respectively. Bayes' theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median (MoM) values. The modeled performance of screening for PE requiring delivery at <32, <37, and ≥37 weeks' gestation was estimated. The modeled performance was compared to the empirical one, which was derived from 5-fold cross validation. We also examined the performance of screening based on risk factors from the medical history, as recommended by the American Congress of Obstetricians and Gynecologists (ACOG). RESULTS: In pregnancies that developed PE, the values of MAP, UTPI, and SFLT were increased and PLGF was decreased. For all biomarkers the deviation from normal was greater for early than for late PE, and therefore the performance of screening was inversely related to the gestational age at which delivery became necessary for maternal and/or fetal indications. Screening by maternal factors predicted 52%, 47%, and 37% of PE at <32, <37, and ≥37 weeks' gestation, respectively, at a false-positive rate of 10%. The respective values for combined screening with maternal factors and MAP, UTPI, and PLGF were 99%, 85%, and 46%; the performance was not improved by the addition of SFLT. In our population of 123,406 pregnancies, the DR of PE at <32, <37, and ≥37 weeks with the ACOG recommendations was 91%, 90%, and 91%, respectively, but at a screen positive rate of 67%. CONCLUSION: The performance of screening for PE by maternal factors and biomarkers in the middle trimester is superior to taking a medical history.

Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 30-34 weeks' gestation.

BACKGROUND: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. We have proposed a 2-stage strategy for the identification of pregnancies at high risk of developing PE. The objective of the first stage, at 11-13 weeks' gestation, is a reduction in the prevalence of the disease through pharmacological intervention in the high-risk group. The objective of the second stage, during the second and/or third trimesters, is to improve perinatal outcome through close monitoring of the high-risk group for earlier diagnosis of the clinical signs of the disease and selection of the appropriate, time, place, and method of delivery. OBJECTIVE: The objective of the study was to examine the performance of screening for PE by a combination of maternal factors with early third-trimester biomarkers. STUDY DESIGN: This was a cohort study and data were derived from consecutive women with singleton pregnancies attending for their routine hospital visit at 30-34 weeks' gestation in 3 maternity hospitals in England between March 2011 and December 2014. In the first phase of the study, only uterine artery pulsatility index (UTPI) was measured and then measurement of mean arterial pressure (MAP) was added, and in the final phase, the serum concentration of placental growth factor (PLGF) was measured and then soluble fms-like tyrosine kinase-1 (SFLT) was added. We had data on UTPI, MAP, PLGF, and SFLT from 30,935, 29,042, 10,123, and 8,264 pregnancies, respectively. The Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median values. Ten-fold cross-validation was used to estimate the performance of screening for PE requiring delivery at < 37 weeks' gestation (preterm-PE) and those delivering at ≥ 37 weeks (term-PE). The empirical performance was compared with model predictions. RESULTS: In pregnancies that developed PE, the values of MAP, UTPI, and SFLT were increased and PLGF was decreased. For all biomarkers the deviation from normal was greater for preterm-PE than term-PE, and therefore, the performance of screening was inversely related to the gestational age at which delivery become necessary for maternal and/or fetal indications. Combined screening by maternal factors, MAP, UTPI, PLGF, and SFLT predicted 98% (95% confidence interval, 88-100%) of preterm-PE and 49% (95% confidence interval, 42-57%) of term-PE, at a false-positive rate of 5%. These empirical detection rates are compatible with the respective model-based rates of 98% and 54%, but the latter were optimistically biased. CONCLUSION: Combination of maternal factors and biomarkers in the early third trimester could predict nearly all cases of preterm-PE and half of those with term-PE, at 5% false-positive rate.

Prediction of stillbirth from maternal demographic and pregnancy characteristics.

OBJECTIVES: To develop a model for prediction of stillbirth based on maternal characteristics and components of medical history and to evaluate the performance of screening with this model for all stillbirths and those due to impaired placentation and to unexplained causes. METHODS: This was a prospective screening study of 113 415 singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation and at 19 + 0 to 24 + 6 weeks. The study population included 113 019 live births and 396 (0.35%) antepartum stillbirths; 230 (58%) were secondary to impaired placentation and 166 (42%) were due to other or unexplained causes. Multivariable logistic regression analysis was used to determine the factors from maternal characteristics and medical history which provided a significant contribution to the prediction of stillbirth. RESULTS: The risk for stillbirth increased with maternal weight (odds ratio (OR), 1.01 per kg above 69 kg), was higher in women of Afro-Caribbean racial origin (OR, 2.01), those with assisted conception (OR, 1.79), cigarette smokers (OR, 1.71), and in those with a history of chronic hypertension (OR, 2.62), systemic lupus erythematosus/antiphospholipid syndrome (OR, 3.61) or diabetes mellitus (OR, 2.55) and was increased in women with a history of previous stillbirth (OR, 4.81). Screening with the model predicted 26% of unexplained stillbirths and 31% of those due to impaired placentation, at a false-positive rate of 10%; within the impaired-placentation group the detection rate of stillbirth < 32 weeks' gestation was higher than that of stillbirth ≥ 37 weeks (38% vs 28%). CONCLUSIONS: A model based on maternal characteristics and medical history recorded in early pregnancy can potentially predict one-third of subsequent stillbirths. The extent to which such stillbirths could be prevented remains to be determined. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Mean arterial pressure at 12, 22, 32 and 36 weeks' gestation in screening for pre-eclampsia.

OBJECTIVE: To examine the distribution of mean arterial pressure (MAP) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: MAP was measured in 77 343 cases at 11-13 weeks, in 31 120 cases at 19-24 weeks, in 29 802 at 30-34 weeks and 5543 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with MAP. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6 and ≥ 37 weeks' gestation was estimated. RESULTS: In pregnancies that developed PE, MAP was increased and the separation in multiples of the median (MoM) values from normal was greater with an earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of the regression lines of MAP MoM with gestational age at delivery in pregnancies that developed PE increased with advancing gestational age at screening. The detection rate (DR), at a false-positive rate of 10%, for PE delivering < 32 weeks was 66% and 72% with screening at 12 and 22 weeks, respectively. The DR for PE delivering at 32 + 0 to 36 + 6 weeks was 54%, 56% and 81% with screening at 12, 22 and 32 weeks. The DR for PE delivering ≥ 37 weeks was 45%, 43%, 49% and 59% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: The performance of combined screening with maternal factors and MAP is superior in screening for early, compared to late, PE and, to a certain extent, improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.