Evaluation of angiogenic factors in prediction of growth-related neonatal morbidity at term and comparison with competing-risks model.

OBJECTIVES: First, to describe the distribution of biomarkers of impaired placentation in small-for-gestational-age (SGA) pregnancies with neonatal morbidity; second, to examine the predictive performance for growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF; and, third, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for SGA in predicting growth-related neonatal morbidity. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, an ultrasound scan and measurement of serum PlGF and sFlt-1. The primary outcome was delivery within 4 weeks after assessment and at < 42 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile, sFlt-1/PlGF ratio > 38 and the competing-risks model for SGA, using combinations of maternal risk factors and Z-scores of estimated fetal weight (EFW) with multiples of the median values of uterine artery pulsatility index, PlGF and sFlt-1, were estimated. The detection rates by the different methods of screening were compared using McNemar's test. RESULTS: In the study population of 29 035 women, prediction of growth-related neonatal morbidity at term provided by the competing-risks model was superior to that of screening by low PlGF concentration or a high sFlt-1/PlGF concentration ratio. For example, at a screen-positive rate (SPR) of 13.1%, as defined by the sFlt-1/PlGF ratio > 38, the competing-risks model using maternal risk factors and EFW predicted 77.5% (95% CI, 71.7-83.3%) of SGA < 10th percentile and 89.3% (95% CI, 83.7-94.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 71.4% (95% CI, 56.5-86.4%) and 90.0% (95% CI, 76.9-100%). These were significantly higher than the respective values of 41.0% (95% CI, 34.2-47.8%) (P < 0.0001), 48.8% (95% CI, 39.9-57.7%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.035) achieved by the application of the sFlt-1/PlGF ratio > 38. At a SPR of 10.0%, as defined by PlGF < 10th percentile, the competing-risks model using maternal factors and EFW predicted 71.5% (95% CI, 65.2-77.8%) of SGA < 10th percentile and 84.3% (95% CI, 77.8-90.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 68.6% (95% CI, 53.1-83.9%) and 85.0% (95% CI, 69.4-100%). These were significantly higher than the respective values of 36.5% (95% CI, 29.8-43.2%) (P < 0.0001), 46.3% (95% CI, 37.4-55.2%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.021) achieved by the application of PlGF < 10th percentile. CONCLUSION: At 36 weeks' gestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA, using maternal risk factors and EFW, is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Screening for pre-eclampsia by maternal serum glycosylated fibronectin and angiogenic markers at 36 weeks' gestation.

OBJECTIVES: First, to examine the predictive performance of maternal serum glycosylated fibronectin (GlyFn) at 35 + 0 to 36 + 6 weeks' gestation in screening for delivery with pre-eclampsia (PE) and delivery with gestational hypertension (GH) at ≥ 37 weeks' gestation, both within 3 weeks and at any time after the examination. Second, to compare the predictive performance for delivery with PE and delivery with GH of various combinations of biomarkers, including GlyFn, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Third, to compare the predictive performance for delivery with PE and delivery with GH by serum PlGF concentration, sFlt-1/PlGF concentration ratio and the competing-risks model with different combinations of biomarkers as above. Fourth, to compare the predictive performance of screening at 11 + 0 to 13 + 6 weeks vs 35 + 0 to 36 + 6 weeks for delivery with PE and delivery with GH at ≥ 37 weeks' gestation. METHODS: This was a case-control study in which maternal serum GlyFn was measured in stored samples from a non-intervention screening study in singleton pregnancies at 35 + 0 to 36 + 6 weeks' gestation using a point-of-care device. We used samples from women who delivered at ≥ 37 weeks' gestation, including 100 who developed PE, 100 who developed GH and 600 controls who did not develop PE or GH. In all cases, MAP, UtA-PI, PlGF and sFlt-1 were measured during the routine visit at 35 + 0 to 36 + 6 weeks. We used samples from patients that had been examined previously at 11 + 0 to 13 + 6 weeks' gestation. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements from the medical history. Similarly, the measured values of MAP, UtA-PI, PlGF and sFlt-1 were converted to MoM. The competing-risks model was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal risk factors, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE. The performance of screening of different strategies was estimated by examining the detection rate (DR) at a 10% fixed false-positive rate (FPR) and McNemar's test was used to compare the DRs between the different methods of screening. RESULTS: The DR, at 10% FPR, of screening by the triple test (maternal risk factors plus MAP, PlGF and sFlt-1) was 83.7% (95% CI, 70.3-92.7%) for delivery with PE within 3 weeks of screening and 80.0% (95% CI, 70.8-87.3%) for delivery with PE at any time after screening, and this performance was not improved by the addition of GlyFn. The performance of screening by a combination of maternal risk factors, MAP, PlGF and GlyFn was similar to that of the triple test, both for delivery with PE within 3 weeks and at any time after screening. The performance of screening by a combination of maternal risk factors, MAP, UtA-PI and GlyFn was similar to that of the triple test, and they were both superior to screening by low PlGF concentration (PE within 3 weeks: DR, 65.3% (95% CI, 50.4-78.3%); PE at any time: DR, 56.0% (95% CI, 45.7-65.9%)) or high sFlt-1/PlGF concentration ratio (PE within 3 weeks: DR, 73.5% (95% CI, 58.9-85.1%); PE at any time: DR, 63.0% (95% CI, 52.8-72.4%)). The predictive performance of screening at 35 + 0 to 36 + 6 weeks' gestation for delivery with PE and delivery with GH at ≥ 37 weeks' gestation was by far superior to screening at 11 + 0 to 13 + 6 weeks. CONCLUSION: GlyFn is a potentially useful biomarker in third-trimester screening for term PE and term GH, but the findings of this case-control study need to be validated by prospective screening studies. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

First trimester screening identifies maternal cardiac maladaptation at mid-gestation.

BACKGROUND: First, a logistic regression model, based on maternal demographic characteristics and medical history and blood pressure at 11-13 weeks' gestation, can identify about 70% of women who develop future chronic hypertension (CH) in the three years following pregnancy, at screen positive rate of 10%. Second, at mid-gestation women who subsequently develop hypertensive disorders of pregnancy (HDP) have increased peripheral vascular resistance and mild cardiac functional and morphological alterations and these cardiovascular abnormalities persist for at least 2 years after delivery. OBJECTIVE: To examine whether the use of the first-trimester risk for subsequent development of CH can help to identify women at high risk for cardiovascular maladaptation at mid-gestation. METHODS: Prospective observational study in 3812 women with singleton pregnancies women attending for a routine hospital visit at 11+0 to 13+6 weeks' gestation and again at 19+1 to 23+3 weeks at King's College Hospital, London, UK between August 2019 and August 2020. The first-trimester visit included recording of maternal demographic characteristics and medical history and measurement of systolic and diastolic blood pressure. At mid-gestation detailed maternal cardiovascular assessment was carried out. The association of risk for development of CH, determined from first-trimester assessment, and cardiovascular indices at mid-gestation was examined. RESULTS: Women who are at high-risk for development of future CH, compared to those at low-risk, had a higher incidence of hypertensive disorders of pregnancy (HDP). In addition, high-risk women, had reduced systolic and diastolic function at mid-gestation. Among women with HDP, those who were high-risk for future CH, compared to those at low-risk, also had worse cardiac function at mid-gestation. CONCLUSION: Use of a model for first-trimester prediction of subsequent development of CH can identify women who show evidence of cardiac maladaptation at mid-gestation. Further studies are needed to clarify whether women who screen as high-risk for future CH, compared to those at low-risk, have reduced cardiac function beyond pregnancy. This article is protected by copyright. All rights reserved.

Incidence of neonatal morbidity in small-for-gestational-age twins based on singleton and twin charts.

OBJECTIVE: To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. METHODS: NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown-rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. RESULTS: The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6-4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4-4.7)). CONCLUSIONS: When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal Medicine Foundation charts for fetal growth in twins.

OBJECTIVE: To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons. METHODS: Gestational-age- and chorionicity-specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown-rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z-scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins. RESULTS: Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch-up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50th percentile was at the 50th percentile of singleton pregnancies at 23 weeks, the 43rd percentile at 28 weeks, the 32nd percentile at 32 weeks and the 22nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50th percentile was at the 36th percentile of singleton pregnancies at 24 weeks, the 29th percentile at 28 weeks, the 19th percentile at 32 weeks and the 12th percentile at 36 weeks. CONCLUSIONS: In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in growth trajectories between twin and singleton pregnancies becomes more pronounced as gestational age increases. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of adverse perinatal outcome at midgestation.

OBJECTIVES: First, to investigate the association between adverse neonatal outcomes and birth weight and gestational age at delivery. Second, to describe the distribution of adverse neonatal outcomes within different risk strata derived by a population stratification scheme based on the midgestation risk assessment for small-for-gestational-age (SGA) neonates using a competing-risks model. METHODS: This was a prospective observational cohort study in women with a singleton pregnancy attending a routine hospital visit at 19 + 0 to 23 + 6 weeks' gestation. The incidence of neonatal unit (NNU) admission for ≥ 48 h was evaluated within different birth-weight-percentile subgroups. The pregnancy-specific risk of delivery with SGA < 10th percentile at < 37 weeks was estimated by the competing-risks model for SGA, combining maternal factors and the likelihood functions of Z-score of sonographically estimated fetal weight and uterine artery pulsatility index multiples of the median. The population was stratified into six risk categories: > 1 in 4, > 1 in 10 to ≤ 1 in 4, > 1 in 30 to ≤ 1 in 10, > 1 in 50 to ≤ 1 in 30, > 1 in 100 to ≤ 1 in 50 and ≤ 1 in 100. The outcome measures were admission to the NNU for a minimum of 48 h, perinatal death and major neonatal morbidity. The incidence of each adverse outcome was estimated in each risk stratum. RESULTS: In the study population of 40 241 women, 0.8%, 2.5%, 10.8%, 10.2%, 19.0% and 56.7% were in the risk strata > 1 in 4, > 1 in 10 to ≤ 1 in 4, > 1 in 30 to ≤ 1 in 10, > 1 in 50 to ≤ 1 in 30, > 1 in 100 to ≤ 1 in 50 and ≤ 1 in 100, respectively. Women in higher-risk strata were more likely to deliver a baby that suffered an adverse outcome. The incidence of NNU admission for ≥ 48 h was highest in the > 1 in 4 risk stratum (31.9% (95% CI, 26.9-36.9%)) and it gradually decreased until the ≤ 1 in 100 risk stratum (5.6% (95% CI, 5.3-5.9%)). The mean gestational age at delivery in SGA cases with NNU admission for ≥ 48 h was 32.9 (95% CI, 32.2-33.7) weeks for risk stratum > 1 in 4 and progressively increased to 37.5 (95% CI, 36.8-38.2) weeks for risk stratum ≤ 1 in 100. The incidence of NNU admission for ≥ 48 h was highest for neonates with birth weight below the 1st percentile (25.7% (95% CI, 23.0-28.5%)) and decreased progressively until the 25th to < 75th percentile interval (5.4% (95% CI, 5.1-5.7%)). Preterm SGA neonates < 10th percentile had significantly higher incidence of NNU admission for ≥ 48 h compared with preterm non-SGA neonates (48.7% (95% CI, 45.0-52.4%) vs 40.9% (95% CI, 38.5-43.3%); P < 0.001). Similarly, term SGA neonates < 10th percentile had significantly higher incidence of NNU admission for ≥ 48 h compared with term non-SGA neonates (5.8% (95% CI, 5.1-6.5%) vs 4.2% (95% CI, 4.0-4.4%); P < 0.001). CONCLUSIONS: Birth weight has a continuous association with the incidence of adverse neonatal outcomes, which is affected by gestational age. Pregnancies at high risk of SGA, estimated at midgestation, are also at increased risk for adverse neonatal outcomes. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of competing-risks model with angiogenic factors in midgestation screening for preterm growth-related neonatal morbidity.

OBJECTIVES: First, to evaluate the predictive performance for preterm growth-related neonatal morbidity of high soluble fms-like tyrosine kinase-1 (sFLT-1) / placental growth factor (PlGF) ratio or low PlGF at mid-gestation, and second, to compare the performance of the high sFLT-1/PlGF ratio or low PlGF with that of the competing risks model for small for gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI). METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 to 24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFLT-1. The primary outcome was delivery <32 and <37 weeks' gestation of SGA neonate with birth weight <10th or <3rd percentile for gestational age, combined with neonatal unit (NNU) admission for ≥48 hours or a composite of major neonatal morbidity. The detection rates in screening by either PlGF <10th percentile, sFLT-1/PlGF ratio >90th percentile and the competing risks model for SGA were estimated and they were compared using McNemar's test. RESULTS: In the study population of 40241 women prediction of preterm growth-related neonatal morbidity provided by the competing risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio. For example, at screen positive rate (SPR) of 10.0%, as defined by the sFLT-1/ PlGF ratio >90th percentile, the competing risks model predicted 70.1% (95% CI 61.0 - 79.2) of SGA <10th percentile and 76.9% (67.6-86.3) of SGA <3rd percentile with NNU admission for ≥48 hours delivered <32 weeks gestation and these were significantly higher than the respective values of 35.0% (25.6-44.6) and 35.9% (25.3 - 46.5), achieved by the application of the sFLT-1/ PlGF ratio >90th percentile (p<0.0001 for both). The respective values for SGA with major neonatal morbidity were 73.8% (64.4-83.2), 77.9% (68.0-87.8), 38.1% (27.7-48.5) and 39.7% (28.1-51.3) (Both p<0.0001). CONCLUSION: At mid-gestation, the prediction of growth-related neonatal morbidity by the competing risks model for SGA is superior to that of high sFlt-1/PlGF ratio or low PlGF. This article is protected by copyright. All rights reserved.

Incidence of stillbirth: effect of deprivation.

OBJECTIVES: To examine the relationship between the English index of multiple deprivation (IMD) and the incidence of stillbirth and assess whether IMD contributes to the prediction of stillbirth provided by the combination of maternal demographic characteristics and elements of medical history. METHODS: This was a prospective, observational study of 159 125 women with a singleton pregnancy who attended their first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation in two maternity hospitals in the UK. The inclusion criterion was delivery at ≥ 24 weeks' gestation of a fetus without major abnormality. Participants completed a questionnaire on demographic characteristics and obstetric and medical history. IMD was used as a measure of socioeconomic status, which takes into account income, employment, education, skills and training, health and disability, crime, barriers to housing and services, and living environment. Each neighborhood is ranked according to its level of deprivation relative to that of other areas into one of five equal groups, with Quintile 1 containing the 20% most deprived areas and Quintile 5 containing the 20% least deprived areas. Logistic regression analysis was used to determine whether IMD provided a significant independent contribution to stillbirth after adjustment for known maternal risk factors. RESULTS: The overall incidence of stillbirth was 0.35% (551/159 125), and this was significantly higher in the most deprived compared with the least deprived group (Quintile 1 vs Quintile 5). The odds ratio (OR) in Quintile 1 was 1.57 (95% CI, 1.16-2.14) for any stillbirth, 1.64 (95% CI, 1.20-2.28) for antenatal stillbirth and 1.89 (95% CI, 1.23-2.98) for placental dysfunction-related stillbirth. In Quintile 1 (vs Quintile 5), there was a higher incidence of factors that contribute to stillbirth, including black race, increased body mass index, smoking, chronic hypertension and previous stillbirth. The OR of black (vs white) race was 2.58 (95% CI, 2.14-3.10) for any stillbirth, 2.62 (95% CI, 2.16-3.17) for antenatal stillbirth and 3.34 (95% CI, 2.59-4.28) for placental dysfunction-related stillbirth. Multivariate analysis showed that IMD did not have a significant contribution to the prediction of stillbirth provided by maternal race and other maternal risk factors. In contrast, in black (vs white) women, the risk of any and antenatal stillbirth was 2.4-fold higher and the risk of placental dysfunction-related stillbirth was 2.9-fold higher after adjustment for other maternal risk factors. CONCLUSIONS: The incidence of stillbirth, particularly placental dysfunction-related stillbirth, is higher in women living in the most deprived areas in South East England. However, in screening for stillbirth, inclusion of IMD does not improve the prediction provided by race, other maternal characteristics and elements of medical history. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Screening for pre-eclampsia by maternal serum glycosylated fibronectin at 11-13 weeks' gestation.

OBJECTIVE: To examine the performance of screening for preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of maternal serum glycosylated fibronectin (GlyFn), mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). METHODS: This was a case-control study in which maternal serum GlyFn was measured using a point-of-care device in stored samples from a non-intervention screening study of singleton pregnancies at 11 + 0 to 13 + 6 weeks' gestation. In the same samples, PlGF was measured by time-resolved fluorometry. We used samples from women who delivered with PE at < 37 weeks' gestation (n = 100), PE at ≥ 37 weeks (n = 100), gestational hypertension (GH) at < 37 weeks (n = 100), GH at ≥ 37 weeks (n = 100) and 1000 normotensive controls with no pregnancy complications. In all cases, MAP and UtA-PI had been measured during the routine 11-13-week visit. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements of medical history. Similarly, the measured values of MAP, UtA-PI and PlGF were converted to MoMs. The competing-risks model was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE or GH at < 37 and ≥ 37 weeks' gestation. Screening performance was estimated by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at 10% fixed false-positive rate (FPR). RESULTS: The maternal characteristics and elements of medical history with a significant effect on the measurement of GlyFn were maternal age, weight, height, race, smoking status and history of PE. In pregnancies that developed PE, GlyFn MoM was increased and the deviation from normal decreased with increasing gestational age at delivery. The DR and AUC of screening for delivery with PE at < 37 weeks' gestation by maternal factors alone were 50% and 0.834, respectively, and these increased to 80% and 0.949, respectively, when maternal risk factors were combined with MAP, UtA-PI and PlGF (triple test). The performance of the triple test was similar to that of screening by a combination of maternal factors, MAP, UtA-PI and GlyFn (DR, 79%; AUC, 0.946) and that of screening by a combination of maternal factors, MAP, PlGF and GlyFn (DR, 81%; AUC, 0.932). The performance of screening for delivery with PE at ≥ 37 weeks' gestation was poor; the DR for screening by maternal factors alone was 35% and increased to only 39% with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. The DR of screening for GH with delivery at < 37 and ≥ 37 weeks' gestation by maternal factors alone was 34% and 25%, respectively, and increased to 54% and 31%, respectively, with use of the triple test. Similar results were obtained when GlyFn replaced PlGF or UtA-PI in the triple test. CONCLUSIONS: GlyFn is a potentially useful biomarker in first-trimester screening for preterm PE, but the findings of this case-control study need to be validated by prospective screening studies. The performance of screening for term PE or GH at 11 + 0 to 13 + 6 weeks' gestation by any combination of biomarkers is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction using serum glycosylated fibronectin and angiogenic factors of superimposed pre-eclampsia in women with chronic hypertension.

OBJECTIVE: To compare the predictive performance for delivery with pre-eclampsia (PE) within 2 weeks of assessment in women with chronic hypertension at 24-41 weeks' gestation between serum glycosylated fibronectin (GlyFn) concentration, serum placental growth factor (PlGF) concentration and soluble fms-like tyrosine kinase-1 (sFlt-1) to PlGF concentration ratio. METHODS: This was a prospective study of 104 women with a singleton pregnancy and chronic hypertension presenting at 24-41 weeks' gestation. Twenty-six (25.0%) cases developed superimposed PE within 2 weeks of sampling. We compared the predictive performance for superimposed PE between GlyFn, PlGF and the sFlt-1/PlGF ratio at a fixed screen-positive rate of approximately 10%. RESULTS: The median gestational age at sampling was 34.1 (interquartile range, 31.5-35.6) weeks and 84.6% (88/104) of cases were sampled at < 36 weeks. The predictive performance for superimposed PE of the three methods of screening was similar, with detection rates of about 23-27%, at a screen-positive rate of 11% and a false-positive rate of about 5%. CONCLUSIONS: Measurement of GlyFn is a simple point-of-care test that can be carried out without need for a laboratory and provide results within 10 min of testing. In this respect, it could potentially replace the angiogenic markers that are used currently in the prediction of imminent PE in high-risk women. However, neither GlyFn nor angiogenic factors are likely to improve the management of women with chronic hypertension because their predictive performance for superimposed PE is poor. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of hypertensive disorders after screening at 36 weeks' gestation: comparison of angiogenic markers with competing-risks model.

OBJECTIVE: To compare the performance at 35 + 0 to 36 + 6 weeks' gestation of screening for delivery with pre-eclampsia (PE) at various timepoints, using one of three approaches: placental growth factor (PlGF) concentration, soluble fms-like tyrosine kinase-1 (sFlt-1) to PlGF concentration ratio, or the competing-risks model, which combines maternal risk factors with biomarkers to estimate patient-specific risk. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation at one of two maternity hospitals in England between 2016 and 2022. During the visit, maternal demographic characteristics and medical history were recorded and serum PlGF, serum sFlt-1 and mean arterial pressure (MAP) were measured. Detection rates (DRs) were evaluated for delivery with PE (defined as per American College of Obstetricians and Gynecologists 2019 criteria) within 1 week, within 2 weeks or at any time after screening, using the following strategies: (i) low PlGF (< 10th percentile); (ii) high sFlt-1/PlGF ratio (> 90th percentile); or (iii) the competing-risks model, in which maternal factors were combined with multiples of the median values of PlGF ('single test'), PlGF and sFlt-1 ('double test') or PlGF, sFlt-1 and MAP ('triple test'). Risk cut-offs corresponded to a screen-positive rate of 10%. DRs were compared between tests. RESULTS: Of 34 782 pregnancies, 831 (2.4%) developed PE. In screening for delivery with PE at any time from assessment, the DR at 10% screen-positive rate was 47% by low PlGF alone, 54% by the single test, 55% by high sFlt-1/PlGF ratio, 61% by the double test and 68% by the triple test. In screening for delivery with PE within 2 weeks from assessment, the respective values were 67%, 74%, 74%, 80% and 87%. In screening for delivery with PE within 1 week from assessment, the respective values were 77%, 81%, 85%, 88% and 91%. For prediction of PE at any time, the DR was significantly higher with the triple test compared to PlGF alone or the sFlt-1/PlGF ratio, with a DR difference (95% CI) of 20.1% (16.7-23.0%) and 12.4% (9.7-15.3%), respectively. Similar results were seen for prediction of PE within 2 weeks (20.6% (14.9-26.8%) and 12.9% (7.7-17.5%), respectively) and prediction of PE within 1 week (13.5% (5.4-21.6%) and 5.4% (0.0-10.8%), respectively). The double test was superior to the sFlt-1/PlGF ratio and the single test was superior to PlGF alone in the prediction of PE within 2 weeks and at any time from assessment, but not within 1 week of assessment. CONCLUSION: At 35 + 0 to 36 + 6 weeks' gestation, the performance of screening for PE by the competing-risks model triple test is superior to that of PlGF alone or the sFlt-1/PlGF ratio for the development of disease within 1 week, within 2 weeks and at any time from screening. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

ASPRE trial: effects of aspirin on mean arterial blood pressure and uterine artery pulsatility index trajectories in pregnancy.

OBJECTIVES: The mechanism by which aspirin prevents pre-eclampsia is poorly understood, and its effects on biomarkers throughout pregnancy are unknown. We aimed to investigate the effects of aspirin on mean arterial pressure (MAP) and mean uterine artery pulsatility index (UtA-PI) using repeated measures from women at increased risk of preterm pre-eclampsia. METHODS: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Pre-eclampsia Prevention (ASPRE) trial using repeated measures of MAP and UtA-PI. In the trial, 1620 women at increased risk of preterm pre-eclampsia were identified using the Fetal Medicine Foundation algorithm at 11 + 0 to 13 + 6 weeks, of whom 798 were randomly assigned to receive 150 mg/day aspirin and 822 were assigned to receive placebo daily from 11-14 weeks to 36 weeks of gestation or delivery, whichever came first. MAP and UtA-PI were measured at baseline and follow-up visits at 19-24, 32-34 and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effects of aspirin on MAP and UtA-PI trajectories over time. RESULTS: Among 798 participants in the aspirin group and 822 in the placebo group, there were 5951 MAP and 5942 UtA-PI measurements. Trajectories of raw and multiples of the median (MoM) values of MAP did not differ significantly between the two groups (MAP MoM analysis: P-value for treatment by gestational age interaction, 0.340). In contrast, trajectories of raw and MoM values of UtA-PI showed a significantly steeper decline in the aspirin group than in the placebo group, with the difference mainly driven by a more pronounced reduction before 20 weeks of gestation (UtA-PI MoM analysis: P-value for treatment by gestational age interaction, 0.006). CONCLUSIONS: In women at increased risk of preterm pre-eclampsia, 150 mg/day aspirin initiated in the first trimester does not affect MAP but is associated with a significant decrease in mean UtA-PI, particularly before 20 weeks of gestation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Incidence of pre-eclampsia: effect of deprivation.

OBJECTIVES: To examine the relationship between the English index of multiple deprivation (IMD) and the incidence of pre-eclampsia (PE), evaluate the distribution of IMD in a cohort of ethnically diverse pregnant women in South East England and assess whether IMD improves the prediction of PE compared with that provided by the 'history-only' competing-risks model (based on maternal characteristics and medical history). METHODS: This was a prospective, observational study of 159 125 women with a singleton pregnancy who attended their first routine hospital visit at 11 + 0 to 13 + 6 weeks' gestation in two maternity hospitals in the UK. The inclusion criteria were delivery at ≥ 24 weeks' gestation of babies without major abnormality. Participants completed a questionnaire on demographic characteristics and obstetric and medical history, which was then reviewed by a doctor together with the woman. Patients were asked to self-identify as white, black, South Asian, East Asian or mixed race. IMD was used as a measure of socioeconomic status, which takes into account income, employment, education, skills and training, health and disability, crime, barriers to housing and services, and living environment. Each neighborhood is ranked according to their level of deprivation relative to that of other areas into one of five equal groups, with Quintile 1 containing the 20% most deprived areas and Quintile 5 containing the 20% least deprived areas. IMD was assigned based on a woman's postcode. Risk factors for PE and its incidence were assessed across IMD using chi-square test or t-test, as appropriate. The relationship between IMD and gestational age at delivery with PE was evaluated by fitting parametric survival models for IMD alone, IMD combined with race and IMD combined with the Fetal Medicine Foundation history-only competing-risks model. RESULTS: The incidence of PE (n = 4088, 2.6%) increased progressively across IMD quintiles, from 2.0% in Quintile 5 (least deprived) to 3.0% in Quintile 1 (most deprived). Compared with white women and those in other racial groups, black women had a higher incidence of PE (4.8%), were less often in IMD Quintiles 4 and 5, and were more often in IMD Quintiles 1 and 2. None of the IMD quintiles improved the prediction of PE compared with that provided by the history-only competing-risks model (which includes race). The history-only competing-risks model with vs without IMD had a similar detection rate for delivery with PE at < 37 weeks' gestation (44.1% (95% CI, 41.1-47.2%) vs 43.9% (95% CI, 40.1-47.0%)) and at any gestational age (35.2% (95% CI, 33.8-36.7%) vs 35.1% (95% CI, 33.7-36.6%)), at a 10% screen-positive rate. CONCLUSIONS: The incidence of PE is higher in women living in the most deprived areas in South East England and in black women (vs those of other racial groups), who also live in areas of higher deprivation. However, in screening for PE, inclusion of IMD does not improve the prediction of PE provided by race and other maternal characteristics and elements of medical history. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Estimated fetal weight at mid-gestation in prediction of pre-eclampsia in singleton pregnancy.

OBJECTIVE: To examine the distribution of birth weight according to gestational age in pregnancies complicated by pre-eclampsia (PE) and assess the potential value of sonographic estimated fetal weight (EFW) at mid-gestation as a predictor of PE. METHODS: The data for this study were derived from prospective screening for adverse obstetric outcome in 93 911 women with a singleton pregnancy attending for routine pregnancy care at 19 + 0 to 24 + 6 weeks' gestation in two UK maternity hospitals. This visit included recording of maternal demographic characteristics and medical history, sonographic EFW and measurement of mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI). The distribution of birth weight of pregnancies with and those without PE was assessed. The competing-risks model was used to estimate the individual, patient-specific risk of delivery with PE at < 32 and < 37 weeks' gestation and at any gestational age. The areas under the receiver-operating-characteristics curves and detection rates (DRs) of delivery with PE, at a 10% false-positive rate (FPR), were assessed for various combinations of maternal risk factors, EFW, MAP and UtA-PI. McNemar's test was used to determine the significance of difference in DR at a 10% FPR between screening with vs without EFW. RESULTS: The study population contained 2843 (3.0%) pregnancies that subsequently developed PE, including 148 (0.2%) that delivered with PE at < 32 weeks' gestation and 654 (0.7%) that delivered with PE at < 37 weeks. Birth weight was < 10th percentile in 82% of pregnancies with PE delivering at < 32 weeks' gestation and this decreased to 21% of those with PE delivering at ≥ 37 weeks. In screening for delivery with PE at < 32 and < 37 weeks' gestation, the DR, at a 10% FPR, achieved by maternal risk factors (51% and 46%, respectively) was improved by addition of EFW (69% and 51%, respectively). Similarly, addition of EFW improved the performance of screening by a combination of maternal risk factors and MAP from 72% to 80% for PE < 32 weeks and from 57% to 60% for PE < 37 weeks. EFW did not improve the predictive performance of screening by a combination of maternal risk factors, MAP and UtA-PI. CONCLUSIONS: In pregnancies complicated by preterm PE, a high proportion of neonates are small-for-gestational age, and sonographic EFW at mid-gestation can improve the prediction of early and preterm PE provided by maternal risk factors and MAP but not the prediction provided by a combination of maternal risk factors, MAP and UtA-PI. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

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.

Second-trimester contingent screening for small-for-gestational-age neonate.

OBJECTIVES: First, to investigate the additive value of second-trimester placental growth factor (PlGF) for the prediction of a small-for-gestational-age (SGA) neonate. Second, to examine second-trimester contingent screening strategies. METHODS: This was a prospective observational study in women with singleton pregnancy undergoing routine ultrasound examination at 19-24 weeks' gestation. We used the competing-risks model for prediction of SGA. The parameters for the prior model and the likelihoods for estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI) were those presented in previous studies. A folded-plane regression model was fitted in the dataset of this study to describe the likelihood of PlGF. We compared the prediction of screening by maternal risk factors against the prediction provided by a combination of maternal risk factors, EFW, UtA-PI and PlGF. We also examined the additive value of PlGF in a policy that uses maternal risk factors, EFW and UtA-PI. RESULTS: The study population included 40 241 singleton pregnancies. Overall, the prediction of SGA improved with increasing degree of prematurity, with increasing severity of smallness and in the presence of coexisting pre-eclampsia. The combination of maternal risk factors, EFW, UtA-PI and PlGF improved significantly the prediction provided by maternal risk factors alone for all the examined cut-offs of birth weight and gestational age at delivery. Screening by a combination of maternal risk factors and serum PlGF improved the prediction of SGA when compared to screening by maternal risk factors alone. However, the incremental improvement in prediction was decreased when PlGF was added to screening by a combination of maternal risk factors, EFW and UtA-PI. If first-line screening for a SGA neonate with birth weight < 10th percentile delivered at < 37 weeks' gestation was by maternal risk factors and EFW, the same detection rate of 90%, at an overall false-positive rate (FPR) of 50%, as that achieved by screening with maternal risk factors, EFW, UtA-PI and PlGF in the whole population can be achieved by reserving measurements of UtA-PI and PlGF for only 80% of the population. Similarly, in screening for a SGA neonate with birth weight < 10th percentile delivered at < 30 weeks, the same detection rate of 90%, at an overall FPR of 14%, as that achieved by screening with maternal risk factors, EFW, UtA-PI and PlGF in the whole population can be achieved by reserving measurements of UtA-PI and PlGF for only 70% of the population. The additive value of PlGF in reducing the FPR to about 10% with a simultaneous detection rate of 90% for a SGA neonate with birth weight < 3rd percentile born < 30 weeks, is gained by measuring PlGF in only 50% of the population when first-line screening is by maternal factors, EFW and UtA-PI. CONCLUSIONS: The combination of maternal risk factors, EFW, UtA-PI and PlGF provides effective second-trimester prediction of SGA. Serum PlGF is useful for predicting a SGA neonate with birth weight < 3rd percentile born < 30 weeks after an inclusive assessment by maternal risk factors and biophysical markers. Similar detection rates and FPRs can be achieved by application of contingent screening strategies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for prediction of small-for-gestational-age neonate at 36 weeks' gestation.

OBJECTIVES: To develop further a competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate by including sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 36 weeks' gestation, and to compare the performance of the new model with that of the traditional EFW < 10th percentile cut-off. METHODS: This was a prospective observational study in 29 035 women with a singleton pregnancy undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. A competing-risks model for the prediction of a SGA neonate was used. The parameters included in the prior-history model were provided in previous studies. An interaction continuous model was used for the EFW likelihood. A folded plane regression model was fitted to describe likelihoods of biomarkers of impaired placentation. Stratification plans were also developed. The new model was evaluated and compared with EFW percentile cut-offs. RESULTS: The performance of the model was better for predicting SGA neonates delivered closer to the point of assessment. The prediction provided by maternal factors alone was improved significantly by the addition of EFW, uterine artery pulsatility index (UtA-PI) and placental growth factor (PlGF) but not by mean arterial pressure or soluble fms-like tyrosine kinase-1. At a 10% false-positive rate, maternal factors and EFW predicted 77.6% and 65.8% of SGA neonates < 10th percentile delivered before 38 and 42 weeks, respectively. The respective figures for SGA < 3rd percentile were 85.5% and 74.2%. Addition of UtA-PI and PlGF resulted in marginal improvement in prediction of SGA < 3rd percentile requiring imminent delivery. A competing-risks approach that combines maternal factors and EFW performed better when compared with fixed EFW percentile cut-offs at predicting a SGA neonate, especially with increasing time interval between assessment and delivery. The new model was well-calibrated. CONCLUSIONS: A competing-risks model provides effective risk stratification for a SGA neonate at 35 + 0 to 36 + 6 weeks' gestation and is superior to EFW percentile cut-offs. The use of biomarkers of impaired placentation in addition to maternal factors and fetal biometry results in small improvement of the predictive performance for a neonate with severe SGA. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for pre-eclampsia and adverse pregnancy outcomes.

OBJECTIVE: The competing-risks model for assessment of risk for pre-eclampsia (PE) at 35-37 weeks' gestation identifies the majority of women who are at high risk of subsequent delivery with PE. We aimed to examine the incidence and relative risk of adverse pregnancy outcomes in patient groups stratified according to the estimated risk of delivery with PE. METHODS: This was a prospective non-interventional, observational study in women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The risk of delivery with PE for each patient in the study population was estimated using the competing-risks model, combining the prior distribution of gestational age at delivery with PE and the likelihood from multiples of the median values of mean arterial pressure, placental growth factor and soluble fms-like tyrosine kinase-1. The patients were assigned to one of the following five risk categories: Group A, ≥ 1 in 2; Group B, 1 in 5 to 1 in 3; Group C, 1 in 20 to 1 in 6; Group D, 1 in 50 to 1 in 21; and Group E, < 1 in 50. The outcome measures were delivery with PE, gestational hypertension (GH), small-for-gestational age (SGA) at birth, delivery by Cesarean section, stillbirth, neonatal death, perinatal death and admission to the neonatal unit (NNU) for at least 48 h. In each risk category, the proportion of women with each adverse outcome was determined and relative risks (RR) were calculated as compared with the lowest-risk Group E. RESULTS: In the study population of 29 035 women, 1.6%, 2.7%, 8.2%, 9.8% and 77.8% were categorized into Groups A, B, C, D and E, respectively. Compared with women in Group E, women in the higher-risk groups were more likely to have an adverse outcome. The RR of delivery with PE in Group A compared with Group E was 65.5 (95% CI, 54.1-79.1) and the respective values were 11.9 (95% CI, 9.1-15.5) for GH, 1.8 (95% CI, 1.5-2.1) for delivery by emergency Cesarean section, 1.5 (95% CI, 1.2-1.8) for delivery by elective Cesarean section, 8.9 (95% CI, 7.4-10.8) for SGA with birth weight < 3rd percentile, 4.8 (95% CI, 4.3-5.4) for SGA with birth weight < 10th percentile, 5.3 (95% CI, 1.4-20.5) for stillbirth and 3.4 (95% CI, 2.8-4.2) for NNU admission for ≥ 48 h. The RR for these pregnancy complications in higher-risk groups (vs Group E) was particularly high for cases with delivery within 2 weeks after assessment. In terms of SGA, both for birth weight < 10th and < 3rd percentiles, the trend in all cases was stronger than that observed when the analysis was confined to normotensive pregnancies. The rates of neonatal death were too small to allow meaningful comparisons between risk groups. CONCLUSION: Pregnant women identified by the competing-risks model to be at high risk of PE are also at increased risk of GH, Cesarean section, stillbirth, SGA and NNU admission for ≥ 48 h. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Machine-learning-based prediction of pre-eclampsia using first-trimester maternal characteristics and biomarkers.

OBJECTIVE: To evaluate the accuracy of predicting the risk of developing pre-eclampsia (PE) according to first-trimester maternal demographic characteristics, medical history and biomarkers using artificial-intelligence and machine-learning methods. METHODS: The data were derived from prospective non-interventional screening for PE at 11-13 weeks' gestation at two maternity hospitals in the UK. The data were divided into three subsets. The first set, including 30 437 subjects, was used to develop the training process, the second set of 10 000 subjects was utilized to optimize the machine-learning hyperparameters and the third set of 20 352 subjects was coded and used for model validation. An artificial neural network was used to predict from the demographic characteristics and medical history the prior risk that was then combined with biomarker values to determine the risk of PE and preterm PE with delivery at < 37 weeks' gestation. An additional network was trained without including race as input. Biomarkers included uterine artery pulsatility index (UtA-PI), mean arterial blood pressure (MAP), placental growth factor (PlGF) and pregnancy-associated plasma protein-A. All markers were entered using raw values without conversion into standardized multiples of the median. The prediction accuracy was estimated using the area under the receiver-operating-characteristics curve (AUC). We further computed the detection rate at 10%, 20% and 40% false-positive rates (FPR). The impact of taking aspirin was also added. Shapley values were calculated to evaluate the contribution of each parameter to the prediction of risk. We used a non-parametric test to compare the expected AUC with the one obtained when we randomly scrambled the labels and kept the predictions. For the general prediction, we performed 10 000 permutations of the labels. When the AUC was higher than the one obtained in all 10 000 permutations, we reported a P-value of < 0.0001. For the race-specific analysis, we performed 1000 permutations. When the AUC was higher than the AUC in permutations, we reported a P-value of < 0.001. RESULTS: The detection rate for preterm PE vs no PE, at a 10% FPR, was 53.3% when screening by maternal factors only, and the corresponding AUC was 0.816; these increased to 75.3% and 0.909, respectively, with the addition of biomarkers into the model. Information on race was important for the prediction accuracy; when race was not used to train the model, at a 10% FPR, the detection rate of preterm PE vs no PE decreased to 34.5-45.5% (for different races) when screening by maternal factors only and to 55.0-62.1% when biomarkers were added. The major predictors of PE were high MAP and UtA-PI, and low PlGF. The accuracy of prediction of all PE cases was lower than that for preterm PE. Aspirin use was recommended for cases who were at high risk of preterm PE. The AUC of all PE vs no PE was 0.770 when screening by maternal factors and 0.817 when the biomarkers were added; the respective detection rates, at a 10% FPR, were 41.3% and 52.9%. CONCLUSIONS: Screening for PE using a non-linear machine-learning-based approach does not require a population-based normalization, and its performance is similar to that of logistic regression. Removing race information from the model reduces its prediction accuracy, especially for the non-white populations when only maternal factors are considered. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Risk of fetal loss after chorionic villus sampling in twin pregnancy derived from propensity score matching analysis.

OBJECTIVE: To estimate the risk of fetal loss associated with chorionic villus sampling (CVS) in twin pregnancy, using propensity score analysis. METHODS: This was a multicenter cohort study of women with twin pregnancy undergoing ultrasound examination at 11-13 weeks' gestation, performed in eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. The risk of death of at least one fetus was compared between pregnancies that had and those that did not have CVS, after propensity score matching (1:1 ratio). This procedure created two comparable groups by balancing the maternal and pregnancy characteristics that lead to CVS being performed, similar to how randomization operates in a randomized clinical trial. RESULTS: The study population of 8581 twin pregnancies included 445 that had CVS. Death of one or two fetuses at any stage during pregnancy occurred in 11.5% (51/445) of pregnancies in the CVS group and in 6.3% (515/8136) in the non-CVS group (P < 0.001). The propensity score algorithm matched 258 cases that had CVS with 258 non-CVS cases; there was at least one fetal loss in 29 (11.2%) cases in the CVS group and in 35 (13.6%) cases in the matched non-CVS group (odds ratio (OR), 0.81; 95% CI, 0.48-1.35; P = 0.415). However, there was a significant interaction between the risk of fetal loss after CVS and the background risk of fetal loss; when the background risk was higher, the risk of fetal loss after CVS decreased (OR, 0.46; 95% CI, 0.23-0.90), while, in pregnancies with a lower background risk of fetal loss, the risk of fetal loss after CVS increased (OR, 2.45; 95% CI, 0.95-7.13). The effects were statistically significantly different (P-value of the interaction = 0.005). For a pregnancy in which the background risk of fetal loss was about 6% (the same as in our non-CVS population), there was no change in the risk of fetal loss after CVS, but, when the background risk was more than 6%, the posterior risk was paradoxically reduced, and when the background risk was less than 6%, the posterior risk increased exponentially; for example, if the background risk of fetal loss was 2.0%, the relative risk was 2.8 and the posterior risk was 5.6%. CONCLUSION: In twin pregnancy, after accounting for the risk factors that lead to both CVS and spontaneous fetal loss and confining the analysis to pregnancies at lower prior risk, CVS seems to increase the risk of fetal loss by about 3.5% above the patient's background risk. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.