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

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

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

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

OBJECTIVE: To estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values 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), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a second-trimester ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE < 32 weeks and < 36 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 32 weeks' gestation, at 32-35 weeks and at ≥ 36 weeks was estimated. In addition to empirical performance, we also derived model-based performance because the number of cases of PE delivering < 32 weeks was low. RESULTS: The study population of 7748 singleton pregnancies included 268 (3.5%) that subsequently developed PE. Using a risk cut-off of 1 in 100 for PE delivering < 32 weeks' gestation and a risk cut-off of 1 in 300 for PE delivering < 36 weeks, the proportion of the population stratified into high-, intermediate- and low-risk was 0.9%, 17.2% and 81.9%, respectively. The high-risk group contained 97% of pregnancies with PE < 32 weeks and 45% of those with PE at 32-35 weeks. The intermediate-risk group contained a further 46% of women with PE at 32-35 weeks. The low-risk group contained only 0.03% of pregnancies with PE < 32 weeks and 9% of those with PE at 32-35 weeks. CONCLUSION: Risk stratification of PE by the combined test at 19-24 weeks' gestation can identify, first, a group which constitutes < 1% of the total population and contains > 95% of those that will develop PE < 32 weeks and are in need of intensive monitoring at 24-31 weeks and, second, a group which constitutes < 20% of the total and contains > 90% of those that will develop PE at 32-35 weeks and are in need of reassessment at 32 weeks. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Proposed clinical management of pregnancies after combined screening for pre-eclampsia at 35-37 weeks' gestation.

OBJECTIVE: To estimate the patient-specific risk of pre-eclampsia (PE) at 35-37 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values 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), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 35-37 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 4 weeks from assessment and PE at < 42 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 40 and ≥ 40 weeks' gestation was estimated. RESULTS: The study population of 3703 singleton pregnancies included 38 (1.0%) with PE < 40 weeks' gestation and 22 (0.6%) with PE ≥ 40 weeks. Using a risk cut-off of 1 in 50 for PE delivering at < 4 weeks after assessment to define the high-risk group and a risk cut-off of < 1 in 100 for PE delivering at < 42 weeks' gestation to define the low-risk group, the proportion of the population stratified into high, intermediate and low risk was 12.7%, 28.8% and 58.5%, respectively. The high-risk group contained 92% of pregnancies with PE at < 40 weeks' gestation and 73% of those with PE at ≥ 40 weeks. The intermediate-risk group contained a further 27% of women with PE at ≥ 40 weeks. In the low-risk group, none of the women developed PE at < 40 or ≥ 40 weeks' gestation. CONCLUSION: The study presents risk stratification of PE by the combined test at 35-37 weeks, aiming to identify a high-risk group in need of intensive monitoring from the time of the initial assessment and up to 40 weeks' gestation, an intermediate-risk group in need of reassessment at 40 weeks' gestation and a low-risk group that can be reassured that they are unlikely to develop PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Screening for pre-eclampsia using sFlt-1/PlGF ratio cut-off of 38 at 30-37 weeks' gestation.

OBJECTIVE: To evaluate a soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio cut-off of 38 for the prediction of pre-eclampsia (PE) in routine assessment in singleton pregnancies at 30-37 weeks' gestation. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 30-37 weeks as part of routine pregnancy care. Serum sFlt-1 and PlGF were measured and their ratio was calculated. We estimated the detection rate (DR), false-positive rate (FPR), positive predictive value (PPV) and negative predictive value (NPV) of sFlt-1/PlGF ratio >38 for the prediction of delivery with PE at < 1, < 4 and ≥ 4 weeks after assessment. RESULTS: The study population of 12 305 singleton pregnancies was examined at a median of 32.4 (range, 30.0-36.9) weeks and included 14 (0.11%), 77 (0.63%) and 227 (1.84%) cases that subsequently delivered with PE at < 1, < 4 or ≥ 4 weeks' after assessment, respectively. The DR, FPR, PPV and NPV of sFlt-1/PlGF ratio > 38 in the prediction of delivery with PE at < 1 week were 78.6%, 4.5%, 1.9% and 99.97%, respectively; the values for delivery with PE at < 4 weeks were 76.6%, 4.1%, 10.4% and 99.85% and for delivery with PE ≥ 4 weeks were 20.7%, 4.3%, 8.3% and 98.47%. CONCLUSION: In routine screening of singleton pregnancies, the performance of a sFlt-1/PlGF ratio > 38 is modest for the prediction of delivery with PE at < 1 and at < 4 weeks after assessment and poor for the prediction of delivery with PE at ≥ 4 weeks after assessment. A sFlt-1/PlGF ratio > 38 predicted 79% of cases delivering with PE at < 1 week after assessment, at a FPR of 4.5%; consequently, a policy of hospitalizing patients with a ratio > 38 would potentially lead to unnecessary hospitalization in 4.5% of pregnancies and a ratio of ≤ 38 would falsely reassure one fifth of women who will deliver with PE within 1 week of assessment. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Comparison of screening for pre-eclampsia at 31-34 weeks' gestation by sFlt-1/PlGF ratio and a method combining maternal factors with sFlt-1 and PlGF.

OBJECTIVE: To estimate the patient-specific risk of pre-eclampsia (PE) at 31-34 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) and to compare the performance of screening to that achieved by the sFlt-1/PlGF ratio. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 31-34 weeks as part of routine pregnancy care. We estimated the performance of screening for PE with delivery within 4 weeks of assessment and PE with delivery from 4 weeks after assessment up to 40 weeks' gestation by the sFlt-1/PlGF ratio and by a method utilizing Bayes' theorem that combines maternal factors and MoM values of sFlt-1 and PlGF. The significance of the difference in screening performance between the two methods was assessed by comparison of the areas under the receiver-operating characteristics curves (AUC). RESULTS: The study population of 8063 singleton pregnancies included 231 (2.9%) that subsequently developed PE. In the prediction of delivery with PE at < 4 weeks from assessment, the performance of the method utilizing Bayes' theorem was similar to that using the sFlt-1/PlGF ratio (AUC, 0.987 (95% CI, 0.979-0.995) vs 0.988 (95% CI, 0.981-0.994); P = 0.961). In contrast, the performance of screening for delivery with PE at ≥ 4 weeks after assessment up to 40 weeks' gestation was better with the method utilizing Bayes' theorem than that with the sFlt-1/PlGF ratio (AUC, 0.884 (95% CI, 0.854-0.914) vs 0.818 (95% CI, 0.775-0.860); P < 0.0001). CONCLUSION: At 31-34 weeks' gestation the performance of screening for PE delivering at < 4 weeks from assessment by the method utilizing Bayes' theorem is similar to that using the sFlt-1/PlGF ratio, but the former is superior to the latter in prediction of PE delivering ≥ 4 weeks from assessment. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Proposed clinical management of pregnancies after combined screening for pre-eclampsia at 30-34 weeks' gestation.

OBJECTIVE: To estimate the patient-specific risk of pre-eclampsia (PE) at 30-34 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values 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), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 30-34 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 4 weeks from assessment and at < 40 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 4 weeks from assessment and delivery with PE from 4 weeks after assessment and up to 40 weeks' gestation was estimated. RESULTS: The study population of 8128 singleton pregnancies included 234 (2.9%) that subsequently developed PE. Using a risk cut-off of 1 in 50 for PE delivering at < 4 weeks and a risk cut-off of 1 in 150 for PE delivering at < 40 weeks' gestation, the proportion of the population stratified into high, intermediate and low risk was about 3%, 26% and 71%, respectively. The high-risk group contained 90% of pregnancies with PE at < 4 weeks and 40% of those with PE at 4 weeks from assessment to 40 weeks' gestation. The intermediate-risk group contained a further 49% of women with PE at 4 weeks from assessment to 40 gestational weeks. In the low-risk group, none of the women developed PE at < 4 weeks and only 0.3% developed PE at 4 weeks to 40 gestational weeks. CONCLUSION: The study presents risk stratification of PE by the combined test at 30-34 weeks, aiming to identify a high-risk group in need of intensive monitoring from the time of the initial assessment and up to 40 weeks' gestation and an intermediate-risk group in need of monitoring from 4 weeks after the initial assessment and up to 40 weeks' gestation. All pregnancies would need to be reassessed at 40 weeks' gestation. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Development of pre-eclampsia within 4 weeks of sFlt-1/PlGF ratio > 38: comparison of performance at 31-34 vs 35-37 weeks' gestation.

OBJECTIVE: To compare the performance of screening by soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio > 38 for the prediction of delivery with pre-eclampsia (PE) at < 1 week and < 4 weeks from assessment when the test is carried out at 31-34 vs 35-37 weeks' gestation. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan as part of routine pregnancy care; the visit was at 30-34 weeks' gestation in the first phase of the study and at 35-37 weeks in the second phase. Serum sFlt-1 and PlGF were measured and their ratio calculated. We estimated the detection rate (DR) and false-positive rate (FPR) of sFlt-1/PlGF ratio > 38 for predicting delivery with PE at < 1 week and < 4 weeks after assessment and compared the performance of screening when the test was carried out at 31 + 0 to 33 + 6 vs 35 + 0 to 36 + 6 weeks' gestation. RESULTS: The study population included 8063 singleton pregnancies that were examined at 31-34 weeks and 3703 at 35-37 weeks. Delivery with PE occurred at < 1, < 4 and ≥ 4 weeks from assessment in five (0.1%), 29 (0.4%) and 202 (2.5%) women assessed at 31-34 weeks, respectively, and in seven (0.2%), 39 (1.1%) and 21 (0.6%) of those assessed at 35-37 weeks. In women without PE, the median sFlt-1/PlGF ratio increased with gestational age at screening and a ratio of 38 was just below the 99th percentile at 32 weeks' gestation and just below the 90th percentile at 36 weeks. In the two gestational windows, the DR of PE delivering < 4 weeks from assessment was similar (75.9% (95% CI, 56.5-89.7%) vs 79.5% (95% CI, 63.5-90.7%)), but the FPR was substantially lower at 31-34 weeks than at 35-37 weeks (1.7% (95% CI, 1.4-2.0%) vs 9.6% (95% CI, 8.7-10.6%)). The number of cases with PE delivering < 1 week from assessment was small, but similarly, in the two gestational windows, the DR was comparable (80.0% (95% CI, 28.4-99.5%) vs 85.7% (95% CI, 42.1-99.6%)), and the FPR was substantially lower at 31-34 weeks than at 35-37 weeks (1.9% (95% CI, 1.6-2.2%) vs 10.2% (95% CI, 9.3-11.3%)). CONCLUSION: The performance of sFlt-1/PlGF ratio > 38 in the prediction of delivery with PE at < 1 and < 4 weeks from assessment is substantially different when the assessment is at 31-34 weeks' gestation compared to at 35-37 weeks. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Birth weight in live births and stillbirths.

OBJECTIVE: To establish a normal range of birth weights for gestational age at delivery and to compare the proportion of live births and stillbirths that are classified as small-for-gestational age (SGA) according to our normal range vs that of the INTERGROWTH-21st standard. METHODS: The study population comprised 113 019 live births and 437 (0.4%) stillbirths. The inclusion criterion for establishing a normal range of birth weights for gestational age was the live birth of a phenotypically normal neonate ≥ 24 weeks' gestation and the exclusion criteria were smoking and prepregnancy hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, pre-eclampsia, gestational hypertension, gestational diabetes mellitus or iatrogenic preterm birth for fetal growth restriction in the current pregnancy. Inclusion criteria were met by 92 018 live births. The proportions of live births and stillbirths with birth weights < 5th and < 10th percentiles of our normal range and those according to the INTERGROWTH-21st standard were determined and compared by the chi-square test and McNemar test. RESULTS: The proportions of live births and stillbirths with a birth weight < 5th percentile according to our standard were significantly higher than and discordant with the proportion according to the INTERGROWTH-21st standard (live birth: 5.6% vs 3.4%; stillbirth: 37.2% vs 22.7%). Similarly, the proportion of live births and stillbirths with a birth weight < 10th percentile according to our standard were significantly higher than and discordant with those according to the INTERGROWTH-21st standard (live birth: 11.2% vs 6.9%; stillbirth: 44.3% vs 32.6%). CONCLUSION: The INTERGROWTH-21st standard underestimates the proportion of SGA live births and stillbirths in our population. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The use of ultrasound and other markers for early detection of preeclampsia.

Preeclampsia (PE) is a multisystem disorder of pregnancy classically characterized with the onset of hypertension after 20 weeks gestation in the presence of proteinuria. PE typically affects 2-8% of pregnancies and is a leading cause of maternal and perinatal morbidity and mortality. This article reviews the most effective biomarkers used in first trimester screening for PE. It explores their use both in isolation and as part of an algorithm to yield the best detection rates. Screening by a combination of maternal risk factors, uterine artery Doppler, mean arterial pressure, maternal serum PAPP-A and PlGF can identify about 75% of cases of preterm PE for a false-positive rate of 10%. By identifying these patients at high risk for PE, appropriately tailored antenatal surveillance can be instigated and prophylactic pharmacological interventions can be prescribed to improve placentation and ultimately, the outcome for both the mother and fetus.

Uterine artery pulsatility index at 30-34 weeks' gestation in the prediction of adverse perinatal outcome.

OBJECTIVE: To investigate the potential value of uterine artery (UtA) Doppler at 30-34 weeks' gestation in the prediction of adverse perinatal outcome. METHODS: This was a screening study in 30 780 singleton pregnancies at 30-34 weeks. UtA pulsatility index (UtA-PI) was measured and the values were converted to multiples of the median (MoM) after adjustment for variables relating to maternal characteristics and medical history that affect the measurements. Multivariable logistic regression analysis was used to determine if measuring UtA-PI improved the prediction of adverse perinatal outcome provided by screening with maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by UtA-PI were estimated for stillbirth, Cesarean section for fetal distress, umbilical arterial cord blood pH ≤ 7.0 or umbilical venous cord blood pH ≤ 7.1 and 5-min Apgar score < 7. RESULTS: The incidence of adverse perinatal outcome was higher in small-for-gestational-age (SGA) fetuses than in non-SGA fetuses, but the majority of cases with each adverse outcome were in the non-SGA group, including about 70% of stillbirths and more than 80% with Cesarean section for fetal distress, low cord blood pH and low Apgar score. The performance of UtA-PI > 95(th) percentile in screening for each adverse outcome was poor with DR of 6-16% and a FPR of 5-6%. The DR of adverse outcome when screening by high UtA-PI was greater in pregnancies complicated by SGA than in non-SGA pregnancies; 24% vs 13% for stillbirth, 15% vs 5% for Cesarean section for fetal distress, 30% vs 9% for low cord blood pH and 20% vs 3% for low 5-min Apgar score, respectively. CONCLUSION: High UtA-PI at 30-34 weeks' gestation may be useful in the prediction of adverse perinatal outcome in pregnancies with a SGA fetus, however, in the absence of SGA, UtA-PI is a poor predictor of adverse outcome. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Biophysical and biochemical markers at 35-37 weeks' gestation in the prediction of adverse perinatal outcome.

OBJECTIVE: To investigate the potential value of biophysical and biochemical markers at 35-37 weeks' gestation in the prediction of adverse perinatal outcome. METHODS: This was a screening study in 3953 singleton pregnancies at 35-37 weeks' gestation. Estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI), umbilical artery (UA)-PI, fetal middle cerebral artery (MCA)-PI, mean arterial pressure (MAP), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured. The detection rate (DR) and false-positive rate (FPR) of screening by each biomarker were estimated for pre-eclampsia (PE), delivery of small-for-gestational-age (SGA) neonates, Cesarean section for fetal distress before or during labor, umbilical arterial cord blood pH ≤ 7.0 or umbilical venous cord blood pH ≤ 7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU). RESULTS: Multivariable regression analysis demonstrated that significant prediction of PE was provided by PlGF, sFlt-1 and MAP, with a DR of 73% at a 10% FPR. Prediction of SGA was provided by EFW, PlGF and UtA-PI, with a DR of 63% at a 10% FPR. Prediction of Cesarean section for fetal distress before labor was provided by EFW and UA-PI with DR of 100% at 10% FPR. Prediction of fetal distress in labor was provided by EFW and sFlt-1, with a DR of 15% at a 10% FPR. There were no significant differences between those with a normal outcome and those with low cord blood pH, low Apgar score or NNU admission for any of the biomarkers assessed. CONCLUSION: At 35-37 weeks' gestation biomarkers of impaired placentation and fetal hypoxemia provide good prediction of PE, SGA and fetal distress before labor, but poor or no prediction of adverse events in labor or after birth.

Prediction of large-for-gestational-age neonates: screening by maternal factors and biomarkers in the three trimesters of pregnancy.

OBJECTIVE: To develop a model based on maternal characteristics and medical history (maternal factors) for the prediction of delivery of large-for-gestational-age (LGA) neonates, and to examine the potential value of first-, second- and third-trimester fetal biometry and biomarkers in improving such a model. METHODS: This was a screening study in 76 300, 54 999, 25 727 and 6181 singleton pregnancies at 11-13, 19-24, 30-34 and 35-37 weeks' gestation, respectively. The a-priori risk for LGA with birth weight > 95(th) percentile (LGA > 95(th) ) was calculated using multivariable logistic regression analysis to determine which of the maternal factors had a significant contribution. Regression analysis was then used to determine whether screening by a combination of maternal factors, fetal biometry and various biophysical and biochemical markers had significant contribution in predicting delivery of LGA neonates. RESULTS: The likelihood of LGA > 95(th) increased with increasing maternal weight and height and was lower in women of Afro-Caribbean and South Asian racial origins, in cigarette smokers and in nulliparous women. The risk was higher in women with pre-existing diabetes mellitus Type I and lower in those with chronic hypertension. In parous women, the risk increased with birth-weight Z-score in previous pregnancy and prior history of gestational diabetes and decreased with interpregnancy interval. Screening by maternal factors at 11-13 weeks predicted 32%, 44% and 60% of LGA > 95(th) at false-positive rates (FPRs) of 5%, 10% and 20%, respectively. With the addition of fetal biometry, the detection rates improved to 37%, 51% and 68% at 19-24 weeks, 50%, 65% and 81% at 30-34 weeks and 60%, 73% and 85% at 35-37 weeks at FPRs of 5%, 10% and 20%, respectively. The addition of biomarkers did not improve the detection rates achieved when screening by a combination of maternal factors and fetal biometry. CONCLUSION: Combined screening by maternal factors and fetal biometry can predict a high proportion of pregnancies that will deliver LGA neonates. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Biophysical and biochemical markers at 30-34 weeks' gestation in the prediction of adverse perinatal outcome.

OBJECTIVE: To investigate the potential value of biophysical and biochemical markers at 30-34 weeks' gestation in the prediction of adverse perinatal outcome. METHODS: This was a screening study in 8268 singleton pregnancies at 30-34 weeks' gestation. Estimated fetal weight (EFW), uterine artery (UtA) pulsatility index (PI), umbilical artery (UA) PI, fetal middle cerebral artery (MCA) PI, mean arterial pressure (MAP), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured. The detection rate (DR) and false-positive rate (FPR) of screening by each biomarker were estimated for stillbirth, pre-eclampsia, delivery of small-for-gestational-age (SGA) neonate, Cesarean section for fetal distress before or during labor, umbilical arterial cord blood pH ≤7.0 or umbilical venous cord blood pH ≤7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU). RESULTS: Multivariable regression analysis demonstrated that significant prediction of PE was provided by PlGF, sFlt-1, MAP and MCA-PI, with a DR of 98% for PE delivering < 37 weeks' gestation and 56% for those delivering ≥ 37 weeks, at a 10% FPR. Prediction of SGA was provided by EFW, PlGF, sFlt-1, UtA-PI, UA-PI and MCA-PI, with a DR of 88% for SGA delivering < 37 and 51% for those delivering ≥ 37 weeks' gestation, at a 10% FPR. Prediction of stillbirth was provided by EFW, UtA-PI and MCA-PI, with DR of 30% at 10% FPR. Prediction of Cesarean section for fetal distress before labor was provided by EFW, sFlt-1, UtA-PI and UA-PI, with a DR of 90% at a 10% FPR. Prediction of fetal distress in labor was provided by EFW and sFlt-1, with a DR of 16% at a 10% FPR. There were no significant differences from the normal outcome group in any of the biomarkers for low cord blood pH, low Apgar score or NNU admission for cases other than those with PE and/or SGA. CONCLUSION: At 30-34 weeks' gestation, biomarkers of impaired placentation and fetal hypoxemia provide good prediction of PE, SGA and fetal distress before labor, but poor or no prediction of stillbirth and adverse events in labor or after birth.

Prediction of small-for-gestational-age neonates: screening by maternal serum biochemical markers at 19-24 weeks.

OBJECTIVE: To investigate the value of maternal serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG) and α-fetoprotein (AFP) at 19-24 weeks' gestation, in combination with maternal factors and fetal biometry, in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE) and examine the potential value of such assessment in deciding whether the third-trimester scan should be performed at 32 and/or 36 weeks' gestation. METHODS: This was a screening study in 9715 singleton pregnancies, including 481 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, Z-scores of fetal head circumference, abdominal circumference and femur length, and log10 multiples of the median (MoM) values of PlGF, sFlt-1, PAPP-A, free ß-hCG or AFP had a significant contribution to the prediction of SGA neonates. A model was developed in selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. RESULTS: Compared to the normal group, the mean log10 MoM value of PlGF was lower, AFP was higher and sFlt-1, PAPP-A and free ß-hCG were not significantly different in the SGA < 5(th) group that delivered < 37 weeks. The detection rate (DR) of combined screening by maternal factors, fetal biometry and serum PlGF and AFP at 19-24 weeks was 100%, 76% and 38% for SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that, if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 46% to be reassessed at 36 weeks; 54% would not require a third-trimester scan. CONCLUSION: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 19-24 weeks.

OBJECTIVE: To investigate the value of combined screening by maternal characteristics and medical history, fetal biometry and biophysical and biochemical markers at 19-24 weeks' gestation, for prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. METHODS: This was a screening study in 7816 singleton pregnancies, including 389 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal biometry, uterine artery pulsatility index (UtA-PI) and maternal serum concentrations of placental growth factor (PlGF) and α-fetoprotein (AFP) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. RESULTS: Significant independent contributions to the prediction of SGA < 5(th) were provided by maternal factors, fetal biometry, UtA-PI and serum PlGF and AFP. The detection rate (DR) of such combined screening at 19-24 weeks was 100%, 78% and 42% for SGA < 5(th) delivering < 32, at 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 44% to be reassessed at 36 weeks; 57% would not require a third-trimester scan. CONCLUSION: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Prediction of small-for-gestational-age neonates: screening by maternal biochemical markers at 30-34 weeks.

OBJECTIVE: To investigate the potential value of serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG) and α-fetoprotein (AFP) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in singleton pregnancies at 30-34 weeks' gestation, including 490 that delivered SGA neonates and 9360 cases that were unaffected by SGA, PE or gestational hypertension (normal outcome). Multivariable logistic regression analysis was used to determine if screening by serum PlGF, sFlt-1, PAPP-A, free ß-hCG and AFP, individually or in combination, improved the prediction of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. RESULTS: Compared to the normal group, the mean log10 multiples of the median (MoM) values of PlGF and AFP were significantly lower and the mean log10 MoM values of sFlt-1 and free ß-hCG were significantly higher in the SGA group with a birth weight < 5(th) percentile (SGA < 5(th)) delivering < 5 weeks following assessment. The best model for prediction of SGA was provided by a combination of maternal factors, EFW and serum PlGF. Such combined screening, predicted, at a 10% false-positive rate, 85%, 93% and 92% of SGA neonates delivering < 5 weeks following assessment with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering ≥ 5 weeks following assessment were 57%, 64% and 71%. CONCLUSION: Combined screening by maternal factors, EFW and serum PlGF at 30-34 weeks' gestation can identify a high proportion of pregnancies that subsequently deliver SGA neonates.

Prediction of small-for-gestational-age neonates: screening by placental growth factor and soluble fms-like tyrosine kinase-1 at 35-37 weeks.

OBJECTIVE: To investigate the potential value of maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) at 35-37 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in singleton pregnancies at 35-37 weeks, including 158 that delivered SGA neonates with birth weight < 5(th) percentile and 3701 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if measuring serum levels of PlGF and sFlt-1 improved the prediction of delivery of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. RESULTS: Compared to the normal group, the median PlGF multiples of the median (MoM) was significantly lower and the median sFlt-1 MoM was significantly higher in the SGA group. Combined screening by maternal factors and EFW at 35-37 weeks predicted, at 10% false-positive rate (FPR), 90%, 92% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment; the respective values for SGA delivering ≥ 37 weeks were 66%, 73% and 80%. When PlGF and sFlt-1 were added to a model that combines maternal factors and EFW, sFlt-1 did not remain as a significant independent predictor of SGA < 5(th). Combined screening by maternal factors, EFW and serum PlGF, predicted, at a 10% FPR, 88%, 96% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment and the respective values for SGA delivering ≥ 37 weeks were 64%, 75% and 80%. CONCLUSION: sFlt-1 does not provide significant independent prediction of SGA, in the absence of PE, in addition to combined testing by maternal factors and fetal biometry at 35-37 weeks; whilst the addition of PlGF alone marginally improves the performance of screening.