Age-related macular degeneration (AMD) is an eye disease characterized by central visual impairment and can cause severe irreversible vision loss. It is an important cause of blindness and central blindness in people over 55 years of age [
Periodontal disease (PD) is an inflammatory and destructive disease that destroys the periodontal support tissue (gingival, periodontal ligament, alveolar bone, and cementum), leading to the formation of periodontal pockets, loss of attachment, and alveolar bone resorption. As the lesion progresses, teeth loosen, gums recede, and eventually tooth loss occurs [
Although the exact pathogenesis of AMD is still unclear, the theory of inflammation and immunology is gaining more and more attention, and the role of various inflammatory factors and immune factors has been confirmed by experiments and histopathological studies [
This study was based on the statement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [
Studies that met the following conditions can be included: (1) the research theme was to explore whether PD is related to AMD; (2) observational studies, including case-control studies, cross-sectional studies, and cohort studies; (3) studies that provided raw data, or relative risk (RRs), odds ratios (ORs), or hazard ratios (HRs), and their 95% CIs; (4) full-text articles were available and published in English, excluding letters to editors, meeting abstracts, case reports, and reviews; and (5) the study included a control group.
When different studies of the same population were included, we selected a longer follow-up period or extract data from more complete studies. The two authors (XWL and WQL) chose independently, and if there were differences, they resolved through discussion or consultation with the third author (CLP).
A computerized search of the PubMed, Embase, Cochrane Library, and Web of Science databases was performed. We collected case-control studies, cross-sectional studies, and cohort studies of the relationship between PD and AMD; the search time limit was from the establishment of the database to April 20, 2020. In addition, the references included in the literature are retrospectively included to supplement the relevant literature. The following keywords and thematic terms were used: “Periodontal Diseases”, “Age-Related Macular Degeneration”, “Drusen”, “Geographic Atrophy”, “Retinal Pigment Epithelial Detachment”, “Choroidal Neovascularization”, and “Polypoidal choroidal vasculopathy”. In Supplementary Materials, we have given specific electronic search criteria for each of the above databases (Appendix
The two authors (XWL and WQL) independently used standardized tables for data extraction, and disputes were resolved through discussion or consultation with the third author (CLP). Contents included the first author, published year, sample, study period, study design, follow-up period, age, AMD patients/participants, PD ascertainment, AMD ascertainment, AMD/age status, adjusted RRs (including ORs/HRs), and 95% CIs, as well as adjustment factors and information required for quality assessment.
Case-control studies and cohort studies used the Newcastle-Ottawa scale (NOS) for risk assessment of bias [
In observational studies, for small-probability events, OR can be considered approximately equal to RR [
A total of 178 relevant literatures were obtained in the initial examination. After layer-by-layer screening, 5 studies were finally included [
Search flow chart of the meta-analysis.
Characteristics and quality assessment of the included studies.
First author, published year | Sample study period | Study design | Follow-up period | Age (yrs) | AMD patients/participants | PD ascertainment | AMD ascertainment | AMD/age status | Risk estimates (95% CI) |
---|---|---|---|---|---|---|---|---|---|
Klein, 2008 | MESA; USA | Cross-sectional | 2 | 45-85 | 265/5887 | Detailed questionnaire | Ocular fundus photographs | Early | |
Karesvuo, 2013 | NPHS; Finland | Cross-sectional | 1 | ≥30 | 54/1751 | Alveolar bone loss | Clinical diagnosis | — | |
Wagley, 2015 | US NHAHES III; US | Cross-sectional | 6 | ≥40 | 940/8208 | >10% of sites with >3 mm of CAL | Ocular fundus photographs | ||
Shin, 2017 | KNHANES; Korea | Cross-sectional | 2 | ≥40 | 732/13072 | CP index scores 3 and 4 | Ocular fundus photographs | ||
Sun, 2019 | TNHIRD; China | Retrospective cohort | 13 | ≥50 | 3014/83322 | ICD-9-CM | ICD-9-CM |
MESA: Multi-Ethnic Study of Atherosclerosis; NPHS: National Population Health Survey 2000; NHAHES: National Health and Nutrition Examination Survey; KNHANES: Korea National Health and Nutrition Examination Survey; TNHIRD: Taiwan National Health Insurance Research Database; ICD: International Classification of Diseases. #All data was calculated by pooling early AMD
Adjusted variables in studies included in the meta-analysis.
Author (year) | Variables of adjustment |
---|---|
Klein (2008) | Age, gender, race/ethnicity, and study site. |
Karesvuo (2013) | Age, smoking, diabetes, carriage of salivary pathogens, and hypertension. |
Wagley (2015) | Age, gender, race/ethnicity, education, poverty income ratio, smoking, hypertension, BMI, CRP, and CVD. |
Shin (2017) | Age, gender, education, house income, smoking, hypertension, CVD, anemia, hepatitis B infection, serum HDL level, BMI, serum ferritin level, and white blood cell count. |
Sun (2019) | Age, gender, hypertension, diabetes, hyperlipidemia, asthma/COPD, CLD, and CKD. |
Abbreviations: BMI: Body Mass Index; CRP: C-reactive protein; CVD: cardiovascular disease; HDL: high-density lipoprotein; COPD: chronic obstructive pulmonary disease; CLD: chronic liver disease and cirrhosis; CKD: chronic kidney disease.
Agency for Healthcare Research and Quality: cross-sectional studies.
Study ID | Source of informationa | Exclusion criteriab | Time periodc | Continuous or notd | Subjective factorse | Quality assessmentf | Explain exclusiong | Controlling confounding factorsh | Handling missing datai | Completeness of data collectionj | Follow-up datak | Score |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Klein 2008 | Yes | Yes | Yes | Yes | Yes | No | No | Yes | No | No | No | 6 |
Karesvuo 2013 | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | No | Yes | No | 8 |
Wagley 2015 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | No | No | 8 |
Shin 2017 | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | No | No | 8 |
a: define the source of information (survey, record review); b: list inclusion criteria for exposed and unexposed subjects (cases and controls) or refer to previous publications; c: indicate time period used for identifying patients; d: indicate whether or not subjects were consecutive if not population-based; e: indicate if evaluators of subjective components of the study were masked to other aspects of the status of the participants; f: describe any assessments undertaken for quality assurance purposes (e.g., test/retest of primary outcome measurements); g: explain any patient exclusions from analysis; h: describe how confounding factors were assessed and/or controlled; i: if applicable, explain how missing data were handled in the analysis; j: summarize patient response rates and completeness of data collection; k: clarify what follow-up was expected and the percentage of patients for which incomplete data or follow-up was obtained.
Newcastle-Ottawa Quality Assessment Scale: cohort studies.
Study ID | Selection | Comparabilitye | Exposure | Total scores | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Representativenessa | Selectionb | Ascertainmentc | Demonstrationd | Important factorf | Additional factorg | Assessmenth | Follow-up | |||
Lengthi | Adequacyj | |||||||||
Sun 2019 | Representative★ | Same source★ | Secure record★ | Yes★ | Yes★ | Yes★ | Record linkage★ | Yes★ | No description | 8★ |
a: representativeness of the exposed cohort; b: selection of the nonexposed cohort; c: ascertainment of exposure; d: demonstration that outcome of interest was not present at the start of study; e: comparability of cohorts on the basis of the design or analysis; f: study controls for selecting the most important factor; g: study controls for any additional factor; h: assessment of outcome; i: was follow-up long enough for outcomes to occur; j: adequacy of follow-up of cohorts. ★: earns a star.
Meta-analysis results using the random-effects model showed that the incidence of AMD in PD patients was 1.35 times that of non-PD patients, and the difference was statistically significant (
Forest plot of studies.
Figure
The results of the sensitivity analysis.
Figure
The results of the subgroup analysis and metaregression.
According to the results of Egger’s (
There is no unified conclusion on whether PD and AMD are related, and the focus of each research result is different. Klein et al. [
In recent years, many studies have shown that periodontal infection may be a risk factor for cardiovascular disease, diabetes, pregnancy complications, respiratory infections, rheumatoid arthritis, and so on [
Our research has the following advantages. First, this study is the first meta-analysis about whether PD and AMD are related. We retrieved and collected all published studies that met the inclusion criteria, and no publication bias was detected. Second, PD and AMD have some common risk factors; all the studies we included provided the effect sizes after adjusting for related confounding factors. In addition, the quality of the included studies were all medium-/high-quality studies, which made our results more reliable. Finally, this study laid the foundation for further exploration of the relationship between PD and AMD and provided a certain theoretical basis for AMD’s mechanism exploration and clinical prevention and treatment.
Our research also has some limitations. First, most of the included studies are cross-sectional studies, which cannot explain the causal relationship between PD and AMD. Second, although most studies were based on scientific examination methods to diagnose PD and AMD, the diagnostic criteria were different, and some diagnoses were based on patient self-reports, which increased the heterogeneity of our research and reduced credibility. Third, we observed significant heterogeneity in the study. Although the subgroup analysis was used to speculate on the source of the heterogeneity, it still had an impact on the reliability of the research results. Fourth, Egger’s test and Begg’s test results did not find obvious evidence, but because of the too few studies included, it is difficult to determine whether there is publication bias. Fifth, the adjustment of confounding factors was not perfect. Although each study had carried out meticulous research design and tried to control the confounding factors, there were still unmeasured or unknown confounding factors, which may introduce deviations. And the confounding factors adjusted between different studies were different, which increased the heterogeneity of the study and affected the reliability of the final result. Finally, due to the limited number of studies, we only analyzed the relationship between PD and AMD in general and could not further explore the impact of PD on AMD patients at different stages or at different ages and the association between PD at different severity levels and AMD.
With the development of the economy and society, the average lifespan of the population has been prolonged, resulting in population aging. It is the responsibility of oral professionals to reduce the incidence of oral infections and possible systemic diseases caused by PD through early treatment. AMD can cause severe irreversible vision loss in the elderly, which is one of the important causes of blindness. At present, most clinical cases have no effective treatment, which seriously affects the lives of patients. We hope that our research will improve the oral health awareness, help in understanding the importance of maintaining periodontal health, and at the same time lay the foundation for AMD’s mechanism exploration and prevention, reduce the risk of AMD, and improve the quality of life in the general population, especially the geriatric population.
In summary, our meta-analysis of 5 studies showed that PD is associated with AMD, and the risk of AMD in patients with PD is increased by 35%, but the current evidence is insufficient to confirm the causal relationship between PD and AMD. Researchers need to perform high-quality, large-scale, multi-centre prospective cohort studies and adjust the confounding factors in considerable detail to explore whether these two important diseases are related to each other and the mechanism of their connection.
The authors declare that there is no conflict of interest regarding the publication of this paper.
This work was supported by the National Natural Science Foundation of China (No.81500862).
Appendix 1: electronic search criteria.