Differences in placental pathology between COVID-19-induced preeclampsia-like syndrome and true preeclampsia

Differences in placental pathology between COVID-19-induced preeclampsia-like syndrome and true preeclampsia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Differences in placental pathology between COVID-19-induced preeclampsia-like syndrome and true preeclampsia Berta SERRANO, Marta GARRIDO-PONTNOU, Erika BONACINA, Itziar GARCIA-RUIZ, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4749296/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background. Women with COVID-19 may develop preeclampsia-like syndrome, which shares some of the clinical features of preeclampsia (PE) but lacking its characteristic angiogenic imbalance (elevated soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (sFlt-1/PlGF ratio)), suggesting the absence of placental involvement. The aim of this study was to investigate whether pathological placental changes associated with PE, such as maternal vascular malperfusion (MVM), may be useful to discriminate true PE from COVID-19-induced PE-like syndrome. Methods. Prospective cohort study conducted from February 2020 to September 2021. Inclusion criteria were pregnancies with SARS-CoV-2 infection that met the diagnostic criteria for PE at ≥ 20 weeks. Cases with a normal sFlt-1/PlGF ratio (≤ 38) were classified as PE-like syndrome and cases with an abnormal sFlt-1/PlGF ratio were classified as true PE. A perinatal pathologist blinded to group allocation performed the placental histopathological examination for signs of MVM following the Amsterdam criteria. Results. During the study period, 106 pregnant women with severe COVID-19 were admitted to the Intensive Care Unit. Among them, 15 (14.2%) met the diagnostic criteria for PE, and 11 placentas (73.3%) were available for histopathological examination. Of the 5 true PE cases (median sFlt-1/PlGF ratio of 137.9; IQR: 63.7-302.2), 80.0% had placentas with maternal vascular malperfusion (MVM). In contrast, none of the 6 PE-like syndrome cases (median sFlt-1/PlGF ratio of 5.53; IQR: 4.02–14.6) had placentas that met the MVM criteria. Conclusions. None of the placentas from cases with PE-like syndrome had histopathological criteria of MVM, while 80.0% of the placentas from cases with true PE showed high-grade MVM. The absence of MVM in PE-like syndrome supports the initial evidence based on angiogenic factors: PE-like syndrome and true PE are different conditions with similar clinical features, but different etiologies. preeclampsia-like syndrome COVID-19 SARS-CoV-2 sFlt-1/PlGF ratio angiogenic factors maternal vascular malperfusion Figures Figure 1 Figure 2 INTRODUCTION On May 2020 a preeclampsia-like syndrome induced by COVID-19 was first described.( 1 ) This syndrome may be present in up to 7.5% of pregnant women with severe COVID-19 and shares some clinical features with true preeclampsia (PE), such as high blood pressure, proteinuria and increased liver enzymes. However, unlike PE, in pregnancies with PE-like syndrome, those clinical features seem to improve after recovering from COVID-19, despite still being pregnant.( 2 ) PE is a multisystem disorder that affects 2–4%( 3 ) of pregnancies worldwide and is a leading cause of maternal and perinatal morbidity and mortality. Clinical and experimental evidence suggests that abnormal trophoblast invasion and failed physiological transformation of the spiral arteries may be the main cause of placental maladaptation and impaired perfusion, which subsequently leads to placental insufficiency, a major contributor to the pathophysiology of PE.( 3 ) One of the most useful tools to identify pregnant women at higher risk of PE is the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (sFlt-1/PlGF ratio).( 4 ) An imbalance of these angiogenic factors is known to be highly specific for underlying placental dysfunction due to underperfusion and it may help to accurately discriminate PE from other conditions with similar clinical features( 5 ), including COVID-19-induced PE-like syndrome.( 2 ) Placental insufficiency may also exhibit a number of placental pathological changes, such as maternal vascular malperfusion (MVM). The Amsterdam Placental Pathology Consensus is widely accepted to describe the most common pathological lesions found in the placenta( 6 ). Recent studies have confirmed that MVM, as defined by the Amsterdam Consensus, may be present in up to 70% of placentas from patients with PE.( 6 ) Unlike true PE, PE-like syndrome is not accompanied by placental angiogenic imbalances and may not be associated with placental underperfusion. Therefore, a histopathological examination of the placenta may be crucial for confirming the different etiologies of these two conditions. The aim of this study was to investigate whether placental pathological changes of MVM associated with PE may be useful to discriminate PE from COVID-19-induced PE-like syndrome. MATERIAL AND METHODS This was a prospective cohort study conducted at Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, from February 2020 to September 2021. Our site was a referral hospital for cases with severe COVID-19 pneumonia, especially in pregnant women. Inclusion criteria were pregnancies at ≥ 20 weeks of gestation with SARS-CoV-2 infection that met the diagnostic criteria for PE. PE was defined as new-onset high blood pressure (systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg), or worsening of previous high blood pressure, in addition to new-onset proteinuria (protein to creatinine ratio > 300), or worsening of previous proteinuria, or at least one of the following signs and symptoms of severe PE: cerebral or visual symptoms, elevation of liver enzymes to twice the normal concentration, platelet count 1.1 mg/dl or pulmonary edema.( 7 ) In this study, in order to diagnose hypertension, at least five out of six consecutive measurements had to be abnormal over a 6-hour time period. SARS-CoV-2 infection was confirmed by real-time polymerase chain reaction (RT-PCR) of nasal and pharyngeal swabs. Maternal serum PlGF and sFlt-1 (pg/ml) were determined using the fully automated Elecsys assay for sFlt-1 and PlGF on an electrochemiluminiscence immunoassay platform (cobas e analyzers; Roche® Diagnostics, Rotkreuz, Switzerland). The sFlt-1/PlGF ratio was then calculated. Values < 38 were considered normal and unlikely to be associated with an underlying placental insufficiency.( 2 ) Women who met the PE diagnostic criteria and had normal sFlt-1/PlGF ratio were classified PE-like syndrome, otherwise, they were classified as true PE.( 2 ) All placentas from COVID-19 patients were sent to the Pathology Department and a histopathological examination was performed using our standard protocol. A perinatal pathologist blinded to group allocation performed the placental examination and classified placental lesions according to the Amsterdam Consensus Recommendations. Histopathological lesions that fall within the MVM spectrum can be macroscopic or microscopic: placental growth restriction (placental weight 5% of the parenchyma at term), retroplacental haemorrhage, accelerated villous maturation (AVM), distal villous hypoplasia (DVH) and decidual arteriopathy.( 6 ) The Amsterdam Consensus does not state how many of these findings are required to make a diagnosis of MVM. Some authors consider that the presence of AVM, with or without other findings,( 6 ) is enough to establish MVM. High-grade MVM may be determined by the presence of AVM plus one or more of the following features: placental weight < 3rd percentile for gestational age, multiple villous infarcts, and DVH.( 8 ) Therefore, in this study, placentas with AVM findings were classified as having MVM. This study was approved by the Vall d’Hebron Barcelona Hospital Campus’ Ethics Committee (PR[AMI]181/2020) on 13 March 2020. All patients included in the study gave their consent according to the criteria of our Ethics Committee. During COVID-19 pandemic written consent was waived due to safety reasons and oral consent was accepted. Statistical Analyses Categorical data were reported as frequency and percentage, and comparisons between groups were estimated by the Chi-square or Fisher tests, as appropriate. Continuous variables were reported as the median and interquartile range (IQR). The statistical significance level was set at p < 0.05. The Stata statistical software package was used for data analysis (StataCorp. 2019. Stata Statistical Software: Release 16 . College Station, TX: StataCorp LLC). RESULTS During the study period, 106 pregnant women who had severe COVID-19 were admitted to the Intensive Care Unit (ICU). Of those, 15 (14.2%) met the PE diagnostic criteria, as they had new-onset hypertension plus other end-organ dysfunctions. Four cases were excluded for the following reasons: placentas were not sent to the Pathology Department in three cases and one case had a significant SARS-CoV-2 infection (Fig. 1 ), consisting of villous trophoblast necrosis with intervillous space collapse, mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition,( 9 ) such that it was not possible to assess the presence of AVM and HVD. The remaining 11 cases were classified in two groups according to sFlt-1/PlGF ratio (< 38 or ≥ 38): five (45.5%) with true PE and six (54.5%) with PE-like syndrome (Fig. 2 ). Median sFlt-1/PlGF ratio was 137.9 (IQR: 63.7-302.2) in the true PE group and 5.53 (IQR: 4.02–14.6) in the PE-like syndrome group. The results of the placental histopathological examinations are shown in Table 1. All placentas that met the MVM criteria had AVM and met at least one criterion for high-grade MVM. In cases with true PE, four of the placentas (80%) met the MVM criteria versus none of the placentas (0%) in cases with PE-like syndrome (Fig. 1 ), being this difference statistically significant (p = 0.015). These findings indicate that MVM had a positive predictive value of 85.7% for confirming PE-like syndrome and a negative predictive value of 100% for excluding PE-like syndrome in COVID-19 patients that met the diagnostic criteria for PE (Table 2 ). DISCUSSION No histological criteria of MVM were observed in placentas from pregnancies with severe COVID-19-induced PE-like syndrome, whereas histopathological signs of MVM were found in 80.0% of placentas from cases with true PE. The absence of MVM suggests that placental insufficiency is unlikely to be the underlying cause of PE-like syndrome, which aligns with the differing sFlt-1/PlGF ratio values between the groups. This study proposes an alternative approach to biomarkers for distinguishing PE-like syndrome from true PE after birth. Several studies have reported that COVID-19 could induce PE-like syndrome in some pregnancies, which is characterized by a normal sFlt-1/PlGF ratio.( 4 , 5 , 10 ) This indicates that angiogenic imbalance may not be involved in the pathogenesis of PE-like syndrome and that PE-related findings in these patients may be attributed to the systemic effects of SARS-CoV-2 infection.( 1 , 2 ) On the other hand, according to the Amsterdam Consensus classification, MVM findings may be identified in up to 70% of cases with hypertensive disorders of pregnancy. Despite numerous studies investigating the association between COVID-19 and PE( 11 – 15 ), none have assessed biomarkers during pregnancy or placental histopathological features after delivery to discriminate true PE from PE-like syndrome. Therefore, evidence supporting an association between PE and COVID-19 is difficult to interpret from those studies, as some cases with PE-like syndrome may have been misdiagnosed as true PE. This study confirms that COVID-19-induced PE-like syndrome and true PE may be distinct conditions with different etiologies that can be distinguished prenatally by the use of the sFlt-1/PlGF ratio or postnatally by placental histopathological findings. Given that PE and PE-like syndrome have different disease courses and clinical impacts, the findings of this study have important clinical implications. As previously demonstrated, patients with PE-like syndrome may benefit from a more conservative management compared to those with true PE.( 1 , 2 ) Incorrect diagnosis of PE in cases with PE-like syndrome may result in unnecessary elective deliveries ≥ 34 weeks of gestation. The degree of association between PE and COVID-19 remains uncertain, as most studies have not excluded PE-like syndrome based on the sFlt-1/PlGF ratio( 11 , 12 , 14 ). According to our findings, the Amsterdam Consensus criteria identified up to 80% of cases with true PE, while no MVM findings were observed in any of the placentas from cases with PE-like syndrome. Therefore, our study has also implications for research, demonstrating that placental histopathological analysis after delivery can distinguish true PE from COVID-19-induced PE-like syndrome. Discriminating both conditions, even after delivery, may help to elucidate any potential association between PE and COVID-19, which may allow to exclude the majority of cases with PE-like syndrome, even in settings where prenatal assessment of sFlt-1/PlGF ratio is not available. The main strength of this study is that it provides novel evidence that confirms different etiopathogenic pathways in PE and COVID-19-induced PE-like syndrome, which should encourage clinicians and researchers to exclude PE-like syndrome in cases with COVID-19 who meet the PE diagnostic criteria. Another strength of the study is that placental histopathological analysis was performed by an expert on perinatal histopathology in a tertiary referral hospital for COVID-19 during pregnancy, ensuring uniformity in placental analysis. Furthermore, the potential for observer bias was minimized by blinding the pathologist to study group allocation. Finally, these findings offer a new diagnostic tool for distinguishing between PE and PE-like syndrome in severe COVID-19. Although this differentiation should ideally be carried out during pregnancy to prevent iatrogenic medical interventions, it could serve as a valuable method for distinguishing between the two conditions after delivery, particularly in settings where sFlt-1/PlGF is not available. One of the main limitations of the study is the low number of cases included and a relatively high proportion of cases with unavailable placental histopathological analysis, since in four cases placental samples were not available or placental examination was not feasible due to severe SARS-CoV-2 infection. Another limitation is that the absence of MVM does not definitively exclude PE, and the presence of MVM in placental tissue is not exclusively due to PE; therefore, further studies should confirm our findings in pregnant women with COVID-19 who meet the diagnostic criteria for PE. Additionally, placental examination is limited to postpartum, making it not suitable for prenatal management of COVID-19 patients meeting PE diagnostic criteria. Finally, some placentas could be affected by COVID-19, which may have influenced the accurate identification of MVM signs. CONCLUSIONS Placentas from pregnancies with PE-like syndrome exhibited no histological evidence of MVM, whereas 80.0% of placentas from true PE cases showed high-grade MVM. The absence of MVM correlates with the prenatal classification based on the sFlt-1/PlGF ratio, suggesting that while true PE and PE-like syndrome share some clinical features, they probably have different etiologies. Abbreviations sFlt-1/PlGF ratio: soluble fms-like tyrosine kinase-1-to-placental growth factor ratio; PE: preeclampsia; PE-like syndrome: preeclampsia-like syndrome; MVM: maternal vascular malperfusion; AVM: accelerated villous maturation Declarations Ethics approval and consent to participate: This study was approved by the Vall d’Hebron University Hospital’s Ethics Committee (PR[AMI]181/2020) on 13 March 2020. Written informed consent was waived due to the rapid emergence of this infectious disease. However, verbal informed consent was obtained from all patients, which was included in the patient’s medical records. Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: Manel Mendoza received lecture fees from Roche Diagnostics. The remaining authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author’s contributions: The initial study outline was designed by Berta Serrano and Manel Mendoza. Manel Mendoza and Anna Suy supervised and coordinated the study. Marta Garrido-Pontnou performed the placental histopathological analysis. Berta Serrano, Erika Bonacina, Itziar García-Ruiz, Pablo García-Manau, Paula García-Aguilar, and Ester del Barco collected data. Berta Serrano and Manel Mendoza wrote the first draft of the manuscript. Nerea Maiz, Elena Carreras, Anna Suy, Nuria Fernández-Hidalgo, Elena Sulleiro, Laura Castillo-Ribelles, and Nerea Maiz, reviewed the manuscript and contributed to its intellectual content. The final version of the manuscript was approved by all authors prior to publication. Acknowledgements: We thank all physicians who facilitated the recruitment at Hospital Universitari Vall d’Hebron and the participants who agreed to take part in the study. Nerea Maiz is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. References Mendoza M, Garcia-Ruiz I, Maiz N, Rodo C, Garcia‐Manau P, Serrano B et al. Preeclampsia‐like syndrome induced by severe COVID‐19: a prospective observational study. BJOG. 2020;10.1111/1471-0528.16339. Serrano B, Bonacina E, Garcia-Ruiz I, Mendoza M, Garcia-Manau P, Garcia-Aguilar P, et al. Confirmation of preeclampsia-like syndrome induced by severe COVID-19: an observational study. Am J Obstet Gynecol MFM. 2023;5(1):100760. Magee LA, Nicolaides KH, von Dadelszen P, Preeclampsia. N Engl J Med. 2022;386(19):1817–32. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. American Journal of Obstetrics & Gynecology. 2012;206(1):58.e1-58.e8. Sibai BM. Imitators of Severe Pre-eclampsia. Semin Perinatol. 2009;33(3):196–205. Slack JC, Parra-Herran C. Life After Amsterdam: Placental Pathology Consensus Recommendations and Beyond. Surg Pathol Clin. 2022;15(2):175–96. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31. Redline RW, Ravishankar S, Bagby CM, Saab ST, Zarei S. Four major patterns of placental injury: a stepwise guide for understanding and implementing the 2016 Amsterdam consensus. Mod Pathol. 2021;34(6):1074–92. Garrido-Pontnou M, Navarro A, Camacho J, Crispi F, Alguacil-Guillén M, Moreno-Baró A, et al. Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise. Mod Pathol. 2021;34(9):1704–9. Inversetti A, Serafini A, Manzoni MF, Dolcetta Capuzzo A, Valsecchi L, Candiani M. Severe Hypothyroidism Causing Pre-Eclampsia-Like Syndrome. Case Rep Endocrinol. 2012;2012:586056. Papageorghiou AT, Deruelle P, Gunier RB, Rauch S, García-May PK, Mhatre M et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol. 2021;225(3):289.e1-289.e17. Conde-Agudelo A, Romero R. SARS-COV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis. Am J Obstet Gynecol [Internet]. 2021 Jul 21 [cited 2021 Sep 20]; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294655/ . Conde-Agudelo A, Romero R. Mechanisms that may underlie a causal association between SARS-COV-2 infection and preeclampsia. Am J Obstet Gynecol. 2021;S0002-9378(21)01004-8. Khalil A, Samara A, Chowdhury T, O’Brien P, Does. COVID-19 cause pre-eclampsia? Ultrasound in Obstetrics & Gynecology [Internet]. [cited 2021 Nov 18];n/a(n/a). https://onlinelibrary.wiley.com/doi/abs/ 10.1002/uog.24809 . Giorgione V, Thilaganathan B. SARS-CoV-2 related myocardial injury might explain the predisposition to preeclampsia with maternal SARS-CoV-2 infection. Am J Obstet Gynecol [Internet]. 2021 Oct 5 [cited 2021 Nov 9]; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490131/ . Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations Competing interest reported. Manel Mendoza received lecture fees from Roche Diagnostics. The remaining authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper. Supplementary Files Table1.docx Table2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4749296","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":338134304,"identity":"f22e1bae-cf87-4e5e-9086-107ba633adf8","order_by":0,"name":"Berta SERRANO","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Berta","middleName":"","lastName":"SERRANO","suffix":""},{"id":338134305,"identity":"79db20e0-480b-461d-b29d-24de943d5458","order_by":1,"name":"Marta GARRIDO-PONTNOU","email":"","orcid":"","institution":"Vall d’Hebron Barcelona Hospital Campus","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"GARRIDO-PONTNOU","suffix":""},{"id":338134306,"identity":"ab12982e-9b62-4798-9a23-fa096fb22707","order_by":2,"name":"Erika BONACINA","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Erika","middleName":"","lastName":"BONACINA","suffix":""},{"id":338134307,"identity":"87c19724-ad90-45ea-8791-7e2905774202","order_by":3,"name":"Itziar GARCIA-RUIZ","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Itziar","middleName":"","lastName":"GARCIA-RUIZ","suffix":""},{"id":338134308,"identity":"87368daf-98f9-42c4-b0a3-eefa3a82793f","order_by":4,"name":"Pablo GARCIA-MANAU","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Pablo","middleName":"","lastName":"GARCIA-MANAU","suffix":""},{"id":338134309,"identity":"1ec744b2-3087-4d09-9151-ae056e61fd18","order_by":5,"name":"Paula GARCIA-AGUILAR","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Paula","middleName":"","lastName":"GARCIA-AGUILAR","suffix":""},{"id":338134310,"identity":"c56411f3-a8f9-4f8b-810d-c545f8611f1e","order_by":6,"name":"Nuria FERNÁNDEZ-HIDALGO","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Nuria","middleName":"","lastName":"FERNÁNDEZ-HIDALGO","suffix":""},{"id":338134311,"identity":"49e715ce-e03b-448d-9de3-0ea25dc50d90","order_by":7,"name":"Elena SULLEIRO","email":"","orcid":"","institution":"Vall d’Hebron Barcelona Hospital Campus","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"SULLEIRO","suffix":""},{"id":338134312,"identity":"3c792759-d4c3-441d-8d9b-b05af6c2296c","order_by":8,"name":"Laura CASTILLO-RIBELLES","email":"","orcid":"","institution":"Vall d’Hebron Barcelona Hospital Campus","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"CASTILLO-RIBELLES","suffix":""},{"id":338134313,"identity":"b2523763-5b20-436e-a7c7-6c42a878f57a","order_by":9,"name":"Nerea MAIZ","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Nerea","middleName":"","lastName":"MAIZ","suffix":""},{"id":338134314,"identity":"5095e242-2b29-4fba-9c14-da562cb0e7a4","order_by":10,"name":"Ester DEL BARCO","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Ester","middleName":"DEL","lastName":"BARCO","suffix":""},{"id":338134315,"identity":"305e33bd-5986-4fcb-bb2f-37ae67b6c52b","order_by":11,"name":"Elena CARRERAS","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"CARRERAS","suffix":""},{"id":338134316,"identity":"23cc418c-e800-4193-84af-4a3036800b41","order_by":12,"name":"Anna SUY","email":"","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"SUY","suffix":""},{"id":338134317,"identity":"df425475-d82d-40e0-b965-b960083e942b","order_by":13,"name":"Manel MENDOZA","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACfmb2ww8+/LCRY2DgIVKLZDtPmuHMnjRjqBYDwloMzjMYSPOwHU5sIFoLw2GGBGMensPpG46fPcDwo+YPYR2MzYwHHs6xSM/dcCYvgbHnGBG2MDMzJBi84bHO3XAgx4CZgY0ILWzMDAYSPGzM6Qbn3wC1/CNCCw9QiyQPm3OCwQ2gLYxtRGiRYIYEsuHMG+8SDvb2GRPWYn/+ODgq5fnO5x588OObHGEtKOAAiepHwSgYBaNgFOACAOx5OOR0wLMFAAAAAElFTkSuQmCC","orcid":"","institution":"Universitat Autònoma de Barcelona","correspondingAuthor":true,"prefix":"","firstName":"Manel","middleName":"","lastName":"MENDOZA","suffix":""}],"badges":[],"createdAt":"2024-07-16 11:21:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4749296/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4749296/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62652542,"identity":"33c7dcce-ec1d-4035-a5b8-4e3c76a92ff6","added_by":"auto","created_at":"2024-08-17 01:01:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1681471,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathology of preeclampsia (A and B), preeclampsia-like syndrome (C and D) and diffuse trophoblastic damage (E and F).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Accelerated villous maturation\u003c/p\u003e\n\u003cp\u003eB: Distal villous hypoplasia\u003c/p\u003e\n\u003cp\u003eC: Normal-looking villi\u003c/p\u003e\n\u003cp\u003eD: Normal decidualization of spiral arteries\u003c/p\u003e\n\u003cp\u003eE: Villous trophoblast necrosis with intervillous space collapse, mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition.\u003c/p\u003e\n\u003cp\u003eF: Immunohistochemical staining for SARS-CoV-2 nucleoprotein shows staining in the injured villi but also in the surrounding normal-looking villi\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4749296/v1/cb2b008ef68eba9bf94b1365.jpg"},{"id":62652544,"identity":"65e566d9-57ec-4540-9807-8b4fd52f2df5","added_by":"auto","created_at":"2024-08-17 01:01:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":168359,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4749296/v1/8f2615bd012a654dbd4be93a.jpg"},{"id":66060108,"identity":"727c64f4-cc2d-442b-a5b5-4e21e644618c","added_by":"auto","created_at":"2024-10-07 10:02:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2217092,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4749296/v1/1866cc73-ba6c-421f-8b9c-86408f888740.pdf"},{"id":62652541,"identity":"01c68085-6151-457d-8870-e298b4d05b97","added_by":"auto","created_at":"2024-08-17 01:01:42","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":16609,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4749296/v1/dae68c1e3ef085f04d0c628f.docx"},{"id":62653388,"identity":"1aeb3d3d-8d25-4b2a-bbcd-f904d9baa9a4","added_by":"auto","created_at":"2024-08-17 01:09:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12722,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4749296/v1/f512e47dc8d49c5bfc2bf68e.docx"}],"financialInterests":"Competing interest reported. Manel Mendoza received lecture fees from Roche Diagnostics. The remaining authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper.","formattedTitle":"Differences in placental pathology between COVID-19-induced preeclampsia-like syndrome and true preeclampsia","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eOn May 2020 a preeclampsia-like syndrome induced by COVID-19 was first described.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) This syndrome may be present in up to 7.5% of pregnant women with severe COVID-19 and shares some clinical features with true preeclampsia (PE), such as high blood pressure, proteinuria and increased liver enzymes. However, unlike PE, in pregnancies with PE-like syndrome, those clinical features seem to improve after recovering from COVID-19, despite still being pregnant.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) PE is a multisystem disorder that affects 2\u0026ndash;4%(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) of pregnancies worldwide and is a leading cause of maternal and perinatal morbidity and mortality. Clinical and experimental evidence suggests that abnormal trophoblast invasion and failed physiological transformation of the spiral arteries may be the main cause of placental maladaptation and impaired perfusion, which subsequently leads to placental insufficiency, a major contributor to the pathophysiology of PE.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) One of the most useful tools to identify pregnant women at higher risk of PE is the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (sFlt-1/PlGF ratio).(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) An imbalance of these angiogenic factors is known to be highly specific for underlying placental dysfunction due to underperfusion and it may help to accurately discriminate PE from other conditions with similar clinical features(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e), including COVID-19-induced PE-like syndrome.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003ePlacental insufficiency may also exhibit a number of placental pathological changes, such as maternal vascular malperfusion (MVM). The Amsterdam Placental Pathology Consensus is widely accepted to describe the most common pathological lesions found in the placenta(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Recent studies have confirmed that MVM, as defined by the Amsterdam Consensus, may be present in up to 70% of placentas from patients with PE.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eUnlike true PE, PE-like syndrome is not accompanied by placental angiogenic imbalances and may not be associated with placental underperfusion. Therefore, a histopathological examination of the placenta may be crucial for confirming the different etiologies of these two conditions.\u003c/p\u003e \u003cp\u003eThe aim of this study was to investigate whether placental pathological changes of MVM associated with PE may be useful to discriminate PE from COVID-19-induced PE-like syndrome.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003eThis was a prospective cohort study conducted at Vall d\u0026rsquo;Hebron Barcelona Hospital Campus, Barcelona, Spain, from February 2020 to September 2021. Our site was a referral hospital for cases with severe COVID-19 pneumonia, especially in pregnant women. Inclusion criteria were pregnancies at \u0026ge;\u0026thinsp;20 weeks of gestation with SARS-CoV-2 infection that met the diagnostic criteria for PE. PE was defined as new-onset high blood pressure (systolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;140 mmHg and/or diastolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;90 mmHg), or worsening of previous high blood pressure, in addition to new-onset proteinuria (protein to creatinine ratio\u0026thinsp;\u0026gt;\u0026thinsp;300), or worsening of previous proteinuria, or at least one of the following signs and symptoms of severe PE: cerebral or visual symptoms, elevation of liver enzymes to twice the normal concentration, platelet count\u0026thinsp;\u0026lt;\u0026thinsp;100.000/\u0026micro;l, serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.1 mg/dl or pulmonary edema.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) In this study, in order to diagnose hypertension, at least five out of six consecutive measurements had to be abnormal over a 6-hour time period. SARS-CoV-2 infection was confirmed by real-time polymerase chain reaction (RT-PCR) of nasal and pharyngeal swabs. Maternal serum PlGF and sFlt-1 (pg/ml) were determined using the fully automated Elecsys assay for sFlt-1 and PlGF on an electrochemiluminiscence immunoassay platform (cobas e analyzers; Roche\u0026reg; Diagnostics, Rotkreuz, Switzerland). The sFlt-1/PlGF ratio was then calculated. Values\u0026thinsp;\u0026lt;\u0026thinsp;38 were considered normal and unlikely to be associated with an underlying placental insufficiency.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Women who met the PE diagnostic criteria and had normal sFlt-1/PlGF ratio were classified PE-like syndrome, otherwise, they were classified as true PE.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAll placentas from COVID-19 patients were sent to the Pathology Department and a histopathological examination was performed using our standard protocol. A perinatal pathologist blinded to group allocation performed the placental examination and classified placental lesions according to the Amsterdam Consensus Recommendations. Histopathological lesions that fall within the MVM spectrum can be macroscopic or microscopic: placental growth restriction (placental weight\u0026thinsp;\u0026lt;\u0026thinsp;10th percentile for gestational age), placental infarction (before term or \u0026gt;\u0026thinsp;5% of the parenchyma at term), retroplacental haemorrhage, accelerated villous maturation (AVM), distal villous hypoplasia (DVH) and decidual arteriopathy.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe Amsterdam Consensus does not state how many of these findings are required to make a diagnosis of MVM. Some authors consider that the presence of AVM, with or without other findings,(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) is enough to establish MVM. High-grade MVM may be determined by the presence of AVM plus one or more of the following features: placental weight\u0026thinsp;\u0026lt;\u0026thinsp;3rd percentile for gestational age, multiple villous infarcts, and DVH.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Therefore, in this study, placentas with AVM findings were classified as having MVM.\u003c/p\u003e \u003cp\u003e This study was approved by the Vall d\u0026rsquo;Hebron Barcelona Hospital Campus\u0026rsquo; Ethics Committee (PR[AMI]181/2020) on 13 March 2020. All patients included in the study gave their consent according to the criteria of our Ethics Committee. During COVID-19 pandemic written consent was waived due to safety reasons and oral consent was accepted.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eCategorical data were reported as frequency and percentage, and comparisons between groups were estimated by the Chi-square or Fisher tests, as appropriate. Continuous variables were reported as the median and interquartile range (IQR). The statistical significance level was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The Stata statistical software package was used for data analysis (StataCorp. 2019. \u003cem\u003eStata Statistical Software: Release 16\u003c/em\u003e. College Station, TX: StataCorp LLC).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eDuring the study period, 106 pregnant women who had severe COVID-19 were admitted to the Intensive Care Unit (ICU). Of those, 15 (14.2%) met the PE diagnostic criteria, as they had new-onset hypertension plus other end-organ dysfunctions. Four cases were excluded for the following reasons: placentas were not sent to the Pathology Department in three cases and one case had a significant SARS-CoV-2 infection (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), consisting of villous trophoblast necrosis with intervillous space collapse, mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition,(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e) such that it was not possible to assess the presence of AVM and HVD. The remaining 11 cases were classified in two groups according to sFlt-1/PlGF ratio (\u0026lt;\u0026thinsp;38 or \u0026ge;\u0026thinsp;38): five (45.5%) with true PE and six (54.5%) with PE-like syndrome (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Median sFlt-1/PlGF ratio was 137.9 (IQR: 63.7-302.2) in the true PE group and 5.53 (IQR: 4.02\u0026ndash;14.6) in the PE-like syndrome group.\u003c/p\u003e\n\u003cp\u003eThe results of the placental histopathological examinations are shown in Table\u0026nbsp;1. All placentas that met the MVM criteria had AVM and met at least one criterion for high-grade MVM.\u003c/p\u003e\n\u003cp\u003eIn cases with true PE, four of the placentas (80%) met the MVM criteria versus none of the placentas (0%) in cases with PE-like syndrome (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), being this difference statistically significant (p\u0026thinsp;=\u0026thinsp;0.015). These findings indicate that MVM had a positive predictive value of 85.7% for confirming PE-like syndrome and a negative predictive value of 100% for excluding PE-like syndrome in COVID-19 patients that met the diagnostic criteria for PE (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNo histological criteria of MVM were observed in placentas from pregnancies with severe COVID-19-induced PE-like syndrome, whereas histopathological signs of MVM were found in 80.0% of placentas from cases with true PE. The absence of MVM suggests that placental insufficiency is unlikely to be the underlying cause of PE-like syndrome, which aligns with the differing sFlt-1/PlGF ratio values between the groups. This study proposes an alternative approach to biomarkers for distinguishing PE-like syndrome from true PE after birth.\u003c/p\u003e \u003cp\u003eSeveral studies have reported that COVID-19 could induce PE-like syndrome in some pregnancies, which is characterized by a normal sFlt-1/PlGF ratio.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) This indicates that angiogenic imbalance may not be involved in the pathogenesis of PE-like syndrome and that PE-related findings in these patients may be attributed to the systemic effects of SARS-CoV-2 infection.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) On the other hand, according to the Amsterdam Consensus classification, MVM findings may be identified in up to 70% of cases with hypertensive disorders of pregnancy. Despite numerous studies investigating the association between COVID-19 and PE(\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), none have assessed biomarkers during pregnancy or placental histopathological features after delivery to discriminate true PE from PE-like syndrome. Therefore, evidence supporting an association between PE and COVID-19 is difficult to interpret from those studies, as some cases with PE-like syndrome may have been misdiagnosed as true PE.\u003c/p\u003e \u003cp\u003eThis study confirms that COVID-19-induced PE-like syndrome and true PE may be distinct conditions with different etiologies that can be distinguished prenatally by the use of the sFlt-1/PlGF ratio or postnatally by placental histopathological findings. Given that PE and PE-like syndrome have different disease courses and clinical impacts, the findings of this study have important clinical implications. As previously demonstrated, patients with PE-like syndrome may benefit from a more conservative management compared to those with true PE.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Incorrect diagnosis of PE in cases with PE-like syndrome may result in unnecessary elective deliveries\u0026thinsp;\u0026ge;\u0026thinsp;34 weeks of gestation.\u003c/p\u003e \u003cp\u003eThe degree of association between PE and COVID-19 remains uncertain, as most studies have not excluded PE-like syndrome based on the sFlt-1/PlGF ratio(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). According to our findings, the Amsterdam Consensus criteria identified up to 80% of cases with true PE, while no MVM findings were observed in any of the placentas from cases with PE-like syndrome. Therefore, our study has also implications for research, demonstrating that placental histopathological analysis after delivery can distinguish true PE from COVID-19-induced PE-like syndrome. Discriminating both conditions, even after delivery, may help to elucidate any potential association between PE and COVID-19, which may allow to exclude the majority of cases with PE-like syndrome, even in settings where prenatal assessment of sFlt-1/PlGF ratio is not available.\u003c/p\u003e \u003cp\u003eThe main strength of this study is that it provides novel evidence that confirms different etiopathogenic pathways in PE and COVID-19-induced PE-like syndrome, which should encourage clinicians and researchers to exclude PE-like syndrome in cases with COVID-19 who meet the PE diagnostic criteria. Another strength of the study is that placental histopathological analysis was performed by an expert on perinatal histopathology in a tertiary referral hospital for COVID-19 during pregnancy, ensuring uniformity in placental analysis. Furthermore, the potential for observer bias was minimized by blinding the pathologist to study group allocation. Finally, these findings offer a new diagnostic tool for distinguishing between PE and PE-like syndrome in severe COVID-19. Although this differentiation should ideally be carried out during pregnancy to prevent iatrogenic medical interventions, it could serve as a valuable method for distinguishing between the two conditions after delivery, particularly in settings where sFlt-1/PlGF is not available.\u003c/p\u003e \u003cp\u003eOne of the main limitations of the study is the low number of cases included and a relatively high proportion of cases with unavailable placental histopathological analysis, since in four cases placental samples were not available or placental examination was not feasible due to severe SARS-CoV-2 infection. Another limitation is that the absence of MVM does not definitively exclude PE, and the presence of MVM in placental tissue is not exclusively due to PE; therefore, further studies should confirm our findings in pregnant women with COVID-19 who meet the diagnostic criteria for PE. Additionally, placental examination is limited to postpartum, making it not suitable for prenatal management of COVID-19 patients meeting PE diagnostic criteria. Finally, some placentas could be affected by COVID-19, which may have influenced the accurate identification of MVM signs.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003ePlacentas from pregnancies with PE-like syndrome exhibited no histological evidence of MVM, whereas 80.0% of placentas from true PE cases showed high-grade MVM. The absence of MVM correlates with the prenatal classification based on the sFlt-1/PlGF ratio, suggesting that while true PE and PE-like syndrome share some clinical features, they probably have different etiologies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003esFlt-1/PlGF ratio: soluble fms-like tyrosine kinase-1-to-placental growth factor ratio; PE: preeclampsia; PE-like syndrome: preeclampsia-like syndrome; MVM: maternal vascular malperfusion; AVM: accelerated villous maturation\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Vall d\u0026rsquo;Hebron University Hospital\u0026rsquo;s Ethics Committee (PR[AMI]181/2020) on 13 March 2020. Written informed consent was waived due to the rapid emergence of this infectious disease. However, verbal informed consent was obtained from all patients, which was included in the patient\u0026rsquo;s medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not\u0026nbsp;applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eManel Mendoza received lecture fees from Roche Diagnostics. The remaining authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u0026nbsp;\u003c/strong\u003eThe initial study outline was designed by Berta Serrano and Manel Mendoza. Manel Mendoza and Anna Suy supervised and coordinated the study.\u0026nbsp;Marta Garrido-Pontnou performed the placental histopathological analysis. Berta Serrano,\u0026nbsp;Erika Bonacina, Itziar Garc\u0026iacute;a-Ruiz, Pablo Garc\u0026iacute;a-Manau, Paula Garc\u0026iacute;a-Aguilar, and Ester del Barco collected data.\u0026nbsp;Berta Serrano and Manel Mendoza wrote the first draft of the manuscript. Nerea Maiz, Elena Carreras, Anna Suy, Nuria Fern\u0026aacute;ndez-Hidalgo, Elena Sulleiro, Laura Castillo-Ribelles, and Nerea Maiz, reviewed the manuscript and contributed to its intellectual content. The final version of the manuscript was approved by all authors prior to publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe thank all physicians who facilitated the recruitment at Hospital Universitari Vall d\u0026rsquo;Hebron and the participants who agreed to take part in the study. Nerea Maiz is a member\u0026nbsp;of the\u0026nbsp;European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA\u0026nbsp;[EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516].\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMendoza M, Garcia-Ruiz I, Maiz N, Rodo C, Garcia‐Manau P, Serrano B et al. Preeclampsia‐like syndrome induced by severe COVID‐19: a prospective observational study. BJOG. 2020;10.1111/1471-0528.16339.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerrano B, Bonacina E, Garcia-Ruiz I, Mendoza M, Garcia-Manau P, Garcia-Aguilar P, et al. Confirmation of preeclampsia-like syndrome induced by severe COVID-19: an observational study. Am J Obstet Gynecol MFM. 2023;5(1):100760.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMagee LA, Nicolaides KH, von Dadelszen P, Preeclampsia. N Engl J Med. 2022;386(19):1817\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerlohren S, Herraiz I, Lapaire O, Schlembach D, Moertl M, Zeisler H et al. The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. American Journal of Obstetrics \u0026amp; Gynecology. 2012;206(1):58.e1-58.e8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSibai BM. Imitators of Severe Pre-eclampsia. Semin Perinatol. 2009;33(3):196\u0026ndash;205.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSlack JC, Parra-Herran C. Life After Amsterdam: Placental Pathology Consensus Recommendations and Beyond. Surg Pathol Clin. 2022;15(2):175\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists\u0026rsquo; Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRedline RW, Ravishankar S, Bagby CM, Saab ST, Zarei S. Four major patterns of placental injury: a stepwise guide for understanding and implementing the 2016 Amsterdam consensus. Mod Pathol. 2021;34(6):1074\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarrido-Pontnou M, Navarro A, Camacho J, Crispi F, Alguacil-Guill\u0026eacute;n M, Moreno-Bar\u0026oacute; A, et al. Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise. Mod Pathol. 2021;34(9):1704\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInversetti A, Serafini A, Manzoni MF, Dolcetta Capuzzo A, Valsecchi L, Candiani M. Severe Hypothyroidism Causing Pre-Eclampsia-Like Syndrome. Case Rep Endocrinol. 2012;2012:586056.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePapageorghiou AT, Deruelle P, Gunier RB, Rauch S, Garc\u0026iacute;a-May PK, Mhatre M et al. Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study. Am J Obstet Gynecol. 2021;225(3):289.e1-289.e17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConde-Agudelo A, Romero R. SARS-COV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis. Am J Obstet Gynecol [Internet]. 2021 Jul 21 [cited 2021 Sep 20]; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294655/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294655/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConde-Agudelo A, Romero R. Mechanisms that may underlie a causal association between SARS-COV-2 infection and preeclampsia. Am J Obstet Gynecol. 2021;S0002-9378(21)01004-8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalil A, Samara A, Chowdhury T, O\u0026rsquo;Brien P, Does. COVID-19 cause pre-eclampsia? Ultrasound in Obstetrics \u0026amp; Gynecology [Internet]. [cited 2021 Nov 18];n/a(n/a). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://onlinelibrary.wiley.com/doi/abs/\u003c/span\u003e\u003cspan address=\"https://onlinelibrary.wiley.com/doi/abs/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/uog.24809\u003c/span\u003e\u003cspan address=\"10.1002/uog.24809\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiorgione V, Thilaganathan B. SARS-CoV-2 related myocardial injury might explain the predisposition to preeclampsia with maternal SARS-CoV-2 infection. Am J Obstet Gynecol [Internet]. 2021 Oct 5 [cited 2021 Nov 9]; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490131/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490131/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"preeclampsia-like syndrome, COVID-19, SARS-CoV-2, sFlt-1/PlGF ratio, angiogenic factors, maternal vascular malperfusion","lastPublishedDoi":"10.21203/rs.3.rs-4749296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4749296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e \u003cp\u003eWomen with COVID-19 may develop preeclampsia-like syndrome, which shares some of the clinical features of preeclampsia (PE) but lacking its characteristic angiogenic imbalance (elevated soluble fms-like tyrosine kinase-1-to-placental growth factor ratio (sFlt-1/PlGF ratio)), suggesting the absence of placental involvement. The aim of this study was to investigate whether pathological placental changes associated with PE, such as maternal vascular malperfusion (MVM), may be useful to discriminate true PE from COVID-19-induced PE-like syndrome.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eProspective cohort study conducted from February 2020 to September 2021. Inclusion criteria were pregnancies with SARS-CoV-2 infection that met the diagnostic criteria for PE at \u0026ge;\u0026thinsp;20 weeks. Cases with a normal sFlt-1/PlGF ratio (\u0026le;\u0026thinsp;38) were classified as PE-like syndrome and cases with an abnormal sFlt-1/PlGF ratio were classified as true PE. A perinatal pathologist blinded to group allocation performed the placental histopathological examination for signs of MVM following the Amsterdam criteria.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e \u003cp\u003eDuring the study period, 106 pregnant women with severe COVID-19 were admitted to the Intensive Care Unit. Among them, 15 (14.2%) met the diagnostic criteria for PE, and 11 placentas (73.3%) were available for histopathological examination. Of the 5 true PE cases (median sFlt-1/PlGF ratio of 137.9; IQR: 63.7-302.2), 80.0% had placentas with maternal vascular malperfusion (MVM). In contrast, none of the 6 PE-like syndrome cases (median sFlt-1/PlGF ratio of 5.53; IQR: 4.02\u0026ndash;14.6) had placentas that met the MVM criteria.\u003c/p\u003e\u003ch2\u003eConclusions.\u003c/h2\u003e \u003cp\u003eNone of the placentas from cases with PE-like syndrome had histopathological criteria of MVM, while 80.0% of the placentas from cases with true PE showed high-grade MVM. The absence of MVM in PE-like syndrome supports the initial evidence based on angiogenic factors: PE-like syndrome and true PE are different conditions with similar clinical features, but different etiologies.\u003c/p\u003e","manuscriptTitle":"Differences in placental pathology between COVID-19-induced preeclampsia-like syndrome and true preeclampsia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 01:01:37","doi":"10.21203/rs.3.rs-4749296/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ca6ec273-5b4e-42e1-8cbe-fde183e12d09","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T09:54:37+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-17 01:01:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4749296","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4749296","identity":"rs-4749296","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}