STUDY PROTOCOL published: 26 July 2022 doi: 10.3389/fcvm.2022.931943 First-Trimester Sequential Screening for Preeclampsia Using Angiogenic Factors: Study Protocol for a Prospective, Multicenter, Real Clinical Setting Study Cristina Trilla 1,2,3 , Cristina Luna 4 , Silvia De León Socorro 5 , Leire Rodriguez 6 , Aina Ruiz-Romero 7 , Josefina Mora Brugués 8 , Taysa Benítez Delgado 9 , Marta Fabre 2,10 , Alicia Martin Martínez 5 , Sara Ruiz-Martinez 2,4 , Elisa Llurba 1,2,3 and Daniel Oros 2,4* 1 Obstetrics and Gynecology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 2 Red RICORS “Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin”, RD21/0012/0001, Instituto de Salud Carlos III, Madrid, Spain, 3 Institut d’Investigació Biomèdica Sant Pau–IIB Sant Pau, Barcelona, Spain, 4 Obstetrics Department, Aragon Institute of Health Research (IIS Aragon), Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain, 5 Department of Obstetrics and Gynecology, Complejo Hospitalario Universitario Insular, Materno Infantil, Las Palmas, Spain, 6 Department of Obstetrics and Gynecology, Biocruces Bizkaia Edited by: Health Research Institute, Osakidetza, University of the Basque Country, Cruces University Hospital, Bilbao, Spain, Federico Prefumo, 7 Department of Obstetrics and Gynaecology, Hospital Universitari Son Llàtzer, Palma de Mallorca, Spain, 8 Biochemistry University of Brescia, Italy Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 9 Biochemistry Reviewed by: Department, Complejo Hospitalario Universitario Insular, Materno Infantil, Las Palmas, Spain, 10 Biochemistry Department, Veronica Giorgione, Aragon Institute of Health Research (IIS Aragon), Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain St George’s Hospital, United Kingdom Francesca Crovetto, Hospital Clinic of Barcelona, Spain Introduction: The incidence of preeclampsia (PE) is about 2–8%, making it one of *Correspondence: the leading causes of perinatal morbidity and maternal mortality in the world. Early Daniel Oros prophylactic low dose administration (150 mg) of acetylsalicylic acid is associated with danoros@unizar.es a significant reduction in the incidence of early-onset PE, intrauterine growth restriction Specialty section: (IUGR), and neonatal mean stay in the intensive care unit (ICU). Universal implementation This article was submitted to of a first-trimester screening system including angiogenic and antiangiogenic markers Hypertension, a section of the journal [the Placental Growth Factor (PlGF) and/or soluble fms-like Tyrosine Kinase-1 (sFlt-1)] has Frontiers in Cardiovascular Medicine shown a prediction rate of 90% for early-onset PE but entails a high financial cost. The Received: 29 April 2022 aim of this study is to determine the predictive and preventive capacity of a universal PE Accepted: 16 June 2022 first-trimester two-step sequential screening model, determining the PlGF only in patients Published: 26 July 2022 previously classified as intermediate risk by means of a multivariate model based on Citation: Trilla C, Luna C, De León Socorro S, resources already used in the standard pregnancy control, in a real clinical setting. We Rodriguez L, Ruiz-Romero A, Mora hypothesize that this screening model will achieve similar diagnostic performance as the Brugués J, Benítez Delgado T, universal determination of PlGF but at a lower economic cost. Fabre M, Martin Martínez A, Ruiz-Martinez S, Llurba E and Oros D Methods and Analysis: This is a prospective, multicentric, cohort study in a real- (2022) First-Trimester Sequential Screening for Preeclampsia Using world clinical setting. Every singleton pregnancy will be recruited at the routine first Angiogenic Factors: Study Protocol pregnancy visit. In a first step, the first-trimester risk of PE will be calculated using a for a Prospective, Multicenter, Real multivariate Gaussian distribution model, based on medical history, mean blood pressure, Clinical Setting Study. Front. Cardiovasc. Med. 9:931943. Pregnancy-Associated Plasma Protein A (PAPP-A), and Uterine Artery Doppler Pulsatility doi: 10.3389/fcvm.2022.931943 Index (UTPI). Patients will be classified into three risk groups for PE: (1) risk ≥ 1/50, Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 July 2022 | Volume 9 | Article 931943 Trilla et al. Two-Step Early Preeclampsia Screening high-risk with no further testing (blinded PlGF); (2) risk between 1/51 and 1/500, medium- risk requiring further testing; and (3) risk ≤ 1/501, low-risk with no further testing. In a second step, the PlGF will only be determined in those patients classified as intermediate risk after this first step, and then reclassified into high- or low-risk groups. Prophylactic administration of aspirin (150 mg/day) will be prescribed only in high risk patients. As a secondary objective, sFlt-1 values will be blindly determined in patients with high and intermediate risk to assess its potential performance in the screening for PE. Ethics and Dissemination: The study will be conducted in accordance with the principles of Good Clinical Practice. This study is approved by the Aragon Research Ethics Committee (CEICA) on 3 July 2020 (15/2020). Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04767438. Keywords: screening, first trimester, sequential, preeclampsia, growth restriction INTRODUCTION patient, selecting those high-risk candidates to start as soon as possible for the prophylactic treatment with low-dose ASA The incidence of preeclampsia (PE) is about 2–8%, making it (16, 17). one of the leading causes of perinatal morbidity, and responsible Universal PE screening has been proven to be cost-effective for 10–15% of the maternal deaths in the world (1, 2). Women (18). PE screening models based on maternal demographic with PE present a higher risk of cardiovascular morbidity, characteristics and risk factors have been proposed (19), with multisystemic complications, and a long-term increased risk a very low detection rate and an excess in false-positive rate for cardiovascular diseases (3) and Mortality (4). Early-onset (20). Hence, different multivariate models have been developed. PE (diagnosed before 32 weeks of gestation) is also frequently A competitive risk approach at 11–13 weeks by means of a associated with intrauterine growth restriction (IUGR), and combination of maternal characteristics (age, parity, medical therefore affecting perinatal outcomes and long-term offspring history as thrombophilia, nephrological diseases, and chronic development (5, 6). Late-onset PE, perhaps clinically less severe hypertension), maternal biophysical variables [mean arterial but much more common, is also an important cause of pressure (MAP) and Doppler of Uterine Arteries (Uterine Artery maternal and neonatal morbidity and mortality with long-term Pulsatility Index, UTPI)], and biochemical variables (PlGF) has consequences (7). shown a prediction rate of 90% for early-PE and 75% for late- Although a complete understanding of the pathogenesis of onset PE, with a 10% false-positive rate (21, 22). Additionally, PE remains unclear, the current theory suggests a two-stage observational retrospective studies have reported that including process. The first stage is caused by shallow invasion of the antiangiogenic biomarkers such as sFlt-1 could improve the trophoblast, resulting in inadequate remodeling of the spiral first-trimester screening performance (23). arteries. This is presumed to lead to the second stage, which Unfortunately, universal implementation of any first- involves the maternal response to endothelial dysfunction and trimester screening system, such as angiogenic and imbalance between angiogenic and antiangiogenic factors (8). antiangiogenic markers (PlGF and/or sFlt-1), entails a high In PE and IUGR, this vascular remodeling does not exist or financial cost, unaffordable for many healthcare systems. For it is incomplete, leading to placental hypoperfusion associated that reason, more economical screening alternatives have been with endothelial cell dysfunction (9). For a correct placental explored. In this line, taking advantage of the resources used on a development, a balance between the production of angiogenic regular basis for the screening of chromosomal abnormalities, an (Placental Growth Factor, PlGF) and antiangiogenic factors alternative multivariate model based on maternal characteristics, (soluble Fms-like tyrosine kinase-1, sFlt-1) is required. PIGF MAP, and Uterine Arteries Pulsatility Index combined with and sFlt-1 are partially produced by the syncytiotrophoblast. Pregnancy-Associated Plasma Protein A levels (PAPP-A), has Angiogenic biomarkers (PlGF and sFlt-1) have shown their shown a detection rate of early-onset PE of 80.8% and for ability to predict PE and its complications (10). late-onset PE of 39.6%, with a 10% false-positive rate (24). We have effective preventive strategies to reduce the incidence Recent retrospective studies with large sample sizes (25, 26) of PE. The nightly low dose (150 mg) administration of acetyl suggest that a two-step screening protocol, performing only salicylic acid (ASA) before 16 weeks of gestational age until term angiogenic markers in 30% of the population classified as is associated with a 90% reduction in the incidence of preterm-PE moderate or high risk of PE after an economical first step (11, 12) and IUGR (13, 14), as well as with a 70% reduction of the (24), would correctly select high-risk patients for developing neonatal mean stay in intensive care units (ICUs) (15). Therefore, PE, but lower-economic cost. However, these results come from it is essential to develop universal PE screening strategies during retrospective cohorts after universal screening models with PlGF, the first trimester of pregnancy to determine the risk of each and therefore with potential intervention biases. Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 July 2022 | Volume 9 | Article 931943 Trilla et al. Two-Step Early Preeclampsia Screening TABLE 1 | Inclusion and exclusion criteria. TABLE 2 | Variables included in the first-step multivariate model for the estimation of the risk of preeclampsia (PE). Inclusion criteria Exclusion criteria Maternal factors • Singleton pregnancies • Abnormal karyotype, structural • Age abnormalities or congenital • Ethnicity • Gestational age between 8 infections at inclusion • Weight and 13+6 weeks according to first trimester crown-rump • Multiple pregnancies • Height length • Smoking status • Parity • Could receive regular follow-up • History of preeclampsia • Written informed consent • Pre-existing diabetes • Pre-existing hypertension • Thrombophilia • Renal diseases The aim of this study is to prospectively determine, in • Autoimmune conditions a real clinical setting, the predictive and preventive capacity Biophysical markers of a universal PE first trimester two-step sequential screening • Mean arterial pressure (MAP) model, determining PlGF only in those patients previously • Mean uterine arteries pulsatility index classified as intermediate risk by means of a multivariate Blood test samples model based on medical history, MAP, PAPP-A, and UTPI. • Pregnancy-associated plasma protein A (PAPP-A) (MoMs) We hypothesize that this screening model will achieve similar diagnostic performance as the universal determination of PlGF but at a lower economic cost. As a secondary objective, in every intermediate and high-risk patient, sFlT-1 values will be determined to assess their potential performance in the screening for PE. Even though this data will Gaussian distribution model validated in our population, based be blinded to the researchers and will not be considered for on maternal conditions, biophysical markers, and maternal the clinical management. We also evaluate the predictive and serum PAPP-A (taken routinely for trisomy screening) (Table 2). preventive capacity of this first-trimester sequential screening No angiogenic factors will be used to determine the risk of PE at model for the development of IUGR. this first step. All patients who meet the inclusion criteria will be offered the opportunity to participate in the study. If they do not wish METHODS AND ANALYSIS to participate, in accordance with a previous pilot study, a risk Study Design cut-off of ≥1:250 for early PE will be considered high risk, This is a multicentric prospective cohort study in a real clinical and therefore prophylactic treatment with ASA 150 mg will be setting. The study will be conducted in five tertiary Spanish recommended (Figure 1). hospitals: Hospital de la Santa Creu i Sant Pau (Barcelona), In those patients who agree to participate in the study, a Complejo Hospitalario Universitario Insular Materno Infantil two-step contingent sequential screening model will be applied (Las Palmas), Hospital Universitario de Cruces (Bilbao), Hospital (Figure 1). According to the estimated risk of PE in the first Son Llàtzer (Mallorca), and Hospital Clínico Universitario screening step, three risk groups of early PE will be defined: (1) Lozano Blesa (Zaragoza). risk ≥ 1/50, high-risk with no further testing (blinded PlGF), (2) risk between 1/51 and 1/500, medium-risk requiring further Study Population and Groups testing, and (3) risk ≤ 1/501, low-risk with no further testing. Participants will be recruited at the routine first pregnancy visit According to a previous pilot study performed in the Hospital de with an obstetrics specialist, always before the 14 weeks of la Santa Creu i Sant Pau and Hospital Universitario de Cruces, we gestation, based on the eligibility criteria presented in Table 1, expect to find 10% of high-risk patients and 20% of intermediate- and followed until delivery. Written informed consent will be risk after the first step of the screening. These results agree with obtained from all recruited patients. This study is approved those published by other authors (25). by the Aragon Research Ethics Committee (CEICA) on 3 July For the second stage, serum concentrations of PlGF will be 2020 (15/2020). Obstetricians will present the study to all the determined in the medium-risk group, giving a final risk at a eligible patients, explaining the study, offering participation, and cut-off value of 1/250. Prophylactic treatment with ASA (150 mg) requesting written informed consent. up to 36 weeks of gestation will be recommended in patients classified as high risk of PE either in the first or second step of Intervention the model. We consider the first-trimester universal screening for PE as With the intention of performing secondary analysis at the a routine clinical practice. Therefore, the first-trimester risk end of the study but never to be considered for clinical decisions, of PE will be calculated in every patient using a multivariate the levels of maternal serum sFlT-1 will be determined and Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 July 2022 | Volume 9 | Article 931943 Trilla et al. Two-Step Early Preeclampsia Screening FIGURE 1 | Study protocol algorithm. TABLE 3 | Study outcomes. Primary outcomes • Preeclampsia diagnoses during pregnancy (International Society for the Study of Hypertension in Pregnancy—ISSHP) (28) Secondary outcomes • Early-onset Preeclampsia: diagnosed before 32 weeks (28) • Severe preeclampsia (ISSHP) (28) • Pregnancy-induced hypertension (28) • Birth weight below the 10th percentile (29) • Intrauterine Growth Restriction (30) • Perinatal mortality (>22 weeks of pregnancy - <28 days postpartum). • Neonatal acidosis (arterial pH <7.10 + base excess >12 mEq/L) • Neonatal Intensive Care Unit admission (days) • Significant neonatal morbidity [convulsions, intraventricular hemorrhage > III grade, periventricular leukomalacia, hypoxic-ischemic encephalopathy, abnormal electroencephalogram, necrotizing enterocolitis, acute renal failure (serum creatinine >1.5 mg/dL) or heart failure (requiring inotropic agents)]. • Gestational age at birth • Type of delivery (vaginal, instrumental, cesarean section) • Economic cost the screening (euros) Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 July 2022 | Volume 9 | Article 931943 Trilla et al. Two-Step Early Preeclampsia Screening blinded for clinicians in patients with an early PE risk ≥ 1/500 (EU) 2016/679 of the European Parliament and of the Council after the first step of screening (Figure 1). of 27 April 2016 regarding the protection of natural persons In Spain, all pregnancies undergo routine ultrasound scans regarding the processing of personal data and the free circulation at ∼12, 20, and 36 weeks of gestation. All women with a high of these data, and in accordance with the provisions of Organic risk for preterm PE will be scheduled for an additional scan at Law 3/2018, of 5 December, on the Protection of Personal Data approximately 28 weeks. and guarantee of digital rights. The patient database will be anonymous and codified. Data checks will be regularly performed MEASUREMENTS AND OUTCOMES to ensure data quality. The number of eligible, included, and excluded of patients will be recorded. Withdrawals will also The most important aim of this project is to develop an efficient record as detailed as possible. first-trimester screening of PE using resources already used during pregnancy control. All the clinical data, sonography, DATA ANALYSIS and blood test results will be collected during the regular pregnancy control without the need for additional appointments, Sample Size explorations, or extraordinary blood extractions. According to the previously described inclusion criteria and Maternal characteristics will be prospectively recorded considering the number of pregnancies controlled and delivered at the time of recruitment. Pregnancy outcomes will be among all participating centers during the study period, we registered during pregnancy and confirmed after delivery. Fetal estimate that 8,200 patients will be potentially invited to crown-rump length (CRL) (27), and transabdominally uterine participate in the study. artery Doppler will be determined in all patients at the routine As the incidence of PE in Spain is ∼3% of pregnancies, first-trimester ultrasound (110 -136 weeks) by experienced fetal approximately 246 patients of our sample will develop PE. We medicine specialists. Blood pressure (BP) will be measured could assume that at least 80% of the patients will consent to once, after 5-min of rest with women seated at the time participate in the study, meaning a final sample of 6,560 singleton of inclusion. The MAP will be calculated as: diastolic BP + pregnancies. Based on a pilot study previously performed, we (systolic–diastolic BP)/3. estimate that 30% of the patients (which means approximately First-trimester routine blood samples will be performed 1,968 pregnancies) will be classified as intermediate or high risk between 100 and 136 weeks. PAPP-A (taken routinely for after the first-trimester screening for PE. This sample size assures trisomy screening) will be initially determined in every patient. enough statistic power, external validity, and extrapolation of the Serum remaining samples will be stored at −80◦ C, to be results to the clinical practice. able to analyze PlGF and sFlT-1 after the first-trimester ultrasound in those patients with an estimated risk of PE risk Statistical Analysis ≥ 1/500 after the first step of screening. The serum will be Continuous variables will be expressed as means ± standard separated by centrifugation at 1,500 g for 10 minutes at 4◦ C, and deviation (SD) or median [interquartile range (IQR)], where concentrations of PAPP-A, PlGF, and sFlT-1 will be determined appropriate. Categorical variables will be expressed as counts by electrochemiluminescence immunoassays, fully automated on (percentages). The variables in the study will be presented the Cobas e 601 analyzer, Roche Diagnostics. Multiples of the using descriptive statistics. Associations between variables median (MoM) values for PAPP-A, PlGF, and sFlT-1, calculated were evaluated using Student’s t-test, chi-square test, or from locally derived normal medians using the above-mentioned Mann–Whitney’s U-test where appropriate. A multivariate multivariate Gaussian distribution model, will be considered for analysis will be performed using the binomial logistic regression. analysis. To calculate the risk of PE, we will use the SsdwLab6 The diagnostic performance of the contingent screening model version 6.1 package (SBP Soft 2007 S.L.), previously developed in will be evaluated by determining the sensitivity, specificity, the pilot study. screen-positive rate, positive predictive value (PPV), and negative The main outcome is the diagnosis of PE during pregnancy, predictive value (NPV) for early PE. All reported p-values are according to the definition of the International Society for the 2-sided and unequal variances were assumed. A p < 0.05 will Study of Hypertension in Pregnancy (ISSHP). Thus, the diagnosis be used to define statistical significance. Statistical analyses will be based on systolic BP ≥ 140 mmHg or diastolic BP will be performed with the IBMSPSS software program, v.26.0 ≥ 90 mmHg on repeated occasions after 20 weeks’ gestation, (IBM-SPSS Inc., Chicago, IL; USA). and proteinuria [dipstick urinalysis ≥ 1+ or protein/creatinine ratio ≥ 30 mg/mmol (0.3 mg/mg)] or another maternal organ DISCUSSION dysfunction. PE will be classified according to gestational age at delivery into early-onset (<34 weeks), preterm (<37 weeks), and Since we have an effective preventive treatment with early term (>37 weeks). Table 3 describes the secondary outcomes that administration of low dose ASA, universal screening for PE will be assessed during the project. is cost effective (18), and a clinical and moral obligation. The objective of this project is to validate a first-trimester screening Data Management of PE protocol that guarantees access to all pregnant women, The processing of the data will be carried out in accordance without sacrificing quality. For this reason, in the first step of with the current legislation, specifically article 28 of Regulation the screening, we will calculate the risk of each patient according Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 July 2022 | Volume 9 | Article 931943 Trilla et al. Two-Step Early Preeclampsia Screening to variables already included in the standard pregnancy control. results with high external validity and transferability to clinical As there is no economic cost involved, we ensure universal reality. Second, for clinical purposes to be able to publish our accessibility for all pregnant women to screening for PE. results as soon as possible, follow-up of the offspring is limited to However, the estimation of angiogenic markers is the strategy the neonatal period. However, this is not an important limitation, with the best performance when it comes to screening the risk since it is not the objective of the project, and since all the of PE (21, 22). By adding PlGF determination (and blinded sFlT- study patients are registered, a long-term cohort study with these 1) to only a reduced proportion of patients, we believe that we neonates could be considered. can offer an early PE screening with maximum quality, while marginally increasing the economic cost. This design has been ETHICS STATEMENT previously proposed after retrospective analysis of randomized clinical trials based on the universal PE screening with PlGF The studies involving human participants were reviewed and (25, 26). Our objective is to validate these results in a multicenter, approved by Aragon Research Ethics Committee (CEICA) on real-world clinical setting study. This sample size assures enough 3 July 2020 (15/2020). The patients/participants provided their statistical power for the main outcomes. We consider that the written informed consent to participate in this study. design and methodology of the project guarantees the external validity of the results. AUTHOR CONTRIBUTIONS Some limitations of our study need to be mentioned. First, our design is not a randomized control trial, therefore it EL, CT, MF, CL, and DO: conception and design of the does not include a control group without intervention. Several research. DO: principal investigator. CT: co-investigator. SD, randomized clinical trials have already shown the efficacy of LR, AR-R, JM, TB, MF, AM, and SR-M: collaborators. CT, the first-trimester PE screening for the early implementation of CL, and DO: wrote the first version of the manuscript, low-dose ASA prophylaxis. Our objective is to validate a two- drafting, and revision of the manuscript. All authors revised it step screening system previously proposed by retrospectively and contributed significantly in writing the final version that analyzing high methodological quality clinical trials in a real was accepted. clinical scenario. We have not considered the creation of a non-intervention group in the design, as our intention is to FUNDING compare our results with all the screening strategies published to date. However, we have quality information on historical This study was supported by the government of Spain, Plan patient cohorts prior to the implementation of PE screening in Estatal de I+D+I and Instituto de Salud Carlos III- Subdirección all centers. As a contingency plan, if we consider it necessary at General de Evaluación y Fomento de la Investigación Sanitaria, the end of the study, we could also compare the results with the project PI19/00692, and the European Regional Development group of patients in whom we have not been able to screen for Fund (FEDER). PE in the first trimester for other reasons. We assume that the study design allows us less control over the results than a clinical ACKNOWLEDGMENTS trial, as it is subjected to the potential biases of routine clinical practice. However, we consider that this is, on the other hand, We would like to thank Roche diagnostics for their support and one of the differentiating points of this project, since it offers us willingness in planning the protocol. REFERENCES Neonatología. (2014). Available onloine at: https://www.seneo.es/images/site/ comisiones/redes/analisis/2014__global.pdf 1. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 7. 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(2018) 132:254– Conflict of Interest: The authors declare that the research was conducted in the 6. doi: 10.1097/AOG.0000000000002709 absence of any commercial or financial relationships that could be construed as a 20. Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D et al. potential conflict of interest. Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and Publisher’s Note: All claims expressed in this article are solely those of the authors biomarkers: results of SPREE. Ultrasound Obstet Gynecol. (2018) 51:743– and do not necessarily represent those of their affiliated organizations, or those of 50. doi: 10.1002/uog.19039 the publisher, the editors and the reviewers. Any product that may be evaluated in 21. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of this article, or claim that may be made by its manufacturer, is not guaranteed or early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. (2011) 31:66– endorsed by the publisher. 74. doi: 10.1002/pd.2660 22. O’Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright Copyright © 2022 Trilla, Luna, De León Socorro, Rodriguez, Ruiz-Romero, Mora A, et al. Accuracy of competing-risks model in screening for pre- Brugués, Benítez Delgado, Fabre, Martin Martínez, Ruiz-Martinez, Llurba and Oros. eclampsia by maternal factors and biomarkers at 11- 13 weeks’ This is an open-access article distributed under the terms of the Creative Commons gestation. Ultrasound Obstet Gynecol. (2017) 49:751–55. doi: 10.1002/uog. Attribution License (CC BY). The use, distribution or reproduction in other forums 17399 is permitted, provided the original author(s) and the copyright owner(s) are credited 23. Crovetto F, Figueras F, Crispi F, Triunfo S, Pugia M, Lasalvia L, et al. and that the original publication in this journal is cited, in accordance with accepted Forms of circulating luteinizing hormone human chorionic gonadotropin academic practice. No use, distribution or reproduction is permitted which does not receptor for the prediction of early and late preeclampsia in the first comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 July 2022 | Volume 9 | Article 931943