An updated two-sample Mendelian randomization study: COVID-19 and pre-eclampsia superimposed on chronic hypertension

An updated two-sample Mendelian randomization study: COVID-19 and pre-eclampsia superimposed on chronic hypertension | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article An updated two-sample Mendelian randomization study: COVID-19 and pre-eclampsia superimposed on chronic hypertension Wanting Tang, Ming Hao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3257125/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 Objective: To investigate the association between COVID-19 and pre-eclampsia superimposed on chronic hypertension (SPE). Design: Two-sample Mendelian randomization study. Setting: COVID-19 Host Genetics Initiative (version R7) and FinnGen consortium (version R9). Patients: A total of 222978 cases and 6284909 controls are derived from three different COVID phenotypes of the COVID-19 Host Genetics Initiative, 154 cases, and 194266 controls with pre-eclampsia superimposed on chronic hypertension (SPE) from FinnGen. Intervention (s) : None. Mains Outcome Measure: SPE. Result(s): Genetic predisposition to three different COVID phenotypes of the COVID-19 was associated with an increased risk of SPE, their IVW ORs (95% CIs) and P-values are 1.39 (1.00-1.92) and 0.04, 1.88 (1.17-3.02) and 0.008, 6.41 (1.27-32.22) and 0.02, respectively. Conclusion (s): This study based on genetic data suggests the causal potential of the association between COVID-19 and SPE. COVID-19 pre-eclampsia superimposed on chronic hypertension pre-eclampsia pregnancy hypertension Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction A case of pneumonia with an unknown etiology was discovered in Wuhan, Hubei Province, China, in late 2019. It was later determined to be a respiratory condition brought on by a new virus, which the World Health Organization later dubbed "COVID-19"(1). Since the start of the COVID-19 pandemic, more than 6 million individuals have perished globally; its fatality rate is 2%–4%. (source: World Health Organization website). But what is striking about the deaths in some countries is that COVID-19 has led to a high death rate among pregnant women with adverse pregnancies(2-4). A prominent factor in maternal and perinatal death and morbidity is pre-eclampsia coupled with chronic hypertension (SPE)(5) chronic hypertension is a common complication in pregnant women about 1%-2%,and it is the highest risk factor for eclampsia(6, 7). The relationship between COVID-19 and hypertension is a topic of discussion among several studies(1, 8-10). The researcher also noted that there is no solid evidence linking hypertension and the severity of COVID-19 patients,despite the fact that COVID-19 does influence healthcare providers' ability to control blood pressure in patients with hypertension(8). Some researchers argued that although patients with high blood pressure associated with COVID-19 have a high mortality rate, it does not prove that there is any link between the two COVID-19 patients with some other underlying diseases (cancer, kidney disease, coronary heart disease, etc.), mortality is even higher, just just because COVID-19 worsens the prognosis of these underlying diseases(11, 12). From the perspective of pregnant women with complicated chronic hypertension, the above research progress cannot determine whether COVID-19 is the inducement factor of hypertension in pregnant women, nor can it further determine whether COVID-19 interferes with the prognosis of chronic hypertension in pregnant women and thus affects the incidence of PE. Regardless of the premise that pregnant women are combined with chronic hypertension, considering the association between PE and COVID-19, some scholars even believe that there are numerous overlapping risk factors for severe COVID-19 and PE, such as smoking, elevated blood pressure, obesity, diabetes, etc, which may be the cause of the association between the two(13, 14). Some scholars try to remove the interference of confounding factors, but in the end, it is still unavoidable(15). However, over time, increasing amounts of evidence have shown that there might be a causal relationship between PE and COVID-19, even though the mechanisms by which they interact are still not fully understood(16-19). The two-sample Mendelian randomization (MR) method will be used to examine the connection between COVID-19 and SPE. The genetic alleles are randomly assigned after conception in this MR method, which is comparable to a randomized controlled trial and less susceptible to confounding or reverse causation(20, 21). At present, there are no articles that use MR to analyze the relationship between the two, not only that other studies between the two are basically blank, thus, our research in this area is essential for managing prenatal pregnancies and increasing the survival rates of COVID-19-infected pregnant women. Considering the deviation of results due to insufficient sample size and conservative data, we used the relatively new data of three different phenotypes of COVID-19 (R7 version), and we used the relatively new data of SPE (R9 version). MATERIALS AND METHODS Study Design Three presumptions must be met by the MR approach( 22 ) (Fig. 1): 1) The genetic variation chosen as an instrumental variable is related with three distinct COVID-19 phenotypes; 2) Genetic variation associated with three different phenotypes of COVID-19 and SPE were not associated with any unmeasured confounding factors; 3) Genetic variation through only three different phenotypes of COVID-19 and SPE event-related, not through alternative means. GWAS Summary Datasets The research is based on publicly available GWAS summary data, which include very severe respiratory confirmed COVID (18152 cases and 1145546 controls, with 13769 participants of European being), hospitalized COVID-19 (44986 cases and 2356386 controls, with 32519 participants of European being), COVID-19 (159840 cases and 2782977 controls, with 122616 participants of European being, others come from all over the world) ( 23 ), these three COVID genotypic data are from the COVID-19 host genetics initiative. SPE (154 cases and 194266 controls, genetic data from the Finns); this data comes from the finnngen database. Instrumental Variable Selection SNPs strongly related with the COVID-19 phenotype were retrieved (P < 5E-8, clump_r2 = 0.001, clump_kb = 10000) ( 23 ) (Supplemental File Tables 1 –3), and all contributing studies were ethically cleared by their respective institutional review boards. All individuals in the contributing studies provided informed consent. To test the MR second hypothesis, we used the PhenoScannerV2 database ( http://www.phenoscanner.medschl.cam.ac.uk/ ) to eliminate SNPs and confounders linked with COVID-19 outcomes. Equation: F = β²/ SE², we only preserve the IV SNPs (F > 10) that have a high efficacy in decreasing possible bias, while removing the P < 5E-8 from the outcome group( 24 ). Table 1 MR Analysis Results, Pleiotropy Test and Heterogeneity Analysis Results Exposure Outcome Methods OR (95%CI) P Pleiotropy:MR‒Egger Heterogeneity analyses intercept P_intercept Method Q Q_pval Very severe respiratory confirmed COVID SPE IVW 1.39(1.00−1.92) 0.04 0.06 0.15 IVW 22.85 0.78 MR‒Egger 0.99(0.57–1.73) 0.99 Weighted median 1.08(0.68–1.70) 0.73 MR‒Egger 20.69 0.83 Weighted mode 1.02(0.63–1.65) 0.91 Sample mode 3.59(1.33–9.67) 0.01 Hospitalized COVID SPE IVW 1.88(1.17–3.02) 0.008 0.06 0.10 IVW 28.32 0.74 MR‒Egger 1.09(0.49–2.41) 0.81 Weighted median 1.18(0.58–2.37) 0.64 MR‒Egger 25.52 0.82 Weighted mode 1.15(0.58–2.30) 0.68 Sample mode 4.04 (0.94–17.34) 0.06 COVID SPE IVW 6.41 (1.27–32.22) 0.02 0.04 0.46 IVW 21.20 0.21 MR‒Egger 2.44 (0.12–48.92) 0.56 Weighted median 2.80 (0.40−19.54) 0.29 MR‒Egger 20.47 0.19 Weighted mode 2.40(0.34–16.91) 0.39 Sample mode 9.21(0.41−205.31) 0.17 MR analysis The major analyses were carried out using the inverse-variance-weighted (IVW) model, which assumes a zero intercept and calculates causality via a fixed-effect meta-analysis, as well as various MR analyses, such as weighted median (WM), MR-Egger, sample mode, and weight mode( 25 ), and cattering plot was drawn to visualize MR results,next, we conduct a sensitivity analysis on the results, which is divided into three steps: 1) Heterogeneity test,the main purpose is to test the differences between different IVs. If the differences between different IVs are large (P < 0.05), then the heterogeneity of these IVs is large; 2) The primary goal of the pleiotropy test is to determine whether numerous IVs have horizontal pleiotropy. It is frequently stated in terms of the MR-Egger method's truncation term. If the intercept term significantly deviates from 0 (P < 0.05), there is horizontal pleiotropy;.3) After removing each IV one at a time, the leave-one-out sensitivity test is primarily utilized to compute the MR results for the remaining IVs. If removing either SNP did not significantly change the result (all lines are to the right of 0), then the MR result is actually robust. However, if the MR results estimated by other IVs after removing a certain IV are significantly different from the total results, then the MR results are sensitive to the IV( 26 , 27 ). Results Tables 1 –3 in the Supplementary File provide detailed information on all independent SNPs associated with exposure, after eliminating the SNP with incompatible alleles. Specifically, there were 35 independent SNPs linked to extremely severe respiratory COVID-19, 42 independent SNPs related to hospitalized COVID-19, and 24 independent SNPs associated with COVID-19. MR Analysis Results, Pleiotropy Test and Heterogeneity Analysis Results The results presented in Table 1 demonstrate a significant causal relationship between COVID-19 and severe pulmonary embolism (SPE), particularly in cases of extremely severe respiratory confirmed COVID-19 and hospitalized COVID-19 patients. The P-value of the inverse variance weighted (IVW) analysis was less than 0.05 for all three groups, indicating strong evidence for causality (IVW: OR = 1.39, P-value = 0.04; OR = 1.88, P-value = 0.008; OR = 6.41, P-value = 0.02) (Table 1 ). Sample mode findings were consistent with IVW results in the MR analysis of extremely severe respiratory confirmed COVID-19 and SPE (P-value = 0.01); on the contrary, the sample mode was not statistically significant in the MR analysis results of the other two groups (P > 0.05) (Table 1 ). However, other methods, such as weighted mode, weight median, and MR‒Egger, did not yield statistically significant results across all three groups (P > 0.05) (Table 1 ). Importantly, both the horizontal pleiotropy test and heterogeneity analysis yielded non-significant outcomes in all three groups (MR‒Egger intercept analysis and Cochrans Q(P > 0.05) (Table 1 ), indicating the credibility of our MR findings. Figure 2 illustrates scatter plots used to investigate genetic associations between COVID-19 and SPE risk, while Fig. 3 depicts funnel plots employed for assessment purposes. Figure 4:leave-one-out testing revealed no problematic SNPs that significantly altered our MR findings (almost all lines are to the right of zero), confirming their robustness. Given absence of horizontal pleiotropy and heterogeneity in our analysis, we consider IVW as a primary requirement for establishing causality between genetically predicted COVID-19 risk factors and SPE. DISCUSSION Through our MR analysis, three COVID-19 phenotypes (extremely severe respiratory COVID, hospitalized COVID, COVID) were found as risk factors for SPE (IVW: OR = 1.39, P-value = 0.04; OR = 1.88, P-value = 0.008; OR = 6.41, P-value = 0.02), at the same time, the reliability and robustness of our results were confirmed by the tests of horizontal pleiotropy and heterogeneity analysis. MR uses the random assignment of genetic variants at conception, irrespective of confounders, to find causal effects that are significantly less confounded and not prone to reverse causation( 28 , 29 ). pre-eclampsia (PE) is a pregnancy condition that is a leading cause of maternal and newborn mortality( 30 , 31 ), and several studies have indicated that the probability of PE in pregnant women with a history of chronic hypertension is 3–5 times higher than that in pregnant women without a history of chronic hypertension.( 32 ), it can be said that PE is extremely harmful to pregnant women and newborns. SPE is even more harmful( 32 , 33 ). Active blood pressure lowering medication before pregnancy can also reduce the incidence of PE by 18% later in pregnant women with a history of chronic hypertension, and a chronic hypertension history reduces the incidence of SPE in pregnant women( 34 ). In this study, we discovered evidence that COVID-19 may be causally connected with an elevated risk of SPE; however, because current research on COVID-19 and SPE is lacking, we can only explore the causal relationship and mechanism of action between COVID-19 and SPE from two perspectives: 1) COVID-19 and PE; 2) Pregnant ladies having a history of persistent hypertension and COVID-19. To some extent, this separation strategy is reasonable: 1) Pregnant women with a history of chronic hypertension have an increased risk of SPE( 32 , 34 ), so we have reason to suspect that COVID-19 has a causal relationship with SPE by affecting the prognosis of chronic hypertension in pregnant women; 2) Some scholars have found that the results of miRNA disorder (up-regulated or down-regulated) in the placenta of SPE are essentially consistent with the miRNA data expressed in the placenta of PE in previous studies( 35 – 44 ), which indicates that the pathogenesis of PE and SPE is extremely similar( 45 ), which allows us to analyze the underlying mechanism of interaction between COVID-19 and SPE by discussing previous literature on COVID-19 and PE. COVID-19 is linked to the occurrence of PE( 46 , 47 ), independent of risk factors and medical history, the severity of COVID-19 does not impact this association( 46 ). While the specific mechanism of PE is unknown, it is obvious that endothelial dysfunction and a pro-inflammatory state play a role in its etiology, which is linked to insufficient trophoblast invasion and remodeling( 48 , 49 ).1) The mechanism of PE from the perspective of inflammation: COVID-19 can activate inflammasome through NF-κB and IL-1β pathways( 50 ), and SARS-Co-V2 can also activate inflammasome (NLRP3), although the mechanism is not well understood( 51 , 52 ), scholars discovered that the NLRP3 level in the uterus of PE rat models is higher, and that activated inflammasomes (NLRP3) play a crucial role in regulating the inflammatory condition of the uterus( 53 ), and meantime the pro-inflammatory state mentioned above is a recognized mechanism for the occurrence of PE, from this point, it seems reasonable to explain the causal relationship we get between the two.2) The mechanism of PE from the perspective of endothelial dysfunction: during pregnancy, COVID-19 can cause specific vascular pathological changes( 54 ), and even COVID-19 can cause intravascular coagulation and thrombosis in non-pregnant patients( 55 , 56 ),from a certain perspective, these pathways can explain the incidence of PE caused by vascular endothelial dysfunction discussed before. Interactions between SARS-CoV-2 and the renin-angiotensin-aldosterone system (RAAS) during patient infection explain this link in the following way: SARS-CoV-2 binding to ACE2 receptors decreases angiotensin 1–7 levels, resulting in vasoconstriction, pro-inflammatory, and pro-coagulant actions, leading to vasculopathy and inflammatory conditions in the uterus( 57 – 60 ), those are acknowledged criteria for the development of PE. Mechanisms of action in COVID-19 and pregnant women with a history of chronic hypertension are discussed Renin-angiotensin-aldosterone system inhibitors (RAAS) and enhanced angiotensin receptor blockers (ANG2) have negative effects on hypertension( 61 ). Angiotensin-converting enzyme (ACE2) can convert ANG1 and ANG2 into ANG1-9 and ANG1-7, respectively, and these enzymes inhibit RAAS activation. Under normal conditions, the protective arm is formed by the Ace2-ANG1-7-MAS receptor, and the pathogenic arm is formed by the ACE-ANG2-AND2 receptor type one receptor axis( 62 ), however, ACE2 is also a SARS-CoV-2 viral receptor( 63 ). Due to viral exposure, ACE2 binds to SARS-CoV-2 in COVID-19 patients, resulting in lowered ACE2 levels and elevated blood pressure( 64 ). From the mechanism mentioned above, we can infer that COVID-19 will cause the worsening of chronic hypertension in pregnant women.There is a large amount of evidence that for SPE patients, the control level of chronic hypertension in pregnant women in the first trimester is directly related to the incidence of SPE( 65 – 68 ), so we have reason to suspect that COVID-19 worsens the control level of chronic hypertension in pregnant women, thus forming a causal relationship with the occurrence of SPE. However, it is regrettable that the current research on COVID and SPE is still in the blank stage, which brings great difficulties to our research and also makes our research present shortcomings: 1) Although the total sample size of SPE used in this paper is large (ncontorls = 194266), the number of cases is small (ncases = 154), which may make the results slightly less convincing, 2) There are too few studies on COVID and SPE to delve too deeply into the underlying mechanisms of action, 3) To avoid racial influence, our findings are mostly based on persons of European heritage; hence, it is unknown whether the findings will apply to other ethnic groups. We hope that further research will address these concerns. CONCLUSION ​In conclusion, this magnetic resonance imaging study reveals that COVID-19 is a risk factor for SPE and that doctors should prevent SARS-CoV-2 infection in pregnant women, which may otherwise result in SPE and increased mortality among neonates and pregnant women.. We also strongly urge researchers to conduct additional research on COVID-19 and SPE for the benefit of neonates and pregnant women. Declarations Funding Statement: None. Disclosure Statement: There is no conflict of interest associated with this paper. Attestation Statement: • The experimental data comes from COVID-19 Host Genetics Initiative and FinnGen consortium, these data are public. • In our paper, the data acquisition method is mentioned in detail. • We accept that our data is reviewed or queried by editors. Data Sharing Statement: The COVID-19 Host Genetics Initiative and the finngen database were used to get summary statistics for the COVID-19 with SPE GWAS. The above three exposure COVID-19 data are available at the following URL: https://www.COVID19hg.org/results/r7/.SPE genetic data can be downloaded at https://storage.googleapis.com/finngen-public-data-r9/summary_stats/finngen_R9_O15_PREEC_OR_FETGRO.gz. Ethics Approval and Consent to Participate The study involving human participants was conducted in compliance with local legislation and institutional requirements, thus exempting it from ethical review and approval. Written informed consent for participation was not deemed necessary according to national legislation and institutional requirements. Author Contributions The study was created by HM and TWT. TWT carried out statistical analysis. The findings were interpreted by all of the writers. The manuscript was written by HM. The manuscript was edited for intellectual content by all writers. The final manuscript was read and approved by all writers. Conflict of Interest The authors declare no conflict of interest. Consent for publication All authors have approved the manuscript and agree with submission to BMC Pregnancy and Childbirth. Funding To carry out the studies described in this publication, no specific support was received from any funding bodies in the public, commercial, or not-for-profit sectors. Acknowledgment We would like to express our heartfelt gratitude to the original GWASs and the associated consortiums for sharing and managing the summary information. References Qian Z, Li ZH, Peng J, Gao QQ, Cai SH, Xu XW. Association between hypertension and prognosis of patients with COVID-19: A systematic review and meta-analysis. Clin Exp Hypertens. 2022;44:451–8. Villar J, Ariff S, Gunier RB, Thiruvengadam R, Rauch S, Kholin A, et al. Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study. JAMA Pediatr. 2021;175:817–26. Di Toro F, Gjoka M, Di Lorenzo G, De Santo D, De Seta F, Maso G, et al. 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Wang K, Gheblawi M, Oudit GYJC. Angiotensin converting enzyme 2: a double-edged sword 2020;142:426-8. Uysal B, Akça T, Akacı O, Uysal F. The Prevalence of Post-COVID-19 Hypertension in Children. Clin Pediatr. 2022;61:453–60. Giannubilo SR, Dell’Uomo B, Tranquilli ALJEJoO, Gynecology, Biology R. Perinatal outcomes, blood pressure patterns and risk assessment of superimposed pre-eclampsia in mild chronic hypertensive pregnancy 2006;126:63–7. Lecarpentier E, Tsatsaris V, Goffinet F, Cabrol D, Sibai B, Haddad BJPo. Risk factors for superimposed pre-eclampsia in women with essential chronic hypertension treated before pregnancy 2013;8:e62140. Nzelu D, Dumitrascu-Biris D, Nicolaides KH. Kametas NAJAJoO, Gynecology. Chronic hypertension: first-trimester blood pressure control and likelihood of severe hypertension, pre-eclampsia, and small for gestational age 2018;218:337. e1-. e7. Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P, Klebanoff M et al. Risk factors for pre-eclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension 1998;339:667 – 71. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFiletable1.csv SupplementaryFiletable2.csv SupplementaryFiletable3.csv 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 In Review Editorial Policies 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-3257125","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":227172727,"identity":"c7bb5266-86b8-4cdb-9d27-b1d3fab323c8","order_by":0,"name":"Wanting Tang","email":"","orcid":"","institution":"Hunan Traditional Chinese Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wanting","middleName":"","lastName":"Tang","suffix":""},{"id":227172728,"identity":"3b0270f8-fe45-49da-85f3-c1b228dd72aa","order_by":1,"name":"Ming Hao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYBACfvb+5x8/VEjw8LM3EKlFsucMG7PEGQs5yZ4DRGoxuJHDxsDbVmFscCOBWFtm5B57IHFGInHmzMcbbzDU2EQT1MLP8y7doKBCIrFfOq3YguFYWm4DQVvaEwwkwLbMzjGTYGw4TFiLwQGgFt42icQNN88Qq+UE0HCgFqD3eYjUItlzLNkY6DBgIAP9kkCMX/jZmw8+/FBRB4zKwxtvfKixIawFxZESCaQoh2ghVccoGAWjYBSMDAAAQKxCPSLN1EsAAAAASUVORK5CYII=","orcid":"","institution":"Taylor's University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Hao","suffix":""}],"badges":[],"createdAt":"2023-08-12 03:59:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3257125/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3257125/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":42019244,"identity":"06d4aeaf-85d4-40f6-a9b4-b72349022239","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":255938,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/51a05598ea8cbdd0764cf9e3.png"},{"id":42019242,"identity":"99f479fc-8c12-4c1d-834d-825dfa4c9f07","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":126258,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/94d6d718293799abe60e1c2a.png"},{"id":42020145,"identity":"7789304c-a08c-4a87-a99c-6f04c0c1e51d","added_by":"auto","created_at":"2023-08-23 15:04:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":78202,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/e82fac2d4361ac05379da814.png"},{"id":42019247,"identity":"a7eb2a8f-1f9d-4ed4-b7a7-2592cee65782","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":189689,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/4c5299ac9ba2984614f6386e.png"},{"id":45319573,"identity":"51b931f8-0b42-433b-8373-0762b70c4602","added_by":"auto","created_at":"2023-10-27 14:07:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":864397,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/209d2578-c15c-4722-9cd1-ea8566029b63.pdf"},{"id":42019241,"identity":"4707cc8c-1b4f-476e-952c-6551e70fbd54","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"csv","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4435,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiletable1.csv","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/9736ab178038713367db2412.csv"},{"id":42019246,"identity":"763c1e96-55a2-40c5-a3a3-f0c9fd2305ae","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"csv","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":5310,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiletable2.csv","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/e686e7cba85346cac81670db.csv"},{"id":42019245,"identity":"07f1c35c-4318-4d04-9714-4fc54e0594d1","added_by":"auto","created_at":"2023-08-23 14:56:04","extension":"csv","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3137,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFiletable3.csv","url":"https://assets-eu.researchsquare.com/files/rs-3257125/v1/c04694e809ba37fa4d32242a.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"An updated two-sample Mendelian randomization study: COVID-19 and pre-eclampsia superimposed on chronic hypertension","fulltext":[{"header":"Introduction","content":"\u003cp\u003eA case of pneumonia with an unknown etiology was discovered in Wuhan, Hubei Province, China, in late 2019. It was later determined to be a respiratory condition brought on by a new virus, which the World Health Organization later dubbed \u0026quot;COVID-19\u0026quot;(1).\u0026nbsp;Since the start of the COVID-19 pandemic, more than 6 million individuals have\u0026nbsp;perished\u0026nbsp;globally; its fatality rate is 2%\u0026ndash;4%.\u0026nbsp;(source: World Health Organization website). But what is striking about the deaths in some countries is that COVID-19 has led to a high death rate among pregnant women with adverse pregnancies(2-4).\u003c/p\u003e\n\u003cp\u003eA prominent factor in maternal and perinatal death and morbidity is\u0026nbsp;pre-eclampsia\u0026nbsp;coupled with chronic hypertension (SPE)(5)\u0026nbsp;chronic hypertension is a common complication in pregnant women about 1%-2%,and it is the highest risk factor for eclampsia(6, 7).\u0026nbsp;The relationship between COVID-19 and hypertension is a topic of discussion among several studies(1, 8-10). The researcher also noted that there is no solid evidence linking hypertension and the severity of COVID-19 patients,despite the fact that COVID-19 does influence healthcare providers\u0026apos; ability to control blood pressure in patients with hypertension(8). Some researchers argued that although patients with high blood pressure associated with COVID-19 have a high mortality rate, it does not prove that there is any link between the two COVID-19 patients with some other underlying diseases (cancer, kidney disease, coronary heart disease, etc.), mortality is even higher, just just because COVID-19 worsens the prognosis of these underlying diseases(11, 12). From the perspective of pregnant women with complicated chronic hypertension, the above research progress cannot determine whether COVID-19 is the inducement factor of hypertension in pregnant women, nor can it further determine whether COVID-19 interferes with the prognosis of chronic hypertension in pregnant women and thus affects the incidence of PE.\u003c/p\u003e\n\u003cp\u003eRegardless of the premise that pregnant women are combined with chronic hypertension, considering the association between PE and COVID-19, some scholars even believe that there are numerous overlapping risk factors for severe COVID-19 and PE, such as smoking, elevated blood pressure, obesity, \u0026nbsp;diabetes, etc, which may be the cause of the association between the two(13, 14). Some scholars try to remove the interference of confounding factors, but in the end, it is still unavoidable(15). However, over time, increasing amounts of evidence have shown that there might be a causal relationship between PE and COVID-19, even though the mechanisms by which they interact are still not fully understood(16-19).\u003c/p\u003e\n\u003cp\u003eThe two-sample Mendelian randomization (MR) method will be used to examine the connection between COVID-19 and SPE. The genetic alleles are randomly assigned after conception in this MR method, which is comparable to a randomized controlled trial and less susceptible to confounding or reverse causation(20, 21). At present, there are no articles that use MR to analyze the relationship between the two, not only that other studies between the two are basically blank, thus, our research in this area is essential for managing prenatal pregnancies and increasing the survival rates of COVID-19-infected pregnant women. Considering the deviation of results due to insufficient sample size and conservative data, we used the relatively new data of three different phenotypes of COVID-19 (R7 version), and we used the relatively new data of SPE (R9 version).\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eStudy Design\u003c/p\u003e \u003cp\u003eThree presumptions must be met by the MR approach(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) (Fig.\u0026nbsp;1): 1) The genetic variation chosen as an instrumental variable is related with three distinct COVID-19 phenotypes; 2) Genetic variation associated with three different phenotypes of COVID-19 and SPE were not associated with any unmeasured confounding factors; 3) Genetic variation through only three different phenotypes of COVID-19 and SPE event-related, not through alternative means.\u003c/p\u003e \u003cp\u003eGWAS Summary Datasets\u003c/p\u003e \u003cp\u003eThe research is based on publicly available GWAS summary data, which include very severe respiratory confirmed COVID (18152 cases and 1145546 controls, with 13769 participants of European being), hospitalized COVID-19 (44986 cases and 2356386 controls, with 32519 participants of European being), COVID-19 (159840 cases and 2782977 controls, with 122616 participants of European being, others come from all over the world) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), these three COVID genotypic data are from the COVID-19 host genetics initiative. SPE (154 cases and 194266 controls, genetic data from the Finns); this data comes from the finnngen database.\u003c/p\u003e \u003cp\u003eInstrumental Variable Selection\u003c/p\u003e \u003cp\u003eSNPs strongly related with the COVID-19 phenotype were retrieved (P\u0026thinsp;\u0026lt;\u0026thinsp;5E-8, clump_r2\u0026thinsp;=\u0026thinsp;0.001, clump_kb\u0026thinsp;=\u0026thinsp;10000) (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) (Supplemental File Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;3), and all contributing studies were ethically cleared by their respective institutional review boards. All individuals in the contributing studies provided informed consent. To test the MR second hypothesis, we used the PhenoScannerV2 database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.phenoscanner.medschl.cam.ac.uk/\u003c/span\u003e\u003cspan address=\"http://www.phenoscanner.medschl.cam.ac.uk/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to eliminate SNPs and confounders linked with COVID-19 outcomes. Equation: F\u0026thinsp;=\u0026thinsp;β\u0026sup2;/ SE\u0026sup2;, we only preserve the IV SNPs (F\u0026thinsp;\u0026gt;\u0026thinsp;10) that have a high efficacy in decreasing possible bias, while removing the P\u0026thinsp;\u0026lt;\u0026thinsp;5E-8 from the outcome group(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMR Analysis Results, Pleiotropy Test and Heterogeneity Analysis Results\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMethods\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ePleiotropy:MR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eHeterogeneity analyses\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eintercept\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP_intercept\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMethod\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eQ_pval\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eVery severe respiratory confirmed COVID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eSPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.39(1.00\u0026minus;1.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e22.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99(0.57\u0026ndash;1.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08(0.68\u0026ndash;1.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e20.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.02(0.63\u0026ndash;1.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.59(1.33\u0026ndash;9.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eHospitalized COVID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eSPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.88(1.17\u0026ndash;3.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e28.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.09(0.49\u0026ndash;2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.18(0.58\u0026ndash;2.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e25.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.15(0.58\u0026ndash;2.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.04 (0.94\u0026ndash;17.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCOVID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eSPE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.41 (1.27\u0026ndash;32.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e21.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.44 (0.12\u0026ndash;48.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.80 (0.40\u0026minus;19.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMR‒Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e20.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.40(0.34\u0026ndash;16.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.21(0.41\u0026minus;205.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMR analysis\u003c/p\u003e \u003cp\u003eThe major analyses were carried out using the inverse-variance-weighted (IVW) model, which assumes a zero intercept and calculates causality via a fixed-effect meta-analysis, as well as various MR analyses, such as weighted median (WM), MR-Egger, sample mode, and weight mode(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), and cattering plot was drawn to visualize MR results,next, we conduct a sensitivity analysis on the results, which is divided into three steps: 1) Heterogeneity test,the main purpose is to test the differences between different IVs. If the differences between different IVs are large (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), then the heterogeneity of these IVs is large; 2) The primary goal of the pleiotropy test is to determine whether numerous IVs have horizontal pleiotropy. It is frequently stated in terms of the MR-Egger method's truncation term. If the intercept term significantly deviates from 0 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), there is horizontal pleiotropy;.3) After removing each IV one at a time, the leave-one-out sensitivity test is primarily utilized to compute the MR results for the remaining IVs. If removing either SNP did not significantly change the result (all lines are to the right of 0), then the MR result is actually robust. However, if the MR results estimated by other IVs after removing a certain IV are significantly different from the total results, then the MR results are sensitive to the IV(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;3 in the Supplementary File provide detailed information on all independent SNPs associated with exposure, after eliminating the SNP with incompatible alleles. Specifically, there were 35 independent SNPs linked to extremely severe respiratory COVID-19, 42 independent SNPs related to hospitalized COVID-19, and 24 independent SNPs associated with COVID-19.\u003c/p\u003e \u003cp\u003eMR Analysis Results, Pleiotropy Test and Heterogeneity Analysis Results\u003c/p\u003e \u003cp\u003eThe results presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e demonstrate a significant causal relationship between COVID-19 and severe pulmonary embolism (SPE), particularly in cases of extremely severe respiratory confirmed COVID-19 and hospitalized COVID-19 patients. The P-value of the inverse variance weighted (IVW) analysis was less than 0.05 for all three groups, indicating strong evidence for causality (IVW: OR\u0026thinsp;=\u0026thinsp;1.39, P-value\u0026thinsp;=\u0026thinsp;0.04; OR\u0026thinsp;=\u0026thinsp;1.88, P-value\u0026thinsp;=\u0026thinsp;0.008; OR\u0026thinsp;=\u0026thinsp;6.41, P-value\u0026thinsp;=\u0026thinsp;0.02) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Sample mode findings were consistent with IVW results in the MR analysis of extremely severe respiratory confirmed COVID-19 and SPE (P-value\u0026thinsp;=\u0026thinsp;0.01); on the contrary, the sample mode was not statistically significant in the MR analysis results of the other two groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, other methods, such as weighted mode, weight median, and MR‒Egger, did not yield statistically significant results across all three groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Importantly, both the horizontal pleiotropy test and heterogeneity analysis yielded non-significant outcomes in all three groups (MR‒Egger intercept analysis and Cochrans Q(P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), indicating the credibility of our MR findings. Figure\u0026nbsp;2 illustrates scatter plots used to investigate genetic associations between COVID-19 and SPE risk, while Fig.\u0026nbsp;3 depicts funnel plots employed for assessment purposes. Figure\u0026nbsp;4:leave-one-out testing revealed no problematic SNPs that significantly altered our MR findings (almost all lines are to the right of zero), confirming their robustness. Given absence of horizontal pleiotropy and heterogeneity in our analysis, we consider IVW as a primary requirement for establishing causality between genetically predicted COVID-19 risk factors and SPE.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThrough our MR analysis, three COVID-19 phenotypes (extremely severe respiratory COVID, hospitalized COVID, COVID) were found as risk factors for SPE (IVW: OR\u0026thinsp;=\u0026thinsp;1.39, P-value\u0026thinsp;=\u0026thinsp;0.04; OR\u0026thinsp;=\u0026thinsp;1.88, P-value\u0026thinsp;=\u0026thinsp;0.008; OR\u0026thinsp;=\u0026thinsp;6.41, P-value\u0026thinsp;=\u0026thinsp;0.02), at the same time, the reliability and robustness of our results were confirmed by the tests of horizontal pleiotropy and heterogeneity analysis. MR uses the random assignment of genetic variants at conception, irrespective of confounders, to find causal effects that are significantly less confounded and not prone to reverse causation(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003epre-eclampsia (PE) is a pregnancy condition that is a leading cause of maternal and newborn mortality(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), and several studies have indicated that the probability of PE in pregnant women with a history of chronic hypertension is 3\u0026ndash;5 times higher than that in pregnant women without a history of chronic hypertension.(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e), it can be said that PE is extremely harmful to pregnant women and newborns. SPE is even more harmful(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Active blood pressure lowering medication before pregnancy can also reduce the incidence of PE by 18% later in pregnant women with a history of chronic hypertension, and a chronic hypertension history reduces the incidence of SPE in pregnant women(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In this study, we discovered evidence that COVID-19 may be causally connected with an elevated risk of SPE; however, because current research on COVID-19 and SPE is lacking, we can only explore the causal relationship and mechanism of action between COVID-19 and SPE from two perspectives: 1) COVID-19 and PE; 2) Pregnant ladies having a history of persistent hypertension and COVID-19. To some extent, this separation strategy is reasonable: 1) Pregnant women with a history of chronic hypertension have an increased risk of SPE(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), so we have reason to suspect that COVID-19 has a causal relationship with SPE by affecting the prognosis of chronic hypertension in pregnant women; 2) Some scholars have found that the results of miRNA disorder (up-regulated or down-regulated) in the placenta of SPE are essentially consistent with the miRNA data expressed in the placenta of PE in previous studies(\u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e), which indicates that the pathogenesis of PE and SPE is extremely similar(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e), which allows us to analyze the underlying mechanism of interaction between COVID-19 and SPE by discussing previous literature on COVID-19 and PE.\u003c/p\u003e \u003cp\u003eCOVID-19 is linked to the occurrence of PE(\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), independent of risk factors and medical history, the severity of COVID-19 does not impact this association(\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). While the specific mechanism of PE is unknown, it is obvious that endothelial dysfunction and a pro-inflammatory state play a role in its etiology, which is linked to insufficient trophoblast invasion and remodeling(\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).1) The mechanism of PE from the perspective of inflammation: COVID-19 can activate inflammasome through NF-κB and IL-1β pathways(\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e), and SARS-Co-V2 can also activate inflammasome (NLRP3), although the mechanism is not well understood(\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e), scholars discovered that the NLRP3 level in the uterus of PE rat models is higher, and that activated inflammasomes (NLRP3) play a crucial role in regulating the inflammatory condition of the uterus(\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e), and meantime the pro-inflammatory state mentioned above is a recognized mechanism for the occurrence of PE, from this point, it seems reasonable to explain the causal relationship we get between the two.2) The mechanism of PE from the perspective of endothelial dysfunction: during pregnancy, COVID-19 can cause specific vascular pathological changes(\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e), and even COVID-19 can cause intravascular coagulation and thrombosis in non-pregnant patients(\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e),from a certain perspective, these pathways can explain the incidence of PE caused by vascular endothelial dysfunction discussed before. Interactions between SARS-CoV-2 and the renin-angiotensin-aldosterone system (RAAS) during patient infection explain this link in the following way: SARS-CoV-2 binding to ACE2 receptors decreases angiotensin 1\u0026ndash;7 levels, resulting in vasoconstriction, pro-inflammatory, and pro-coagulant actions, leading to vasculopathy and inflammatory conditions in the uterus(\u003cspan additionalcitationids=\"CR58 CR59\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e), those are acknowledged criteria for the development of PE.\u003c/p\u003e \u003cp\u003eMechanisms of action in COVID-19 and pregnant women with a history of chronic hypertension are discussed Renin-angiotensin-aldosterone system inhibitors (RAAS) and enhanced angiotensin receptor blockers (ANG2) have negative effects on hypertension(\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e). Angiotensin-converting enzyme (ACE2) can convert ANG1 and ANG2 into ANG1-9 and ANG1-7, respectively, and these enzymes inhibit RAAS activation. Under normal conditions, the protective arm is formed by the Ace2-ANG1-7-MAS receptor, and the pathogenic arm is formed by the ACE-ANG2-AND2 receptor type one receptor axis(\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e), however, ACE2 is also a SARS-CoV-2 viral receptor(\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e). Due to viral exposure, ACE2 binds to SARS-CoV-2 in COVID-19 patients, resulting in lowered ACE2 levels and elevated blood pressure(\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e). From the mechanism mentioned above, we can infer that COVID-19 will cause the worsening of chronic hypertension in pregnant women.There is a large amount of evidence that for SPE patients, the control level of chronic hypertension in pregnant women in the first trimester is directly related to the incidence of SPE(\u003cspan additionalcitationids=\"CR66 CR67\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e), so we have reason to suspect that COVID-19 worsens the control level of chronic hypertension in pregnant women, thus forming a causal relationship with the occurrence of SPE.\u003c/p\u003e \u003cp\u003eHowever, it is regrettable that the current research on COVID and SPE is still in the blank stage, which brings great difficulties to our research and also makes our research present shortcomings: 1) Although the total sample size of SPE used in this paper is large (ncontorls\u0026thinsp;=\u0026thinsp;194266), the number of cases is small (ncases\u0026thinsp;=\u0026thinsp;154), which may make the results slightly less convincing, 2) There are too few studies on COVID and SPE to delve too deeply into the underlying mechanisms of action, 3) To avoid racial influence, our findings are mostly based on persons of European heritage; hence, it is unknown whether the findings will apply to other ethnic groups. We hope that further research will address these concerns.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003e​In conclusion, this magnetic resonance imaging study reveals that COVID-19 is a risk factor for SPE and that doctors should prevent SARS-CoV-2 infection in pregnant women, which may otherwise result in SPE and increased mortality among neonates and pregnant women.. We also strongly urge researchers to conduct additional research on COVID-19 and SPE for the benefit of neonates and pregnant women.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Statement:\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statement:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThere is no conflict of interest associated with this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAttestation Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp;The experimental data comes from COVID-19 Host Genetics Initiative and FinnGen consortium, these data are public.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp;In our paper, the data acquisition method is mentioned in detail.\u003c/p\u003e\n\u003cp\u003e\u0026bull; \u0026nbsp;We accept that our data is reviewed or queried by editors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe COVID-19 Host Genetics Initiative and the finngen database were used to get summary statistics for the COVID-19 with SPE GWAS. The above three exposure COVID-19 data are available at the following URL: https://www.COVID19hg.org/results/r7/.SPE genetic data can be downloaded at https://storage.googleapis.com/finngen-public-data-r9/summary_stats/finngen_R9_O15_PREEC_OR_FETGRO.gz.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study involving human participants was conducted in compliance with local legislation and institutional requirements, thus exempting it from ethical review and approval. Written informed consent for participation was not deemed necessary according to national legislation and institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was created by HM and TWT. TWT carried out statistical analysis. The findings were interpreted by all of the writers. The manuscript was written by HM. The manuscript was edited for intellectual content by all writers. The final manuscript was read and approved by all writers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have approved the manuscript and agree with submission to BMC Pregnancy and Childbirth.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo carry out the studies described in this publication, no specific support was received from any funding bodies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our heartfelt gratitude to the original GWASs and the associated consortiums for sharing and managing the summary information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eQian Z, Li ZH, Peng J, Gao QQ, Cai SH, Xu XW. 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Risk factors for pre-eclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension 1998;339:667 \u0026ndash; 71.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"COVID-19, pre-eclampsia superimposed on chronic hypertension, pre-eclampsia, pregnancy hypertension, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-3257125/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3257125/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eTo investigate the association between COVID-19\u0026nbsp;and pre-eclampsia\u0026nbsp;superimposed on chronic hypertension (SPE).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign:\u0026nbsp;\u003c/strong\u003eTwo-sample Mendelian randomization study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting: \u003c/strong\u003e\u0026nbsp;COVID-19\u0026nbsp;Host Genetics Initiative\u0026nbsp;(version R7) and FinnGen consortium\u0026nbsp;(version R9).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients:\u003c/strong\u003e\u0026nbsp;A total of 222978 cases and 6284909 controls are\u0026nbsp;derived from\u0026nbsp;three different COVID phenotypes of the COVID-19 Host Genetics Initiative,\u0026nbsp;154 cases, and 194266 controls with\u0026nbsp;pre-eclampsia\u0026nbsp;superimposed on chronic hypertension\u0026nbsp;(SPE)\u0026nbsp;from FinnGen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention (s)\u003c/strong\u003e: None.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMains Outcome Measure: \u003c/strong\u003eSPE. Result(s): Genetic predisposition to three different COVID phenotypes of the COVID-19 was associated with an increased risk of SPE, \u0026nbsp;their IVW ORs\u0026nbsp;(95% CIs) and P-values\u0026nbsp;are\u0026nbsp;1.39 (1.00-1.92) and 0.04,\u0026nbsp;1.88 (1.17-3.02) and 0.008,\u0026nbsp;6.41 (1.27-32.22) and 0.02, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion (s):\u003c/strong\u003e This study based on genetic data suggests the causal potential of the association between COVID-19 and SPE.\u003c/p\u003e","manuscriptTitle":"An updated two-sample Mendelian randomization study: COVID-19 and pre-eclampsia superimposed on chronic hypertension","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-23 14:55:59","doi":"10.21203/rs.3.rs-3257125/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":"f6ce288b-84e7-4638-8ce6-9abd9cef4545","owner":[],"postedDate":"August 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-10-27T13:59:29+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-23 14:55:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3257125","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3257125","identity":"rs-3257125","version":["v1"]},"buildId":"pf3fE39SIOqb-0xH_OWvX","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}