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.

Litwinska M ，Litwinska E ，Astudillo A ，Syngelaki A ，Wright A ，Nicolaides KH ... -  《-》

Stratification of pregnancy care based on risk of pre-eclampsia derived from uterine artery Doppler at 19-24 weeks' gestation.

There were two objectives of this study. First, to examine the value of uterine artery pulsatility index (UtA-PI) at 19-24 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE) and to compare the performance of screening between the use of, first, fixed cut-offs of UtA-PI, second, percentile cut-offs of UtA-PI adjusted for gestational age, third, a competing-risks model combining maternal demographic characteristics and medical history with UtA-PI, and, fourth, a competing-risks model combining maternal factors with UtA-PI and mean arterial pressure (MAP). Second, to stratify pregnancy care based on the estimated risk of PE at 19-24 weeks' gestation from UtA-PI and combinations of maternal factors with UtA-PI and 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 the gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiples of the median (MoM) values of UtA-PI and MAP. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category (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. We also examined the performance of screening by maternal factors and UtA-PI MoM, fixed cut-offs of UtA-PI and percentile cut-offs of UtA-PI adjusted for gestational age. Calibration for risks for PE < 36 weeks' gestation by the combination of maternal factors, UtA-PI MoM and MAP MoM was assessed by plotting the observed incidence of PE against the predicted incidence. Additionally, we developed reference ranges of transabdominal and transvaginal measurement of UtA-PI according to gestational age. In the study population of 96 678 singleton pregnancies, there were 2866 (3.0%) that subsequently developed PE, including 467 (0.5%) that delivered at < 36 weeks' gestation. If the objective of screening was to identify about 90% of cases of delivery with PE at < 28, < 32 and < 36 weeks and the method of screening was a combination of maternal factors, UtA-PI MoM and MAP MoM, the proportion of the population stratified into very high-risk, high-risk, intermediate-risk and low-risk groups would be 2.4%, 3.9%, 17.8% and 75.9%, respectively; the respective values were 6.0%, 3.0%, 21.0% and 70.0% if screening was by maternal factors and UtA-PI MoM, 5.7%, 7.5%, 49.8% and 37.0% if screening was by fixed cut-offs of UtA-PI and 6.9%, 5.2%, 49.0% and 38.9% if screening was by percentile cut-offs of UtA-PI. In the validation of the prediction model based on a combination of maternal factors and MoM values of UtA-PI and MAP, calibration plots demonstrated good agreement between the predicted risk and the observed incidence of PE. All pregnant women should have screening for PE at 20 and 36 weeks' gestation. The findings at 20 weeks can be used to identify the subgroups that require additional monitoring and reassessment at 28 and 32 weeks. The performance of screening by a combination of maternal factors and MoM values of UtA-PI and MAP at 19-24 weeks for delivery with PE at < 28, < 32 and < 36 weeks' gestation is superior to that of screening by a combination of maternal factors and UtA-PI MoM, by fixed cut-offs of UtA-PI or by percentile cut-offs of UtA-PI. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Litwinska M ，Litwinska E ，Lisnere K ，Syngelaki A ，Wright A ，Nicolaides KH ... -  《-》

Management of pregnancies after combined screening for pre-eclampsia at 19-24 weeks' gestation.

To estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 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). On the basis of the risk of PE, the women would be stratified into high-, intermediate- and low-risk management groups. The high-risk group would require close monitoring for high blood pressure and proteinuria at 24-31 weeks. The intermediate-risk group, together with the undelivered pregnancies from the high-risk group, would have reassessment of risk for PE at 32 weeks to identify those who would require close monitoring for high blood pressure and proteinuria at 32-35 weeks. All pregnancies would have reassessment of risk for PE at 36 weeks to define the plan for further monitoring and delivery. This was a prospective observational study of women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 32 and 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 (MoM) values of MAP, UtA-PI, PlGF and sFlt-1. Different risk cut-offs were used to vary the proportion of the population stratified into high-, intermediate- and low-risk groups, and the performance of screening for delivery with PE at < 32 weeks' gestation and at 32 + 0 to 35 + 6 weeks was estimated. The study population of 16 254 singleton pregnancies included 467 (2.9%) that subsequently developed PE (23 delivered at < 32 weeks, 58 delivered at 32 + 0 to 35 + 6 weeks and 386 delivered at ≥ 36 weeks). Using a risk of > 1 in 25 for PE at < 32 weeks' gestation and risk of > 1 in 150 for PE at < 36 weeks, the proportion of the population stratified into the high-risk group was about 1% of the total, and the proportion of cases of PE at < 32 weeks' gestation contained within this high-risk group varied from about 35% with screening by maternal factors and MAP, to 78% with maternal factors, MAP and UtA-PI, and up to 100% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1. Similarly, the proportion of the population requiring reassessment of risk at 32 weeks' gestation and the proportion of cases of PE at 32 + 0 to 35 + 6 weeks contained within this population varied, respectively, from about 18% and 79% with screening by maternal factors and MAP, to 10% and 90% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1. In the new pyramid of pregnancy care, assessment of risk for PE at 19-24 weeks' gestation can stratify the population into those requiring intensive monitoring at 24-31 weeks and those in need of reassessment at 32 weeks. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Litwinska M ，Syngelaki A ，Wright A ，Wright D ，Nicolaides KH ... -  《-》

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

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. 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. 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%. 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.

Mazer Zumaeta A ，Wright A ，Syngelaki A ，Maritsa VA ，Da Silva AB ，Nicolaides KH ... -  《-》

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.

Litwinska M ，Litwinska E ，Bouariu A ，Syngelaki A ，Wright A ，Nicolaides KH ... -  《-》