Ultrasound Obstet Gynecol 2021; 57: 84–90 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.22071. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Diagnostic accuracy of first-trimester combined screening for early-onset and preterm pre-eclampsia at 8–10 compared with 11–13 weeks’ gestation M. MENDOZA , P. GARCIA-MANAU, S. ARÉVALO, M. AVILÉS, B. SERRANO, M. Á. SÁNCHEZ-DURÁN, I. GARCIA-RUIZ, E. BONACINA and E. CARRERAS Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain K E Y W O R D S: early-onset pre-eclampsia; first-trimester; PlGF; pre-eclampsia; screening; uterine artery Doppler CONTRIBUTION PlGF were assessed from the routine first-trimester blood What are the novel findings of this work? test (at 8 + 0 to 13 + 6 weeks). Women were classified The performance of combined first-trimester screening in into two groups depending on whether serum biomark- predicting early-onset and preterm pre-eclampsia (PE) is ers were assessed at 8 + 0 to 10 + 6 weeks or at 11 + 0 similar when serum levels of pregnancy-associated plasma to 13 + 6 weeks. Probability scores for early-onset and protein-A and placental growth factor are measured preterm PE were calculated by using two different algo- before or after 11 weeks’ gestation. rithms: the multivariate Gaussian-distribution model and The Fetal Medicine Foundation (FMF) competing-risks What are the clinical implications of this work? model. Receiver-operating-characteristics (ROC) curves Measurement of serum biomarkers for both PE and were produced and detection rates at fixed 5% and 10% aneuploidy screening before the first-trimester scan false-positive rates were computed to compare the perfor- permits risk calculation for both screening tests at the mance of these algorithms when PAPP-A and PlGF were time of the scan without compromising PE screening assessed before vs after 11 weeks. performance. Results Of the 2641 women included, serum biomarkers were assessed before 11 weeks in 1675 (63.4%) and at or after 11 weeks in 966 (36.6%). Of these, 90 (3.4%) ABSTRACT women developed PE, including 11 (0.4%) cases of Objectives To compare the ability of first-trimester early-onset PE and 30 (1.1%) of preterm PE. Five (45.5%) combined screening for pre-eclampsia (PE) to predict cases of early-onset and 16 (53.3%) of preterm PE were early-onset and preterm PE when pregnancy-associated identified in the group in which serum biomarkers were plasma protein-A (PAPP-A) and placental growth factor assessed at 8 + 0 to 10 + 6 weeks and six (54.5%) cases (PlGF) were assessed before vs after 11 weeks’ gestation. of early-onset and 14 (46.7%) of preterm PE in the group in which serum biomarkers were assessed at 11 + 0 to Methods This was a secondary analysis of a prospective 13 + 6 weeks. In the prediction of early-onset and preterm cohort study of singleton pregnancies undergoing rou- PE using the Gaussian algorithm, no differences were tine first-trimester screening conducted at Vall d’Hebron observed between the areas under the ROC curves (AUCs) University Hospital, Barcelona, Spain, between October when PAPP-A and PlGF were measured before or after 2015 and September 2017. Demographic characteris- 11 weeks. In the prediction of early-onset and preterm PE tics, obstetric history, maternal history and biophysical using the FMF algorithm, no differences were observed markers (mean uterine artery pulsatility index and mean between AUCs for any of the combinations used for risk arterial blood pressure (MAP)) were recorded at the calculation when the serum biomarkers were obtained first-trimester scan (at 11 + 0 to 13 + 6 weeks’ gesta- before vs after 11 weeks, except for the combination of tion). Maternal serum concentrations of PAPP-A and PAPP-A and MAP, which showed a greater AUC for the Correspondence to: Dr M. Mendoza, Maternal Fetal Medicine Unit, Department of Obstetrics, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona, Spain (e-mail: mmendoza@vhebron.net) Accepted: 29 April 2020 © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd ORIGINAL PAPER on behalf of International Society of Ultrasound in Obstetrics and Gynecology. Pre-eclampsia screening before and after 11 weeks 85 prediction of early-onset PE when PAPP-A was measured (PAPP-A) and PlGF were assessed before, compared with at or after 11 weeks. after, 11 weeks. Conclusions The prediction of early-onset and preterm PE is similar when serum biomarkers are measured METHODS before or after 11 weeks. This allows the use of a two-step approach for PE risk assessment that permits This was a secondary analysis of data from the population immediate risk calculation at the time of the first-trimester that participated in the development of the first-trimester scan. © 2020 The Authors. Ultrasound in Obstetrics & Gaussian algorithm to predict early-onset PE6 . That Gynecology published by John Wiley & Sons Ltd on prospective cohort study was conducted at Vall d’Hebron behalf of International Society of Ultrasound in Obstetrics University Hospital, Barcelona, Spain, from October and Gynecology. 2015 to September 2017. The local ethics committee (CEIC-VHIR PR(AMI)265/2018) approved the study protocol. A total of 3777 unselected singleton pregnant INTRODUCTION women attending for their routine first-trimester scan (from 11 + 0 to 13 + 6 weeks) were invited to participate, Pre-eclampsia (PE) occurs in approximately 2–8% of of whom 2946 agreed and provided written informed pregnancies1 . It is the primary cause of maternal consent. Of these, 305 (10.4%) participants were admission to the intensive care unit and is responsible excluded owing to missing outcome data (n = 86), major for approximately 15% of all pregnancy-related deaths in fetal defects or chromosomopathies (n = 13), miscarriage developed countries2,3 . In recent years, several studies or fetal death before 24 weeks (n = 15) or insufficient published by The Fetal Medicine Foundation (FMF) remaining blood sample to measure PlGF (n = 191). None have shown that their algorithm constructed by a of the remaining 2641 participants had received ASA at combination of maternal history and biochemical and any time during their pregnancy. biophysical markers in the first trimester of pregnancy can After gestational age (GA) had been confirmed effectively predict early-onset and preterm PE4 , allowing by fetal crown–rump length measurement during the commencement of acetylsalicylic acid (ASA) before scan11 , demographic characteristics, obstetric history, 16 weeks’ gestation, which has proved to significantly maternal history, biophysical markers and biochemical reduce the risk of developing PE5 . markers were recorded in an electronic database. In Recently, our group participated in the development of all participants, transabdominal mean uterine artery a new first-trimester Gaussian model constructed using pulsatility index (UtA-PI)12 and mean arterial blood the same variables as in the FMF algorithm, which also pressure (MAP) were assessed during the first-trimester has a good performance in the prediction of early-onset scan at 11 + 0 to 13 + 6 weeks. Maternal blood samples PE6 . In both studies4,6 , maternal characteristics and were analyzed to establish the serum concentrations of biophysical markers were assessed at the time of the PAPP-A and PlGF. One sample was obtained from each first-trimester ultrasound examination (between 11 + 0 woman during the routine first-trimester blood test for and 13 + 6 weeks). However, serum biomarkers were aneuploidy screening, at 8 + 0 to 13 + 6 weeks. Maternal assessed between 11 + 0 and 13 + 6 weeks in the FMF serum levels of PAPP-A (mU/L) and PlGF (pg/mL) study while in our study they were assessed between were determined by fully automated Elecsys assays for 8 + 0 and 13 + 6 weeks, preferably before the ultrasound PAPP-A and PlGF on an immunoassay platform (Cobas e assessment, using a two-step approach. The reason for analyzers; Roche Diagnostics, Rotkreuz, Switzerland). As assessing serum biomarkers early in the first trimester was PAPP-A and PlGF values change with GA, they were that the blood samples were drawn at the time of routine transformed to multiples of the median to be used in risk first-trimester aneuploidy screening, which is usually done assessment6 . before the first-trimester scan since the performance of In all patients, blood pressure (BP) was measured first-trimester biochemical screening for trisomy 21 is best at 11 + 0 to 13 + 6 weeks by a nurse using an done at 9–10 weeks7,8 . Placental growth factor (PlGF) automatic BP measurement device (Microlife WatchBP is the most valuable biomarker used in both algorithms. Home; Microlife Corporation, Taipei, Taiwan); a single Even though PlGF has been shown to have excellent measurement was obtained in one arm (right or left) precision and reliability from 5 + 0 weeks onwards for after a 5-min rest while the woman was seated. MAP discriminating between PE and normal pregnancies9 , a was calculated as: diastolic BP + (systolic BP – diastolic recent study found that its predictive capacity for PE BP)/3. increases after 11 weeks10 . Therefore, it is reasonable to PE was defined according to the guidelines of the believe that the precision of these algorithms may drop International Society for the Study of Hypertension in when PlGF is measured before 11 weeks; however, the Pregnancy as systolic BP ≥ 140 mmHg and/or diastolic BP performance of these algorithms in the early and late ≥ 90 mmHg confirmed by repeat measurements over a few first trimester has not been compared. The aim of this hours, developing after 20 weeks’ gestation in a previously study was to evaluate the performance of the FMF and normotensive woman, accompanied by proteinuria of the Gaussian algorithms in predicting early-onset and ≥ 300 mg per 24 h or a spot urine protein-to-creatinine preterm PE when pregnancy-associated plasma protein-A ratio ≥ 0.3 mg/mg or dipstick urinalysis ≥ 1+ when a © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2021; 57: 84–90. on behalf of International Society of Ultrasound in Obstetrics and Gynecology. 86 Mendoza et al. quantitative method was not available13 . Early-onset and In the prediction of early-onset PE and preterm PE preterm PE were defined as PE necessitating delivery using the Gaussian algorithm, no significant differences before 34 weeks and before 37 weeks, respectively. were observed in the areas under the ROC curves Women were classified into two groups according to (AUCs) for any of the combinations of markers evaluated whether the blood sample for biomarker assessment when the biochemical markers were assessed at 8 + 0 was drawn before or after 11 weeks’ gestation. We to 10 + 6 weeks compared with 11 + 0 to 13 + 6 weeks. then coded the variables required for the prediction Additionally, no substantial differences were observed formulae according to the description provided in in the detection rates at fixed 5% and 10% FPRs. The the articles and calculated the probability score for predictive capacity and detection rates in screening for early-onset PE using two different algorithms: the early-onset and preterm PE by the markers involved in multivariate Gaussian-distribution model and the FMF the Gaussian algorithm are shown in Tables 2 and 3, competing-risks model4,6 . respectively. Receiver-operating-characteristics (ROC) curves were In the prediction of early-onset PE using the FMF produced and detection rates at fixed 5% and 10% algorithm, no significant differences were observed in the false-positive rates (FPR) were computed for all com- AUCs for any of the combinations of markers evaluated binations of markers involved in the risk assessment, to when the biochemical markers were assessed before vs compare the performance of the two algorithms for pre- after 11 weeks, except for the combination of PAPP-A dicting early-onset and preterm PE when PAPP-A and and MAP, which showed a greater AUC when PAPP-A PlGF were measured before and after 11 weeks14 . was measured at or after 11 weeks. However, despite this significant difference, no substantial differences were observed in the detection rates at fixed 5% and 10% FPRs. Statistical analysis The predictive capacity and detection rates in screening Rcmdr package for R version 2.3-1 software (The R for early-onset PE using the FMF algorithm are shown in Foundation, Vienna, Austria) was used for statistical Table 4. analysis. Differences in categorical data between the In the prediction of preterm PE using the FMF groups were assessed using the χ-square or Fisher’s exact algorithm, no significant differences were observed in the test, as appropriate, and are reported as n (%). Differences AUCs for any of the combinations of markers evaluated in continuous variables between the groups were assessed when PAPP-A and PlGF were assessed before, compared using the Mann–Whitney U-test and are reported as with at or after, 11 weeks. In addition, no substantial median (interquartile range). Statistical significance was differences were observed in the detection rates at fixed set at P < 0.05. 5% and 10% FPRs. The predictive capacity and detection rates in screening for preterm PE using the FMF algorithm are shown in Table 5. RESULTS PAPP-A and PlGF were assessed before 11 weeks in 1675 DISCUSSION (63.4%) of the 2641 women, and at or after 11 weeks in 966 (36.6%). Ninety (3.4%) women developed PE, This study provides evidence that multimarker algorithms including 30 (1.1%) cases of preterm PE and 11 (0.4%) have a similar performance in predicting early-onset and of early-onset PE. Five (45.5%) cases of early-onset preterm PE when PlGF and PAPP-A are measured at 8 + 0 and 16 (53.3%) of preterm PE were identified in to 10 + 6 weeks or at 11 + 0 to 13 + 6 weeks’ gestation. the group in which serum biomarkers were assessed The timing of measurement of the serum biomarkers at 8 + 0 to 10 + 6 weeks and six (54.5%) cases of did not affect the performance of the Gaussian or the early-onset and 14 (46.7%) of preterm PE in the group FMF algorithm in predicting preterm PE when PAPP-A in which serum biomarkers were assessed at 11 + 0 to or PlGF was used alone or in combination with other 13 + 6 weeks. markers. However, for the FMF model, the combination Baseline characteristics of the study population were of PAPP-A and MAP had a lower predictive capacity compared between the two groups (assessment of for early-onset PE when PAPP-A was measured before biochemical markers before 11 vs at or after 11 weeks) 11 weeks compared with at or after 11 weeks, which is and are shown in Table 1. In women who developed probably due to the low number of cases with early-onset early-onset PE, no significant differences were observed PE. between the two groups apart from GA at the time of A previous study evaluating the external validity of the PAPP-A and PlGF assessment. In women who developed available algorithms for the first-trimester prediction of PE preterm PE, PAPP-A and PlGF levels and the GA at found that they underperformed if applied to an external their measurement were significantly different between the population15 . Additionally, PlGF seems to better identify two groups. When non-affected women were evaluated, patients at risk for PE when measured after 11 weeks10 . significant differences were observed between the two Nonetheless, the performance of combined screening for groups in ethnicity, smoking status, obstetric history, early-onset and preterm PE with biomarkers assessed PAPP-A and PlGF levels and GA at their measurement, at different points in gestation has not been assessed UtA-PI and GA at ultrasound assessment. previously. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2021; 57: 84–90. on behalf of International Society of Ultrasound in Obstetrics and Gynecology. Pre-eclampsia screening before and after 11 weeks 87 Our results have important clinical implications. They PE does not deteriorate when serum biomarker levels show that a two-step approach to first-trimester PE screen- are measured before 11 weeks. Additionally, a two-step ing (combination of serum markers (PAPP-A and PlGF) approach allows PE screening results to be provided imme- measured at 8–10 weeks and biophysical markers (MAP diately after the first-trimester ultrasound assessment. and UtA-PI) measured at 11–13 weeks) is feasible, since The main limitation of this study is the low number its performance for predicting early-onset and preterm of cases with early-onset PE and the relatively low Table 1 Baseline characteristics and biophysical and biochemical measurements in women who developed early-onset (before 34 weeks) pre-eclampsia (PE), those who developed preterm (before 37 weeks) PE and those who did not develop PE before 37 weeks’ gestation, according to whether pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured before or after 11 weeks PE before 34 + 0 weeks (n = 11) PE before 37 + 0 weeks (n = 30) No PE before 37 + 0 weeks (n = 2611) Biochemical markers measured at: Biochemical markers measured at: Biochemical markers measured at: 8 + 0 to 11 + 0 to 8 + 0 to 11 + 0 to 8 + 0 to 11 + 0 to 10 + 6 weeks 13 + 6 weeks 10 + 6 weeks 13 + 6 weeks 10 + 6 weeks 13 + 6 weeks Parameter (n = 5) (n = 6) P (n = 16) (n = 14) P (n = 1659) (n = 952) P Age (years) 34.0 34.5 0.642 34.0 37.0 0.143 32.0 32.0 0.222 (34.0–37.0) (31.3–37.0) (28.8–37.0) (32.8–38.0) (28.0–36.0) (28.0–36.0) BMI (kg/m2 ) 23.2 23.1 0.537 25.1 23.1 0.096 23.9 23.8 0.521 (22.7–32.1) (22.2–25.5) (23.2–28.7) (21.8–26.0) (21.4–27.4) (21.2–27.5) Ethnicity 0.455 0.734 < 0.001 White 4 (80.0) 6 (100) 13 (81.3) 12 (85.7) 1441 (86.9) 768 (80.7) < 0.001 Black 0 (0) 0 (0) 0 (0) 1 (7.1) 34 (2.0) 37 (3.9) 0.008 Mixed 1 (20.0) 0 (0) 2 (12.5) 0 (0) 109 (6.6) 100 (10.5) < 0.001 Asian 0 (0) 0 (0) 1 (6.3) 1 (7.1) 40 (2.4) 23 (2.4) 1.0 South-East Asian 0 (0) 0 (0) 0 (0) 0 (0) 35 (2.1) 24 (2.5) 0.497 Smoker 1 (20.0) 0 (0) 0.455 1 (6.3) 2 (14.3) 0.586 214 (12.9) 95 (10.0) 0.028 ART 0 (0) 1 (16.7) 1.0 0 (0) 2 (14.3) 0.209 60 (3.6) 33 (3.5) 0.731 Insemination 0 (0) 1 (16.7) 0 (0) 1 (7.1) 10 (0.6) 6 (0.6) IVF 0 (0) 0 (0) 0 (0) 0 (0) 31 (1.9) 21 (2.2) IVF with egg donation 0 (0) 0 (0) 0 (0) 1 (7.1) 19 (1.1) 6 (0.6) Medical history 1.0 1.0 0.695 Chronic hypertension 2 (40.0) 1 (16.7) 3 (18.8) 2 (14.3) 15 (0.9) 9 (0.9) Diabetes mellitus 0 (0) 0 (0) 1 (6.3) 0 (0) 25 (1.5) 10 (1.1) Autoimmune disease 0 (0) 0 (0) 1 (6.3) 2 (14.3) 63 (3.8) 42 (4.4) APS 0 (0) 0 (0) 1 (6.3) 0 (0) 4 (0.2) 4 (0.4) Obstetric history 0.250 0.484 0.002 Nulliparous 0 (0) 2 (33.3) 6 (37.5) 7 (50.0) 813 (49.0) 406 (42.6) 0.002 Previous PE 1 (20.0) 1 (16.7) 4 (25.0) 1 (7.1) 16 (1.0) 14 (1.5) 0.256 Previous FGR 0 (0) 0 (0) 0 (0) 1 (7.1) 18 (1.1) 5 (0.5) 0.191 Biophysical variable GA at first-trimester US 12.6 13.1 0.116 12.7 12.6 0.530 12.6 12.9 < 0.001 (weeks) (12.1–12.6) (12.6–13.2) (12.1–12.9) (12.3–13.3) (12.1–12.9) (12.4–13.3) MAP (mmHg) 94.3 96.3 0.931 90.5 94.5 0.693 84.0 84.7 0.829 (91.0–101.7) (89.5–104.9) (87.9–93.8) (83.0–104.1) (78.7–90.3) (78.3–90.7) MAP MoM 1.14 1.22 0.931 1.14 1.16 0.866 1.05 1.06 0.844 (1.10–1.37) (1.14–1.22) (1.10–1.21) (1.05–1.30) (0.97–1.14) (0.97–1.14) Mean UtA-PI 2.54 1.89 0.247 2.15 1.89 0.618 1.69 1.65 0.002 (2.25–2.80) (1.88–2.76) (1.71–2.32) (1.71–2.21) (1.36–2.08) (1.31–2.00) Mean UtA-PI MoM 1.67 1.18 0.537 1.24 1.12 0.552 1.03 1.03 0.834 (1.19–1.81) (1.12–1.91) (1.06–1.46) (1.00–1.33) (0.84–1.26) (0.83–1.26) Biochemical variable GA at PAPP-A + PlGF 9.9 12.1 0.008 10.0 11.8 < 0.001 10.1 11.6 < 0.001 measurement (weeks) (9.6–10.3) (11.5–12.3) (9.5–10.5) (11.4–12.2) (9.7–10.6) (11.1–12.3) PAPP-A (mU/L) 607.3 1801.0 0.177 604.8 1869.5 < 0.001 1033.0 2395.5 < 0.001 (602.3–1119.0) (1447.0–2201.5) (307.8–1071.0) (1387.0–3513.5) (655.9–1575.5) (1499.0–3832.3) PAPP-A MoM 0.93 0.69 0.314 0.68 0.73 0.574 1.05 1.06 0.769 (0.71–1.09) (0.61–0.74) (0.53–1.06) (0.61–0.85) (0.74–1.50) (0.72–1.51) PlGF (pg/mL) 19.77 27.00 0.329 22.67 30.60 0.017 28.23 41.36 < 0.001 (19.03–22.35) (20.69–40.15) (19.00–26.24) (25.10–47.48) (22.0–35.89) (31.92–54.40) PlGF MoM 0.65 0.71 1.0 0.85 0.69 0.257 0.96 0.95 0.256 (0.62–0.86) (0.45–0.97) (0.70–0.96) (0.52–1.00) (0.77–1.19) (0.74–1.19) Data are reported as median (interquartile range) or n (%). APS, antiphospholipid syndrome; ART, assisted reproductive technology; BMI, body mass index; FGR, fetal growth restriction; GA, gestational age; IVF, in-vitro fertilization; MAP, mean arterial pressure; MoM, multiples of the median; UtA-PI, uterine artery pulsatility index; US, ultrasound. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2021; 57: 84–90. on behalf of International Society of Ultrasound in Obstetrics and Gynecology. 88 Mendoza et al. number of cases with preterm PE; thus, our results ultrasound assessment) between the two cohorts of should be considered with caution and validated in unaffected women, the most important being that the a larger cohort to ascertain whether the timing of first-trimester scan was performed slightly later in women biomarker assessment affects the screening performance in whom serum biomarkers were measured at or after of multimarker first-trimester algorithms for the detection 11 weeks (median GA, 12.9 vs 12.6 weeks). Nevertheless, of early-onset PE. Furthermore, there were statistically this difference is small and probably not clinically significant differences in baseline characteristics (ethnicity, significant. Finally, MAP was assessed by a single BP smoking status, obstetric history, UtA-PI and GA at measurement in one arm, which has been shown to Table 2 Detection rate (DR) and area under receiver-operating-characteristics curve (AUC) for prediction of pre-eclampsia before 34 weeks’ gestation by Gaussian model, according to whether pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured before or after 11 weeks 8 + 0 to 10 + 6 weeks (n = 5) 11 + 0 to 13 + 6 weeks (n = 6) DR (% (95% CI)) at: DR (% (95% CI)) at: Method of screening AUC (95% CI) 5% FPR 10% FPR AUC (95% CI) 5% FPR 10% FPR P* A-priori risk plus: MAP 0.746 (0.540–0.952) 40.0 (0–80.0) 40.0 (0–80.0) 0.887 (0.818–0.956) 33.3 (0–66.7) 50.0 (0–83.3) 0.364 UtA-PI 0.863 (0.700–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.812 (0.649–0.974) 33.3 (0–66.7) 50.0 (16.7–83.3) 0.733 PAPP-A 0.615 (0.279–0.951) 20.0 (0–60.0) 40.0 (0–80.0) 0.803 (0.626–0.980) 33.3 (0–66.7) 50.0 (0–83.3) 0.277 PlGF 0.829 (0.732–0.927) 40.0 (0–80.0) 40.0 (0–80.0) 0.712 (0.479–0.945) 33.3 (0–66.7) 33.3 (0–66.7) 0.478 PlGF + UtA-PI 0.923 (0.844–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.841 (0.687–0.995) 50.0 (16.7–83.3) 50.0 (16.7–83.3) 0.530 MAP + PlGF 0.864 (0.746–0.982) 40.0 (0–80.0) 40.0 (0–80.0) 0.936 (0.894–0.978) 33.3 (0–66.7) 66.7 (33.3–100) 0.566 MAP + UtA-PI 0.901 (0.793–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.916 (0.822–1.000) 66.7 (33.3–100) 66.7 (33.3–100) 0.901 PAPP-A + PlGF 0.790 (0.684–0.896) 20.0 (0–60.0) 40.0 (0–80.0) 0.751 (0.556–0.946) 33.3 (0–66.7) 50.0 (16.7–83.3) 0.816 MAP + PAPP-A 0.744 (0.542–0.947) 40.0 (0–80.0) 40.0 (0–80.0) 0.910 (0.853–0.968) 33.3 (0–66.7) 66.7 (16.7–100) 0.272 UtA-PI + PAPP-A 0.849 (0.666–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.846 (0.707–0.986) 50.0 (16.7–83.3) 50.0 (16.7–83.3) 0.984 MAP + UtA-PI + PAPP-A 0.891 (0.772–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.929 (0.850–1.000) 66.7 (33.3–100) 66.7 (33.3–100) 0.752 MAP + UtA-PI + PlGF 0.943 (0.881–1.000) 60.0 (20.0–100) 80.0 (20.0–100) 0.958 (0.925–0.990) 50.0 (16.7–83.3) 83.3 (50.0–100) 0.871 MAP + PAPP-A + PlGF 0.838 (0.709–0.967) 40.0 (0–80.0) 40.0 (0–80.0) 0.930 (0.889–0.971) 33.3 (0–73.9) 66.7 (16.7–100) 0.488 UtA-PI + PlGF + PAPP-A 0.912 (0.820–1.000) 60.0 (20.0–100) 60.0 (20.0–100) 0.842 (0.689–0.995) 50.0 (16.7–83.3) 50.0 (16.7–83.3) 0.600 MAP + UtA-PI + PlGF + PAPP-A 0.935 (0.866–1.000) 60.0 (20.0–100) 80.0 (20.0–100) 0.950 (0.915–0.986) 50.0 (16.7–83.3) 83.3 (50.0–100) 0.879 *Comparison between AUCs was by two-tailed P-value. FPR, false-positive rate; MAP, mean arterial pressure; UtA-PI, uterine artery pulsatility index. Table 3 Detection rate (DR) and area under receiver-operating-characteristics curve (AUC) for prediction of pre-eclampsia before 37 weeks’ gestation by Gaussian model, according to whether pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured before or after 11 weeks 8 + 0 to 10 + 6 weeks (n = 16) 11 + 0 to 13 + 6 weeks (n = 14) DR (% (95% CI)) at: DR (% (95% CI)) at: Method of screening AUC (95% CI) 5% FPR 10% FPR AUC (95% CI) 5% FPR 10% FPR P* A-priori risk plus: MAP 0.757 (0.647–0.866) 25.0 (6.3–43.8) 37.5 (18.8–68.8) 0.736 (0.590–0.883) 28.6 (7.1–50.0) 35.7 (7.1–64.3) 0.841 UtA-PI 0.724 (0.564–0.884) 43.8 (18.8–68.8) 50.0 (25.0–75.0) 0.688 (0.541–0.835) 28.6 (7.1–50.0) 35.7 (14.3–64.3) 0.738 PAPP-A 0.678 (0.520–0.835) 25.0 (6.3–50.0) 43.8 (18.8–68.8) 0.748 (0.621–0.875) 14.3 (0–35.7) 35.7 (7.1–64.3) 0.511 PlGF 0.719 (0.593–0.846) 25.0 (6.3–43.8) 25.0 (6.3–43.8) 0.712 (0.569–0.855) 35.7 (14.3–64.3) 35.7 (14.3–64.3) 0.948 PlGF + UtA-PI 0.746 (0.589–0.903) 37.5 (12.5–62.5) 43.8 (18.8–68.8) 0.719 (0.571–0.866) 42.9 (14.3–71.4) 42.9 (14.3–71.4) 0.798 MAP + PlGF 0.802 (0.717–0.888) 25.0 (6.3–50.0) 31.3 (12.5–56.3) 0.799 (0.654–0.944) 28.6 (7.1–57.1) 57.1 (28.6–85.7) 0.976 MAP + UtA-PI 0.798 (0.701–0.894) 31.3 (12.5–56.3) 31.3 (12.5–56.3) 0.765 (0.604–0.926) 42.9 (14.3–71.4) 50.0 (21.4–78.6) 0.743 PAPP-A + PlGF 0.723 (0.595–0.851) 25.0 (6.3–43.8) 25.0 (6.3–50.0) 0.777 (0.648–0.906) 35.7 (14.3–64.3) 42.9 (21.4–71.4) 0.636 MAP + PAPP-A 0.780 (0.678–0.883) 37.5 (18.8–62.5) 43.8 (18.8–68.8) 0.765 (0.620–0.910) 28.6 (7.1–50.0) 42.9 (14.3–71.4) 0.883 UtA-PI + PAPP-A 0.744 (0.585–0.902) 43.8 (18.8–68.8) 50.0 (25.0–75.0) 0.709 (0.565–0.853) 21.4 (7.1–50.0) 35.7 (14.3–64.3) 0.742 MAP + UtA-PI + PAPP-A 0.815 (0.720–0.909) 31.3 (12.5–56.3) 37.5 (12.5–62.5) 0.779 (0.619–0.938) 42.9 (21.4–71.4) 50.0 (28.4–78.6) 0.714 MAP + UtA-PI + PlGF 0.804 (0.687–0.920) 31.3 (12.5–56.3) 37.5 (12.5–62.5) 0.793 (0.636–0.950) 42.9 (21.4–71.4) 50.0 (21.4–78.6) 0.911 MAP + PAPP-A + PlGF 0.803 (0.721–0.885) 31.3 (12.5–62.5) 37.5 (12.5–62.5) 0.801 (0.660–0.941) 28.6 (7.1–57.1) 50.0 (21.4–78.6) 0.984 UtA-PI + PlGF + PAPP-A 0.749 (0.592–0.906) 37.5 (12.5–62.5) 43.8 (18.8–68.8) 0.722 (0.575–0.969) 42.9 (14.3–71.4) 42.9 (14.3–71.4) 0.798 MAP + UtA-PI + PlGF + PAPP-A 0.772 (0.639–0.904) 31.3 (12.5–56.3) 50.0 (25.0–75.0) 0.795 (0.640–0.950) 35.7 (14.3–64.3) 64.3 (35.7–85.7) 0.803 *Comparison between AUCs was by two-tailed P-value. FPR, false-positive rate; MAP, mean arterial pressure; UtA-PI, uterine artery pulsatility index. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2021; 57: 84–90. on behalf of International Society of Ultrasound in Obstetrics and Gynecology. Pre-eclampsia screening before and after 11 weeks 89 give significantly higher values than does assessment rendering the groups still comparable for the purpose of using the average of two measurements in both arms16 . this study. Since the latter is the methodology used in the FMF In conclusion, the Gaussian and the FMF algorithms algorithm, it could have influenced its performance to have a similar performance in predicting early-onset PE predict PE in our cohort. However, the inaccuracies and preterm PE when PAPP-A and PlGF are measured that might have resulted from the use of a single before or after 11 weeks, allowing the use of a two-step measurement for PE risk assessment by the FMF algorithm risk assessment for PE. This approach allows immediate would have affected all participants similarly, thereby PE risk calculation at the time of the first-trimester scan. Table 4 Detection rate (DR) and area under receiver-operating-characteristics curve (AUC) for prediction of pre-eclampsia before 34 weeks’ gestation by Fetal Medicine Foundation competing-risks model, according to whether pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured before or after 11 weeks 8 + 0 to 10 + 6 weeks (n = 5) 11 + 0 to 13 + 6 weeks (n = 6) DR (% (95% CI)) at: DR (% (95% CI)) at: Method of screening AUC (95% CI) 5% FPR 10% FPR AUC (95% CI) 5% FPR 10% FPR P* A-priori risk plus: MAP 0.655 (0.377–0.934) 40.0 (0–80.0) 40.0 (0–80.0) 0.844 (0.778–0.909) 16.7 (0–50.0) 16.7 (0–50.0) 0.259 UtA-PI 0.744 (0.478–1.000) 40.0 (0–80.0) 40.0 (0–80.0) 0.809 (0.610–1.000) 33.3 (0–66.7) 66.7 (33.3–100) 0.697 PAPP-A 0.472 (0.098–0.846) 40.0 (0–80.0) 40.0 (0–80.0) 0.750 (0.547–0.954) 33.3 (0–66.7) 33.3 (0–66.7) 0.105 PlGF 0.742 (0.540–0.944) 20.0 (0–60.0) 40.0 (0–80.0) 0.752 (0.509–0.995) 33.3 (0–66.7) 33.3 (0–66.7) 0.954 PlGF + UtA-PI 0.856 (0.716–0.995) 40.0 (0–80.0) 60.0 (20.0–100) 0.838 (0.622–1.000) 50.0 (16.3–83.3) 66.7 (16.7–100) 0.903 MAP + PlGF 0.801 (0.630–0.972) 40.0 (0–80.0) 40.0 (0–80.0) 0.905 (0.833–0.977) 33.3 (0–83.3) 50.0 (16.7–83.3) 0.473 MAP + UtA-PI 0.812 (0.623–1.000) 40.0 (0–80.0) 40.0 (0–80.0) 0.914 (0.838–0.990) 50.0 (16.7–83.3) 66.7 (16.7–100) 0.470 PAPP-A + PlGF 0.723 (0.517–0.930) 20.0 (0–60.0) 40.0 (0–80.0) 0.769 (0.540–0.997) 33.3 (0–66.7) 33.3 (0–83.3) 0.790 MAP + PAPP-A 0.356 (0.075–0.638) 40.0 (0–80.0) 40.0 (0–80.0) 0.892 (0.844–0.941) 16.7 (0–50.0) 50.0 (16.7–83.3) < 0.001 UtA-PI + PAPP-A 0.719 (0.426–1.000) 40.0 (0–80.0) 60.0 (20.0–100) 0.855 (0.697–1.000) 50.0 (0–83.3) 66.7 (33.3–100) 0.403 MAP + UtA-PI + PAPP-A 0.790 (0.580–0.999) 40.0 (0–80.0) 40.0 (0–80.0) 0.937 (0.881–0.992) 50.0 (16.7–83.3) 66.7 (33.3–100) 0.292 MAP + UtA-PI + PlGF 0.886 (0.770–1.000) 40.0 (0–80.0) 60.0 (20.0–100) 0.954 (0.905–1.000) 83.3 (33.3–100) 83.3 (50.0–100) 0.552 MAP + PAPP-A + PlGF 0.789 (0.617–0.961) 40.0 (0–80.0) 40.0 (0–80.0) 0.916 (0.853–0.978) 50.0 (0–83.3) 50.0 (16.7–100) 0.379 UtA-PI + PlGF + PAPP-A 0.847 (0.700–0.994) 40.0 (0–80.0) 60.0 (20.0–100) 0.847 (0.642–1.000) 50.0 (16.7–83.3) 66.7 (16.7–100) 1.00 MAP + UtA-PI + PlGF + PAPP-A 0.926 (0.838–1.000) 60.0 (20.0–100) 80.0 (40.0–100) 0.967 (0.944–0.989) 66.7 (33.3–100) 100 (100–100) 0.669 *Comparison between AUCs was by two-tailed P-value. FPR, false-positive rate; MAP, mean arterial pressure; UtA-PI, uterine artery pulsatility index. Table 5 Detection rate (DR) and area under receiver-operating-characteristics curve (AUC) for prediction of pre-eclampsia before 37 weeks’ gestation by Fetal Medicine Foundation competing-risks model, according to whether pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured before or after 11 weeks 8 + 0 to 10 + 6 weeks (n = 16) 11 + 0 to 13 + 6 weeks (n = 14) DR (% (95% CI)) at: DR (% (95% CI)) at: Method of screening AUC (95% CI) 5% FPR 10% FPR AUC (95% CI) 5% FPR 10% FPR P* A-priori risk plus: MAP 0.722 (0.604–0.840) 31.3 (12.5–56.3) 31.3 (12.5–56.3) 0.734 (0.593–0.875) 21.4 (0–42.9) 28.6 (7.1–50.0) 0.910 UtA-PI 0.749 (0.617–0.882) 18.8 (0–37.7) 43.8 (25.0–68.8) 0.721 (0.566–0.876) 21.4 (0–42.9) 50.0 (28.4–78.6) 0.791 PAPP-A 0.689 (0.529–0.850) 12.5 (0–37.5) 31.3 (12.5–56.3) 0.722 (0.592–0.853) 21.4 (0–42.9) 35.7 (14.3–57.1) 0.759 PlGF 0.738 (0.633–0.842) 12.5 (0–37.5) 31.3 (12.5–56.3) 0.737 (0.593–0.880) 35.7 (14.3–57.1) 35.7 (14.3–57.1) 0.992 PlGF + UtA-PI 0.746 (0.637–0.855) 18.8 (0–43.8) 37.5 (18.8–62.5) 0.745 (0.603–0.886) 42.9 (21.4–71.4) 50.0 (21.4–78.6) 0.992 MAP + PlGF 0.785 (0.700–0.869) 31.3 (6.3–50.0) 37.5 (18.8–62.5) 0.797 (0.659–0.936) 35.7 (14.3–64.3) 42.9 (21.4–71.4) 0.904 MAP + UtA-PI 0.803 (0.721–0.885) 25.0 (6.3–50.0) 37.5 (18.8–62.5) 0.766 (0.605–0.926) 35.7 (14.3–64.3) 50.0 (21.4–78.6) 0.712 PAPP-A + PlGF 0.746 (0.637–0.855) 12.5 (0–43.8) 43.8 (18.8–68.8) 0.745 (0.603–0.886) 35.7 (14.3–64.3) 35.7 (14.3–64.3) 0.992 MAP + PAPP-A 0.741 (0.625–0.857) 31.3 (6.3–56.3) 43.8 (18.8–68.8) 0.754 (0.612–0.896) 14.3 (0–42.9) 28.6 (7.1–57.1) 0.901 UtA-PI + PAPP-A 0.767 (0.627–0.907) 37.5 (12.5–68.8) 56.3 (31.3–81.3) 0.751 (0.610–0.892) 28.6 (7.1–57.1) 50.0 (29.9–78.6) 0.877 MAP + UtA-PI + PAPP-A 0.815 (0.726–0.905) 31.3 (12.5–56.3) 43.8 (18.8–68.8) 0.783 (0.624–0.942) 35.7 (14.3–57.1) 57.1 (28.6–85.7) 0.744 MAP + UtA-PI + PlGF 0.830 (0.760–0.899) 18.8 (0–37.7) 43.8 (18.8–68.8) 0.804 (0.649–0.958) 42.9 (14.3–71.4) 57.1 (28.6–85.7) 0.785 MAP + PAPP-A + PlGF 0.793 (0.709–0.877) 31.3 (12.5–56.3) 43.8 (18.8–68.8) 0.803 (0.665–0.942) 35.7 (14.3–64.3) 50.0 (21.4–78.6) 0.919 UtA-PI + PlGF + PAPP-A 0.789 (0.683–0.894) 25.0 (6.3–43.8) 37.5 (12.5–62.5) 0.764 (0.621–0.907) 42.9 (14.3–71.4) 50.0 (29.9–78.6) 0.805 MAP + UtA-PI + PlGF + PAPP-A 0.818 (0.713–0.924) 31.3 (6.3–50.0) 50.0 (25.0–81.3) 0.820 (0.669–0.971) 42.9 (14.3–71.4) 57.1 (28.6–85.7) 0.983 *Comparison between AUCs was by two-tailed P-value. FPR, false-positive rate; MAP, mean arterial pressure; UtA-PI, uterine artery pulsatility index. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd Ultrasound Obstet Gynecol 2021; 57: 84–90. on behalf of International Society of Ultrasound in Obstetrics and Gynecology. 90 Mendoza et al. ACKNOWLEDGMENTS 6. Serra B, Mendoza M, Scazzocchio E, Meler E, Nolla M, Sabrià E, Rodrı́guez I, Carreras E. A new model for screening for early-onset preeclampsia. Am J Obstet Gynecol 2020; 222: 608.e1–608.e18. We thank Erika Bokor for English language correction 7. Wright D, Spencer K, Kagan KK, Tørring N, Petersen OB, Christou A, Kallikas J, of the manuscript, all the physicians who facilitated the Nicolaides KH. First-trimester combined screening for trisomy 21 at 7–14 weeks’ gestation. Ultrasound Obstet Gynecol 2010; 36: 404–411. recruitment of individuals at the Hospital Universitari 8. 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