Received: 17 February 2022 | Revised: 12 April 2022 | Accepted: 14 April 2022 DOI: 10.1111/aogs.14371 ORIGINAL RESEARCH ARTICLE Shared risk factors for COVID-­19 and preeclampsia in the first trimester: An observational study Berta Serrano1 | Manel Mendoza1 | Paula Garcia-­Aguilar1 | Erika Bonacina1 | 1 1 1 1 Itziar Garcia-­Ruiz | Pablo Garcia-­Manau | Judit Gil | Mireia Armengol-­Alsina | 2 3 4 Nuria Fernandez-­Hidalgo | Elena Sulleiro | Rosa Maria Lopez-­Martinez | 5 6 7 8 Marta Ricart | Lourdes Martin | Eva Lopez-­Quesada | Angels Vives | 9 1 Anna Maroto | Nerea Maiz | Anna Suy1 | Elena Carreras1 1 Maternal Fetal Medicine Unit, Department of Obstetrics, Vall d'Hebron Abstract Barcelona Hospital Campus, Universitat Introduction: The association between preeclampsia and coronavirus disease 2019 Autònoma de Barcelona, Barcelona, Spain 2 Department of Infectous Diseases, Vall (COVID-­19) is under study. Previous publications have hypothesized the existence of d'Hebron Barcelona Hospital Campus, shared risk factors for both conditions or a deficient trophoblastic invasion as possible Universitat Autònoma de Barcelona, Barcelona, Spain explanations for this association. The primary aim of this study was to examine base- 3 Department of Microbiology, Vall line risk factors measured in the first-­trimester combined screening for preeclampsia d'Hebron Barcelona Hospital Campus, in pregnant women with COVID-­19 compared with the general population. A second- Barcelona, Spain 4 ary aim of this study was to compare risk factors among patients with mild and severe Biochemistry Department, Vall d'Hebron Barcelona Hospital Campus, Universitat COVID-­19. Autònoma de Barcelona, Barcelona, Spain 5 Material and Methods: This was an observational retrospective study conducted Maternal-­Fetal Medicine Unit, Department of Obstetrics, Hospital at Vall d'Hebron Hospital Campus (Catalonia, Spain). Study patients were 231 preg- Universitari Germans Trias i Pujol, nant women undergoing the first-­trimester screening for preeclampsia and positive Universitat Autònoma de Barcelona, Badalona, Spain for severe acute respiratory syndrome coronavirus 2 between February 2020 and 6 Maternal-­Fetal Medicine Unit, September 2021. The reference cohort were 13 033 women of the general population Department of Obstetrics, Hospital from six centers across Catalonia from May 2019 to June 2021. Based on the need Universitari de Tarragona Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain for hospitalization, patients were classified in two groups: mild and severe COVID-­19. 7 Maternal-­Fetal Medicine Unit, First-­trimester screening for preeclampsia included maternal history, mean arterial Department of Obstetrics, Hospital Universitari Mútua Terrassa, Universitat blood pressure, mean uterine artery pulsatility index (UtAPI), placental growth factor de Barcelona, Terrassa, Spain (PlGF), and pregnancy-­associated plasma protein-­A (PAPP-­A). 8 Maternal-­Fetal Medicine Unit, Results: The proportion of cases at high risk for preeclampsia was significantly Department of Obstetrics, Consorci Sanitari de Terrassa, Universitat higher among the COVID-­19 group compared with the general population (19.0% Internacional de Catalunya, Terrassa, and 13.2%, respectively; p = 0.012). When analyzing risk factors for preeclampsia Spain Abbreviations: MAP, mean arterial blood pressurePAPP-­A pregnancy-­associated plasma protein-­APlGFplacental growth factorUtAPImean uterine artery pulsatility index. Berta Serrano and Manel Mendoza contributed equally to this work (co-­f irst authors). Anna Suy and Elena Carreras are contributed equally to this work (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. © 2022 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. 2022;101:803–808.  wileyonlinelibrary.com/journal/aogs | 803 804 | SERRANO et al. 9 Maternal-­Fetal Medicine Unit, Department of Obstetrics, Hospital individually, women with COVID-­19 had higher median body mass index (25.2 vs Universitari de Girona Doctor Josep 24.5, p = 0.041), higher UtAPI multiple of the median (MoM) (1.08 vs 1.00, p < 0.001), Trueta, Universitat de Girona, Girona, Spain higher incidence of chronic hypertension (2.8% vs 0.9%, p = 0.015), and there were fewer smokers (5.7% vs 11.6%, p = 0.007). The MoMs of PlGF and PAPP-­A did not Correspondence Nerea Maiz, Department of Obstetrics, differ significantly between both groups (0.96 vs 0.97, p = 0.760 and 1.00 vs 1.01, Maternal Fetal Medicine Unit, Vall p = 0.432; respectively). d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Conclusions: In patients with COVID-­19, there was a higher proportion of women at Passeig de la Vall d'Hebron, 119–­129, high risk for preeclampsia at the first-­trimester screening than in the general popula- 08035 Barcelona, Spain. Email: nmaiz@vhebron.net tion, mainly because of maternal risk factors, rather than placental signs of a deficient trophoblastic invasion. Funding information This study was supported by Roche Diagnostics, who provided the reagents KEYWORDS used for PlGF measurements. Roche coronavirus disease 2019, first trimester, placental growth factor, preeclampsia, risk factors, Diagnostics had no influence on the study screening, severe acute respiratory syndrome coronavirus 2, uterine artery Doppler design, data collection, data analysis, or interpretation of results. 1 | I NTRO D U C TI O N Key message The relation of severe acute respiratory syndrome coronavirus 2 Pregnant women with COVID-­19 are at a higher risk for (SARS-­CoV-­2) and pregnancy has been under study since the outset preeclampsia mainly because of maternal risk factors of the coronavirus pandemic. Evidence shows that pregnant women rather than placental signs of deficient trophoblastic with coronavirus disease 2019 (COVID-­19) are at an increased risk of invasion. severe pregnancy complications, including preeclampsia, admission to the intensive care unit, preterm birth, or maternal mortality.1 One of the first studies about COVID-­19 and pregnancy, pub- lished in February 2020, suggested an increased preeclampsia inci- the first-­trimester combined screening for preeclampsia in pregnant dence among pregnant women with COVID-­19. 2 This was confirmed women with COVID-­19 vs the general population. The secondary 3,4 in further studies. Recently, a large meta-­analysis that included 28 aim was to compare these baseline characteristics and markers be- studies showed an increased preeclampsia incidence risk, with an tween women with mild and severe COVID-­19. odds ratio of 1.62 (95% confidence interval 1.45–­1.82).5 Different theories have been suggested regarding the association between preeclampsia and COVID-­19.4-­8 One of them hypothesizes 2 | M ATE R I A L A N D M E TH O DS that preeclampsia and COVID-­19 are associated because of sharing risk factors for endothelial damage, such as obesity, hypertension, This was an observational retrospective study conducted at Vall diabetes, and maternal age. Early uteroplacental insufficiency could d'Hebron Barcelona Hospital Campus, Barcelona, Spain. For the study be an additional risk factor for endothelial damage, thereby increas- group, inclusion criteria were women (a) attending our site with con- ing the risk of developing COVID-­19, mostly in its severe forms. firmed SARS-­CoV-­2 infection at any point during pregnancy and (b) The question is whether early uteroplacental insufficiency due undergoing the first-­trimester combined screening for preeclampsia. to abnormal trophoblastic invasion increases the risk of developing The recruitment period for the SARS-­CoV-­2 group was from February COVID-­19 and its severity, or whether the association between both 2020 to September 2021. Our center was a referral hospital for se- conditions is driven by the fact that COVID-­19 and preeclampsia vere COVID-­19 pneumonia, especially during pregnancy; therefore, share risk factors for endothelial damage increasing the risk of both cases were both patients from our area and patients referred from conditions. across Catalonia. For the population group, data were obtained from 9 If abnormal trophoblastic invasion makes patients more vul- the general population attending first-­trimester screening for preec- nerable to COVID-­19 (or more likely to develop a severe form of lampsia in six centers across Catalonia (Vall d'Hebron Barcelona COVID-­19), women with COVID-­19 would have lower placental Hospital Campus, Hospital Universitari Germans Trias i Pujol, Hospital growth factor (PlGF) levels, lower pregnancy-­associated plasma pro- Universitari de Tarragona Joan XXIII, Hospital Universitari Mútua tein-­A (PAPP-­A), and increased mean uterine artery pulsatility index Terrassa, Consorci Sanitari de Terrassa, and Hospital Universitari de (UtAPI) compared with the reference population. Girona Doctor Josep Trueta) between May 2019 and June 2021. The primary aim of this study was to examine baseline risk fac- Infection with SARS-­CoV-­2 was confirmed either by real-­time tors, as well as biochemical and biophysical markers measured in polymerase chain reaction or an antigen test. Several changes SERRANO et al. | 805 in screening protocols have occurred during the study period, 2021. A previous study assessing the screening performance of the whereas scientific evidence or assistance care needs were changing. first-­trimester screening for preeclampsia was approved by the same Therefore, our study population included both patients systemati- institution (PR[AMI]147/2021), and, therefore, data from the general cally screened at hospital admission and patients screened because population was prospectively recorded. of symptomatology or close contact. In the study group, severity of the symptoms was the criterion used for classification: mild forms of COVID-­19, including asymptomatic and symptomatic women not 3 | R E S U LT S requiring hospitalization, and severe forms of COVID-­19, including patients requiring hospitalization due to severe pneumonia. For the study group (or COVID-­19 group), 231 women fulfilled In Catalonia, the first-­trimester screening for preeclampsia is the inclusion criteria. In the population group (or reference group), routinely performed during the first-­trimester scan between 11+0 13 033 women underwent the routine first-­trimester screening for and 13+6 weeks of pregnancy. Gestational age is confirmed by fetal preeclampsia. crown–­rump length measurement during this scan.10 Demographic characteristics, obstetric history, maternal history, and biophysical and biochemical markers are documented in the clinical records. 3.1 | Comparison of the COVID-­19 and Biophysical markers, including transabdominal mean UtAPI and reference groups mean arterial blood pressure (MAP), are assessed during the first-­ trimester scan. Biochemical markers, including serum PAPP-­A and In the COVID-­19 group, 44 out of 231 (19.0%) cases were identified PlGF, are measured at the routine first-­trimester blood test (from to be at a high risk for preeclampsia at the first-­trimester screen- 8+0 to 13+6 weeks of pregnancy). Maternal serum PAPP-­A and PlGF ing, and this incidence was significantly higher than the 1719 out of levels were determined by the fully automated Elecsys assays for 13 033 (13.2%) found in the general population (p = 0.012). When PAPP-­A and PlGF on an immunoassay platform (cobas e analyzers; preeclampsia risk factors were examined individually, we found that Roche Diagnostics, Rotkreuz, Switzerland). MAP, UtAPI, PAPP-­A , women with COVID-­19 had higher UtAPI and BMI, higher incidence and PlGF values were transformed into multiples of the median of chronic hypertension, and fewer were smokers. No significant (MoM) by adjusting by gestational age, body mass index (BMI), eth- differences were found in MAP, PlGF, PAPP-­A , maternal age, black 11 nicity, and smoking. First-­trimester risk for preeclampsia was then race, or history of preeclampsia or diabetes mellitus between the calculated.11 High risk for preeclampsia was defined as a risk for COVID-­19 group and the general population (Table 1). early-­onset preeclampsia ≥1/170 as this is the recommended cut-­off for the Gaussian algorithm,11 which is the algorithm used for first-­ trimester preeclampsia risk assessment in Catalonia. This cut-­off 3.2 | Comparison between mild and severe value provides a 90.9% detection rate for early-­onset preeclampsia forms of COVID-­19 at a 12.7% false-­positive rate.12 All examiners were certified by the Fetal Medicine Foundation for preeclampsia risk assessment and In the COVID-­19 group, 160 (69.3%) women developed mild Doppler ultrasound assessment. COVID-­19 and 71 (30.7%) women developed severe COVID-­19. Of the 160 women with mild COVID-­19, 25 (15.6%) were at a high risk for preeclampsia in the first-­trimester screening. Likewise, of the 71 2.1 | Statistical analyses women with severe COVID-­19, 19 (26.8%) were also at a high risk for preeclampsia in the first-­trimester screening. Nevertheless, this Categorical data were reported as frequency and percentage, and difference was not statistically significant (p = 0.071). In women with comparisons between groups were estimated by chi-­squared or severe COVID-­19, MAP in the first trimester was higher, as was BMI. Fisher tests, as appropriate. Continuous variables were reported as No other significant differences were found in other markers or risk the median and interquartile range, and Mann–­Whitney U test was factors for preeclampsia between the groups with mild and severe used to assess differences between groups. The statistical signifi- forms of COVID-­19 (Table 2). cance level was set at p values less than 0.05. The statistical software package R (version 4.0.3) was used for data analysis (R Foundation for Statistical Computing, Vienna, 4 | DISCUSSION Austria).13 This study shows a higher prevalence of risk factors for preeclamp- sia during the first trimester in women with COVID-­19 as compared 2.2 | Ethical approval with the reference population. In the COVID-­19 group the propor- tion of high BMI and chronic hypertension was higher, whereas the This study was approved by the Vall d'Hebron Barcelona Hospital proportion of smokers was lower, which are also risk factors for Campus Ethics Committee (PR[AMI]556/2021) on November 5, developing preeclampsia. Regarding biochemical and biophysical 806 | SERRANO et al. TA B L E 1 Comparison of preeclampsia General population risk factors between the COVID-­19 group COVID-­19 (N = 231) (N = 13 033) p value and the general population High risk of preeclampsia 44 (19.0%) 11 719 (13.2%) 0.012 Mean arterial pressure 1.09 (1.01–­1.18) 1.09 (1.01–­1.17) 0.906 (MoM) Uterine artery PI (MoM) 1.08 (0.88–­1.31) 1.00 (0.82–­1.20) <0.001 PlGF (MoM) 0.96 (0.77–­1.89) 0.97 (0.77–­1.20) 0.760 PAPP-­A (MoM) 1.00 (0.69–­1.42) 1.01 (0.71–­1.47) 0.432 BMI (kg/m2) 25.2 (22.2–­29.4) 24.5 (21.8–­28.3) 0.041 Maternal age (y) 31.8 (26.8–­36.2) 32.6 (28.2–­36.4) 0.065 Black race 7/230 (3.0%) 402 (3.1%) 1 Chronic hypertension 6/218 (2.8%) 104/11698 (0.9%) 0.015 History of preeclampsia 9/218 (4.1%) 261/11917 (2.2%) 0.100 Smoking 13/229 (5.7%) 1494/12847 (11.6%) 0.007 Nulliparous 66/219 (30.1%) 4249/11664 (36.4%) 0.065 Assisted reproduction 8/231 (3.5%) 303/13033 (2.3%) 0.361 technique Diabetes mellitus 2/228 (0.9%) 158/12552 (1.3%) 1.0 Note: Continuous variables are shown as the median and interquartile range (first and third quartiles). Categorical data are shown as absolute frequency and percentage. Abbreviations: BMI, body mass index; COVID-­19, coronavirus disease 2019; MoM, multiples of the median; PAPP-­A , pregnancy-­associated plasma protein-­A; PI, pulsatility index; PlGF, placental growth factor. TA B L E 2 Comparison of preeclampsia Mild (N = 160) Severe (N = 71) p value risk factors between mild and severe High risk of preeclampsia 25 (15.6%) 19 (26.8%) 0.071 forms of COVID-­19 Mean arterial pressure (MoM) 1.08 (1.00–­1.16) 1.12 (1.05–­1.22) 0.008 Uterine artery PI (MoM) 1.07 (0.85–­1.33) 1.09 (0.94–­1.26) 0.756 PlGF (MoM) 0.97 (0.77–­1.22) 0.96 (0.77–­1.11) 0.862 PAPP-­A (MoM) 0.97 (0.68–­1.39) 1.02 (0.73–­1.53) 0.308 2 BMI (kg/m ) 23.7 (21.7–­27.6) 28.2 (24.6–­3 0.8) <0.001 Maternal age (y) 31.3 (26.3–­36.0) 34.1 (28.0–­37.9) 0.069 Black race 5 (3.1%) 2 (2.9%) 1.0 Chronic hypertension 3 (2.0%) 3 (4.6%) 0.366 History of preeclampsia 7 (4.6%) 2 (3.1%) 1.0 Smoking 12 (7.6%) 1 (1.4%) 0.069 Nulliparous 49 (31.8%) 17 (26.2%) 0.426 Assisted reproduction 5 (3.1%) 3 (4.2%) 0.704 technique Diabetes mellitus 1 (0.6%) 1 (1.4%) 0.521 Note: Continuous variables are shown as median and interquartile range (first and third quartiles). Categorical data are shown as absolute frequency and percentage. Abbreviations: BMI, body mass index; COVID-­19, coronavirus disease 2019; PAPP-­A , pregnancy-­ associated plasma protein-­A; PI, pulsatility index; PlGF, placental growth factor; MoM, multiples of the median. markers, no differences were found in PlGF levels. However, in the However, women with severe COVID-­19 had significantly higher COVID-­19 group there was a small but significant increase in UtAPI BMI and MAP at the first-­trimester screening. (1.08 MoM vs 1.00 MoM). The association between preeclampsia and COVID-­19 has been When we examined the COVID-­19 group according to severity studied since the beginning of the coronavirus pandemic. Some stud- (mild or severe), no differences were observed in PlGF and UtAPI. ies have hypothesized that the association between preeclampsia SERRANO et al. | 807 and COVID-­19 may be explained by the fact that both conditions for preeclampsia at the first trimester mainly due to maternal risk share common systemic risk factors, including obesity, advanced factors and that placental insufficiency is unlikely to explain this maternal age, diabetes, or hypertension.4,8 However, the potential association. Another strength of this study is the large number of association between preeclampsia and COVID-­19 due to specific participants. Additionally, the first-­trimester screening for pre- placental risk factors has never been examined. eclampsia was routinely performed; therefore, despite this being a Giorgione and Thilaganathan suggested that subclinical cardio- retrospective study, maternal risk factors, MAP, PAPP-­A , PlGF, and vascular dysfunction in a general population may induce placen- UtAPI were prospectively recorded for all patients at the time of the tal malperfusion and ischemia, so increasing preeclampsia risk.8 routine first-­trimester scan. Therefore, subclinical cardiovascular dysfunction due to COVID-­19 One of the main limitations of this study is its retrospective na- may lead to acquired uteroplacental malperfusion, potentially ture. Additionally, this study may have a selection bias. On the one causing preeclampsia. Despite placental malperfusion in the third hand, cases in the study group with severe disease might be over-­ trimester and abnormal placentation in the first trimester being represented, as our site was a referral hospital for patients with severe two different entities, they both induce placental ischemia, which COVID-­19 with pneumonia in Catalonia. On the other hand, asymp- increases the risk of developing preeclampsia. For this reason, we tomatic cases in the study cohort might also be over-­represented, be- agree that maternal systemic risk factors may explain in part the as- cause a real-­time polymerase chain reaction was incorporated during sociation between COVID-­19 and preeclampsia. However, we could the pandemic as a routine test for all admitted patients. not confirm this hypothesis in this study. Another limitation of the study is that the timing of infection was Other studies have demonstrated a clear association between not analyzed because the moment of COVID-­19 infection was not diabetes, increased BMI, and the risk of developing COVID-­19.15 relevant for the aim of this study. Additionally, the general popula- Additionally, these studies showed that severe COVID-­19 was as- tion used as the reference group cannot be considered purely a con- sociated with higher maternal age, higher BMI, hypertension, and trol group due to the lack of specific information about SARS-­CoV-­2 16 diabetes. Our results support these findings. infection. For this reason, some asymptomatic and mild COVID-­19 The findings of this study support the hypothesis that women cases might be found in the reference group. Nevertheless, this with COVID-­19 are at a higher risk for preeclampsia than the general might have reduced the chances of finding differences between population; however, it seems that this was due mainly to shared groups making our findings even more meaningful. maternal risk factors (BMI and hypertension), as there was no signif- icant difference in PlGF and PAPP-­A levels, and the small difference in UtAPI was probably not correlated with abnormal trophoblastic 5 | CO N C LU S I O N invasion, as first-­trimester MoM UtAPI values in our population ranged from 1.12 to 1.67 in women that subsequently developed pre- In patients with COVID-­19, there was a higher proportion of women eclampsia, whereas MoM UtAPI values were 1.03 in women without at a high risk for preeclampsia at the first-­trimester screening than preeclampsia.14 Despite UtAPI MoMs being adjusted for maternal in the general population, mainly due to maternal risk factors, rather age, ethnicity, and BMI, other maternal conditions could influence than placental signs of a deficient trophoblastic invasion. their values, which could also explain this difference. Determining Likewise, when comparing according to COVID-­19 severity, the whether the association of preeclampsia and COVID-­19 was due to proportion of women with a high risk for preeclampsia tended to be shared risk factors or whether it was driven by placental predispo- greater among those with severe forms of COVID-­19 and it was due sition is crucial to provide appropriate treatment and surveillance. to maternal risk factors only. Our data provide evidence that preeclampsia and COVID-­19 share systemic risk factors; however, our data suggest that placental insuf- AC K N OW L E D G M E N T S ficiency is unlikely to be involved in the development of COVID-­19 We thank María del Mar Jiménez Quesada for English language cor- or its severity. Aspirin mechanisms of action for preeclampsia pre- rections of the manuscript. One of the authors is a member of the vention involve anti-­inflammatory and cardiovascular effects but European Reference Network on Rare Congenital Malformations mostly the improvement of trophoblastic invasion.9 Given that the and Rare Intellectual Disability ERN-­ITHACA (EU Framework INTERCOVID study showed no benefit of aspirin treatment in re- Partnership Agreement ID: 3HP-­HP-­FPA ERN-­01-­2016/739516). ducing the risk of preeclampsia in women with COVID-­199 and that abnormal trophoblastic invasion seems not to be related to the de- C O N FL I C T O F I N T E R E S T velopment or severity of COVID-­19, aspirin treatment is unlikely to MM, LM, and IGR received lecture fees from Roche Diagnostics. The be effective for reducing COVID-­19 risk in pregnancies at a high risk other authors declare that they have no conflicts of interest. for preeclampsia in the first trimester; nevertheless, more research is needed to ascertain the role of aspirin in pregnant women with AU T H O R C O N T R I B U T I O N S COVID-­19. BS, MM, AS, NM, and EC had full access to all of the data in the study The main strength of the present study is that it provides and take full responsibility for the integrity of the data and accuracy novel evidence that women with COVID-­19 are at a higher risk of the data analysis. NM, MM, AS, and EC conceived and designed 808 | SERRANO et al. 4. Papageorghiou AT, Deruelle P, Gunier RB, et al. Preeclampsia and the study. BS, MM, PGA, EB, IGR, PGM, NFH, ES, NM, and AS con- COVID-­19: results from the INTERCOVID prospective longitudinal tributed to literature research. BS, MM, JG, MAA, RMLM, MR, LM, study. Am J Obstet Gynecol. 2021;225:289.e1-­289.e17. ELQ, AV, and AM contributed to data collection and confirmation. 5. Conde-­A gudelo A, Romero R. SARS-­COV-­2 infection during preg- nancy and risk of preeclampsia: a systematic review and meta-­ BS, MM, and NM contributed to data analysis and data interpreta- analysis. Am J Obstet Gynecol. 2022;226:68-­89.e3. tion. BS and MM were in charge of writing the manuscript draft. EC 6. Conde-­A gudelo A, Romero R. Mechanisms that may underlie a and AS made substantial revisions to the manuscript. All authors causal association between SARS-­COV-­2 infection and preeclamp- read and approved the final manuscript. sia. Am J Obstet Gynecol. 2022;226:280-­281. 7. Khalil A, Samara A, Chowdhury T, O'Brien P. Does COVID-­19 cause pre-­eclampsia? Ultrasound Obstet Gynecol. 2022;59:146-­152. ORCID 8. Giorgione V, Thilaganathan B. SARS-­COV-­2 related myocardial in- Berta Serrano https://orcid.org/0000-0002-1264-9195 jury might explain the predisposition to preeclampsia with maternal Manel Mendoza https://orcid.org/0000-0002-3030-3833 SARS-­COV-­2 infection. Am J Obstet Gynecol. 2022;226:279-­280. Paula Garcia-­A guilar https://orcid.org/0000-0002-5526-7656 9. Rolnik DL, Nicolaides KH, Poon LC. Prevention of preeclampsia with aspirin. Am J Obstet Gynecol. 2022;226:S1108-­S1119. Erika Bonacina https://orcid.org/0000-0002-8042-8247 10. Robinson HP, Fleming JE. A critical evaluation of sonar “crown-­rump Itziar Garcia-­Ruiz https://orcid.org/0000-0002-0717-7795 length” measurements. Br J Obstet Gynaecol. 1975;82:702-­710. Pablo Garcia-­Manau https://orcid.org/0000-0002-2415-1626 11. Serra B, Mendoza M, Scazzocchio E, et al. A new model for screening Mireia Armengol-­Alsina https://orcid.org/0000-0002-2087-5176 for early-­onset preeclampsia. Am J Obstet Gynecol. 2020;222:608. e1-­608.e18. Nuria Fernandez-­Hidalgo https://orcid. 12. Mendoza M, Tur H, Garcia-­Manau P, et al. Cut-­off values for gauss- org/0000-0002-2115-344X ian first-­trimester screening for early-­onset preeclampsia with ma- Elena Sulleiro https://orcid.org/0000-0002-9783-6060 ternal history, biochemical markers and uterine artery doppler. J Rosa Maria Lopez-­Martinez https://orcid. Gynecol Obstet Hum Reprod. 2021;50:101827. 13. R: The R Project for Statistical Computing. Accessed November 9, org/0000-0002-8450-6986 2021. https://www.r-­proje​c t.org/ Marta Ricart https://orcid.org/0000-0003-0099-6525 14. Mendoza M, Garcia-­Manau P, Arévalo S, et al. Diagnostic accuracy Lourdes Martin https://orcid.org/0000-0003-1781-5305 of first-­trimester combined screening for early-­onset and preterm Anna Maroto https://orcid.org/0000-0003-3225-9095 preeclampsia at 8-­10 weeks compared to 11–­13 weeks gestation. Ultrasound Obstet Gynecol. 2021;57:84-­90. Nerea Maiz https://orcid.org/0000-0001-8261-6383 15. 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