Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study

Can periodontitis lead to adverse pregnancy outcomes：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 Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study Tianxing Yan, Yiping Wei, Wenjie Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3628808/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 Objectives We aim to investigate the potential uni-directional association from periodontitis to the Adverse pregnancy outcomes (APOs) by Mendelian randomization (MR) method. Materials and Methods The present study used genetic instruments for periodontitis as exposures. The outcomes included low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB). The data were collected from the FinnGen consortium R9 datasets and second release analysis in Neale lab of UK Biobank data. Causal analysis uses the inverse variant weighted (IVW), MR Egger and Weighted median methods. A set of sensitivity analyses also be used to test the robustness of the results comprehensive. Results The IVW analysis indicate no association of genetically predicted periodontitis will cause the APOs (LBW [IVW OR = 1.003, P = 0.619], PD [IVW OR = 0.984, P = 0.630], PET [IVW OR = 1.005, P = 0.895], SAB [IVW OR = 0.964, P = 0.221]). Results of the other methods did not show significant differences. Sensitivity analyses showed that horizontal pleiotropy could not distort the results of the causal estimation. Conclusions The outcomes indicated there was no potential causal effect of periodontitis on APOs. Clinical Relevance Mendelian Randomization studies effectively prevent reverse causality and confounding factors. It complements previous studies, thereby informing clinical diagnosis and deepening understanding of periodontitis and systemic diseases. Periodontitis Adverse pregnancy outcomes Mendelian randomization GWAS Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Periodontitis is a chronic multi-factorial inflammatory disease caused by plaque biofilm that result in irreversible destruction of alveolar bone and connective tissue of the tooth[ 1 ]. With a high overall prevalence, periodontitis affects 45 to 50 percent of the world's population[ 2 ]. Adverse pregnancy outcomes (APOs) covers all pathological pregnancy and childbirth complications, which result in maternal, fetal, and neonatal deaths mainly[ 3 ]. Several observational studies have shown that pregnant women with periodontitis have a higher risk of APOs than healthy ones. In 1996, Offenbacher found for the first time that pregnant women with periodontitis had a 7.5 times higher risk of delivering preterm and low-birth-weight babies than healthy women[ 4 ]. Subsequent studies have proposed that periodontitis and a sustained immune response may lead to APOs such as low birth weight, preeclampsia, preterm labor[ 5 , 6 ]. However, a prospective study showed that periodontal conditions in non-smoking pregnant women in the first trimester of pregnancy did not cause preterm labor or low birth weight[ 7 ]. Previous studies have been limited by many confounding factors, thus requiring new methods to explore whether periodontitis can lead to APOs. Mendelian randomization (MR) genetic variation is an effective method using genetic proxies that are specifically related to a particular evaluate to explore the the causal effect between risk factors and the results[ 8 ]. Using instrumental variables (IV) to analyze the causal relationship[ 9 ], the results will not be affected by confounding and reverse causation. Therefore we conducted a two-sample MR analysis to explore whether periodontitis will cause four most common APOs, including low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB). Materials and methods To validly demonstrate a causal effect, the IVs in MR must follow three assumptions[ 10 , 11 ]: (1) correlation hypothesis: IVs must correlate strongly with exposure; (2) exclusivity hypothesis: IVs must be independent of outcomes; (3) independence hypothesis: IVs be independent of confounding factors. Figure 1 shows a schematic of this Mendelian randomization study. Data sources Data of periodontitis, PD, PET and SAB were obtained from the GWAS results on the FinnGen consortium R9 ( https://www.finngen.fi/en )[ 12 ]. FinnGen Project is lead by the University of Helsinki, and all the study was approved by the ethics committee and institutional review board. According to the Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) definition, comparable standards was used to categorize periodontitis cases[ 13 ]. Detailed data in the FinnGen consortium can be found on the FinnGen webpage. The outcome of the birthweight was using data of the weight of the first-born child to measure the LBW from the Neale lab second release analysis of UK Biobank data ( http://www.nealelab.is/uk-biobank/ ). We conducted a two-sample MR study to determine if the periodontitis is the cause factor to APOs using the GWAS summary data on chronic periodontitis (4434 cases and 259,234 controls), PD (8,507 cases and 162,777 controls), PET (7,212 cases and 194,266 controls), SAB (9,113 cases and 89,340 controls), first child birthweight (155,202 cases). All the data were obtained from the samples were all from people of European ancestry (Table S1 ). Instrumental variable selection Ensuring the accuracy of conclusions, we perform the following quality control steps. We control locus-wide significance level (p < 1 × 10 − 5 ) in selecting instrumental variables (IVs) to obtain a more comprehensive result[ 14 ]. Included genetic variants may have potential linkage disequilibrium (LD), we excluded the SNPs by using the PLINK clumping method (r2 > 0.001 and clump window < 10,000 kb) to avoid the impact. During the harmonizing process, we pick out palindromic SNPs to make sure the effects of SNPs equivalent between exposure and outcome. To assess weak instrumental variable bias, we calculated the F-statistics of the IVs that we used. The F-statistic for periodontitis ranged from 19.53 to 27.62, fulfilling the assumption of F > 10 for MR analysis[ 15 ]. Mendelian randomization analysis The two-sample MR analysis perform IVW method, MR Egger and Weighted median method to estimate the causal effect of periodontitis with APOs[ 16 ]. And the IVW methd is the primary method for its strong ability to detect causality[ 17 ]. Sensitivity analysis was used to ensure the accuracy of the results. The MR-Egger regression was used to confirm the presence of horizontal pleiotropy among the selected SNPs[ 18 ]. If horizontal pleiotropy was detected, the analyses were conducted again after excluding the pleiotropy SNPs. Cochran's Q test was performed to evaluate the heterogeneity among SNPs[ 19 ]. The effects of a single SNP on the overall estimates were assessed by leave-one-out sensitivity analysis[ 20 ]. The strength of the selected IVs was evaluated through the F-statistic to determine whether the estimates of causality were affected by weak instrumental bias. The weak IVs need to be pick out if F statistics < 10[ 21 ].All steps were performed by using R package TwoSampleMR in R (version 4.1.2)[ 22 ]. For the forest plot drawing, we used the R package Forestplot[ 23 ]. Results After harmonizing the data of periodontitis with APOs, we obtained 25 SNPs of periodontitis as genetic instruments. The IVW analysis result indicated there was no causal inference of periodontitis on four kinds of APOs, as well as in the MR-Egger regression and weighted median methods (Figs. 2 and 3 and Table S2). All the F-statistic values wew greater than 10, and the average value is 21.42 (Table S4). SNPs used as instruments and their association with the outcomes are showed in Table S5.The MR-Egger analysis did not show horizontal pleiotropy (periodontitis on risk of SAB (intercept = -0.01032, P = 0.40747 ), GDM (intercept = 0.00495, P = 0.73047 ), PET (intercept = 0.01901, P = 0.23085 ), PD (intercept = -0.00650, P = 0.64093 ), LBW (intercept = -0.00016, P = 0.95315 ) ) (Table S3). There is no obvious abnormalities in leave-one-out analysis results (Fig. 4 ). Our results do not support periodontitis is the causal factor to APOs. Discussion Our results showed that there was not a causal inference of genetically defined periodontitis to four types of APOs, which is contradictory to the observational studies before. The extant studies indicate periodontitis has a prospective effect on the progression of APOs. One study hypothesized that changes in progesterone and estrogen levels during pregnancy would affect the chemotaxis of gingival tissue cells, enzymes, cytokines, and antioxidants, which would contribute to the inflammatory response to gingival tissue and the subgingival microbiota. These changes indirectly lead to increased gingival inflammation[ 24 ]. It has also been shown that periodontal disease causes inflammatory mediators such as cytokines or pathogens to enter the amniotic fluid or embryonic tissues through the blood stream[ 25 ].However, these phenomena may be the first manifestations of more serious diseases, such as adult cardiovascular and metabolic diseases[ 26 ]. Although numerous observational studies have shown that periodontitis during pregnancy can promote the occurrence of low birth weight and premature birth in newborns[ 5 , 6 ]. But at the same time, many researchers have also observed that periodontitis does not necessarily lead to adverse pregnancy outcomes[ 7 ]. Meanwhile, many systematic reviews have found that improving maternal periodontal health does not necessarily improve adverse pregnancy outcomes[ 27 ]. We believe that periodontitis may not be the most important cause of adverse pregnancy outcomes, and the occurrence of periodontitis may indicate more serious physical problems. Therefore, GWAS research with larger scale and more accurate classification is more needed. This study has irreplaceable advantages. First, Mendelian Randomization can simulate randomized control trials to discover the causality, reducing a large amount of time cost, and money. Second, compared with conventional designed observational studies, the genetic potency of the IVs can prevent the effect of reverse causal effect and confounding bias. Third, we perform the first MR analysis focused on the causality between APOs and periodontitis. Considering the high prevalence of periodontitis in the pregnant population worldwide, revealing the causality effect between two diseases is instructive. Fourth, we use four common types of APOs so we can gain more nuanced conclusions. However, our study also has limitations due to the lack of data. We've only studied the relationship between European populations, so the consistency and scalability among other populations still need to be validated. The other types of the oral diseases should also be focused on. GWAS studies based on inter-age and inter-ethnicity should be continued in the future. We used Mendelian randomization method for the first time to test the possible role of periodontitis in adverse pregnancy outcomes, and used different testing methods to ensure the accuracy of the results. It was ultimately found that existing research data cannot prove that periodontitis at the genetic level can lead to adverse pregnancy outcomes. Conclusion Based on the different MR analysis methods, there is no evidence to support a causal effect on periodontitis to APOs. Declarations Acknowledgements We want to acknowledge the participants and investigators of the FinnGen study and developers of the R. packages we used in this study. Declaration or funding This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors. Author contributions All authors have made substantial contributions to the conception and design of the study. Yan Tianxing was involved in data collection, data analysis and visualization. Wei Yiping were involved drafting the manuscript, and revising it critically. Hu Wennjie was involved in project administration and giving final approval for the version to be published. Ethics declarations Ethics approval FinnGen Project is lead by the University of Helsinki. The relevant study from UK Biobank database is conducted by Neale lab second release analysis. All the study was approved by the ethics committee and institutional review board. Conflict of interest statement The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Data available statement The summary statistics of the GWAS studies can be found in supplementary material (Table S1). References Genco RJ and Sanz M (2020) Clinical and public health implications of periodontal and systemic diseases: An overview. 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Biological Conservation 260:108849. doi: https://doi.org/10.1016/j.biocon.2020.108849 Wu M, Chen S-W and Jiang S-Y (2015) Relationship between Gingival Inflammation and Pregnancy. Mediators of Inflammation 2015. doi: 10.1155/2015/623427 Starzynska A, Wychowanski P, Nowak M, Sobocki BK, Jereczek-Fossa BA and Slupecka-Ziemilska M (2022) Association between Maternal Periodontitis and Development of Systematic Diseases in Offspring. International Journal of Molecular Sciences 23. doi: 10.3390/ijms23052473 Kim CS, Park JS, Park J, Nam JS, Kang ES, Ahn CW, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB and Kim DJ (2006) The relation between birth weight and insulin resistance in Korean adolescents. Yonsei Medical Journal 47:85–92. doi: 10.3349/ymj.2006.47.1.85 Fogacci MF, Vettore MV and Thome Leao AT (2011) The Effect of Periodontal Therapy on Preterm Low Birth Weight A Meta- Analysis . Obstetrics and Gynecology 117:153–165. doi: 10.1097/AOG.0b013e3181fdebc0 Additional Declarations No competing interests reported. Supplementary Files COISupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3628808","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":251122269,"identity":"238e2f4c-d361-46cc-884e-d6d7145a0379","order_by":0,"name":"Tianxing Yan","email":"","orcid":"","institution":"Peking University School and Hospital of Stomatology \u0026 National Center for Stomatology \u0026 National","correspondingAuthor":false,"prefix":"","firstName":"Tianxing","middleName":"","lastName":"Yan","suffix":""},{"id":251122270,"identity":"3a3ecfb1-a1f6-4cfd-8d30-d37dd58187b1","order_by":1,"name":"Yiping Wei","email":"","orcid":"","institution":"Peking University School and Hospital of Stomatology \u0026 National Center for Stomatology \u0026 National Clinical Research Center for Oral Diseases \u0026 National Engineering Research Center of Oral Biomaterials and Digital Medical Devices","correspondingAuthor":false,"prefix":"","firstName":"Yiping","middleName":"","lastName":"Wei","suffix":""},{"id":251122271,"identity":"5f4e2b27-aaad-448b-930c-29fe356004fb","order_by":2,"name":"Wenjie Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3Pv2uDQBTA8XcITieuL1iSf+FE6A/SP0YJ6GJDoJCxtctNzuXAv6IU7GoR7BIyW+pQ6B/QQhYhKfQ0oZNKuxV63+F8wn3gHYBK9Qdj7UkRTNDb0SVR89F/QEbR70gzZAey/x0gJxjab4uj07Hzwv1RvYO5drti8LHMwUyiTnImQscRFJ3jqigsg8MlSUJGxDoHrLLuxcqL1KIUvbQMuCXf4d1Iohk8B4ZuH3nYSnJ9LwLeLLYnn8Mk1SRxGfoFUv1AyBBZvW+axWxRFbOpwVG+xV88xuuAYtlDnnxvY8RXEzPh9nO9O5/byezutV5Ox6boJm0klge2I4IdAWRyov33m+pvAjAZvqpSqVT/sC8ICFoZPMzNjwAAAABJRU5ErkJggg==","orcid":"","institution":"Peking University School and Hospital of Stomatology \u0026 National Center for Stomatology \u0026 National Clinical Research Center for Oral Diseases \u0026 National Engineering Research Center of Oral Biomaterials and Digital Medical Devices","correspondingAuthor":true,"prefix":"","firstName":"Wenjie","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2023-11-18 05:14:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3628808/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3628808/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":46878178,"identity":"ffbc8dd6-73be-4bc2-b33a-2e1d02a26fb9","added_by":"auto","created_at":"2023-11-21 21:22:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":251918,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic design of a two-sample Mendelian randomization study of periodontitis and APOs. This design assumes a unidirectional association between periodontitis and APOs, but no association with confounders. Genetic variants can influence APOs through periodontitis. SNP stands for single nucleotide diversity.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/137b8eee3ec74bc32aa0fbd7.jpg"},{"id":46878180,"identity":"7d83b739-0a56-44a4-ad6c-29b8fd4ebd1d","added_by":"auto","created_at":"2023-11-21 21:22:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208292,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot. Mendelian randomization estimates for the relationship between genetically instrumented periodontitis and APOs, and vice versa. CI, confidence interval; IVW, inverse-variance weighted; OR, odds ratio.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/c8361cc8640cfbba684195a7.jpg"},{"id":46878177,"identity":"b3597677-7ea4-4b72-8ae0-b537ba4ce6ca","added_by":"auto","created_at":"2023-11-21 21:22:25","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":427316,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of genetic association between periodontitis and APOs. A. Genetic association of periodontitis with spontaneous abortion. B. Genetic association of periodontitis with pre-eclampsia or eclampsia. C. Genetic association of periodontitis with preterm labour and delivery. D. Genetic association of periodontitis with birth weight of first child.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/68c1fa7be1c4a2575d30a7f9.jpg"},{"id":46878179,"identity":"0cbd3dde-b576-4151-91e9-2d97ed2a1fb5","added_by":"auto","created_at":"2023-11-21 21:22:25","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":560757,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Forest plots of causal effects of periodontitis-associated single nucleotide polymorphisms (SNPs) on spontaneous abortion.(B) Forest plots of causal effects of periodontitis-associated SNPs on pre-eclampsia or eclampsia.(C) Forest plots of causal effects of periodontitis-associated SNPs on preterm labour and delivery.(D) Forest plots of causal effects of periodontitis-associated SNPs on birth weight of first child.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/5b5d4c095968a5e40a6a247d.jpg"},{"id":53883855,"identity":"d3715e8c-f7fa-45e3-a7b7-f6649241bb81","added_by":"auto","created_at":"2024-04-01 18:30:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":523629,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/01ca000e-1afb-4f0a-91bd-273d00a48eff.pdf"},{"id":46878175,"identity":"90fec1df-89ec-4876-aa1b-b6962d1edda7","added_by":"auto","created_at":"2023-11-21 21:22:25","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":57245,"visible":true,"origin":"","legend":"","description":"","filename":"COISupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-3628808/v1/9b6becfc45a0ff027ce34225.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePeriodontitis is a chronic multi-factorial inflammatory disease caused by plaque biofilm that result in irreversible destruction of alveolar bone and connective tissue of the tooth[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. With a high overall prevalence, periodontitis affects 45 to 50 percent of the world's population[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Adverse pregnancy outcomes (APOs) covers all pathological pregnancy and childbirth complications, which result in maternal, fetal, and neonatal deaths mainly[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Several observational studies have shown that pregnant women with periodontitis have a higher risk of APOs than healthy ones. In 1996, Offenbacher found for the first time that pregnant women with periodontitis had a 7.5 times higher risk of delivering preterm and low-birth-weight babies than healthy women[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Subsequent studies have proposed that periodontitis and a sustained immune response may lead to APOs such as low birth weight, preeclampsia, preterm labor[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, a prospective study showed that periodontal conditions in non-smoking pregnant women in the first trimester of pregnancy did not cause preterm labor or low birth weight[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Previous studies have been limited by many confounding factors, thus requiring new methods to explore whether periodontitis can lead to APOs.\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) genetic variation is an effective method using genetic proxies that are specifically related to a particular evaluate to explore the the causal effect between risk factors and the results[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Using instrumental variables (IV) to analyze the causal relationship[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], the results will not be affected by confounding and reverse causation. Therefore we conducted a two-sample MR analysis to explore whether periodontitis will cause four most common APOs, including low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB).\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eTo validly demonstrate a causal effect, the IVs in MR must follow three assumptions[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]: (1) correlation hypothesis: IVs must correlate strongly with exposure; (2) exclusivity hypothesis: IVs must be independent of outcomes; (3) independence hypothesis: IVs be independent of confounding factors. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a schematic of this Mendelian randomization study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData sources\u003c/h2\u003e \u003cp\u003eData of periodontitis, PD, PET and SAB were obtained from the GWAS results on the FinnGen consortium R9 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.finngen.fi/en\u003c/span\u003e\u003cspan address=\"https://www.finngen.fi/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. FinnGen Project is lead by the University of Helsinki, and all the study was approved by the ethics committee and institutional review board. According to the Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) definition, comparable standards was used to categorize periodontitis cases[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Detailed data in the FinnGen consortium can be found on the FinnGen webpage. The outcome of the birthweight was using data of the weight of the first-born child to measure the LBW from the Neale lab second release analysis of UK Biobank data (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nealelab.is/uk-biobank/\u003c/span\u003e\u003cspan address=\"http://www.nealelab.is/uk-biobank/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). We conducted a two-sample MR study to determine if the periodontitis is the cause factor to APOs using the GWAS summary data on chronic periodontitis (4434 cases and 259,234 controls), PD (8,507 cases and 162,777 controls), PET (7,212 cases and 194,266 controls), SAB (9,113 cases and 89,340 controls), first child birthweight (155,202 cases). All the data were obtained from the samples were all from people of European ancestry (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInstrumental variable selection\u003c/h2\u003e \u003cp\u003eEnsuring the accuracy of conclusions, we perform the following quality control steps. We control locus-wide significance level (p\u0026thinsp;\u0026lt;\u0026thinsp;1 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;5\u003c/sup\u003e) in selecting instrumental variables (IVs) to obtain a more comprehensive result[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Included genetic variants may have potential linkage disequilibrium (LD), we excluded the SNPs by using the PLINK clumping method (r2\u0026thinsp;\u0026gt;\u0026thinsp;0.001 and clump window\u0026thinsp;\u0026lt;\u0026thinsp;10,000 kb) to avoid the impact. During the harmonizing process, we pick out palindromic SNPs to make sure the effects of SNPs equivalent between exposure and outcome. To assess weak instrumental variable bias, we calculated the F-statistics of the IVs that we used. The F-statistic for periodontitis ranged from 19.53 to 27.62, fulfilling the assumption of F\u0026thinsp;\u0026gt;\u0026thinsp;10 for MR analysis[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMendelian randomization analysis\u003c/h2\u003e \u003cp\u003eThe two-sample MR analysis perform IVW method, MR Egger and Weighted median method to estimate the causal effect of periodontitis with APOs[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. And the IVW methd is the primary method for its strong ability to detect causality[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Sensitivity analysis was used to ensure the accuracy of the results. The MR-Egger regression was used to confirm the presence of horizontal pleiotropy among the selected SNPs[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. If horizontal pleiotropy was detected, the analyses were conducted again after excluding the pleiotropy SNPs. Cochran's Q test was performed to evaluate the heterogeneity among SNPs[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The effects of a single SNP on the overall estimates were assessed by leave-one-out sensitivity analysis[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The strength of the selected IVs was evaluated through the F-statistic to determine whether the estimates of causality were affected by weak instrumental bias. The weak IVs need to be pick out if F statistics\u0026thinsp;\u0026lt;\u0026thinsp;10[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].All steps were performed by using R package TwoSampleMR in R (version 4.1.2)[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. For the forest plot drawing, we used the R package Forestplot[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAfter harmonizing the data of periodontitis with APOs, we obtained 25 SNPs of periodontitis as genetic instruments. The IVW analysis result indicated there was no causal inference of periodontitis on four kinds of APOs, as well as in the MR-Egger regression and weighted median methods (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Table S2). All the F-statistic values wew greater than 10, and the average value is 21.42 (Table S4). SNPs used as instruments and their association with the outcomes are showed in Table S5.The MR-Egger analysis did not show horizontal pleiotropy (periodontitis on risk of SAB (intercept = -0.01032, P\u0026thinsp;=\u0026thinsp;0.40747 ), GDM (intercept\u0026thinsp;=\u0026thinsp;0.00495, P\u0026thinsp;=\u0026thinsp;0.73047 ), PET (intercept\u0026thinsp;=\u0026thinsp;0.01901, P\u0026thinsp;=\u0026thinsp;0.23085 ), PD (intercept = -0.00650, P\u0026thinsp;=\u0026thinsp;0.64093 ), LBW (intercept = -0.00016, P\u0026thinsp;=\u0026thinsp;0.95315 ) ) (Table S3). There is no obvious abnormalities in leave-one-out analysis results (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Our results do not support periodontitis is the causal factor to APOs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results showed that there was not a causal inference of genetically defined periodontitis to four types of APOs, which is contradictory to the observational studies before.\u003c/p\u003e \u003cp\u003eThe extant studies indicate periodontitis has a prospective effect on the progression of APOs. One study hypothesized that changes in progesterone and estrogen levels during pregnancy would affect the chemotaxis of gingival tissue cells, enzymes, cytokines, and antioxidants, which would contribute to the inflammatory response to gingival tissue and the subgingival microbiota. These changes indirectly lead to increased gingival inflammation[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It has also been shown that periodontal disease causes inflammatory mediators such as cytokines or pathogens to enter the amniotic fluid or embryonic tissues through the blood stream[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].However, these phenomena may be the first manifestations of more serious diseases, such as adult cardiovascular and metabolic diseases[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough numerous observational studies have shown that periodontitis during pregnancy can promote the occurrence of low birth weight and premature birth in newborns[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. But at the same time, many researchers have also observed that periodontitis does not necessarily lead to adverse pregnancy outcomes[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Meanwhile, many systematic reviews have found that improving maternal periodontal health does not necessarily improve adverse pregnancy outcomes[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We believe that periodontitis may not be the most important cause of adverse pregnancy outcomes, and the occurrence of periodontitis may indicate more serious physical problems. Therefore, GWAS research with larger scale and more accurate classification is more needed.\u003c/p\u003e \u003cp\u003eThis study has irreplaceable advantages. First, Mendelian Randomization can simulate randomized control trials to discover the causality, reducing a large amount of time cost, and money. Second, compared with conventional designed observational studies, the genetic potency of the IVs can prevent the effect of reverse causal effect and confounding bias. Third, we perform the first MR analysis focused on the causality between APOs and periodontitis. Considering the high prevalence of periodontitis in the pregnant population worldwide, revealing the causality effect between two diseases is instructive. Fourth, we use four common types of APOs so we can gain more nuanced conclusions.\u003c/p\u003e \u003cp\u003eHowever, our study also has limitations due to the lack of data. We've only studied the relationship between European populations, so the consistency and scalability among other populations still need to be validated. The other types of the oral diseases should also be focused on. GWAS studies based on inter-age and inter-ethnicity should be continued in the future.\u003c/p\u003e \u003cp\u003eWe used Mendelian randomization method for the first time to test the possible role of periodontitis in adverse pregnancy outcomes, and used different testing methods to ensure the accuracy of the results. It was ultimately found that existing research data cannot prove that periodontitis at the genetic level can lead to adverse pregnancy outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on the different MR analysis methods, there is no evidence to support a causal effect on periodontitis to APOs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to acknowledge the participants and investigators of the FinnGen study and developers of the R. packages we used in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration or funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have made substantial contributions to the conception and design of the study. Yan Tianxing was involved in data collection, data analysis and visualization. \u0026nbsp;Wei Yiping were involved drafting the manuscript, and revising it critically. Hu Wennjie was involved in project administration and giving final approval for the version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinnGen Project is lead by the University of Helsinki. The relevant study from UK Biobank database is conducted by Neale lab second release analysis. All the study was approved by the ethics committee and institutional review board.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eof interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData available statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe summary statistics of the GWAS studies can be found in supplementary material (Table S1).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGenco RJ and Sanz M (2020) Clinical and public health implications of periodontal and systemic diseases: An overview. 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B, Taedoumg H, Zemagho L, Thomas S, Baya F, Saiz G, Espejo JS, Chen D, Hamilton A, Li Y, Luo T, Niu S, Xu H, Zhou Z, \u0026Aacute;lvarez-D\u0026aacute;vila E, Escobar JCA, Arellano-Pe\u0026ntilde;a H, Duarte JC, Calder\u0026oacute;n J, Bravo LMC, Cuadrado B, Cuadros H, Duque A, Duque LF, Espinosa SM, Franke-Ante R, Garc\u0026iacute;a H, G\u0026oacute;mez A, Gonz\u0026aacute;lez-M R, Id\u0026aacute;rraga-Piedrah\u0026iacute;ta \u0026Aacute;, Jimenez E, Jurado R, Oviedo WL, L\u0026oacute;pez-Camacho R, Cruz OAM, Polo IM, Paky E, P\u0026eacute;rez K, Pijachi A, Pizano C, Prieto A, Ramos L, Correa ZR, Richardson J, Rodr\u0026iacute;guez E, Rodriguez M GM, Rudas A, Stevenson P, Chudomelov\u0026aacute; M, Dancak M, H\u0026eacute;dl R, Lhota S, Svatek M, Mukinzi J, Ewango C, Hart T, Yakusu EK, Lisingo J, Makana J-R, Mbayu F, Toirambe B, Mukendi JT, Kvist L, Nebel G, B\u0026aacute;ez S, C\u0026eacute;ron C, Griffith DM, Andino JEG, Neill D, Palacios W, Pe\u0026ntilde;uela-Mora MC, Rivas-Torres G, Villa G, Demissie S, Gole T, Gonfa T, Ruokolainen K, Baisie M, B\u0026eacute;n\u0026eacute;det F, Betian W, Bezard V, Bonal D, Chave J, Droissart V, Gourlet-Fleury S, Hladik A, Labri\u0026egrave;re N, Naisso P, R\u0026eacute;jou-M\u0026eacute;chain M, Sist P, Blanc L, Burban B, Derroire G, Dourdain A, Stahl C, Bengone NN, Chezeaux E, Ondo FE, Medjibe V, Mihindou V, White L, Culmsee H, Rangel CD, Horna V, Wittmann F, Adu-Bredu S, Affum-Baffoe K, Foli E,Balinga M, Roopsind A, Singh J, Thomas R, Zagt R, Murthy IK, Kartawinata K, Mirmanto E, Priyadi H, Samsoedin I, Sunderland T, Yassir I, Rovero F, Vinceti B, H\u0026eacute;rault B,Aiba S-I, Kitayama K, Daniels A, Tuagben D, Woods JT, Fitriadi M, Karolus A, Khoon KL, Majalap N, Maycock C, Nilus R, Tan S, Sitoe A, Coronado G I, Ojo L, de Assis R,Poulsen AD, Sheil D, Pezo KA, Verde HB, Moscoso VC, Oroche JCC, Valverde FC, Medina MC, Cardozo ND, de Rutte Corzo J, del Aguila Pasquel J, Llampazo GF, Freitas L, Cabrera DG, Villacorta RG, Cabrera KG, Soria DG, Saboya LG, Rios JMG, Pizango GH, Coronado EH, Huamantupa-Chuquimaco I, Huasco WH, Aedo YTH, Pe\u0026ntilde;a JLM, Mendoza AM, Rodriguez VM, Vargas PN, Ramos SCP, Camacho NP, Cruz AP, Arevalo FR, Huaymacari JR, Rodriguez CR, Paredes MAR, Bayona LR, del Pilar Rojas Gonzales R, Pe\u0026ntilde;a MER, Revilla NS, Shareva YCS, Trujillo RT, Gamarra LV, Martinez RV, Arenas JV, Amani C, Ifo SA, Bocko Y, Boundja P, Ekoungoulou R, Hockemba M, Nzala D, Fofanah A, Taylor D, Ba\u0026ntilde;ares-de Dios G, Cayuela L, la Cerda \u0026Iacute;G-d, Mac\u0026iacute;a M, Stropp J, Playfair M, Wortel V, Gardner T, Muscarella R,Priyadi H, Rutishauser E, Chao K-J, Munishi P, B\u0026aacute;nki O, Bongers F, Boot R, Fredriksson G, Reitsma J, ter Steege H, van Andel T, van de Meer P, van der Hout P, van Nieuwstadt M, van Ulft B, Veenendaal E, Vernimmen R, Zuidema P, Zwerts J, Akite P, Bitariho R,Chapman C, Gerald E, Leal M, Mucunguzi P, Abernethy K, Alexiades M, Baker TR, Banda K, Banin L, Barlow J, Bennett A, Berenguer E, Berry N, Bird NM, Blackburn GA, Brearley F, Brienen R, Burslem D, Carvalho L, Cho P, Coelho F, Collins M, Coomes D, Cuni-Sanchez A, Dargie G, Dexter K, Disney M, Draper F, Duan M, Esquivel-Muelbert A, Ewers R, Fadrique B, Fauset S, Feldpausch TR, Fran\u0026ccedil;a F, Galbraith D, Gilpin M, Gloor E, Grace J, Hamer K, Harris D, Jeffery K, Jucker T, Kalamandeen M, Klitgaard B, Levesley A, Lewis SL,Lindsell J, Lopez-Gonzalez G, Lovett J, Malhi Y, Marthews T, McIntosh E, Melga\u0026ccedil;o K,Milliken W, Mitchard E, Moonlight P, Moore S, Morel A, Peacock J, Peh KSH, Pendry C, Pennington RT, de Oliveira Pereira L, Peres C, Phillips OL, Pickavance G, Pugh T, Qie L, Riutta T, Roucoux K, Ryan C, Sarkinen T, Valeria CS, Spracklen D, Stas S,Sullivan M, Swaine M, Talbot J, Taplin J, van der Heijden G, Vedovato L, Willcock S, Williams M, Alves L, Loayza PA, Arellano G, Asa C, Ashton P, Asner G, Brncic T,Brown F, Burnham R, Clark C, Comiskey J, Damasco G, Davies S, Di Fiore T, Erwin T,Farfan-Rios W, Hall J, Kenfack D, Lovejoy T, Martin R, Montiel OM, Pipoly J, Pitman N, Poulsen J, Primack R, Silman M, Steininger M, Swamy V, Terborgh J, Thomas D, Umunay P, Uriarte M, Torre EV, Wang O, Young K, Aymard C GA, Hern\u0026aacute;ndez L, Fern\u0026aacute;ndez RH, Ram\u0026iacute;rez-Angulo H, Salcedo P, Sanoja E, Serrano J, Torres-Lezama A, Le TC, Le TT and Tran HD (2021)Taking the pulse of Earth's tropical forests using networks of highly distributed plots. Biological Conservation 260:108849. doi: https://doi.org/10.1016/j.biocon.2020.108849\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu M, Chen S-W and Jiang S-Y (2015) Relationship between Gingival Inflammation and Pregnancy. Mediators of Inflammation 2015. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2015/623427\u003c/span\u003e\u003cspan address=\"10.1155/2015/623427\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStarzynska A, Wychowanski P, Nowak M, Sobocki BK, Jereczek-Fossa BA and Slupecka-Ziemilska M (2022) Association between Maternal Periodontitis and Development of Systematic Diseases in Offspring. International Journal of Molecular Sciences 23. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms23052473\u003c/span\u003e\u003cspan address=\"10.3390/ijms23052473\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim CS, Park JS, Park J, Nam JS, Kang ES, Ahn CW, Cha BS, Lim SK, Kim KR, Lee HC, Huh KB and Kim DJ (2006) The relation between birth weight and insulin resistance in Korean adolescents. Yonsei Medical Journal 47:85\u0026ndash;92. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3349/ymj.2006.47.1.85\u003c/span\u003e\u003cspan address=\"10.3349/ymj.2006.47.1.85\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFogacci MF, Vettore MV and Thome Leao AT (2011) The Effect of Periodontal Therapy on Preterm Low Birth Weight \u0026lt; i \u0026gt; A Meta\u0026lt;\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/i\u0026gt;-\u0026lt;i \u0026gt; Analysis\u003c/span\u003e\u003cspan address=\"http:///i%3E-%3Ci %3E Analysis\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Obstetrics and Gynecology 117:153\u0026ndash;165. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/AOG.0b013e3181fdebc0\u003c/span\u003e\u003cspan address=\"10.1097/AOG.0b013e3181fdebc0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\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":"Periodontitis, Adverse pregnancy outcomes, Mendelian randomization, GWAS","lastPublishedDoi":"10.21203/rs.3.rs-3628808/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3628808/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eWe aim to investigate the potential uni-directional association from periodontitis to the Adverse pregnancy outcomes (APOs) by Mendelian randomization (MR) method.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThe present study used genetic instruments for periodontitis as exposures. The outcomes included low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB). The data were collected from the FinnGen consortium R9 datasets and second release analysis in Neale lab of UK Biobank data. Causal analysis uses the inverse variant weighted (IVW), MR Egger and Weighted median methods. A set of sensitivity analyses also be used to test the robustness of the results comprehensive.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe IVW analysis indicate no association of genetically predicted periodontitis will cause the APOs (LBW [IVW OR\u0026thinsp;=\u0026thinsp;1.003, P\u0026thinsp;=\u0026thinsp;0.619], PD [IVW OR\u0026thinsp;=\u0026thinsp;0.984, P\u0026thinsp;=\u0026thinsp;0.630], PET [IVW OR\u0026thinsp;=\u0026thinsp;1.005, P\u0026thinsp;=\u0026thinsp;0.895], SAB [IVW OR\u0026thinsp;=\u0026thinsp;0.964, P\u0026thinsp;=\u0026thinsp;0.221]). Results of the other methods did not show significant differences. Sensitivity analyses showed that horizontal pleiotropy could not distort the results of the causal estimation.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe outcomes indicated there was no potential causal effect of periodontitis on APOs.\u003c/p\u003e\u003ch2\u003eClinical Relevance\u003c/h2\u003e \u003cp\u003eMendelian Randomization studies effectively prevent reverse causality and confounding factors. It complements previous studies, thereby informing clinical diagnosis and deepening understanding of periodontitis and systemic diseases.\u003c/p\u003e","manuscriptTitle":"Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-21 21:22:20","doi":"10.21203/rs.3.rs-3628808/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":"cd9d8791-dbce-463b-931a-4fe55d153b36","owner":[],"postedDate":"November 21st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-01T18:22:16+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-21 21:22:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3628808","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3628808","identity":"rs-3628808","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}