Received: 2 July 2023 | Revised: 10 September 2023 | Accepted: 12 September 2023 DOI: 10.1111/aogs.14687 ORIGINAL RESEARCH ARTICLE Clinical effectiveness of routine first-­trimester combined screening for pre-­eclampsia in Spain with the addition of placental growth factor Pablo Garcia-­Manau1,2 | Erika Bonacina1,2 | Berta Serrano1,2 | Sara Caamiña3 | Marta Ricart4 | Eva Lopez-­Quesada5 | Àngels Vives6 | Monica Lopez7 | Elena Pintado8 | Anna Maroto9 | Sara Catalan1 | Marta Dalmau1 | Ester Del Barco1 | Alina Hernandez1 | Marta Miserachs1 | Marta San Jose1 | Mireia Armengol-­Alsina1 | Elena Carreras1 | Manel Mendoza1,2 1 Universitat Autònoma de Barcelona, Barcelona, Spain Abstract Introduction: Pre-­eclampsia affects 2%–­8% of pregnancies and is one of the leading 2 Department of Obstetrics, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain 3 causes of maternal and perinatal morbidity and mortality. First-­trimester screening Department of Obstetrics, Hospital Universitario Nuestra Señora de using an algorithm that combines maternal characteristics, mean arterial blood pres- Candelaria, Santa Cruz de Tenerife, Spain sure, uterine artery pulsatility index and biomarkers (pregnancy-­associated plasma 4 Department of Obstetrics, Hospital protein-­A and placental growth factor) is the method that achieves a greater diagnos- Universitari Germans Trias i Pujol, Badalona, Spain tic accuracy. It has been shown that daily salicylic acid administration before 16 weeks 5 Department of Obstetrics, Hospital in women at a high risk for pre-­eclampsia can reduce the incidence of preterm pre-­ Universitari Mútua Terrassa, Terrassa, Spain eclampsia. However, no previous studies have evaluated the impact of routine first-­ 6 Department of Obstetrics, Consorci trimester combined screening for pre-­eclampsia with placental growth factor after Sanitari de Terrassa, Terrassa, Spain being implemented in the clinical practice. 7 Department of Obstetrics, Hospital Universitari de Tarragona Joan XXIII, Material and methods: This was a multicenter cohort study conducted in eight dif- Tarragona, Spain ferent maternities across Spain. Participants in the reference group were prospec- 8 Department of Obstetrics, Hospital tively recruited between October 2015 and September 2017. Participants in the Universitario de Getafe, Getafe, Spain 9 study group were retrospectively recruited between March 2019 and May 2021. Department of Obstetrics, Hospital Universitari de Girona Dr. Josep Trueta, Pre-­eclampsia risk was calculated between 11+0 and 13+6 weeks using the Gaussian Girona, Spain algorithm combining maternal characteristics, mean arterial pressure, uterine arteries Correspondence pulsatility index, pregnancy-­associated plasma protein-­A and placental growth factor. Manel Mendoza, Universitat Autònoma Patients with a risk greater than 1/170 were prescribed daily salicylic acid 150 mg de Barcelona, 119-­129, 08035 Barcelona, Spain. Email: manel.mendoza@vallhebron.cat Abbreviations: ASA, salicylic acid; BMI, body mass index; CI, confidence interval; FMF, fetal medicine foundation; ICU, intensive care unit; MAP, mean arterial pressure; OR, odds ratio; PAPP-­A , pregnancy-­associated plasma protein-­A ; PE, pre-­eclampsia; PlGF, placental growth factor; SGA, small for gestational age; UtAPI, uterine artery pulsatility index. Pablo Garcia-­Manau and Erika Bonacina contributed equally as co-­f irst authors. Elena Carreras and Manel Mendoza contributed equally as co-­last authors. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Acta Obstet Gynecol Scand. 2023;102:1711–1718.  wileyonlinelibrary.com/journal/aogs | 1711 1712 | GARCIA-­MANAU et al. until 36 weeks. Patients in the reference group did not receive salicylic acid during gestation. Results: A significant reduction was observed in preterm pre-­eclampsia (OR 0.47; 95% CI: 0.30–­0.73), early-­onset (<34 weeks) pre-­eclampsia (OR 0.35; 95% CI: 0.16–­0.77), preterm small for gestational age newborn (OR 0.57; 95% CI: 0.40–­0.82), spontane- ous preterm birth (OR 0.72; 95% CI: 0.57–­0.90), and admission to intensive care unit (OR 0.55; 95% CI: 0.37–­0.81). A greater treatment adherence resulted in a significant reduction in adverse outcomes. Conclusions: Routine first-­trimester screening for pre-­eclampsia with placental growth factor leads to a reduction in preterm pre-­eclampsia and other pregnancy complications. Aspirin treatment compliance has a great impact on the effectiveness of this screening program. KEYWORDS aspirin, placental growth factor, PlGF, pre-­eclampsia, salicylic acid, screening 1 | I NTRO D U C TI O N Key message Pre-­eclampsia (PE) affects around 2%–­8% of pregnancies and is one of the leading causes of maternal and perinatal morbidity and Routine first-­trimester screening for pre-­eclampsia with 1 mortality, being the most frequent cause of maternal admission placental growth factor reduced preterm and early-­onset to intensive care units (ICU) and resulting in significant health care pre-­eclampsia, preterm small for gestational age, sponta- costs. 2,3 For this reason, an optimal screening method has been in- neous preterm birth and intensive care unit admissions. vestigated for years. Currently, the method that combines maternal Aspirin compliance has a great impact on the effectiveness characteristics (medical history, mean arterial pressure [MAP], uter- of this screening program. ine artery pulsatility index [UtAPI] and biomarkers placental growth factor [PlGF] and in some cases pregnancy-­associated plasma pro- tein-­A [PAPP-­A]) has the greatest diagnostic accuracy.4,5 Thus, dif- real-­life clinical practice.13 For this reason, it is advisable to prospec- ferent scientific organizations recommend universal first-­trimester tively assess the clinical impact of a new strategy after being imple- screening for PE using this method.6,7 mented in the clinical practice.14 The clinical impact of the routine Different algorithms have been developed for identifying first-­trimester combined screening for PE with PlGF has never been women at a high risk for early-­onset and preterm PE.5,8,9 The most investigated. Therefore, the aim of this study was to assess the clin- used and widely validated algorithm is the one developed by the ical effectiveness after implementing a routine first-­trimester com- Fetal Medicine Foundation. Nevertheless, in most Spanish mater- bined screening for PE with PlGF by the Gaussian algorithm. nities the Gaussian algorithm is used for routine screening in the first trimester, as it allows assessment of the UtAPI by Doppler ul- trasound either transabdominally or transvaginally, and measure- 2 | M ATE R I A L A N D M E TH O DS ment of the biomarkers between 8+0 and 13+6 weeks,10 rendering it easy to integrate with the first-­trimester aneuploidy screening, and This was a multicenter cohort study. The Strengthening the Report- highly adaptable in different settings. The Gaussian algorithm was ing of Observational Studies in Epidemiology (STROBE) statement designed to predict early-­onset PE; however, it has shown a similar was followed for writing this report.15 Participants in the reference performance to that of the Fetal Medicine Foundation algorithm for group were obtained from a secondary analysis of a study for the predicting preterm PE, early-­onset PE and small for gestational age development of the Gaussian algorithm to predict early-­onset PE at (SGA) fetuses in a Spanish population.11 the first trimester conducted at Vall d'Hebron University Hospital The ASPRE trial showed that daily administration of 150 mg between October 2015 and September 2017. Data from this cohort of salicylic acid (ASA) before 16 weeks reduces the incidence of of pregnant individuals have previously been published.5,16 A total of preterm PE by 62% and may also reduce the incidence of early-­onset 3777 patients were assessed at the routine first-­trimester scan. Of PE, early-­onset SGA and preterm SGA by 82%, 40% and 20%, re- those, 2946 were enrolled; 305 (10.4%) were excluded from all anal- spectively.12 These favorable findings were observed in a research ysis for the following reasons: missing outcome data (n = 86), major context; however, a screening strategy may be less effective in fetal defects (n = 13), miscarriage <24 weeks (n = 15), and insufficient GARCIA-­MANAU et al. | 1713 blood sample (n = 191). In addition to these exclusions, birthweight of early-­onset PE ≥1/17020 were considered at a high risk for PE and data were unavailable for an additional 158 (5.4%) patients. Con- referred before 16+6 weeks to a specialized clinic where ASA was sequently, 463 (15.7%) participants were excluded from the SGA prescribed at a dose of 150 mg at night (Tromalyt box of 28 tablets; analysis. None of the participants included in the reference group Mylan Pharmaceuticals, S.L; Madrid, Spain) until 36 weeks. Six boxes received ASA during gestation, as it was an exclusion criterion. In the are usually required to complete treatment and compliance in the study group, 11 586 patients from eight different maternities across study group was checked using pharmacy dispensing records. Spain attending the first-­trimester ultrasound were retrospectively PE was defined in both groups according to the criteria of the Amer- analyzed between March 2019 and May 2021. PE risk was calculated ican College of Obstetricians and Gynecologists.21 Patients diagnosed for all as part of their routine prenatal care. Of those, 1121 (10%) with PE with severe features were delivered at 34 weeks and delivery were excluded from all analysis for the following reasons: missing was delayed until 37 weeks in cases of PE without severe features. If outcome data (n = 905), major fetal defects (n = 110), and miscar- any of the following was present, delivery was indicated at any time riage <24 weeks (n = 106). In addition to these exclusions, birthweight during pregnancy: pulmonary edema, serum creatinine >1.1 mg/dL, ol- data were unavailable for an additional 1332 (11.8%) patients. Con- iguria (≤500 mL in 24 h or ≤ 20 mL/h), persistent hypertension despite sequently, 2453 (21.8%) participants were excluded from the SGA appropriate antihypertensive therapy (≥2 antihypertensive drugs), per- analysis. More details can be seen in the flow chart (Figure 1). sistent cerebral or visual symptoms, placental abruption or eclampsia. During the first-­trimester scan, between 11+0 and 13+6 weeks, PE was classified as early-­onset or preterm when delivery was required gestational age was confirmed by fetal crown-­rump length mea- due to PE before 34 or 37 weeks, respectively. Term PE (≥37 weeks) 17 surements. Demographic characteristics, obstetric and maternal was not recorded for that study as ASA treatment has not been proven history and MAP and UtAPI (measured transvaginally or transabdom- to reduce the incidence of this condition.22 All cases diagnosed with 18,19 inally) were assessed and recorded for all participants. Serum early-­onset and preterm PE were cross-­checked to confirm that diag- PAPP-­A (mU/L) and PlGF (pg/mL) levels were measured in maternal nosis and elective delivery followed the criteria previously described. +0 +6 10 blood samples between 8 and 13 weeks by means of the fully SGA was defined as birthweight below the 10th percentile accord- automated Elecsys assays on an electrochemiluminescence immu- ing to local charts23 and was considered early-­onset if delivery occurred noassay platform (Cobas analyzer; Roche Diagnostics, Rotkreuz, before 32 weeks and preterm if delivery occurred before 37 weeks. Switzerland). MAP, PlGF and PAPP-­A values were then transformed Maternal admission to the ICU was recorded only when the in- 5 to multiples of the median. All data were introduced in the prenatal dication was related to PE or its complications (eclampsia or hemor- screening software SsdwLab6 (SBP Soft 2007 S.L; Girona, Spain), rhage due to placental abruption). Other reasons for maternal ICU which was already being used for common trisomies screening in admission were not recorded. On the other hand, as participating all participant sites. PE risk was then calculated in the study group sites had different neonatal care units and different criteria for ad- using the Gaussian algorithm by combining maternal characteristics, mission due to the existence of transitional care units in some of maternal history, MAP, UtAPI, PAPP-­A and PlGF. Women with a risk them, neonatal admission to the ICU was not recorded in this study. F I G U R E 1 Recruitment flow chart. 1714 | GARCIA-­MANAU et al. Categorical data are reported as frequency and percentage and 2.1 | Ethics statement continuous data as mean and standard deviation or as median and interquartile range. Comparisons between groups were estimated The study protocol was approved by the Institutional Review Board by chi-­squared or Fisher's tests, as appropriate. Mann–­Whitney U at each participating site (PR-­AMI-­147/2021) on March 23, 2021. test was used to assess differences between groups. Treatment ef- All participants in the untreated group signed the written informed fect was quantified as the odds ratio (OR) with a 95% confidence in- consent. For the retrospective cohort of treated participants (study terval (CI) in the study group. The statistical software R Commander, group), written informed consent was waived. R package version 2.3–­1, was used for data analyses. Statistical sig- nificance level was set at p < 0.05. The incidence of preterm PE in our population before implemen- 3 | R E S U LT S tation of routine first-­trimester PE screening was 1.14%.10 Sample size calculation was based on an expected reduction in the incidence of Baseline characteristics in the untreated and treated groups were preterm PE by 62% (from 1.14% to 0.43%), 22 with a statistical power significantly different for age, body mass index, assisted reproduc- of 80% and an estimated dropout rate of 5%. Therefore, in order to tive technique with ovarian stimulation, obstetric history, MAP, detect such reduction at a significance level of 5%, 2546 women had UtAPI, PAPP-­A and PlGF (Table 1). to be recruited for each group. Since untreated controls with UtAPI Preterm PE occurred in 30 of 2641 participants (1.14%) in the and PlGF assessed at the first trimester are no longer available in our untreated group vs 54 of 10 134 patients (0.53%) in the treated region and as we aimed to investigate the effect of aspirin treatment group (OR 0.47; 95% CI: 0.30–­0.73; p < 0.001). Early-­onset PE on the incidence of rarer complications such as early-­onset PE, we occurred in 11 patients (0.42%) in the untreated group vs 15 pa- decided to include more cases than controls in a 4:1 ratio, which is the tients (0.15%) in the treated group (OR 0.35; 95% CI: 0.16–­0.77; maximum accepted ratio for case–­control studies.24 p = 0.009). Preterm SGA occurred in 44 of 2483 patients (1.77%) in Reference group Study group TA B L E 1 Baseline characteristics of the Characteristic (n = 2641) (n = 10 134) p-­value study population. Age in years, median (IQR) 32.0 (28.0–­36.0) 32.8 (28.5–­36.6) <0.001 2 BMI in kg/m , median (IQR) 23.8 (21.3–­27.5) 24.5 (21.8–­28.4) <0.001 Ethnicity 0.444 Other 2569 (97.3) 9884 (97.5) Black 72 (2.7) 250 (2.5) Smoking status 312 (11.8) 1039 (10.3) 0.073 ART with ovarian stimulation 78 (3.0) 219 (2.2) 0.020 Medical history Chronic Hypertension 29 (1.1) 132 (1.3) 0.645 Diabetes mellitus 36 (1.4) 130 (1.3) 0.773 Obstetric history Nulliparous 1232 (46.6) 4155 (41.0) 0.002 Previous pre-­eclampsia 35 (1.3) 229 (2.3) 0.005 Biophysical variables GA at first-­trimester ultrasound in 12.6 (12.1–­13.0) 12.6 (12.3–­13.0) 0.472 weeks, median (IQR) MoM MAP, median (IQR) 1.05 (0.97–­1.14) 1.09 (1.00–­1.18) <0.001 MoM UtAPI, median (IQR) 1.03 (0.84–­1.26) 1.01 (0.82–­1.21) <0.001 Biochemical variables GA for PAPP-­A and PlGF 10.6 (10.0–­11.3) 10.7 (10.0–­11.9) <0.001 measurement, median (IQR) MoM PAPP-­A , median (IQR) 1.05 (0.73–­1.50) 1.02 (0.72–­1.46) 0.040 MoM PlGF, median (IQR) 0.96 (0.75–­1.19) 0.98 (0.77–­1.22) 0.008 Note: Categorical data are reported as frequency and percentage. Continuous data are reported as the median and interquartile range. Abbreviations: ART, assisted reproductive technique; BMI, body mass index; GA, gestational age; IQR, interquartile range; MAP, mean arterial pressure; MoM, multiples of median; PAAP-­A , pregnancy-­associated plasma protein-­A; PlGF, placental growth factor; UtAPI, uterine artery pulsatility index. GARCIA-­MANAU et al. | 1715 the untreated group vs 89 of 8802 women (1.01%) in the treated of days at the ICU was 133 in the untreated group versus 270 in the group (OR 0.57; 95% CI: 0.40–­0.82; p = 0.003). Spontaneous treated group (OR 0.53; 95% CI: 0.43–­0.65; p < 0.001). We would preterm birth (SPB) <37 weeks occurred in 104 patients (3.9%) like to clarify that despite 270 days was more than 133 days, since in the untreated group vs 287 (2.8%) in the treated group (OR the treated group was approximately four times larger, the OR was 0.72; 95% CI: 0.57–­0.90; p = 0.005). More details can be found in <1. Other adverse outcomes, such as incidence of early-­onset SGA, Figure 2. Admission to the ICU was required in 37 women (1.40%) SPB <34 weeks, placental abruption and stillbirth, were not signifi- in the untreated group vs 78 participants (0.77%) in the treated cantly different between both groups (Table 2). group (OR 0.55; 95% CI: 0.37–­0.81; p = 0.003) and the total number During the study period, 1520 patients (15.0%) were at a high risk for PE. Of those, 1406 (92.5%) took ASA; in 39 patients (2.6%) treatment could not be confirmed and 75 patients (4.9%) did not take ASA due to the following reasons: ASA was not prescribed (10), allergy or contraindications (18), treatment was refused by the pa- tient (28), patient did not attend the medical appointment before 16 weeks (16) and other (3). Among the 1363 patients that took ASA, compliance was >50% in 1292 (94.8%) and > 90% in 1183 (86.8%). The 1393 patients with verified ASA treatment compliance in the treated group were classified into three groups according to treat- ment adherence during the study period: <50%, ≥50% and ≥90% of tablet intake. The risk for PE and baseline characteristics did not differ significantly between women with a compliance <50% and ≥50%, except for maternal age and UtAPI (Table S1). When compar- ing the occurrence of adverse outcomes between participants with treatment compliance <50% and those with treatment compliance ≥50% and ≥90%, we observed that greater treatment compliance resulted in a significant reduction of adverse outcomes, especially when compliance was ≥90% (Table 3). 4 | DISCUSSION In this study, routine first-­trimester combined screening for PE with PlGF and subsequent aspirin treatment resulted in a significant re- duction of preterm PE by 53%, early-­onset PE by 65%, preterm SGA by 43%, SPB by 28%, maternal ICU admission by 45% and length of stay in the ICU by 47%. On the other hand, this screening program did not show any significant impact on the incidence of early-­onset SGA, placental abruption or stillbirth. One of the main strengths of this study was the large sample size from eight maternity hospitals across Spain, which increases the external validity of our findings. Additionally, the favorable results of our study demonstrate the effectiveness of the first-­trimester com- bined screening for PE also in real-­life conditions and the importance of ASA treatment compliance for the screening to be effective. We acknowledge some limitations to this study. First, partici- pants in the treated group were recruited from eight different sites, while patients in the untreated group were obtained from a single site. This may have resulted in groups not being comparable. How- ever, differences in baseline characteristics, such as biophysical and F I G U R E 2 Proportion of women developing (A) pre-­eclampsia, biochemical markers, were small and therefore may not be clini- (B) small-­for-­gestational-­age newborns, or (C) spontaneous preterm birth according to gestational age at delivery in the treated and cally relevant. Regarding obstetric history and maternal character- the untreated cohorts (untreated cohort, gray bars and dotted line; istics; maternal age, body mass index and nulliparity rate, previous treated cohort, black bars and dashed line). PE and assisted reproductive technique were significantly different 1716 | GARCIA-­MANAU et al. TA B L E 2 Adverse pregnancy outcomes in the study population. Reference group (n = 2483 for SGA, Study group (n = 8802 for SGA, Outcome n = 2641 for other outcomes) n = 10 134 for other outcomes) Odds ratio (95% CI) Early-­onset adverse outcomes SGA newborn <32 weeks 8 (0.32) 15 (0.17) 0.53 (0.22–­1.25) Pre-­eclampsia <34 weeks 11 (0.42) 15 (0.15) 0.35 (0.16–­0.77) Spontaneous preterm birth <34 weeks 16 (0.61) 67 (0.66) 1.09 (0.63–­1.89) Adverse outcomes <37 weeks Pre-­eclampsia 30 (1.14) 54 (0.53) 0.47 (0.30–­0.73) Spontaneous preterm birth <37 weeks 104 (3.9) 287 (2.8) 0.72 (0.57–­0.90) SGA newborn <37 weeks 44 (1.77) 89 (1.01) 0.57 (0.40–­0.82) Other adverse outcomes Stillbirth 10 (0.38) 29 (0.29) 0.76 (0.37–­1.55) Placental abruption 13 (0.49) 39 (0.38) 0.78 (0.42–­1.47) Maternal ICU admission ICU admission 37 (1.40) 78 (0.77) 0.55 (0.37–­0.81) Total days in ICU 133 270 0.53 (0.43–­0.65) Note: Data are reported as n (%). Abbreviations: CI, confidence interval; ICU, intensive care unit; SGA, small for gestational age. TA B L E 3 Effect of aspirin compliance in the incidence of complications. Compliance <50% Compliance ≥50% Compliance ≥90% Odds ratio Outcome n = 71 n = 1292 Odds ratio (95% CI)a n = 1183 (95% CI)a Early-­onset PE 4 (5.6%) 4 (0.31%) 0.06 (0.01–­0.22) 4 (0.34%) 0.06 (0.01–­0.25) Preterm PE 6 (8.5%) 21 (1.6%) 0.19 (0.08–­0.49) 18 (1.5%) 0.18 (0.07–­0.47) SPB at <37 weeks 2 (2.8%) 52 (4.0%) 1.43 (0.34–­5.98) 47 (4.0%) 1.41 (0.34–­5.92) Preterm SGA 1 (1.4%) 34 (2.6%) 1.87 (0.25–­13.85) 31 (2.6%) 1.86 (0.25–­13.83) ICU admission 6 (8.5%) 31 (2.4%) 0.28 (0.11–­0.70) 26 (2.2%) 0.26 (0.10–­0.65) ICU stay (days) 20 124 0.33 (0.19–­0.56) 108 0.32 (0.19–­0.55) Note: Data are reported as n (%). Abbreviations: CI, confidence interval; ICU, intensive care unit; PE, pre-­eclampsia; SGA, small for gestational age; SPB, spontaneous preterm birth. a Compared to compliance <50%. between groups. However, some of these risk factors were more algorithm but only in a subgroup of medium-­r isk patients using prevalent in the untreated group and vice versa, thereby rendering a contingent scheme. That study showed that measuring PlGF groups still comparable. Second, the fact that the treated group was only in 21.5% of the screened patients allows to reduce PE by recruited retrospectively and with respect to the untreated group, 68.4% and reduce costs. 25 However, sample size in that study was and not simultaneously, may limit the internal validity of our findings. too small as to drive any solid conclusions and the incidence of For this reason, we cannot exclude the possibility that changes in preterm PE (1.9%) was slightly higher than expected in our popula- the characteristics of the population or in the clinical practice may tion (1.1%). 26 Another previous study evaluated the effectiveness have influenced the results. Third, birthweight was not available in of the first-­t rimester combined screening for PE using the Gauss- 19.9% (2237/11255) of participants in the treated group, which may ian algorithm with all markers except PlGF, showing a moderate have influenced our results regarding the effect of ASA treatment to reduction in preterm PE of 45% and in maternal ICU admission prevent SGA newborns. Finally, criteria for neonatal admission were of 43%. Unfortunately, that study was underpowered and failed different among the different hospitals, rendering these findings not to show any impact in the rates of early-­onset PE, SGA, preterm comparable. birth, placental abruption or stillbirth. 26 Regarding the Fetal Med- No previous studies have evaluated the clinical impact of per- icine Foundation algorithm, its effectiveness in clinical practice forming routine combined screening for PE with PlGF using the with PlGF has not been yet assessed. Nevertheless, three studies Gaussian algorithm in clinical practice. A recent study has as- have evaluated the clinical impact of such algorithm without PlGF. sessed the clinical benefit of incorporating PlGF to the Gaussian Two studies were conducted by the same group and in the same GARCIA-­MANAU et al. | 1717 cohort of participants. They compared the incidence of PE and early-­onset PE by 65%, preterm SGA by 43%, SPB by 28%, maternal SGA in a cohort of 4841 women screened for PE using the Fetal ICU admission by 45% and length of stay in the ICU by 47%. As ASA Medicine Foundation algorithm without PlGF and treated with treatment compliance has a great impact on the effectiveness of this daily ASA 150 mg with the incidences in a cohort of 7720 women screening program, an adequate pre-­and post-­screening counseling screened according to the NICE criteria and treated with daily ASA may improve compliance to ASA treatment and its preventive effect. 75 mg. They showed that aspirin treatment compliance increased from 28.9% to 99% and the combined screening strategy resulted AU T H O R C O N T R I B U T I O N S in a significant reduction of 23% in PE incidence and 45% in term MM and EC had full access to all study data and accept respon- SGA incidence. 27,28 The third study was conducted in a small co- sibility for the integrity of such data and the accuracy of data hort of 1272 women showing a significant reduction of 68% of analysis. MM and EC conceived and designed the study. PG-M, early-­onset PE, compared to untreated controls. 29 EB, BS, SC, MR, EL-Q , ÀV, ML, SC, MD, EDB, AH, MM, MSJ, MA-­A As in previous studies, treatment compliance in our study was and EC contributed to the literature research and data collection high (≥90% in >85% of women) after implementing the combined and confirmation. PG-­M , EB, EC and MM contributed to the data 27,29 screening for PE. However, 12.2% (185/1520) of women at high analysis and data interpretation. PG-­M and EB were responsible risk for PE did not take aspirin or compliance was <50% or unknown. for writing the draft of the manuscript. MM and EC made sub- By contrast, in a secondary analysis of the ASPRE trial, treatment stantial revisions to the manuscript. All authors contributed to compliance was <50% in only 5% of participants.30 We also show revision of the manuscript, and read and approved the submitted that despite baseline risk for PE being the same in both groups, version. the reduction of PE and other related complications was greater in women with compliance ≥50% and particularly when compliance AC K N OW L E D G M E N T S was ≥90% as compared with women with a compliance <50%. These We thank all the physicians who facilitated the recruitment at all 30 findings agree with a previous study; however, the effect of treat- participating sites and Roche Diagnostics for providing the reagents ment compliance in the clinical practice had not been previously used in this study. confirmed. Since aspirin treatment compliance has a great impact on the effectiveness of the screening, a greater proportion of patients F U N D I N G I N FO R M AT I O N with unknown or poor compliance (<50%) in our study as compared This study had no funding. Roche Diagnostics provided the placental to the ASPRE trial may partly account for the lower reduction in growth factor used in this study. preterm PE in our study (53% vs. 62%). The screen-­positive rate was 15.0% which was only 2% higher C O N F L I C T O F I N T E R E S T S TAT E M E N T than the percentage of 13% expected in our population using a MM received lecture fees from Roche Diagnostics. The remaining cutoff of 1/170. 20 Usually, screening for PE using combined algo- authors report no conflict of interest. rithms include cutoffs that correspond to a 10% false-­positive rate. However, PE screening performance in non-­black women is poorer ORCID than in black women and therefore, screen-­positive rates should be Pablo Garcia-­Manau https://orcid.org/0000-0002-2415-1626 higher for a predominantly white population so as to achieve ade- Erika Bonacina https://orcid.org/0000-0002-8042-8247 quate detection rates.31 Given that >90% of our population are of Berta Serrano https://orcid.org/0000-0002-1264-9195 Caucasian or Latin-­American origin, a screen-­positive rate of around Ester Del Barco https://orcid.org/0000-0002-1484-9027 15% is probably more appropriate. 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