Maternal Periodontitis May Cause Lower Birth Weight in Children: Genetic Evidence from a Comprehensive Mendelian Randomization Study on Periodontitis and Pregnancy

Maternal Periodontitis May Cause Lower Birth Weight in Children: Genetic Evidence from a Comprehensive Mendelian Randomization Study on Periodontitis and Pregnancy | 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 Maternal Periodontitis May Cause Lower Birth Weight in Children: Genetic Evidence from a Comprehensive Mendelian Randomization Study on Periodontitis and Pregnancy Xixiong Chen, Xiao Li, Kun Yang, Jinlin Fang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3462357/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Mar, 2024 Read the published version in Clinical Oral Investigations → Version 1 posted You are reading this latest preprint version Abstract Objectives This study aims to comprehensively investigate the potential genetic link between periodontitis and adverse pregnancy outcomes using a two-sample Mendelian Randomization approach. Materials and Methods We employed robust genetic instruments for chronic periodontitis as exposure data from the FinnGen database. Data encompassing various pregnancy stage outcomes, including pre-pregnancy conditions (irregular menstruation, endometriosis, abnormal reproductive bleeding, and female infertility), pregnancy complications (hemorrhage, spontaneous miscarriage, and abnormalities in products), and post-pregnancy factors (single spontaneous delivery, labor duration, and birth weight of the child), were obtained from the UK Biobank. The random-effects inverse-variance weighted (IVW) method was utilized to compute primary estimates while diligently assessing potential directional pleiotropy and heterogeneity. Results Our findings indicate a negative association between periodontitis and labor duration (odds ratio [OR] = 0.999; 95% confidence interval [CI]: 0.999 to 1.000; P = 0.017). Individuals with periodontitis are more likely to deliver lower-weight infants (OR = 0.983; 95% CI: 0.972 to 0.995; P = 0.005). We found no evidence of pleiotropy or heterogeneity in aforementioned two associations. We did not observe casual links with pre-pregnancy conditions and pregnancy complications. Conclusions This Mendelian Randomization study underscores the genetic influence of periodontitis on specific adverse pregnancy outcomes, particularly concerning labor duration and lower birth weight deliveries. Clinical Relevance: Our study emphasizes the critical importance of maintaining periodontal health during pregnancy and offers genetic evidence supporting these associations. Further investigation is required to delve deeper into the specific underlying mechanisms. Dentistry periodontitis spontaneous miscarriage birth weight Mendelian Randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Periodontitis is a chronic inflammatory condition that targets the tissues surrounding the teeth, resulting in gum recession, tooth mobility, and potential tooth loss[ 1 ]. Epidemiological surveys by reveal that in China, 63.3% of individuals suffer from periodontal disease, with 30.6% experiencing severe periodontitis (stage III or IV) [ 2 ]. Globally, the prevalence of periodontitis is estimated at around 62%, with severe periodontitis affecting 23.6%[ 3 ] . Furthermore, beyond its impact on periodontal tissues, periodontitis also has implications for other bodily systems. Some observational studies have shown that periodontitis may pose potential risks for female reproductive difficulties and adverse pregnancy outcomes, such as female infertility [ 4 ], endometriosis [ 5 ], spontaneous miscarriages occurring before 20 weeks of gestation [ 6 ], and the delivery of low-weight babies, defined as those weighing less than 2.5kg at birth[ 7 , 8 ]. Given the relatively high incidence of periodontitis, global concern of female reproductive difficulties[ 9 ] and adverse pregnancy outcomes[ 10 ], combined with the reality that that periodontitis can be significantly improved and controlled, so it is crucial to thoroughly investigate the relationship between periodontitis and pregnancy. However, establishing a definitive causal relationship between periodontitis and some pregnancy difficulties and outcomes remains challenging due to confounding risks and measurement errors. Ethical concerns and the extended duration required for high-quality randomized clinical trials further complicated matters. To shed light on the causal nature of the effect of periodontitis on pregnancy, Mendelian Randomization (MR) has emerged as a promising strategy. This approach utilizes summary statistics from large-scale genome-wide association studies (GWAS). In our research, we aim to comprehensively explore the impact of periodontitis throughout pregnancy, considering various outcomes at different stages. We have selected irregular menstruation, endometriosis, abnormal reproductive bleeding, and female infertility as pre-pregnancy outcomes, as these factors can significantly influence the success rate of pregnancy [ 11 ]. During pregnancy, we will examine outcomes such as hemorrhage, spontaneous miscarriage, and abnormalities in products of conception. After pregnancy, we will assess single spontaneous delivery, labor duration, and the birth weight of the child as outcomes during this stage. Materials and Methods Assumptions A robust MR estimate is based on three fundamental assumptions[ 12 ]: (i) the instrumental variables (IVs) have a strong association with the exposure; (ii) the IVs are free from confounding factors; (iii) the IVs influence the outcomes solely through their impact on the exposure and not through an alternative causal pathway(Fig. 1 ). Data sources To avoid sample overlapping[ 13 ], the data for exposure and outcomes were sourced from two completely separate consortia. The genome-wide association summary statistics (GWAS) related to chronic periodontitis were obtained from the R9 version of the FinnGen website ( https://r9.finngen.fi/ ), encompassing 263,668 samples (4,434 cases and 259,234 controls). All data for various outcomes are from the UK Biobank (UKBB)( http://www.nealelab.is/uk-biobank ). It's worth noting that a portion of the data in the UKBB database originates from finngen sources, so we have ensured not to utilize it as outcome data. All samples are from European populations. Detailed sample information is provided in Table 1 . Table 1 the detail of data information Phenotype Consortium Source Variable type Sample size ncase ncontrol Chronic periodontitis FinnGen finngen categorical 263,668 4434 259234 Excessive, frequent and irregular menstruation UKBB ICD-10 categorical 361194 8475 352719 Abnormal uterine and vaginal bleeding UKBB ICD-10 categorical 361194 2455 358739 Endometriosis UKBB ICD-10 categorical 361194 1496 359698 Female infertility UKBB ICD-10 categorical 361194 696 360498 Hemorrhage in early pregnancy UKBB ICD-10 categorical 361194 738 360456 Other abnormal products of conception UKBB ICD-10 categorical 361194 1106 360088 Number of spontaneous miscarriages UKBB Phesant ordinal 60300 / / Single spontaneous delivery UKBB ICD-10 categorical 361194 1672 359522 Long labour UKBB ICD-10 categorical 361194 1060 360134 Birth weight of the first child UKBB phesant ordinal 155202 / / Ordinal data statement: Number of spontaneous miscarriages [score1: 0; score 2: 1; score 3:>1]; Birth weight of the first child [score1:7 pounds] Selection of genetic instrumental variables A qualified genetic instrument[ 14 ]should demonstrate a robust association with the exposure (p＜5× 10 − 6 ). Additionally, it should exhibit no significant linkage disequilibrium [LD] (r2 < 0.001) even when considering a window size of 10 MB. Single Nucleotide Polymorphisms (SNPs) that exhibited significant associations with the outcome (p < 5 × 10 − 8 ) were excluded. The strength of the selected SNPs should be evaluated by calculating each SNP's F-statistic. Only those SNPs with F＞ 10 are eligible for subsequent analysis using the following formulas [ 15 , 16 ]: $$F=\frac{{R}^{2}}{1-{R}^{2}}\times \frac{N-K-1}{K}$$ $${R}^{2}=2\times MAF\times \left(1-MAF\right)\times {beta}^{2}$$ To explore the presence of horizontal pleiotropy, we conducted MR Pleiotropy RESidual Sum and Outlier (MR PRESSO) analysis, with particular attention to any outliers in cases where horizontal pleiotropy was identified in less than 50% of the instruments [ 17 ].To further validate our selected SNPs and ensure their independence from the outcome, we employed PhenoScanner[ 18 ]to find any SNPs to be associated with the outcome and then were systematically removed from our analysis. Mendelian Randomization analyses Three distinct MR methods, including random-effects inverse-variance weighted (IVW), MR Egger, and weighted median, were employed to assess the causal relationship between exposure and outcomes. In general, the primary results were derived from the IVW method, which combined the Wald ratio of each SNP on the outcome to obtain a pooled causal estimate. The results obtained through the other two methods can be considered supplementary to IVW. These complementary methods enhance the robustness of MR results across a broader spectrum of scenarios. The MR-Egger method is assumed that the instrument's strength is independent of the direct effect of the instrument on the outcome, even in the presence of pleiotropy [ 19 ].Conversely, the weighted median method can be reliably estimated when at least half of the weighted variance introduced by horizontal pleiotropy is valid [ 20 ]. For significant estimates, we conducted MR-Egger intercept test to examine horizontal pleiotropy. We also implemented leave-one-out analyses to scrutinize potential outliers. Additionally, the Cochran’s Q test was utilized to detect any significant heterogeneity in the results. Furthermore, we employed a funnel plot as a visual tool to assess the possibility of directional pleiotropy. This comprehensive approach allowed us to delve deeper into the potential sources of bias and provide a more robust evaluation of our findings. R software (version 4.3.1) and R Package “TwoSampleMR” and “MRPRESSO” were used to conduct all statistical analyses in the MR analysis. The study frame chart is presented in Fig. 2 . Results In total, 17 index SNPs were selected for the genetic prediction of chronic periodontitis. All of their F-statistics ranged from 43 to 124 to ensure the robustness of the instrumental variables (IVs) (supplementary table S1). We conducted a comprehensive Mendelian Randomization (MR) study on periodontitis concerning pregnancy. The causal effect of IVW was used as the main result. The MR results were presented in Fig. 3 . In our research, we found no genetic association between periodontitis and certain pregnancy difficulties, including excessive, frequent, and irregular menstruation (OR = 0.999, 95% CI: 0.997 to 1.001, P = 0.139), abnormal uterine and vaginal bleeding (OR = 1.000, 95% CI: 1.000 to 1.001, P = 0.298), Endometriosis (OR = 0.999, 95% CI: 0.999 to 1.000, P = 0.352), and female infertility (OR = 1.000, 95% CI: 1.000 to 1.001, P = 0.571) (Fig. 3 ). The results of the Cochran‘s Q test showed no heterogeneity(Table 2). No outliers were identified by MR PRESSO (Table 2), leave-one-out plots (supplementary figure S1), and funnel plots (supplementary figure S2) concerning the relationship between periodontitis and the aforementioned outcomes. MR Egger intercept tests also rejected the presence of horizontal pleiotropy (Table 2). During pregnancy, we evaluated the effects of periodontitis on outcomes such as hemorrhage in early pregnancy, other abnormal products of conception, and the number of spontaneous miscarriages. Heterogeneity was observed when we selected other abnormal products of conception as the outcome (Cochran's Q = 26.79, P Cochran's Q =0.044). However, the results were acceptable because we employed the random-effects IVW method[ 21 ]. There was no genetic association found between periodontitis and hemorrhage in early pregnancy (OR = 1.000, 95% CI: 1.000 to 1.001, P = 0.520), other abnormal products of conception (OR = 1.000, 95% CI: 1.000 to 1.001, P = 0.431) and occurrence of spontaneous miscarriages (OR = 0.989, 95% CI: 0.972 to 1.006, P = 0.186). Furthermore, there was no evidence of pleiotropy between periodontitis and outcomes during pregnancy, as indicated by MR PRESSO tests, MR Egger intercept tests (Table 2), leave-one-out plots (supplementary figure S1), and funnel plots (supplementary figure S2). After pregnancy, we assessed the effects of periodontitis on delivery and the weight of newborns. There was no genetic correlation observed between periodontitis and single spontaneous delivery (OR = 1.000, 95% CI: 0.999 to 1.001, P = 0.718). Surprisingly, periodontitis was associated with a reduction in labor duration (OR = 0.999, 95% CI: 0.999 to 1.000, P = 0.017). The weak association observed in our study is consistent with the results obtained through MR Egger (OR = 0.999, 95% CI: 0.998 to 0.999, P = 0.010). For the birth weight of the first child, women with periodontitis appeared to deliver babies with lower birth weight (OR = 0.983, 95% CI: 0.972 to 0.995, P = 0.005). There was no significant evidence of pleiotropy and heterogeneity between periodontitis and single spontaneous delivery, labor duration, and birth weight of the first child (Table 2) (supplementary figure S1, S2) . Table 2 Summary of Heterogeneity and Multiplicity Results Outcomes Cochran's Q P Cochran's Q MR Egger intercept P MR Egger intercept Global test RSSobs P Global Excessive, frequent and irregular menstruation 8.552 0.931 -9.90 × 10 -05 0.728 10.748 0.929 abnormal uterine and vaginal bleeding 12.35 0.720 -1.45 × 10 -04 0.363 13.946 0.817 Endometriosis 21.905 0.146 -2.26 × 10 -04 0.110 26.495 0.135 Female infertility 9.479 0.892 -1.12 × 10 -04 0.189 11.418 0.917 Hemorrhage in early pregnancy 10.44 0.843 -1.63 × 10 -04 0.072 11.935 0.872 Other abnormal products of conception 26.79 0.044 -4.40 × 10 -05 0.751 30.194 0.071 Number of spontaneous miscarriages 14.601 0.554 3.94 × 10 -03 0.241 17.801 0.524 Single spontaneous delivery 19.205 0.258 -1.25 × 10 -04 0.378 26.243 0.119 Long labour 8.981 0.914 1.99 × 10 -04 0.065 11.093 0.911 Birth weight of first child 10.066 0.863 8.78 × 10 -04 0.698 23.116 0.265 Abbreviations: RSSobs [observed residual sum of squares]. Discussion To the best of our knowledge, this is the first comprehensive MR study aimed at evaluating the causal relationship between periodontitis and pregnancy, as well as delivery outcomes. Our primary objective was to assess whether periodontitis, from a genetic perspective, increases the risk of pregnancy difficulties (including abnormal menstruation, abnormal reproductive bleeding, endometriosis, and female infertility), leads to adverse pregnancies (involving hemorrhage in early pregnancy, abnormalities in products of conception, and spontaneous miscarriages), and affects delivery outcomes (such as single spontaneous delivery, labor duration, and the birth weight of the first child). To mitigate potential bias, we took several relevant actions. First, we ensured that the samples for exposure and outcomes were deprived from completely separate European populations, thus effectively eliminating issues related to sample overlapping, which can lead to Type 1 errors and spurious trait associations.[ 22 ]. Second, we rigorously selected robust genetic instruments with F-statistics exceeding 40, signifying their high relevance to chronic periodontitis. Third, w we utilized a variety of methods, including the leave-one-out test, MR-PRESSO analysis, MR Egger intercept analysis, and funnel plots, to address directional pleiotropy and exclude any abnormal outliers. Only by following these rigorous steps can we accurately interpret the results. As for the outcomes, we identified causal relationships between periodontitis and labor duration, as well as birth weight. The natural labor process initiates with regular uterine contractions and concludes when the baby, placenta, and membranes are delivered[ 23 ]. Our research shows a subtle negative genetic association[ 24 ] between periodontitis and labor duration, determined by the random-effect IVW method (OR = 0.999, 95% CI: 0.999 to 1.000, P = 0.017) and the MR Egger method (OR = 0.999, 95% CI: 0.998 to 0.999, P = 0.010)(Fig. 3). These subtle effects warrant further validation with additional positive cases. Regrettably, there is a dearth of observational studies investigating the relationship between periodontitis and labour duration. This discrepancy may be attributed to the lack of universal or standardized definitions of normal labor duration[ 25 ]. Nevertheless, there are plausible explanations for this connection. Some studies[ 26 , 27 ]have confirmed intrauterine colonization with oral microbes, even in clinically healthy pregnancies, which means that pathogenic bacteria from periodontal sources can colonize the uterus and have the potential to affect the fetus. Additionally, certain periodontal-origin inflammatory mediators, such as IL-2, IL-6, IL-10, TNF-α, and PGE-2, can initiate metabolic processes via the bloodstream[ 28 ]. IL-1, IL-6, and TNF‐α may stimulate the production of prostaglandins in the chorion, which can stimulate uterine contractions, cervical ripening, and accelerate the labor process[ 10 ]. Regarding low birth weight of newborns, defined as a weight less than 2.5kg at birth, numerous observational studies[ 29 , 30 ] have highlighted the risk of periodontitis for pregnant women delivering low-weight children. In our research, we used ordinal data for the birth weight of the first child as the outcome. Unlike categorical variables, ordinal data offers three different scores to define the level of weight (Table 1). The correct interpretation of ordinal results[ 31 ] suggests that pregnant women with periodontitis may deliver children with lower-weight level (OR = 0.983, 95% CI: 0.972 to 0.995, P = 0.005) . While our weight classification (7 pounds ≈ 3.175kg) does not precisely align with the standard for low birth weight (2.5kg), our research sheds light on the causal effect of periodontitis on birth weight. This finding is further supported by numerous laboratory studies. These studies[ 32 – 34 ] have detected various periodontal pathogens, such as Fusobacterium nucleatum , Porphyromonas gingivalis , Campylobacter rectus , Tannerella forsythia , Prevotella nigrescens , and Streptococcus mitis in the amniotic fluid from mothers. Additionally, focal injury induced by Campylobacter rectus has been associated with a significant decrease in the size of the labyrinth layer, responsible for nutrient exchange between the mother and fetus. This suggests insufficient fetal nutrition, potentially justifying impaired growth[ 35 ]. Moreover, these placentas were linked to reduced expression of genes related to placental and fetal growth[ 36 ]. Beyond focal infection, the maternal immune system also plays a crucial role. As a semi-allograft, the fetus carries external DNA from the father, which must be tolerated by the mother throughout pregnancy[ 37 ]. Unfortunately, periodontal microbe infections trigger a shift in the maternal immune response toward a pathogenic inflammatory response, disrupting the maternal-fetal interface's homeostasis[ 38 ]. Some infectious diseases may disturb the Th17/Treg proportion, leading to increased Th1/Th17 cell numbers and activity. The Th1 response activates decidual macrophages, which release excessive TNF-α and nitric oxide, detrimental to the fetus[ 38 , 39 ]. The potential biological mechanism is depicted in Fig. 4. However, several aspects remain unexplained within this theory. Firstly, there is insufficient evidence to determine which periodontal treatment is superior in preventing adverse obstetric outcomes in some studies [40, 41] . Secondly, the current evidence does not provide answers as to why some women develop adverse pregnancy outcomes while others do not, despite concurrent bacterial colonization [42] . Thirdly, our study does not currently support a link between periodontitis and an increased rate of spontaneous abortion. Furthermore, due to insufficient sample size, preterm birth was not included as an outcome, which warrants further investigation. In our study, we have exclusively delved into this association within the confines of European populations, with no certainty regarding its prevalence in other geographical regions. While the use of funnel plots for scrutinizing the exclusion of inverse associations may be subject to some subjectivity, we advocate contemplating the application of reverse MR to gain further insights into the directionality of these associations. Given the constraints imposed by our available data, our findings furnish genetic evidence, opening doors for researchers to investigate the ramifications of periodontitis on adverse pregnancy outcomes, specifically focusing on labor duration and birth weight. Subsequent research endeavors should strive to unravel the precise mechanisms underpinning these effects and seek effective therapeutic strategies to avert adverse outcomes in individuals afflicted by periodontitis. Declarations Acknowledgments: We thank FinnGen Consortium and the UK Biobank Consortium for providing GWAS data. Funding: This study is not associated with any funding. Conflict of Interest Statement: Conflict of Interest: The authors declare that they have no conflict of interest. Contributions: XXC and XL designed the study, wrote the first draft of the manuscript and verified the underlying data. KY and JLF conducted statistical analyses. XXC and JLF played roles in acquisition of the data and analyses. 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Cureus. 2022;14(11):e31735. Epub 20221121. doi: 10.7759/cureus.31735. PubMed PMID: 37377463; PubMed Central PMCID: PMCPMC10292180. Catalan A, Tognin S, Hammoud R, Aymerich C, Pedruzo B, Bilbao-Gonzalez A, et al. Understanding the relationship between time spent outdoors, mental well-being and health-related behaviours in a Spanish sample: A real time smartphone-based study. Psychiatry Res. 2023;329:115494. Epub 20230925. doi: 10.1016/j.psychres.2023.115494. PubMed PMID: 37783095. Narita Y, Kodama H. Identification of the specific microbial community compositions in saliva associated with periodontitis during pregnancy. Clin Oral Investig. 2022;26(7):4995-5005. Epub 20220329. doi: 10.1007/s00784-022-04468-z. PubMed PMID: 35352183. Chopra A, Radhakrishnan R, Sharma M. Porphyromonas gingivalis and adverse pregnancy outcomes: a review on its intricate pathogenic mechanisms. Crit Rev Microbiol. 2020;46(2):213-36. Epub 20200408. doi: 10.1080/1040841X.2020.1747392. PubMed PMID: 32267781. Chaemsaithong P, Lertrut W, Kamlungkuea T, Santanirand P, Singsaneh A, Jaovisidha A, et al. Maternal septicemia caused by Streptococcus mitis: a possible link between intra-amniotic infection and periodontitis. Case report and literature review. BMC Infect Dis. 2022;22(1):562. Epub 20220620. doi: 10.1186/s12879-022-07530-z. PubMed PMID: 35725441; PubMed Central PMCID: PMCPMC9208128. Offenbacher S, Riche EL, Barros SP, Bobetsis YA, Lin D, Beck JD. Effects of maternal Campylobacter rectus infection on murine placenta, fetal and neonatal survival, and brain development. J Periodontol. 2005;76(11 Suppl):2133-43. doi: 10.1902/jop.2005.76.11-S.2133. PubMed PMID: 16277586. Bobetsis YA, Barros SP, Lin DM, Arce RM, Offenbacher S. Altered gene expression in murine placentas in an infection-induced intrauterine growth restriction model: a microarray analysis. J Reprod Immunol. 2010;85(2):140-8. Epub 20100516. doi: 10.1016/j.jri.2010.04.001. PubMed PMID: 20478622; PubMed Central PMCID: PMCPMC2904600. La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett. 2014;162(1 Pt A):41-8. Epub 20140701. doi: 10.1016/j.imlet.2014.06.013. PubMed PMID: 24996040. Wen X, Fu X, Zhao C, Yang L, Huang R. The bidirectional relationship between periodontal disease and pregnancy via the interaction of oral microorganisms, hormone and immune response. Front Microbiol. 2023;14:1070917. Epub 20230126. doi: 10.3389/fmicb.2023.1070917. PubMed PMID: 36778874; PubMed Central PMCID: PMCPMC9908602. Zenclussen AC. Adaptive immune responses during pregnancy. Am J Reprod Immunol. 2013;69(4):291-303. Epub 20130219. doi: 10.1111/aji.12097. PubMed PMID: 23418773. Polyzos NP, Polyzos IP, Zavos A, Valachis A, Mauri D, Papanikolaou EG, et al. Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis. BMJ. 2010;341:c7017. Epub 20101229. doi: 10.1136/bmj.c7017. PubMed PMID: 21190966; PubMed Central PMCID: PMCPMC3011371. Iheozor-Ejiofor Z, Middleton P, Esposito M, Glenny AM. Treating periodontal disease for preventing adverse birth outcomes in pregnant women. Cochrane Database Syst Rev. 2017;6(6):CD005297. Epub 20170612. doi: 10.1002/14651858.CD005297.pub3. PubMed PMID: 28605006; PubMed Central PMCID: PMCPMC6481493. Romero R, Miranda J, Kusanovic JP, Chaiworapongsa T, Chaemsaithong P, Martinez A, et al. Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques. J Perinat Med. 2015;43(1):19-36. doi: 10.1515/jpm-2014-0249. PubMed PMID: 25720095; PubMed Central PMCID: PMCPMC5881909. 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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-3462357","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":241085535,"identity":"95a56988-5a97-451d-882d-94480e3e8c25","order_by":0,"name":"Xixiong Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDACCSDmASJ+ZsbGBwkVNcRrkZFsZ242eHDmGPFabAzOs7dJPmxhJqyDf3bzsQdv24C6DjO2VSQ2sDHwt3cn4LfkzrF0wzlnGHgYmxnbbiTukGGQOHN2A14tBhI5ZtI8FQw8zMwgLWfYgCK5hLTkf5PmMWDgYQNqKUhsYyZGSw4b2BYeoBYGorRI3EgzkwT5RYKZsVki4cwxHoJ+4Z+R/EwCGGL29uePP/z4o6JGjr+9F78WKPgPZ/EQo3wUjIJRMApGAQEAAKwiP9z9DEggAAAAAElFTkSuQmCC","orcid":"","institution":"First people’s Hospital of Linping District","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xixiong","middleName":"","lastName":"Chen","suffix":""},{"id":241085536,"identity":"886c4990-3e58-4c7c-b0de-096643125c17","order_by":1,"name":"Xiao Li","email":"","orcid":"","institution":"First people’s Hospital of Linping District","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Li","suffix":""},{"id":241085537,"identity":"65c128f9-d2fb-4e1a-a47e-b477aadcd973","order_by":2,"name":"Kun Yang","email":"","orcid":"","institution":"First people’s Hospital of Yuhang District","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kun","middleName":"","lastName":"Yang","suffix":""},{"id":241085538,"identity":"862da6fe-1c2c-485a-a5f7-b1df1b6ba0ff","order_by":3,"name":"Jinlin Fang","email":"","orcid":"","institution":"Shaoxing Seventh people’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jinlin","middleName":"","lastName":"Fang","suffix":""}],"badges":[],"createdAt":"2023-10-18 13:13:15","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-3462357/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3462357/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00784-024-05591-9","type":"published","date":"2024-03-05T06:11:30+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":44949534,"identity":"02ef3113-f1e2-4b40-a8c5-247afc513bdb","added_by":"auto","created_at":"2023-10-19 21:15:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29153,"visible":true,"origin":"","legend":"\u003cp\u003ethe basic assumptions of Mendelian randomization\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/2862d7e7733c4dc3daf34ca3.png"},{"id":44949540,"identity":"a430f779-08ef-4770-97ea-636609071e93","added_by":"auto","created_at":"2023-10-19 21:15:43","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":146672,"visible":true,"origin":"","legend":"\u003cp\u003eThe study frame chart of Mendelian Randomization study\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/3b9155b2a7cc5133554d2ed2.jpeg"},{"id":44949535,"identity":"0ad952d7-c076-41a2-84b1-5df6616f9e61","added_by":"auto","created_at":"2023-10-19 21:15:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":247383,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot summarizing the MR results.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/208ac7b803dc23609db63d31.png"},{"id":44949770,"identity":"303fb6e1-150b-4cbf-9fe0-5d4e168928ea","added_by":"auto","created_at":"2023-10-19 21:23:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":357995,"visible":true,"origin":"","legend":"\u003cp\u003eBiological mechanism of maternal periodontitis resulting in reduced labour duration and lower birth weight child\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/090a7148b2ff8da18984e369.png"},{"id":53056010,"identity":"ce9d43d5-db1e-49b2-9d32-aa873af1f125","added_by":"auto","created_at":"2024-03-20 06:11:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1115025,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/b5b8eb57-3c84-4891-b765-0d3e2614714b.pdf"},{"id":44949539,"identity":"12a7b7ed-3d76-4e75-af8e-d2c786c3cb5c","added_by":"auto","created_at":"2023-10-19 21:15:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":636905,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfigureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/d614fce13ce8fdf7d0350c8d.pdf"},{"id":44950735,"identity":"0fcff1a0-c57a-4741-a1ef-e9ab1e066d17","added_by":"auto","created_at":"2023-10-19 21:31:43","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":296577,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfigureS2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/2fa5bada454b28690d5ff0b0.pdf"},{"id":44949536,"identity":"c901f6e9-3bfa-431e-89d4-b341eb495df0","added_by":"auto","created_at":"2023-10-19 21:15:43","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":25017,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarytableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3462357/v1/78a0444bba8d190302fc81d3.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eMaternal Periodontitis May Cause Lower Birth Weight in Children: Genetic Evidence from a Comprehensive Mendelian Randomization Study on Periodontitis and Pregnancy\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePeriodontitis is a chronic inflammatory condition that targets the tissues surrounding the teeth, resulting in gum recession, tooth mobility, and potential tooth loss[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Epidemiological surveys by reveal that in China, 63.3% of individuals suffer from periodontal disease, with 30.6% experiencing severe periodontitis (stage III or IV) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Globally, the prevalence of periodontitis is estimated at around 62%, with severe periodontitis affecting 23.6%[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] .\u003c/p\u003e \u003cp\u003eFurthermore, beyond its impact on periodontal tissues, periodontitis also has implications for other bodily systems. Some observational studies have shown that periodontitis may pose potential risks for female reproductive difficulties and adverse pregnancy outcomes, such as female infertility [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], endometriosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], spontaneous miscarriages occurring before 20 weeks of gestation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and the delivery of low-weight babies, defined as those weighing less than 2.5kg at birth[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the relatively high incidence of periodontitis, global concern of female reproductive difficulties[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and adverse pregnancy outcomes[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], combined with the reality that that periodontitis can be significantly improved and controlled, so it is crucial to thoroughly investigate the relationship between periodontitis and pregnancy.\u003c/p\u003e \u003cp\u003eHowever, establishing a definitive causal relationship between periodontitis and some pregnancy difficulties and outcomes remains challenging due to confounding risks and measurement errors. Ethical concerns and the extended duration required for high-quality randomized clinical trials further complicated matters. To shed light on the causal nature of the effect of periodontitis on pregnancy, Mendelian Randomization (MR) has emerged as a promising strategy. This approach utilizes summary statistics from large-scale genome-wide association studies (GWAS).\u003c/p\u003e \u003cp\u003eIn our research, we aim to comprehensively explore the impact of periodontitis throughout pregnancy, considering various outcomes at different stages. We have selected irregular menstruation, endometriosis, abnormal reproductive bleeding, and female infertility as pre-pregnancy outcomes, as these factors can significantly influence the success rate of pregnancy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. During pregnancy, we will examine outcomes such as hemorrhage, spontaneous miscarriage, and abnormalities in products of conception. After pregnancy, we will assess single spontaneous delivery, labor duration, and the birth weight of the child as outcomes during this stage.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eAssumptions\u003c/h2\u003e\n\u003cp\u003eA robust MR estimate is based on three fundamental assumptions[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]: (i) the instrumental variables (IVs) have a strong association with the exposure; (ii) the IVs are free from confounding factors; (iii) the IVs influence the outcomes solely through their impact on the exposure and not through an alternative causal pathway(Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eData sources\u003c/h2\u003e\n\u003cp\u003eTo avoid sample overlapping[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e], the data for exposure and outcomes were sourced from two completely separate consortia. The genome-wide association summary statistics (GWAS) related to chronic periodontitis were obtained from the R9 version of the FinnGen website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://r9.finngen.fi/\u003c/span\u003e\u003c/span\u003e), encompassing 263,668 samples (4,434 cases and 259,234 controls). All data for various outcomes are from the UK Biobank (UKBB)(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.nealelab.is/uk-biobank\u003c/span\u003e\u003c/span\u003e). It's worth noting that a portion of the data in the UKBB database originates from finngen sources, so we have ensured not to utilize it as outcome data. All samples are from European populations. Detailed sample information is provided in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ethe detail of data information\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePhenotype\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eConsortium\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSource\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable type\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSample size\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003encase\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003encontrol\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic periodontitis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFinnGen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003efinngen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e263,668\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4434\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e259234\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExcessive, frequent and irregular menstruation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8475\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e352719\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAbnormal uterine and vaginal bleeding\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2455\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e358739\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEndometriosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1496\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e359698\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale infertility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e696\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e360498\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHemorrhage in early pregnancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e738\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e360456\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther abnormal products of conception\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1106\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e360088\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNumber of spontaneous miscarriages\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePhesant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eordinal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e60300\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSingle spontaneous delivery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1672\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e359522\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLong labour\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICD-10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ecategorical\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e361194\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1060\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e360134\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight of the first child\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUKBB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ephesant\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eordinal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e155202\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eOrdinal data statement: Number of spontaneous miscarriages [score1: 0; score 2: 1; score 3:\u0026gt;1]; Birth weight of the first child [score1:\u0026lt;7 pounds; score 2: =7 pounds; score 3:\u0026gt;7 pounds]\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eSelection of genetic instrumental variables\u003c/h2\u003e\n\u003cp\u003eA qualified genetic instrument[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]should demonstrate a robust association with the exposure (p＜5\u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e). Additionally, it should exhibit no significant linkage disequilibrium [LD] (r2\u0026thinsp;\u0026lt;\u0026thinsp;0.001) even when considering a window size of 10 MB. Single Nucleotide Polymorphisms (SNPs) that exhibited significant associations with the outcome (p\u0026thinsp;\u0026lt;\u0026thinsp;5 \u0026times; 10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e) were excluded. The strength of the selected SNPs should be evaluated by calculating each SNP's F-statistic. Only those SNPs with F＞ 10 are eligible for subsequent analysis using the following formulas [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]:\u003c/p\u003e\n\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\n\u003cdiv id=\"FileID_Equa\" class=\"mathdisplay\"\u003e$$F=\\frac{{R}^{2}}{1-{R}^{2}}\\times \\frac{N-K-1}{K}$$\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\n\u003cdiv id=\"FileID_Equb\" class=\"mathdisplay\"\u003e$${R}^{2}=2\\times MAF\\times \\left(1-MAF\\right)\\times {beta}^{2}$$\u003c/div\u003e\n\u003c/div\u003e\n\u003cp\u003eTo explore the presence of horizontal pleiotropy, we conducted MR Pleiotropy RESidual Sum and Outlier (MR PRESSO) analysis, with particular attention to any outliers in cases where horizontal pleiotropy was identified in less than 50% of the instruments [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e].To further validate our selected SNPs and ensure their independence from the outcome, we employed PhenoScanner[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]to find any SNPs to be associated with the outcome and then were systematically removed from our analysis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eMendelian Randomization analyses\u003c/h2\u003e\n\u003cp\u003eThree distinct MR methods, including random-effects inverse-variance weighted (IVW), MR Egger, and weighted median, were employed to assess the causal relationship between exposure and outcomes. In general, the primary results were derived from the IVW method, which combined the Wald ratio of each SNP on the outcome to obtain a pooled causal estimate. The results obtained through the other two methods can be considered supplementary to IVW. These complementary methods enhance the robustness of MR results across a broader spectrum of scenarios. The MR-Egger method is assumed that the instrument's strength is independent of the direct effect of the instrument on the outcome, even in the presence of pleiotropy [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e].Conversely, the weighted median method can be reliably estimated when at least half of the weighted variance introduced by horizontal pleiotropy is valid [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. For significant estimates, we conducted MR-Egger intercept test to examine horizontal pleiotropy. We also implemented leave-one-out analyses to scrutinize potential outliers. Additionally, the Cochran\u0026rsquo;s Q test was utilized to detect any significant heterogeneity in the results. Furthermore, we employed a funnel plot as a visual tool to assess the possibility of directional pleiotropy. This comprehensive approach allowed us to delve deeper into the potential sources of bias and provide a more robust evaluation of our findings. R software (version 4.3.1) and R Package \u0026ldquo;TwoSampleMR\u0026rdquo; and \u0026ldquo;MRPRESSO\u0026rdquo; were used to conduct all statistical analyses in the MR analysis. The study frame chart is presented in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn total, 17 index SNPs were selected for the genetic prediction of chronic periodontitis. All of their F-statistics ranged from 43 to 124 to ensure the robustness of the instrumental variables (IVs) (supplementary table S1). We conducted a comprehensive Mendelian Randomization (MR) study on periodontitis concerning pregnancy. The causal effect of IVW was used as the main result. The MR results were presented in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eIn our research, we found no genetic association between periodontitis and certain pregnancy difficulties, including excessive, frequent, and irregular menstruation (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.997 to 1.001, P\u0026thinsp;=\u0026thinsp;0.139), abnormal uterine and vaginal bleeding (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI: 1.000 to 1.001, P\u0026thinsp;=\u0026thinsp;0.298), Endometriosis (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.999 to 1.000, P\u0026thinsp;=\u0026thinsp;0.352), and female infertility (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI: 1.000 to 1.001, P\u0026thinsp;=\u0026thinsp;0.571) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The results of the Cochran\u0026lsquo;s Q test showed no heterogeneity(Table\u0026nbsp;2). No outliers were identified by MR PRESSO (Table\u0026nbsp;2), leave-one-out plots (supplementary figure S1), and funnel plots (supplementary figure S2) concerning the relationship between periodontitis and the aforementioned outcomes. MR Egger intercept tests also rejected the presence of horizontal pleiotropy (Table\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eDuring pregnancy, we evaluated the effects of periodontitis on outcomes such as hemorrhage in early pregnancy, other abnormal products of conception, and the number of spontaneous miscarriages. Heterogeneity was observed when we selected other abnormal products of conception as the outcome (Cochran\u0026apos;s Q\u0026thinsp;=\u0026thinsp;26.79, P\u003csub\u003eCochran\u0026apos;s Q\u003c/sub\u003e=0.044). However, the results were acceptable because we employed the random-effects IVW method[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. There was no genetic association found between periodontitis and hemorrhage in early pregnancy (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI: 1.000 to 1.001, P\u0026thinsp;=\u0026thinsp;0.520), other abnormal products of conception (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI: 1.000 to 1.001, P\u0026thinsp;=\u0026thinsp;0.431) and occurrence of spontaneous miscarriages (OR\u0026thinsp;=\u0026thinsp;0.989, 95% CI: 0.972 to 1.006, P\u0026thinsp;=\u0026thinsp;0.186). Furthermore, there was no evidence of pleiotropy between periodontitis and outcomes during pregnancy, as indicated by MR PRESSO tests, MR Egger intercept tests (Table\u0026nbsp;2), leave-one-out plots (supplementary figure S1), and funnel plots (supplementary figure S2).\u003c/p\u003e\n\u003cp\u003eAfter pregnancy, we assessed the effects of periodontitis on delivery and the weight of newborns. There was no genetic correlation observed between periodontitis and single spontaneous delivery (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI: 0.999 to 1.001, P\u0026thinsp;=\u0026thinsp;0.718). Surprisingly, periodontitis was associated with a reduction in labor duration (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.999 to 1.000, P\u0026thinsp;=\u0026thinsp;0.017). The weak association observed in our study is consistent with the results obtained through MR Egger (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.998 to 0.999, P\u0026thinsp;=\u0026thinsp;0.010). For the birth weight of the first child, women with periodontitis appeared to deliver babies with lower birth weight (OR\u0026thinsp;=\u0026thinsp;0.983, 95% CI: 0.972 to 0.995, P\u0026thinsp;=\u0026thinsp;0.005). There was no significant evidence of pleiotropy and heterogeneity between periodontitis and single spontaneous delivery, labor duration, and birth weight of the first child (Table\u0026nbsp;2) (supplementary figure S1, S2) .\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;2 Summary of Heterogeneity and Multiplicity Results\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eCochran\u0026apos;s Q\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003csub\u003eCochran\u0026apos;s Q\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003eMR Egger intercept\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003csub\u003eMR Egger intercept\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003eGlobal test RSSobs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003eP\u003csub\u003eGlobal\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eExcessive, frequent and irregular menstruation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e8.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.931\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-9.90\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-05\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.728\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e10.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.929\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eabnormal uterine and vaginal bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e12.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.720\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-1.45\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e13.946\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.817\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eEndometriosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e21.905\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-2.26\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e26.495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eFemale infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e9.479\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.892\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-1.12\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e11.418\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.917\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eHemorrhage in early pregnancy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e10.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.843\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-1.63\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e11.935\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.872\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eOther abnormal products of conception\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e26.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-4.40\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-05\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e30.194\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of spontaneous miscarriages\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e14.601\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e3.94\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-03\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.241\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e17.801\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.524\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eSingle spontaneous delivery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e19.205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.258\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e-1.25\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e26.243\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.119\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eLong labour\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e8.981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.914\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e1.99\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e11.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.911\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.142857142857146%\" valign=\"top\"\u003e\n \u003cp\u003eBirth weight of first child\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.119047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e10.066\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.482142857142858%\" valign=\"top\"\u003e\n \u003cp\u003e0.863\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e8.78\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e-04\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.30952380952381%\" valign=\"top\"\u003e\n \u003cp\u003e0.698\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.476190476190476%\" valign=\"top\"\u003e\n \u003cp\u003e23.116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.994047619047619%\" valign=\"top\"\u003e\n \u003cp\u003e0.265\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: RSSobs [observed residual sum of squares].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first comprehensive MR study aimed at evaluating the causal relationship between periodontitis and pregnancy, as well as delivery outcomes. Our primary objective was to assess whether periodontitis, from a genetic perspective, increases the risk of pregnancy difficulties (including abnormal menstruation, abnormal reproductive bleeding, endometriosis, and female infertility), leads to adverse pregnancies (involving hemorrhage in early pregnancy, abnormalities in products of conception, and spontaneous miscarriages), and affects delivery outcomes (such as single spontaneous delivery, labor duration, and the birth weight of the first child).\u003c/p\u003e\n\u003cp\u003eTo mitigate potential bias, we took several relevant actions. First, we ensured that the samples for exposure and outcomes were deprived from completely separate European populations, thus effectively eliminating issues related to sample overlapping, which can lead to Type 1 errors and spurious trait associations.[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. Second, we rigorously selected robust genetic instruments with F-statistics exceeding 40, signifying their high relevance to chronic periodontitis. Third, w we utilized a variety of methods, including the leave-one-out test, MR-PRESSO analysis, MR Egger intercept analysis, and funnel plots, to address directional pleiotropy and exclude any abnormal outliers.\u003c/p\u003e\n\u003cp\u003eOnly by following these rigorous steps can we accurately interpret the results. As for the outcomes, we identified causal relationships between periodontitis and labor duration, as well as birth weight.\u003c/p\u003e\n\u003cp\u003eThe natural labor process initiates with regular uterine contractions and concludes when the baby, placenta, and membranes are delivered[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our research shows a subtle negative genetic association[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] between periodontitis and labor duration, determined by the random-effect IVW method (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.999 to 1.000, P\u0026thinsp;=\u0026thinsp;0.017) and the MR Egger method (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI: 0.998 to 0.999, P\u0026thinsp;=\u0026thinsp;0.010)(Fig.\u0026nbsp;3). These subtle effects warrant further validation with additional positive cases.\u003c/p\u003e\n\u003cp\u003eRegrettably, there is a dearth of observational studies investigating the relationship between periodontitis and labour duration. This discrepancy may be attributed to the lack of universal or standardized definitions of normal labor duration[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Nevertheless, there are plausible explanations for this connection. Some studies[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]have confirmed intrauterine colonization with oral microbes, even in clinically healthy pregnancies, which means that pathogenic bacteria from periodontal sources can colonize the uterus and have the potential to affect the fetus. Additionally, certain periodontal-origin inflammatory mediators, such as IL-2, IL-6, IL-10, TNF-\u0026alpha;, and PGE-2, can initiate metabolic processes via the bloodstream[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. IL-1, IL-6, and TNF‐\u0026alpha; may stimulate the production of prostaglandins in the chorion, which can stimulate uterine contractions, cervical ripening, and accelerate the labor process[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eRegarding low birth weight of newborns, defined as a weight less than 2.5kg at birth, numerous observational studies[\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e] have highlighted the risk of periodontitis for pregnant women delivering low-weight children. In our research, we used ordinal data for the birth weight of the first child as the outcome. Unlike categorical variables, ordinal data offers three different scores to define the level of weight (Table\u0026nbsp;1). The correct interpretation of ordinal results[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e] suggests that pregnant women with periodontitis may deliver children with lower-weight level \u003cem\u003e(OR\u0026thinsp;=\u0026thinsp;0.983, 95% CI: 0.972 to 0.995, P\u0026thinsp;=\u0026thinsp;0.005)\u003c/em\u003e. While our weight classification (7 pounds\u0026thinsp;\u0026asymp;\u0026thinsp;3.175kg) does not precisely align with the standard for low birth weight (2.5kg), our research sheds light on the causal effect of periodontitis on birth weight. This finding is further supported by numerous laboratory studies. These studies[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e] have detected various periodontal pathogens, such as \u003cem\u003eFusobacterium nucleatum\u003c/em\u003e, \u003cem\u003ePorphyromonas gingivalis\u003c/em\u003e, \u003cem\u003eCampylobacter rectus\u003c/em\u003e, \u003cem\u003eTannerella forsythia\u003c/em\u003e, \u003cem\u003ePrevotella nigrescens\u003c/em\u003e, and \u003cem\u003eStreptococcus mitis\u003c/em\u003e in the amniotic fluid from mothers. Additionally, focal injury induced by \u003cem\u003eCampylobacter rectus\u003c/em\u003e has been associated with a significant decrease in the size of the labyrinth layer, responsible for nutrient exchange between the mother and fetus. This suggests insufficient fetal nutrition, potentially justifying impaired growth[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Moreover, these placentas were linked to reduced expression of genes related to placental and fetal growth[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eBeyond focal infection, the maternal immune system also plays a crucial role. As a semi-allograft, the fetus carries external DNA from the father, which must be tolerated by the mother throughout pregnancy[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]. Unfortunately, periodontal microbe infections trigger a shift in the maternal immune response toward a pathogenic inflammatory response, disrupting the maternal-fetal interface's homeostasis[\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. Some infectious diseases may disturb the Th17/Treg proportion, leading to increased Th1/Th17 cell numbers and activity. The Th1 response activates decidual macrophages, which release excessive TNF-\u0026alpha; and nitric oxide, detrimental to the fetus[\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e]. The potential biological mechanism is depicted in Fig.\u0026nbsp;4.\u003c/p\u003e\n\u003cp\u003eHowever, several aspects remain unexplained within this theory. Firstly, there is insufficient evidence to determine which periodontal treatment is superior in preventing adverse obstetric outcomes in some studies\u003cem\u003e[40, 41]\u003c/em\u003e. Secondly, the current evidence does not provide answers as to why some women develop adverse pregnancy outcomes while others do not, despite concurrent bacterial colonization\u003cem\u003e[42]\u003c/em\u003e. Thirdly, our study does not currently support a link between periodontitis and an increased rate of spontaneous abortion. Furthermore, due to insufficient sample size, preterm birth was not included as an outcome, which warrants further investigation.\u003c/p\u003e\n\u003cp\u003eIn our study, we have exclusively delved into this association within the confines of European populations, with no certainty regarding its prevalence in other geographical regions. While the use of funnel plots for scrutinizing the exclusion of inverse associations may be subject to some subjectivity, we advocate contemplating the application of reverse MR to gain further insights into the directionality of these associations.\u003c/p\u003e\n\u003cp\u003eGiven the constraints imposed by our available data, our findings furnish genetic evidence, opening doors for researchers to investigate the ramifications of periodontitis on adverse pregnancy outcomes, specifically focusing on labor duration and birth weight. Subsequent research endeavors should strive to unravel the precise mechanisms underpinning these effects and seek effective therapeutic strategies to avert adverse outcomes in individuals afflicted by periodontitis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe thank FinnGen Consortium and the UK Biobank Consortium for providing GWAS data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis study is not associated with any funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement:\u0026nbsp;\u003c/strong\u003eConflict of Interest: The authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions:\u0026nbsp;\u003c/strong\u003eXXC and XL designed the study, wrote the first draft of the manuscript and verified the underlying data. KY and JLF conducted statistical analyses. XXC and JLF played roles in acquisition of the data and analyses. XXC, XL, KY and JLF participated in data interpretations, revised and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSlots J. Periodontitis: facts, fallacies and the future. Periodontol 2000. 2017;75(1):7-23. doi: 10.1111/prd.12221. PubMed PMID: 28758294.\u003c/li\u003e\n\u003cli\u003eJiao J, Jing W, Si Y, Feng X, Tai B, Hu D, et al. The prevalence and severity of periodontal disease in Mainland China: Data from the Fourth National Oral Health Survey (2015-2016). J Clin Periodontol. 2021;48(2):168-79. Epub 20201118. doi: 10.1111/jcpe.13396. PubMed PMID: 33103285.\u003c/li\u003e\n\u003cli\u003eTrindade D, Carvalho R, Machado V, Chambrone L, Mendes JJ, Botelho J. Prevalence of periodontitis in dentate people between 2011 and 2020: A systematic review and meta-analysis of epidemiological studies. J Clin Periodontol. 2023;50(5):604-26. 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PubMed PMID: 25720095; PubMed Central PMCID: PMCPMC5881909.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Department of Stomatology, First people’s Hospital of Linping District, Hangzhou, China","isAcceptedByJournal":true,"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, spontaneous miscarriage, birth weight, Mendelian Randomization","lastPublishedDoi":"10.21203/rs.3.rs-3462357/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3462357/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThis study aims to comprehensively investigate the potential genetic link between periodontitis and adverse pregnancy outcomes using a two-sample Mendelian Randomization approach.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eWe employed robust genetic instruments for chronic periodontitis as exposure data from the FinnGen database. Data encompassing various pregnancy stage outcomes, including pre-pregnancy conditions (irregular menstruation, endometriosis, abnormal reproductive bleeding, and female infertility), pregnancy complications (hemorrhage, spontaneous miscarriage, and abnormalities in products), and post-pregnancy factors (single spontaneous delivery, labor duration, and birth weight of the child), were obtained from the UK Biobank. The random-effects inverse-variance weighted (IVW) method was utilized to compute primary estimates while diligently assessing potential directional pleiotropy and heterogeneity.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOur findings indicate a negative association between periodontitis and labor duration (odds ratio [OR]\u0026thinsp;=\u0026thinsp;0.999; 95% confidence interval [CI]: 0.999 to 1.000; P\u0026thinsp;=\u0026thinsp;0.017). Individuals with periodontitis are more likely to deliver lower-weight infants (OR\u0026thinsp;=\u0026thinsp;0.983; 95% CI: 0.972 to 0.995; P\u0026thinsp;=\u0026thinsp;0.005). We found no evidence of pleiotropy or heterogeneity in aforementioned two associations. We did not observe casual links with pre-pregnancy conditions and pregnancy complications.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis Mendelian Randomization study underscores the genetic influence of periodontitis on specific adverse pregnancy outcomes, particularly concerning labor duration and lower birth weight deliveries.\u003c/p\u003e\u003ch2\u003eClinical Relevance:\u003c/h2\u003e \u003cp\u003eOur study emphasizes the critical importance of maintaining periodontal health during pregnancy and offers genetic evidence supporting these associations. Further investigation is required to delve deeper into the specific underlying mechanisms.\u003c/p\u003e","manuscriptTitle":"Maternal Periodontitis May Cause Lower Birth Weight in Children: Genetic Evidence from a Comprehensive Mendelian Randomization Study on Periodontitis and Pregnancy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-19 21:15:38","doi":"10.21203/rs.3.rs-3462357/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":"69343529-ffc6-4bec-a9df-7ab671a297b9","owner":[],"postedDate":"October 19th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":25475332,"name":"Dentistry"}],"tags":[],"updatedAt":"2024-03-20T06:11:30+00:00","versionOfRecord":{"articleIdentity":"rs-3462357","link":"https://doi.org/10.1007/s00784-024-05591-9","journal":{"identity":"clinical-oral-investigations","isVorOnly":false,"title":"Clinical Oral Investigations"},"publishedOn":"2024-03-05 06:11:30","publishedOnDateReadable":"March 5th, 2024"},"versionCreatedAt":"2023-10-19 21:15:38","video":"","vorDoi":"10.1007/s00784-024-05591-9","vorDoiUrl":"https://doi.org/10.1007/s00784-024-05591-9","workflowStages":[]},"version":"v1","identity":"rs-3462357","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3462357","identity":"rs-3462357","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}