Hypothyroidism and Preeclampsia or Eclampsia: A Mendelian Randomization Study

Hypothyroidism and Preeclampsia or Eclampsia: A Mendelian Randomization Study | 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 Hypothyroidism and Preeclampsia or Eclampsia: A Mendelian Randomization Study Yafei XIE, Qiaozhi YIN This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3883932/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 Numerous observational studies have consistently demonstrated an elevated risk of preeclampsia or eclampsia among individuals with hypothyroidism; however, the establishment of a causal relationship between these conditions has remained inconclusive due to inherent confounding biases in traditional retrospective and prospective studies. This study employs two-sample Mendelian randomization to investigate the causal impact of hypothyroidism on preeclampsia and eclampsia. Methods Independent single nucleotide polymorphisms (SNPs) strongly associated with hypothyroidism were selected as instrumental variables from a FinnGen Consortium comprising 26,306 hypothyroid patients of European origin and 187,684 controls, and the pooled statistics for pre-eclampsia or eclampsia included 3,903 cases and 114,735 controls. Inverse variance-weighted (IVW) was used as the primary estimate, supplemented by MR-Egger and weighted medians. Heterogeneity and horizontal polymorphisms were assessed using MR-PRESSO to remove biased SNPs, Cochran's Q test and MR-Egger intercept analysis. Result Individuals with higher genetic liability for hypothyroidism were more likely to develop preeclampsia or eclampsia (OR,1.105; 95%CI,1.02–1.12; p < 0.05). Conclusion We discovered that the risk of preeclampsia or eclampsia in women with genetically indicated hypothyroidism has existed since development. Our findings may encourage hypothyroid women of reproductive age to seek treatment before trying to get pregnant in order to lower their risk of preeclampsia or eclampsia during pregnancy. Hypothyroidism Preeclampsia or eclampsia Mendelian randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Hypertension in pregnancy is a prevalent complication, encompassing gestational hypertension, preeclampsia or eclampsia, chronic hypertension complicated by preeclampsia, and chronic hypertension in pregnancy. Among these conditions, preeclampsia or eclampsia significantly impacts the well-being of both mothers and infants, resulting in approximately 46,000 maternal deaths and 500,000 fetal or neonatal deaths annually [1]. Hypertensive disorders of pregnancy are the second leading cause of maternal mortality worldwide (following hemorrhage), accounting for 14% of deaths. It is estimated that over 30 billion women and children globally face an increased risk of long-term health issues due to prior exposure to pre-eclampsia [2]. The pathogenesis of pre-eclampsia or eclampsia is intricate; however, it clinically manifests through three key features: hypertension, edema, and proteinuria. Severe cases can lead to hypoxia as well as edema and necrosis in vital organs such as the heart, liver, kidneys, and brain among pregnant women [3]. Existing research has linked preeclampsia or eclampsia with potential risk factors like systemic lupus erythematosus (SLE), chronic hypertension diabetes mellitus ,and body mass index (BMI) [4]. Despite decades of investigation into its etiology—particularly full-term and postpartum cases—the causes behind preeclampsia or eclampsia remain unknown. Preventive therapy only slightly reduces the risk for women; therefore identifying more reliable risk variables becomes crucial for early recognition and prediction of pre-eclamptic conditions. Hypothyroidism (short for hypothyroidism) is a metabolic disorder in which the synthesis and secretion of thyroid hormone (TH) is reduced due to a decrease in thyroid function or other causes[5].The risk of primary hypothyroidism is ten times higher in women than in men [6]. Preeclampsia or eclampsia may be increased in women with hypothyroidism before or during pregnancy, according to recent observational studies. A cohort study involving 46,528 pregnant women found that subclinical hypothyroidism during pregnancy was linked to a higher risk of preeclampsia [7]. The aim of this study was to determine whether there is a causal relationship between hypothyroidism and preeclampsia or eclampsia. Randomised controlled clinical trials (RCTs) are the gold standard for determining causality, however RCTs have drawbacks since they are susceptible to common confounders including behavioral and environmental exposures [8].MR is a measure of causality of disease-related risk factors using an index of genetic variance In order to reduce the danger of bias brought on by confounding bias or reverse causality inherent in observational research[8]. Thus, if the assumptions underlying the Mendelian randomisation approach hold true, the use of genetic variants known to affect hypothyroidism as their proxy instrumental variables (IVs) may provide indirect evidence for a causal effect of hypothyroidism on the risk of pre-eclampsia or eclampsia in pregnancy. Methods Study design To determine the cause-and-effect relationship between hypothyroidism and preeclampsia or eclampsia, we conducted a two-sample MR. SNP was used as an instrumental variable. There are three crucial presumptions that must always be true in order to optimize the accuracy of the results. First, the selected IVs are associated with risk factors (hypothyroidism). Second, IVs is not associated with confounders between exposure (hypothyroidism) and outcome（preeclampsia or eclampsia). Third, IVs has no direct effect on outcome (preeclampsia or eclampsia), but only affect outcome through exposure (Hypothyroidism). （Figure 1） Data sources The Finnish database (FinnGen Consortium) provides a reliable tool for MR analyses [9]. In our study, summary-level statistics for hypothyroidism were obtained from a large-scale meta-analysis of the publicly available Finnish database (FinnGen Consortium) version R9, which involves exposure data hypothyroidism (26,306 cases and 187,684 controls,16,380,461SNPs), and outcome data pre-eclampsia or eclampsia ( 3903 cases and 114,735 controls,16,379,723SNPs).A threshold of P < 0.05 was used to select SNPs and all SNPs and associated data were obtained from studies that analysed only populations of European descent separately in order to remove population stratification bias. Genetic instrumental variable selection criteria SNPs with strong associations (P<0.05) and independent inheritance (R2 < 0.001, kb = 10, 000) were selected from the hypothyroidism and pre-eclampsia or eclampsia GWAS databases with no evidence of linkage disequilibrium (LD) in the pooled RA or infertility GWAS data.In addition, it is of genome-wide significance to see if these SNPs are associated with potential risk factors from the PhenoScanner database and to remove SNPs that are associated with these potential confounders. (http://www.phenoscanner.medschl.cam.ac.uk/). We estimate IVs strength using the F-statistic to prevent bias brought on by weak IVs. F>10 indicates that the instrument has sufficient strength, which means that the IVs has sufficient estimation effect on the subsequent MR analysis without weak instrumental bias. When F<10, it indicates a weak SNP and should be eliminated.（R2 stands for the exposure variance explained by each IVs, N for the GWAS sample size, and K for the quantity of SNPs examined by MR.） MR analysis We employed the MR-Egger, weighted median, and random effects inverse variance weighting (IVW) in the MR analysis.The principal method of MR analysis used the IVW methodology to evaluate the causal effects between the exposure and the result since it gave accurate causal estimates in the absence of directional pleiotropy[10]. MR-Egger and weighted median were used to complement the analysis. For IVs with P < 0.05 from the IVW analysis, we performed MR-PRESSO with the MRPRESSO package, which detects, removes potentially polymorphic IVs (outliers) and provides estimates adjusted for outliers. Sensitivity analysis We conducted tests for heterogeneity and pleiotropy to ensure the stability of the results of the MR analysis. Cochran's Q test was used to calculate the level of heterogeneity, and MR-Egger regression and IVW methods were used to detect heterogeneity in IVs, with P<0.05 reflecting the presence of considerable heterogeneity. We checked for pleiotropy by MR-Egger intercept regression, and P < 0.05 was considered significant pleiotropy, and then the study results were unreliable. In addition, we also conducted a "leave-one-out" sensitivity analysis, in which one SNP was sequentially missing from the MR reanalysis to singling out the potential effects of SNPs. Finally, the visualization results of the MR analysis are presented through scatter plots and forest plots. The analysis was performed using R software (4.2.3) and RStudio (2023.03.0), as well as the R packages TwoSampleMR and MR-PRESSO. Results Fifty-one SNPs extracted in preeclampsia or eclampsia were identified as eligible IVs (LD<0.001) (p10. Detailed information is provided in Supplementary Information Table 1. MR analysis results Two-sample MR analysis showed a strong causal relationship between hypothyroidism and preeclampsia or eclampsia, presenting positive results. The random-effects model IVW [OR, 1.105; 95% CI, 1.02-1.12; p<0.05], and the weighted median (Weighted median) [OR, 1.13; 95% CI, 1.01-1.26; p<0.05] obtained OR estimates similar to those of the IVW method but did not find a significant MR Egger correlation. The results of the three MR analysis methods (Table 2). visualisation of the MR results was demonstrated by scatter plots (Figure 2). Table 2 Results of MR analysis of hypothyroidism and pre-eclampsia or eclampsia Methods OR 95%CI P Value MR Egger 1.219 0.998-1.490 0.058 Weighted median 1.128 1.007-1.262 0.042 Inverse variance weighted 1.105 1.017-1.120 0.018 Sensitivity analysis results In the sensitivity analysis of the causal relationship between hypothyroidism and pre-eclampsia or eclampsia, the results of MR Egger and IVW analyses were statistically significant (p<0.05) for the presence of heterogeneity, which was assessed using a random-effects model, and the results showed a strong association between hypothyroidism and pre-eclampsia or eclampsia (p=0.018). In addition, MR-Egger intercept regression was used to test for horizontal pleiotropy, and the results showed that horizontal pleiotropy did not exist (P=0.30). In our study, no abnormal SNPs were found using MR-PRESSO. leave-one-out plots of the causal association of hypothyroidism with preeclampsia or eclampsia showed that causal estimates were not affected by certain SNPs (Figure 3). Discussion This is the first time that a causal relationship between hypothyroidism and preeclampsia or eclampsia has been analysed by two-sample MR. The results indicate a possible causative link between hypothyroidism and pre- or eclampsia as well as a risk factor for both conditions. This result is consistent with previous observational studies, in which women with hypothyroidism were found to be more likely to develop preeclampsia or eclampsia in a retrospective study based on a population of 41,647 [11]. Due to the following reasons, hypothyroidism is positively correlated with preeclampsia or eclampsia.firstly, impaired infiltration of extravillous trophoblasts (EVTs), resulting in "shallow placenta implantation" and severe lack of remodelling of the small spiral arteries of the uterus, and remodelling of the blood vessels of the metaphysis layer only, with the diameter of the spiral arteries of the uterus being 1/2 of that of a normal pregnancy, resulting in an increase in vascular resistance. The vascular resistance is increased and placental perfusion is reduced, resulting in a series of symptoms of pre-eclampsia.Animal experiments have shown that increased the population of glycogen cells in the spongiotrophoblast of hypothyroid rats interfered with the vascular development of the placental labyrinth and may prevent EVT from migrating toward the decidua [12].Therefore, it is reasonable to assume that Insufficient EVT invasion in patients with hypothyroidism leads to an increased risk of preeclampsia or eclampsia.Secondly, vascular endothelial growth factor (VEGF) has emerged as an important biomarker for preeclampsia.Maternal hypothyroidism in rats has been found to lead to reduced placental T4 and T3 levels, which reduces the expression of pro-angiogenic factors such as foetal liver kinase (FLK1) and VEGF, resulting in impaired angiogenesis and insufficient remodelling of spiral arteries, triggering pre-eclampsia or eclampsia [13].It is thus hypothesised that down-regulation of VEGF expression in patients with hypothyroidism may induce pre-eclampsia or eclampsia during pregnancy.Finally, hypothyroidism results in elevated levels of serum thyroid stimulating hormone (TSH), decreased levels of the vasodilator nitric oxide (NO), disturbed lipid metabolism, lipid aggregation, increased blood viscosity, decreased vascular elasticity, and elevated systolic blood pressure,leading to an increase in systemic vascular resistance and the onset of pre-eclampsia or eclampsia[14]. Although the mechanisms described above suggest a possible causal relationship between hypothyroidism and preeclampsia or eclampsia, these hypotheses have not been thoroughly tested due to the lack of robust RCTs providing strong evidence. The advantage of two-sample MR in our study is that SNPs are distributed randomly at conception, and the method is not subject to confounding factors and reverse causal associations in traditional epidemiologic studies based on whole-genome sequencing data. Furthermore, genotype-disease associations are used to represent the role of exposing factors on the disease and to better reveal the potential causal effects between hypothyroidism and preeclampsia or eclampsia. This study is the first to show that women with hypothyroidism may be at risk for preeclampsia or eclampsia that is challenging to modify at the level of genes and genetic variations. Our findings provide important literature support for future research in this area, but further studies are still needed to explain the mechanisms involved. There are still shortcomings in our study. First, the population we analyzed was limited to Europeans. Although this makes it easier for us to eliminate the population division bias and ensure the reliability of the MR analysis results, the causal effect of hypothyroidism and preeclampsia or eclampsia in other populations remains unknown. Second, our study suggests that hypothyroidism causes preeclampsia or eclampsia in terms of genetic variation, but the underlying mechanisms require further investigation. Conclusion This is the first study to use two-sample MR analysis to address the causal relationship between hypothyroidism and preeclampsia or eclampsia. Our research provides evidence that hypothyroidism increases the risk of preeclampsia or eclampsia in pregnant women and that the risk ratio is directly connected.Our findings could help women of childbearing age with hypothyroidism to intervene early before preparing for pregnancy with the expectation of reducing the risk of preeclampsia or eclampsia. Early diagnosis of hypothyroidism during pregnancy would have a preventive effect on the development and progression of preeclampsia or eclampsia, thereby improving the quality of maternal and infant survival and reducing maternal mortality.Early detection of hypothyroidism during pregnancy might have a preventative effect on the onset and progression of preeclampsia or eclampsia, improving the quality of maternal and newborn survival and lowering maternal mortality. Declarations Ethical Approval All original studies acquired ethical review approval and informed consent. Availability of data and materials All data are publicly available.The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potenContributors. Funding This study was supported by the Chengdu Science and Technology Bureau(2021-YF05-02042-SN). Author contributions YFX designed the study, wrote the first draft of the manuscript and verified the underlying data. QZY conducted statistical analysestial conflict of interest.All authors contributed to the article and approved the submitted version. References Magee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J Med. 2022 May 12;386(19):1817-1832. doi: 10.1056/NEJMra2109523. PMID: 35544388. Davis, E. et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics 129, e1552 (2012). Viana-Mattioli S, Fonseca-Alaniz MH, Pinheiro-de-Sousa I, Krieger JE, Sandrim VC. Missing links in preeclampsia cell model systems of endothelial dysfunction. Trends Mol Med. 2023 Jul;29(7):541-553. doi: 10.1016/j.molmed.2023.04.003. Epub 2023 May 10. PMID: 37173223. Dimitriadis E, Rolnik DL, Zhou W, Estrada-Gutierrez G, Koga K, Francisco RPV, Whitehead C, Hyett J, da Silva Costa F, Nicolaides K, Menkhorst E. Pre-eclampsia. Nat Rev Dis Primers. 2023 Feb 16;9(1):8. doi: 10.1038/s41572-023-00417-6. Erratum in: Nat Rev Dis Primers. 2023 Jul 3;9(1):35. PMID: 36797292. Hegedüs L, Bianco AC, Jonklaas J, Pearce SH, Weetman AP, Perros P. Primary hypothyroidism and quality of life. Nat Rev Endocrinol. 2022 Apr;18(4):230-242. doi: 10.1038/s41574-021-00625-8. Epub 2022 Jan 18. PMID: 35042968; PMCID: PMC8930682. Teumer, A. et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat. Commun. 9, 4455 (2018). Toloza FJK, Derakhshan A, Männistö T, Bliddal S, Popova PV, Carty DM, Chen L, Taylor P, Mosso L, Oken E, Suvanto E, Itoh S, Kishi R, Bassols J, Auvinen J, López-Bermejo A, Brown SJ, Boucai L, Hisada A, Yoshinaga J, Shilova E, Grineva EN, Vrijkotte TGM, Sunyer J, Jiménez-Zabala A, Riaño-Galan I, Lopez-Espinosa MJ, Prokop LJ, Singh Ospina N, Brito JP, Rodriguez-Gutierrez R, Alexander EK, Chaker L, Pearce EN, Peeters RP, Feldt-Rasmussen U, Guxens M, Chatzi L, Delles C, Roeters van Lennep JE, Pop VJM, Lu X, Walsh JP, Nelson SM, Korevaar TIM, Maraka S. Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis. Lancet Diabetes Endocrinol. 2022 Apr;10(4):243-252. doi: 10.1016/S2213-8587(22)00007-9. Epub 2022 Mar 4. PMID: 35255260; PMCID: PMC10314731. Vanni VS, De Lorenzo R, Privitera L, Canti V, Viganò P, Rovere-Querini P. Safety of fertility treatments in women with systemic autoimmune diseases (SADs). Expert Opin Drug Saf. 2019 Sep;18(9):841-852. doi: 10.1080/14740338.2019.1636964. Epub 2019 Jul 12. PMID: 31238745. The FinnGen Consortium FinnGen Documentation of R9 Release. 2023. [(accessed on 23 June 2023)]. Available online: https://finngen.gitbook.io/documentation/ Ha E, Bae SC, Kim K. Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2021 May;80(5):558-565. doi: 10.1136/annrheumdis-2020-219065. Epub 2020 Dec 11. PMID: 33310728; PMCID: PMC8053349. Wang J, Gong XH, Peng T, Wu JN. Association of Thyroid Function During Pregnancy With the Risk of Pre-eclampsia and Gestational Diabetes Mellitus. Endocr Pract. 2021 Aug;27(8):819-825. doi: 10.1016/j.eprac.2021.03.014. Epub 2021 Apr 6. PMID: 33831553. Silva JF, Vidigal PN, Galvão DD, Boeloni JN, Nunes PP, Ocarino NM, Nascimento EF, Serakides R. Fetal growth restriction in hypothyroidism is associated with changes in proliferative activity, apoptosis and vascularisation of the placenta. Reprod Fertil Dev 2012; 24:923–931. Silva JF, Ocarino NM, Serakides R. Maternal thyroid dysfunction affects placental profile of inflammatory mediators and the intrauterine trophoblast migration kinetics. Reproduction. 2014 Jun;147(6):803-16. doi: 10.1530/REP-13-0374. Epub 2014 Feb 17. PMID: 24534949. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018 May;14(5):259-269. doi: 10.1038/nrendo.2018.10. Epub 2018 Feb 23. PMID: 29472712; PMCID: PMC6013028. Additional Declarations No competing interests reported. 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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-3883932","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268541414,"identity":"cdfea3d0-2a1c-4164-ab7d-f3e2fd5d96cc","order_by":0,"name":"Yafei XIE","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yafei","middleName":"","lastName":"XIE","suffix":""},{"id":268541415,"identity":"bd1b367a-8b04-4225-b55a-baf09f9f43b2","order_by":1,"name":"Qiaozhi YIN","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYBACfvbmg49/GEjYMTYcPkCcFsmeY8nGDAUWycyNxxKI02JwI8dMmOFDBWN78xkDIl12IMeMucBAgpm37czHG28Y7OR0GwjoYGw4VvZ4hoEEn2TP2c2WcxiSjc0OENDCzNi83YAHaIvhjLPbpHkYDiRuI6SFjZnBTAKohXH//TfPiNPCw8ZiJg3S0thwho04LRI8bMmGQL8kAz1lbDnHgAi/2N9/fPDBhz91oKh8eONNhZ0cQS1oVhIbNUhaSNUxCkbBKBgFIwIAAA8TRGpqSFKFAAAAAElFTkSuQmCC","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Qiaozhi","middleName":"","lastName":"YIN","suffix":""}],"badges":[],"createdAt":"2024-01-21 07:17:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3883932/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3883932/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50186126,"identity":"53bc9d26-b795-40af-9d13-5b379fe262d9","added_by":"auto","created_at":"2024-01-25 20:38:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":157936,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of MR design\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/a97895e7fa77ba1ea36a22a0.png"},{"id":50186123,"identity":"73bbf9e4-3d5d-41ce-bcc6-c63fa5b1d4c5","added_by":"auto","created_at":"2024-01-25 20:38:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32483,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of the distribution of preeclampsia or eclampsia as an outcome to estimate the individual prevalence of hypothyroidism.Three independent MR methodologies' trend lines show a causal relationship. Weighted median (light green), MR Egger (dark blue), and inverse variance weighted (light blue).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/52d4cd199aae5e4d1440511b.png"},{"id":50186883,"identity":"1c6f903b-fcf3-40cb-aa1e-4c428d4ee7c1","added_by":"auto","created_at":"2024-01-25 20:46:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":70154,"visible":true,"origin":"","legend":"\u003cp\u003eLeave-one-out sensitivity analysis of the causal relationship between hypothyroidism and pre-eclampsia or eclampsia\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/2b2cf0e411ea9c9e400e1b2b.png"},{"id":50186127,"identity":"a728368d-d40c-4fc0-a03e-d389bba04db8","added_by":"auto","created_at":"2024-01-25 20:38:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":259817,"visible":true,"origin":"","legend":"\u003cp\u003eThree potential mechanisms by which hypothyroidism is positively associated with pre-eclampsia or eclampsia\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/8177e7a02e67d0c25c5e857e.png"},{"id":56045593,"identity":"231be821-8a2f-417f-81d0-399f22674d22","added_by":"auto","created_at":"2024-05-07 21:17:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1196713,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/e319ffa8-9624-40ad-b2a7-386e6e6dd156.pdf"},{"id":50186125,"identity":"81dd89a8-55a4-4237-8cf8-dc7ed36f6f6f","added_by":"auto","created_at":"2024-01-25 20:38:25","extension":"csv","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":22427,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformationTable1.csv","url":"https://assets-eu.researchsquare.com/files/rs-3883932/v1/7708f45c7e953be9026dce57.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"Hypothyroidism and Preeclampsia or Eclampsia: A Mendelian Randomization Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHypertension in pregnancy is a prevalent complication, encompassing gestational hypertension, preeclampsia or eclampsia, chronic hypertension complicated by preeclampsia, and chronic hypertension in pregnancy. Among these conditions, preeclampsia or eclampsia significantly impacts the well-being of both mothers and infants, resulting in approximately 46,000 maternal deaths and 500,000 fetal or neonatal deaths annually [1]. Hypertensive disorders of pregnancy are the second leading cause of maternal mortality worldwide (following hemorrhage), accounting for 14% of deaths. It is estimated that over 30\u0026nbsp;billion women and children globally face an increased risk of long-term health issues due to prior exposure to pre-eclampsia [2]. The pathogenesis of pre-eclampsia or eclampsia is intricate; however, it clinically manifests through three key features: hypertension, edema, and proteinuria. Severe cases can lead to hypoxia as well as edema and necrosis in vital organs such as the heart, liver, kidneys, and brain among pregnant women [3]. Existing research has linked preeclampsia or eclampsia with potential risk factors like systemic lupus erythematosus (SLE), chronic hypertension diabetes mellitus ,and body mass index (BMI) [4]. Despite decades of investigation into its etiology\u0026mdash;particularly full-term and postpartum cases\u0026mdash;the causes behind preeclampsia or eclampsia remain unknown. Preventive therapy only slightly reduces the risk for women; therefore identifying more reliable risk variables becomes crucial for early recognition and prediction of pre-eclamptic conditions.\u003c/p\u003e \u003cp\u003eHypothyroidism (short for hypothyroidism) is a metabolic disorder in which the synthesis and secretion of thyroid hormone (TH) is reduced due to a decrease in thyroid function or other causes[5].The risk of primary hypothyroidism is ten times higher in women than in men [6]. Preeclampsia or eclampsia may be increased in women with hypothyroidism before or during pregnancy, according to recent observational studies. A cohort study involving 46,528 pregnant women found that subclinical hypothyroidism during pregnancy was linked to a higher risk of preeclampsia [7].\u003c/p\u003e \u003cp\u003eThe aim of this study was to determine whether there is a causal relationship between hypothyroidism and preeclampsia or eclampsia. Randomised controlled clinical trials (RCTs) are the gold standard for determining causality, however RCTs have drawbacks since they are susceptible to common confounders including behavioral and environmental exposures [8].MR is a measure of causality of disease-related risk factors using an index of genetic variance In order to reduce the danger of bias brought on by confounding bias or reverse causality inherent in observational research[8].\u003c/p\u003e \u003cp\u003eThus, if the assumptions underlying the Mendelian randomisation approach hold true, the use of genetic variants known to affect hypothyroidism as their proxy instrumental variables (IVs) may provide indirect evidence for a causal effect of hypothyroidism on the risk of pre-eclampsia or eclampsia in pregnancy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine the cause-and-effect relationship between hypothyroidism and preeclampsia or eclampsia, we conducted a two-sample MR. SNP was used as an instrumental variable. There are three crucial presumptions that must always be true in order to optimize the accuracy of the results. First, the selected IVs are associated with risk factors (hypothyroidism). Second, IVs is not associated with confounders between exposure (hypothyroidism) and outcome（preeclampsia or eclampsia). Third, IVs has no direct effect on outcome (preeclampsia or eclampsia), but only affect outcome through exposure (Hypothyroidism).\u0026nbsp;（Figure 1）\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData sources\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Finnish database (FinnGen Consortium) provides a reliable tool for MR analyses [9]. In our study, summary-level statistics for hypothyroidism were obtained from a large-scale meta-analysis of the publicly available Finnish database (FinnGen Consortium) version R9, which involves exposure data hypothyroidism (26,306 cases and 187,684 controls,16,380,461SNPs), and outcome data pre-eclampsia or eclampsia ( 3903 cases and 114,735 controls,16,379,723SNPs).A threshold of P \u0026lt; 0.05 was used to select SNPs and all SNPs and associated data were obtained from studies that analysed only populations of European descent separately in order to remove population stratification bias.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic instrumental variable selection criteria\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSNPs with strong associations (P\u0026lt;0.05) and independent inheritance (R2 \u0026lt; 0.001, kb = 10, 000) were selected from the hypothyroidism and pre-eclampsia or eclampsia GWAS databases with no evidence of linkage disequilibrium (LD) in the pooled RA or infertility GWAS data.In addition, it is of genome-wide significance to see if these SNPs are associated with potential risk factors from the PhenoScanner database and to remove SNPs that are associated with these potential confounders. (http://www.phenoscanner.medschl.cam.ac.uk/). We estimate IVs strength using the F-statistic to prevent bias brought on by weak IVs. F\u0026gt;10 indicates that the instrument has sufficient strength, which means that the IVs has sufficient estimation effect on the subsequent MR analysis without weak instrumental bias. When F\u0026lt;10, it indicates a weak SNP and should be eliminated.（R2 stands for the exposure variance explained by each IVs, N for the GWAS sample size, and K for the quantity of SNPs examined by MR.）\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"399\" height=\"51\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMR analysis\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe employed the MR-Egger, weighted median, and random effects inverse variance weighting (IVW) in the MR analysis.The principal method of MR analysis used the IVW methodology to evaluate the causal effects between the exposure and the result since it gave accurate causal estimates in the absence of directional pleiotropy[10]. MR-Egger and weighted median were used to complement the analysis. For IVs with P \u0026lt; 0.05 from the IVW analysis, we performed MR-PRESSO with the MRPRESSO package, which detects, removes potentially polymorphic IVs (outliers) and provides estimates adjusted for outliers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted tests for heterogeneity and pleiotropy to ensure the stability of the results of the MR analysis. Cochran\u0026apos;s Q test was used to calculate the level of heterogeneity, and MR-Egger regression and IVW methods were used to detect heterogeneity in IVs, with P\u0026lt;0.05 reflecting the presence of considerable heterogeneity. We checked for pleiotropy by MR-Egger intercept regression, and P \u0026lt; 0.05 was considered significant pleiotropy, and then the study results were unreliable. In addition, we also conducted a \u0026quot;leave-one-out\u0026quot; sensitivity analysis, in which one SNP was sequentially missing from the MR reanalysis to singling out the potential effects of SNPs. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, the visualization results of the MR analysis are presented through scatter plots and forest plots. The analysis was performed using R software (4.2.3) and RStudio (2023.03.0), as well as the R packages TwoSampleMR and MR-PRESSO.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-one SNPs extracted in preeclampsia or eclampsia were identified as eligible IVs (LD\u0026lt;0.001) (p\u0026lt; 5e-08) and F\u0026gt;10. Detailed information is provided in Supplementary Information Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMR analysis results\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo-sample MR analysis showed a strong causal relationship between hypothyroidism and preeclampsia or eclampsia, presenting positive results. The random-effects model IVW [OR, 1.105; 95% CI, 1.02-1.12; p\u0026lt;0.05], and the weighted median (Weighted median) [OR, 1.13; 95% CI, 1.01-1.26; p\u0026lt;0.05] obtained OR estimates similar to those of the IVW method but did not find a significant MR Egger correlation. The results of the three MR analysis methods (Table 2). visualisation of the MR results was demonstrated by scatter plots (Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 Results of MR analysis of hypothyroidism and pre-eclampsia or eclampsia\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.72654690618762%\" valign=\"top\" style=\"width: 38.5845%;\"\u003e\n \u003cp\u003eMethods\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.159680638722556%\" valign=\"top\" style=\"width: 21.2329%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.95808383233533%\" valign=\"top\" style=\"width: 21.9178%;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.365269461077844%\" valign=\"top\" style=\"width: 18.2648%;\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.72654690618762%\" valign=\"top\" style=\"width: 38.5845%;\"\u003e\n \u003cp\u003eMR Egger\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.159680638722556%\" style=\"width: 21.2329%;\"\u003e\n \u003cp\u003e1.219\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.95808383233533%\" style=\"width: 21.9178%;\"\u003e\n \u003cp\u003e0.998-1.490\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.365269461077844%\" style=\"width: 18.2648%;\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.72654690618762%\" valign=\"top\" style=\"width: 38.5845%;\"\u003e\n \u003cp\u003eWeighted median\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.159680638722556%\" style=\"width: 21.2329%;\"\u003e\n \u003cp\u003e1.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.95808383233533%\" style=\"width: 21.9178%;\"\u003e\n \u003cp\u003e1.007-1.262\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.365269461077844%\" style=\"width: 18.2648%;\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.72654690618762%\" valign=\"top\" style=\"width: 38.5845%;\"\u003e\n \u003cp\u003eInverse variance weighted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.159680638722556%\" valign=\"top\" style=\"width: 21.2329%;\"\u003e\n \u003cp\u003e1.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.95808383233533%\" valign=\"top\" style=\"width: 21.9178%;\"\u003e\n \u003cp\u003e1.017-1.120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.365269461077844%\" valign=\"top\" style=\"width: 18.2648%;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis results\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the sensitivity analysis of the causal relationship between hypothyroidism and pre-eclampsia or eclampsia, the results of MR Egger and IVW analyses were statistically significant (p\u0026lt;0.05) for the presence of heterogeneity, which was assessed using a random-effects model, and the results showed a strong association between hypothyroidism and pre-eclampsia or eclampsia (p=0.018). In addition, MR-Egger intercept regression was used to test for horizontal pleiotropy, and the results showed that horizontal pleiotropy did not exist (P=0.30). In our study, no abnormal SNPs were found using MR-PRESSO. leave-one-out plots of the causal association of hypothyroidism with preeclampsia or eclampsia showed that causal estimates were not affected by certain SNPs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(Figure 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first time that a causal relationship between hypothyroidism and preeclampsia or eclampsia has been analysed by two-sample MR. The results indicate a possible causative link between hypothyroidism and pre- or eclampsia as well as a risk factor for both conditions. This result is consistent with previous observational studies, in which women with hypothyroidism were found to be more likely to develop preeclampsia or eclampsia in a retrospective study based on a population of 41,647 [11].\u003c/p\u003e \u003cp\u003eDue to the following reasons, hypothyroidism is positively correlated with preeclampsia or eclampsia.firstly, impaired infiltration of extravillous trophoblasts (EVTs), resulting in \"shallow placenta implantation\" and severe lack of remodelling of the small spiral arteries of the uterus, and remodelling of the blood vessels of the metaphysis layer only, with the diameter of the spiral arteries of the uterus being 1/2 of that of a normal pregnancy, resulting in an increase in vascular resistance. The vascular resistance is increased and placental perfusion is reduced, resulting in a series of symptoms of pre-eclampsia.Animal experiments have shown that increased the population of glycogen cells in the spongiotrophoblast of hypothyroid rats interfered with the vascular development of the placental labyrinth and may prevent EVT from migrating toward the decidua [12].Therefore, it is reasonable to assume that Insufficient EVT invasion in patients with hypothyroidism leads to an increased risk of preeclampsia or eclampsia.Secondly, vascular endothelial growth factor (VEGF) has emerged as an important biomarker for preeclampsia.Maternal hypothyroidism in rats has been found to lead to reduced placental T4 and T3 levels, which reduces the expression of pro-angiogenic factors such as foetal liver kinase (FLK1) and VEGF, resulting in impaired angiogenesis and insufficient remodelling of spiral arteries, triggering pre-eclampsia or eclampsia [13].It is thus hypothesised that down-regulation of VEGF expression in patients with hypothyroidism may induce pre-eclampsia or eclampsia during pregnancy.Finally, hypothyroidism results in elevated levels of serum thyroid stimulating hormone (TSH), decreased levels of the vasodilator nitric oxide (NO), disturbed lipid metabolism, lipid aggregation, increased blood viscosity, decreased vascular elasticity, and elevated systolic blood pressure,leading to an increase in systemic vascular resistance and the onset of pre-eclampsia or eclampsia[14].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAlthough the mechanisms described above suggest a possible causal relationship between hypothyroidism and preeclampsia or eclampsia, these hypotheses have not been thoroughly tested due to the lack of robust RCTs providing strong evidence.\u003c/p\u003e \u003cp\u003eThe advantage of two-sample MR in our study is that SNPs are distributed randomly at conception, and the method is not subject to confounding factors and reverse causal associations in traditional epidemiologic studies based on whole-genome sequencing data. Furthermore, genotype-disease associations are used to represent the role of exposing factors on the disease and to better reveal the potential causal effects between hypothyroidism and preeclampsia or eclampsia. This study is the first to show that women with hypothyroidism may be at risk for preeclampsia or eclampsia that is challenging to modify at the level of genes and genetic variations. Our findings provide important literature support for future research in this area, but further studies are still needed to explain the mechanisms involved.\u003c/p\u003e \u003cp\u003eThere are still shortcomings in our study. First, the population we analyzed was limited to Europeans. Although this makes it easier for us to eliminate the population division bias and ensure the reliability of the MR analysis results, the causal effect of hypothyroidism and preeclampsia or eclampsia in other populations remains unknown. Second, our study suggests that hypothyroidism causes preeclampsia or eclampsia in terms of genetic variation, but the underlying mechanisms require further investigation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis is the first study to use two-sample MR analysis to address the causal relationship between hypothyroidism and preeclampsia or eclampsia. Our research provides evidence that hypothyroidism increases the risk of preeclampsia or eclampsia in pregnant women and that the risk ratio is directly connected.Our findings could help women of childbearing age with hypothyroidism to intervene early before preparing for pregnancy with the expectation of reducing the risk of preeclampsia or eclampsia. Early diagnosis of hypothyroidism during pregnancy would have a preventive effect on the development and progression of preeclampsia or eclampsia, thereby improving the quality of maternal and infant survival and reducing maternal mortality.Early detection of hypothyroidism during pregnancy might have a preventative effect on the onset and progression of preeclampsia or eclampsia, improving the quality of maternal and newborn survival and lowering maternal mortality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll original studies acquired ethical review approval and informed consent.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are publicly available.The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potenContributors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Chengdu Science and Technology Bureau(2021-YF05-02042-SN).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYFX designed the study, wrote the first draft of the manuscript and verified the underlying data. QZY conducted statistical analysestial conflict of interest.All authors contributed to the article and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMagee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J Med. 2022 May 12;386(19):1817-1832. doi: 10.1056/NEJMra2109523. PMID: 35544388.\u003c/li\u003e\n \u003cli\u003eDavis, E. et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. \u003cem\u003ePediatrics\u003c/em\u003e 129, e1552 (2012).\u003c/li\u003e\n \u003cli\u003eViana-Mattioli S, Fonseca-Alaniz MH, Pinheiro-de-Sousa I, Krieger JE, Sandrim VC. Missing links in preeclampsia cell model systems of endothelial dysfunction. Trends Mol Med. 2023 Jul;29(7):541-553. doi: 10.1016/j.molmed.2023.04.003. Epub 2023 May 10. PMID: 37173223.\u003c/li\u003e\n \u003cli\u003eDimitriadis E, Rolnik DL, Zhou W, Estrada-Gutierrez G, Koga K, Francisco RPV, Whitehead C, Hyett J, da Silva Costa F, Nicolaides K, Menkhorst E. Pre-eclampsia. Nat Rev Dis Primers. 2023 Feb 16;9(1):8. doi: 10.1038/s41572-023-00417-6. Erratum in: Nat Rev Dis Primers. 2023 Jul 3;9(1):35. PMID: 36797292.\u003c/li\u003e\n \u003cli\u003eHeged\u0026uuml;s L, Bianco AC, Jonklaas J, Pearce SH, Weetman AP, Perros P. Primary hypothyroidism and quality of life. Nat Rev Endocrinol. 2022 Apr;18(4):230-242. doi: 10.1038/s41574-021-00625-8. Epub 2022 Jan 18. PMID: 35042968; PMCID: PMC8930682.\u003c/li\u003e\n \u003cli\u003eTeumer, A. et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. \u003cem\u003eNat. Commun.\u003c/em\u003e 9, 4455 (2018).\u003c/li\u003e\n \u003cli\u003eToloza FJK, Derakhshan A, M\u0026auml;nnist\u0026ouml; T, Bliddal S, Popova PV, Carty DM, Chen L, Taylor P, Mosso L, Oken E, Suvanto E, Itoh S, Kishi R, Bassols J, Auvinen J, L\u0026oacute;pez-Bermejo A, Brown SJ, Boucai L, Hisada A, Yoshinaga J, Shilova E, Grineva EN, Vrijkotte TGM, Sunyer J, Jim\u0026eacute;nez-Zabala A, Ria\u0026ntilde;o-Galan I, Lopez-Espinosa MJ, Prokop LJ, Singh Ospina N, Brito JP, Rodriguez-Gutierrez R, Alexander EK, Chaker L, Pearce EN, Peeters RP, Feldt-Rasmussen U, Guxens M, Chatzi L, Delles C, Roeters van Lennep JE, Pop VJM, Lu X, Walsh JP, Nelson SM, Korevaar TIM, Maraka S. Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis. Lancet Diabetes Endocrinol. 2022 Apr;10(4):243-252. doi: 10.1016/S2213-8587(22)00007-9. Epub 2022 Mar 4. PMID: 35255260; PMCID: PMC10314731.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Vanni VS, De Lorenzo R, Privitera L, Canti V, Vigan\u0026ograve; P, Rovere-Querini P. Safety of fertility treatments in women with systemic autoimmune diseases (SADs). Expert Opin Drug Saf. 2019 Sep;18(9):841-852. doi: 10.1080/14740338.2019.1636964. Epub 2019 Jul 12. PMID: 31238745.\u003c/li\u003e\n \u003cli\u003eThe FinnGen Consortium FinnGen Documentation of R9 Release. 2023. [(accessed on 23 June 2023)]. Available online: \u003ca href=\"https://finngen.gitbook.io/documentation/\"\u003ehttps://finngen.gitbook.io/documentation/\u003c/a\u003e\u003c/li\u003e\n \u003cli\u003eHa E, Bae SC, Kim K. Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2021 May;80(5):558-565. doi: 10.1136/annrheumdis-2020-219065. Epub 2020 Dec 11. PMID: 33310728; PMCID: PMC8053349.\u003c/li\u003e\n \u003cli\u003eWang J, Gong XH, Peng T, Wu JN. Association of Thyroid Function During Pregnancy With the Risk of Pre-eclampsia and Gestational Diabetes Mellitus. Endocr Pract. 2021 Aug;27(8):819-825. doi: 10.1016/j.eprac.2021.03.014. Epub 2021 Apr 6. PMID: 33831553.\u003c/li\u003e\n \u003cli\u003eSilva JF, Vidigal PN, Galv\u0026atilde;o DD, Boeloni JN, Nunes PP, Ocarino NM, Nascimento EF, Serakides R. Fetal growth restriction in hypothyroidism is associated with changes in proliferative activity, apoptosis and vascularisation of the placenta. Reprod Fertil Dev 2012; 24:923\u0026ndash;931.\u003c/li\u003e\n \u003cli\u003eSilva JF, Ocarino NM, Serakides R. Maternal thyroid dysfunction affects placental profile of inflammatory mediators and the intrauterine trophoblast migration kinetics. Reproduction. 2014 Jun;147(6):803-16. doi: 10.1530/REP-13-0374. Epub 2014 Feb 17. PMID: 24534949.\u003c/li\u003e\n \u003cli\u003eSinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018 May;14(5):259-269. doi: 10.1038/nrendo.2018.10. Epub 2018 Feb 23. PMID: 29472712; PMCID: PMC6013028.\u003c/li\u003e\n\u003c/ol\u003e"}],"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":"Hypothyroidism, Preeclampsia or eclampsia, Mendelian randomization","lastPublishedDoi":"10.21203/rs.3.rs-3883932/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3883932/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eNumerous observational studies have consistently demonstrated an elevated risk of preeclampsia or eclampsia among individuals with hypothyroidism; however, the establishment of a causal relationship between these conditions has remained inconclusive due to inherent confounding biases in traditional retrospective and prospective studies. This study employs two-sample Mendelian randomization to investigate the causal impact of hypothyroidism on preeclampsia and eclampsia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIndependent single nucleotide polymorphisms (SNPs) strongly associated with hypothyroidism were selected as instrumental variables from a FinnGen Consortium comprising 26,306 hypothyroid patients of European origin and 187,684 controls, and the pooled statistics for pre-eclampsia or eclampsia included 3,903 cases and 114,735 controls. Inverse variance-weighted (IVW) was used as the primary estimate, supplemented by MR-Egger and weighted medians. Heterogeneity and horizontal polymorphisms were assessed using MR-PRESSO to remove biased SNPs, Cochran's Q test and MR-Egger intercept analysis.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eIndividuals with higher genetic liability for hypothyroidism were more likely to develop preeclampsia or eclampsia (OR,1.105; 95%CI,1.02\u0026ndash;1.12; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe discovered that the risk of preeclampsia or eclampsia in women with genetically indicated hypothyroidism has existed since development. Our findings may encourage hypothyroid women of reproductive age to seek treatment before trying to get pregnant in order to lower their risk of preeclampsia or eclampsia during pregnancy.\u003c/p\u003e","manuscriptTitle":"Hypothyroidism and Preeclampsia or Eclampsia: A Mendelian Randomization Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-25 20:38:20","doi":"10.21203/rs.3.rs-3883932/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":"09335a41-dfe0-4ab0-9dc3-7ef046079c7a","owner":[],"postedDate":"January 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-07T21:09:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-25 20:38:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3883932","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3883932","identity":"rs-3883932","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}