Periodontitis,Edentulism,and Risk of Mortality: A Systematic Review with Meta-analyses

Abstract

Periodontitis has been independently associated with the chronic noncommunicable diseases that most frequently lead to death worldwide. The aim of the present systematic review was to study whether people with periodontitis/edentulism are at increased risk of all-cause and cause-specific mortality as compared with those without periodontitis/edentulism. Cohort studies were included that 1) evaluated periodontitis or edentulism as exposures in relation to all-cause or cause-specific mortality as an outcome and 2) reported effect estimates as hazard ratios, risk ratios, or odds ratios with 95% CIs or crude numbers. Two review authors independently searched for eligible studies, screened the titles and abstracts, did full-text analysis, extracted the data from the published reports, and performed the risk-of-bias assessment. In case of disagreement, a third review author was consulted. Study results were summarized through random effects meta-analyses. A total of 57 studies were included, involving 48 cohorts and 5.71 million participants. Periodontitis was associated with increased risk of all-cause mortality (risk ratio, 1.46 [95% CI, 1.15 to 1.85]) and mortality due to cardiovascular diseases (1.47 [1.14 to 1.90]), cancer (1.38 [1.24 to 1.53]), coronary heart disease (2.58 [2.20 to 3.03]), cerebrovascular diseases (3.11 [2.42 to 3.98]), but not pneumonia (0.98 [0.69 to 1.38]). Edentulism (all types) was associated with increased risk of all-cause mortality (1.66 [1.46 to 1.88]) and mortality due to cardiovascular diseases (2.03 [1.50 to 2.74]), cancer (1.55 [1.24 to 1.94]), pneumonia (1.72 [1.07 to 2.78]), coronary heart disease (2.98 [2.43 to 3.65]), and cerebrovascular diseases (3.18 [2.24 to 4.51]). Periodontitis and its ultimate sequela (edentulism) are associated with an increased risk of all-cause and cause-specific mortality (PROSPERO CRD42018100095).

Keywords

periodontal diseases periomedicine oral diseases systemic diseases epidemiology risk factors

Introduction

Periodontitis was recently defined as a chronic multifactorial inflammatory disease associated with dysbiotic dental biofilms and characterized by progressive destruction of the tooth-supporting apparatus. Its primary features include the loss of periodontal tissue support, manifested through clinical attachment loss and radiographically assessed alveolar bone loss, and the presence of periodontal pocketing and gingival bleeding (Papapanou et al. 2018). Periodontitis, including its mildest forms, affects about 50% of adults (Eke et al. 2012; Eke et al. 2020). Severe periodontitis (stage 3 or 4) is the sixth-most common human disease, and it is estimated to affect 9.8% of the global adult population (Bernabe et al. 2020). If untreated, severe periodontitis results in tooth loss, frequently leading to masticatory dysfunction and nutritional compromise, aesthetic impairment, altered speech, low self-esteem, and a poorer overall quality of life. Its terminal sequela is the loss of all teeth (edentulism; Papapanou et al. 2018), what represents a significant health care, social, and economic burden, being both a source and a consequence of social inequality throughout the world. Its relevance as a global public health challenge, with other oral diseases (mainly dental caries and oral cancer), was recently emphasized (Peres et al. 2019; Watt et al. 2019), calling for greater global attention to implement appropriate measures to reduce this burden of oral diseases and thus their important health and economic impact on individuals and health care systems (Tonetti et al. 2017; Peres et al. 2019; Watt et al. 2019).

Furthermore, multiple epidemiologic, experimental, and interventional studies have evidenced how periodontitis may affect systemic health. In fact, severe periodontitis has been independently associated with the majority of chronic noncommunicable diseases (NCDs) of aging and premature mortality (Genco and Sanz 2020). These associations have been explained, not only by the share among most NCDs of genetic and environmental risk factors, but also through common chronic inflammatory pathways. The primary etiologic factor in the initiation and progression of periodontitis is a dysbiotic state within the bacterial communities of the subgingival niche that triggers an aberrant chronic inflammatory response leading to periodontal tissue destruction (Hajishengallis and Korostoff 2017). During the course of the disease, some of these pathogens, with the locally produced inflammatory cytokines, can enter the bloodstream and trigger the host response by multiple mechanisms, thus leading to an increase in the systemic inflammatory burden (Loos 2005; Romandini et al. 2018; Sanz et al. 2018; Sanz et al. 2020). Because of these mechanisms, periodontitis has been independently associated with an increased risk of most chronic NCDs (Genco and Sanz 2020), in particular cardiovascular diseases (CVDs; Mattila et al. 1989; Tonetti and Van Dyke 2013; LaMonte et al. 2017; Sanz et al. 2020), diabetes (Chapple and Genco 2013), hypertension (Muñoz Aguilera et al. 2020), obesity (Suvan et al. 2015), chronic renal disease (Sharma et al. 2016), obstructive lung disease (Hobbins et al. 2017), pneumonia (Gomes-Filho et al. 2020), and cancer (Nwizu et al. 2020). These diseases and their sequelae represent the most prevalent causes leading to death worldwide (World Health Organization 2020). Consequently, periodontitis could also be a risk factor for the ultimate medical outcome (mortality).

Growing epidemiologic data implicate chronic inflammation/infection due to periodontitis as a risk factor for cause-specific death and all-cause mortality, although not all studies have provided similar results. Extracting consistent data on this relation would provide relevant information that might be applied by health care providers and policy makers. Therefore, the aim of this systematic review was to summarize all existing epidemiologic data from cohort studies on periodontitis and its sequela in most advanced cases (edentulism) and the risk of all-cause and cause-specific mortality and to weight the available evidence through meta-analyses of the study results.

Materials and Methods

This systematic review is reported according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses; Moher et al. 2009) and MOOSE guidelines (Meta-analysis of Observational Studies in Epidemiology; Stroup et al. 2000). A detailed protocol was designed before the start of this study and registered on PROSPERO (CRD42018100095).

Focused Question

The focused question was as follows: In any population, is there an increased risk of mortality in participants experiencing periodontitis/edentulism when compared with those without periodontitis/edentulism?

Inclusion and Exclusion Criteria

The inclusion criteria were organized with PECOS:

Population: All types of populations, without restrictions on age groups, country, and sex. Studies only including participants with specific medical conditions or undergoing specific medical procedures (e.g., hemodialysis) were excluded.

Exposure: Periodontitis or edentulism at baseline.

Comparison: Absence of periodontitis (in case of periodontitis as exposure) or absence of edentulism (in case of edentulism as exposure) at baseline.

Type of outcome measures: Mortality, either all cause or cause specific, expressed in terms of number of deaths or as an estimate (hazard ratio [HR], risk ratio [RR], or odds ratio [OR]).

Types of studies: Cohort studies.

Search Methods for the Identification of Studies

Two review authors (M.R. and G.B.) performed in duplicate the systematic search in 4 electronic databases (MEDLINE via PubMed, Embase, Scopus, Web of Science) from outset to November 15, 2019. The complete search strategies for all electronic databases are reported in the Appendix. No restrictions on language or date of publication were placed when the electronic databases were searched.

Four key dentistry journals were also hand-searched from outset to November 30, 2019, in duplicate by 2 review authors (G.B. and J.B.): Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology, and Journal of Periodontal Research. The same authors also checked in duplicate the reference lists of all included studies. All studies identified by at least 1 review author were included in the next phase (study selection).

Study Selection

The titles and abstracts (when available) of all identified studies were screened independently by 2 review authors (G.B. and J.B.). If articles appeared to meet the inclusion criteria or in case there were insufficient data in the title and abstract, the full report was obtained to make the final decision. Disagreements were resolved by discussion. Where resolution was not possible, a third review author was consulted (M.R.). The interreviewer reliability of the screening method was calculated (percentage agreement and kappa correlation coefficient).

The full text of the selected studies was evaluated independently by 2 review authors (M.R. and J.B.) to establish whether they met the inclusion criteria. Disagreements were resolved by discussion, and if resolution was not possible, a third review author was consulted (G.B.). The reasons for excluding the studies after the full-text evaluation were recorded. The interreviewer reliability of the screening method was also calculated at this stage (percentage agreement and kappa correlation coefficient).

Multiple publications from a given study data set were included when they presented different analyses in terms of exposures/outcomes; otherwise, the article with the longest follow-up was included. If one article reported a better estimate than another within the same sample population (e.g., adjusted HR vs. crude numbers), it was selected, even in case of shorter follow-up.

All studies meeting the inclusion criteria were included and underwent data extraction and assessment of risk of bias.

Data Extraction and Management

As part of the calibration process, the first 8 studies were extracted in triplicate (M.R., G.B., G.A.) with use of predefined data extraction forms (Appendix). Data from the remaining studies were extracted independently and in duplicate by 2 review authors (G.B. and G.A.). All the extracted data and eventual disagreements were discussed by the 2 review authors in the presence of a third review author (M.R.), who took the final decision when resolution was not possible. All corresponding authors of potentially eligible studies were contacted for clarifications, missing information, or additional estimates.

The following measures of risk were extracted in order of preference: HR, RR, OR, and crude numbers. Edentulism was defined as the status of being without natural teeth. If the included study reported >1 estimate according to different periodontitis case definitions, the one closest to the European Federation of Periodontology’s sensitive case definition was selected for periodontitis, while the one closest to its specific case definition was selected for severe periodontitis (Tonetti et al. 2005). Otherwise, the study was categorized as reporting about either periodontitis or severe periodontitis according to the same criteria. When possible, models adjusted for age, sex, and smoking status (Jha et al. 2013; Eke et al. 2016; World Health Organization 2020), but not adjusted factors involved in the causal pathway between periodontitis and mortality (e.g. biomarkers), were selected. When available, weighted complex sample estimates were used for population-representative studies.

The risk-of-bias assessment was conducted with the Newcastle-Ottawa Scale for quality assessment of cohort studies (Wells et al. 2000). The adjustment level of the selected models was also evaluated and categorized as adequately adjusted, possibly overadjusted, and possibly underadjusted. The detailed methods for risk-of-bias and adjustment-level evaluations are reported in the Appendix.

Data Analysis

Where necessary (e.g., in presence of crude numbers), a relative risk measure was estimated for each independent study (measured with HR or RR, in order of preference, according to data availability). Multiple meta-analyses with random effects models (DerSimonian and Kacker 2007) were then carried out independently with periodontitis, severe periodontitis, and edentulism as exposures and all-cause mortality and cause-specific mortalities as outcomes. Meta-analyses were performed in the presence of at least 2 studies for each group or subgroup. When different metrics (i.e., HRs, RRs, ORs) were available for studies in the same meta-analysis, they were merged, as the event (mortality) was considered as rare; consequently, they could be considered very similar (Higgins et al. 2016). The meta-analyses were in most cases expressed as RRs with 95% CIs. However, sensitivity analyses were also carried out by only including studies expressing HRs.

Interstudy heterogeneity was also assessed, initially by carefully examining the characteristics of the included studies. In addition, in each meta-analysis, the extent and impact of heterogeneity was assessed by visually inspecting the forrest plots and by calculating Cochran’s test, τ², and I² statistics. The I² statistic was used to quantify heterogeneity, with values of 25%, 50%, and 75% considered low, moderate, and high, respectively (Higgins et al. 2003).

Subgroup analyses were then carried out on the basis of age (≥65 y, <65 y, mixed ages), sex (male, female, mixed), region (Europe, North America, Asia, other), periodontitis/edentulism assessment (verified clinically, self-reported), systemic health status at baseline (systemically healthy, diseased, and mixed), length of follow-up (at least 10 y, <10 y), adjustment level 1 (adequately adjusted, possibly overadjusted, possibly underadjusted), adjustment level 2 (crude, adjusted), and risk of bias (low, moderate, high). Whenever possible, subgroup analyses were based on subgroup estimates reported in the included studies or provided by the study authors; otherwise, the studies were categorized in a subgroup.

Moreover, sensitivity analyses were carried out by excluding deaths due to suicides/injuries and including only high-quality studies (i.e., reporting HRs and with at least 10 y of follow-up, clinically verified periodontitis/edentulism, low risk of bias, and adequately adjusted multivariate models).

Finally, publication bias was evaluated by visually inspecting funnel plots for each meta-analysis in which the natural log RR/HR was plotted against the standard error. For meta-analyses with at least 10 studies, the risk of publication bias was also evaluated with Egger’s and Begg’s tests.

All the analyses were carried out with RStudio 1.2.5033 software (RStudio) and the statistical significance was set on P values <0.05.

Results

Study Selection

The initial database search yielded 8,353 entries, of which 1,809 were retrieved in MEDLINE (via PubMed), 2,942 in Embase, 1,728 in Scopus, and 1,874 in Web of Science. An additional 25 articles were identified through cross-reference checking and hand-searching. After exclusion of all duplicates, the number of entries was 5,507. Of these, 5,395 studies were discarded after review of the titles and abstracts (agreement, 99.31%; k = 0.84; P < 0.001). An additional 55 articles were excluded after full-text review and application of the eligibility criteria (reasons for exclusion after full-text analysis are reported in Appendix Table 1; agreement, 88.60%; k = 0.77;P < 0.001). A flowchart that depicts this selection process is displayed in Figure 1.

Table.

Overview of the Included Studies.

			Length of Follow-up					Main Estimates Provided
Reference	Region	No.^a	Max	Mean	Median	RoB	Adjustment	Periodontitis	Severe Periodontitis	Edentulism
Adolph (2017)	France	76,188	6	3.4		Mod	Under			All: RR, 8.61 (5.95-12.46)
Ajwani (2003a)	Finland	364	10	10.0	10	Low	Adeq	All: HR, 1.58 (0.96-2.61); CVD: 1.97 (1.01-3.85)		All: HR, 1.48 (0.95-2.31); CVD: 1.40 (0.76-2.59)
Ando (2014)	Japan	7,779	8	5.6		Mod	Under			All: RR, 2.09 (1.74-2.52); CVD: 2.32 (1.55-3.48); Can: 2.26 (1.67-3.05); non-Can and non-CVD: 1.89 (1.32-2.71)
Ansai (2013)	Japan	656	12		12	Mod	Under			All: RR, 1.09 (0.97-1.22)
Avlund (2009)^b	Denmark	335	21	21.0	21	Low	Adeq		All: HR, 1.37 (0.97-1.92)
Awano (2008)	Japan	697	4	4.0	4	Mod	Under	All: HR, 0.6 (0.4-0.9); Pne: 1.1 (0.4-3.0)	All: HR, 1.0 (0.5-2.0); Pne: 3.9 (1.1-13.9)	All: RR, 1.26 (0.89-1.79); Pne: 1.90 (0.72-5.01)
Beck (1996)^c	USA	1,094		≅18		Low	Over	CHD: OR, 1.9 (1.10-3.43)
Brown (2009)	USA	41,000	16			Low	Under			All, CVD: only subgroup analysis for age
Caplan (2017)	Iowa (USA)	535	7.5			Mod	Under			All: HR, 1.42 (1.10-1.85)
Chen (2015)	Taiwan	100,263	6	3.8		Low	Over	All: HR, 1.34 (1.26-1.42); CVD: 1.25 (1.11-1.41)
Demmer (2011)^d	USA	9,091	21			Low	Under	All: RR, 1.96 (1.85-2.09)		All: RR, 2.09 (2.01-2.18)
DeStefano (1993)^d	USA	9,760	16		14	Low	Over	CHD: RR, 2.66 (2.16-3.28)		CHD: RR, 2.69 (2.30-3.14)
Dietrich (2008)^c	USA	1,197	35		24	Mod	Under			CHD: RR, 2.61 (1.67-4.08)
Garcia (1998)^c	USA	804	28	≅25		Low	Adeq		All: HR, 1.85 (1.25-2.74)
Gomes (2016)^e	USA	278	44	17.4		Low	Under	All: RR, 2.15 (1.64-2.82); CVD: 2.87 (1.71-4.80)		CVD: RR, 3.51 (1.72-7.18)
Gonzalez-Navarro (2018)	USA	6,640				Low	Adeq	All: HR, 1.01 (0.88-1.15)
Hämäläinen (2003)	Finland	226	10	10.0	10	Mod	Under			All: HR, 2.56 (1.12-5.85)
Hansen (2016)	Denmark	100,694	15	15.0	15	Low	Adeq	All: HR, 2.70 (2.60-2.81); CVD: 2.02 (1.87-2.18)
Heikkilä (2018)	Finland	68,273	13	10.1	10.1	Low	Under	Can: RR, 1.18 (1.01-1.39)
Helenius-Hietala (2019)	Finland	6,165	13			Low	Under	Nonliver death: HR, 1.01 (0.83-1.24)		Nonliver death: HR, 0.95 (0.77-1.19)
Hiratsuka (2019)	Japan	846	13	12.9	10.8	Low	Adeq			All: HR, 1.57 (1.19-2.06)
Holm-Pedersen (2008)^b	Denmark	573	21	21.0	21	Low	Adeq			All: HR, 1.26 (1.03-1.55)
Holmlund (2010)	Sweden	7,674	29		12	Low	Adeq		All: HR, 1.37 (0.74-2.54); CVD: 1.62 (0.59-4.46)
Hu (2015)	Taiwan	55,651	6	3.0		Low	Adeq			All: HR, 2.28 (2.07-2.52)
Hujoel (2003)^d	USA	11,328	21			Low	Under	Can: HR, 1.56 (1.25-1.92)		Can: HR, 1.43 (1.16-1.76)
Iwasaki (2018)	Japan	469	10	8.7		Low	Adeq	All: HR, 1.09 (0.63-1.89)		All: HR, 1.40 (0.67-2.90)
Janket (2014)	Finland	473	20		18.8	Low	Over	All: HR, 0.87 (0.53-1.43); CVD: 0.75 (0.38-1.49)		All: HR, 1.50 (1.05-2.14); CVD: 1.73 (1.08-2.76)
Jansson (2018)	Sweden	1,393	44			Low	Under	All: OR, 1.40 (1.03-1.92)		All: OR, 4.46 (1.46-13.60)
Joshy (2016)	NSW (Australia)	172,630	5	4.3	3.9	Mod	Under			All: RR, 2.90 (2.54-3.31)
Kim (2013)	USA	5,588	7			Low	Adeq	All: OR, 1.36 (0.97-1.90)
LaMonte (2017)	USA	57,001		6.7		Mod	Adeq	All: HR, 1.08 (1.00-1.16); CVD: 1.01 (0.86-1.18)		All: HR, 1.47 (1.32-1.63); CVD: 1.59 (1.28-1.98)
Lee (2019)	South Korea	4,404,970	9		7.6	Low	Over			All: HR, 1.52 (1.39-1.65)
Liljestrand (2015)	Finland	7,629	13.9		13.8	Low	Adeq			All: HR, 1.68 (1.26-2.24)
Linden (2012)	Northern Ireland	1,558			16.6	Low	Over	All: HR, 1.30 (1.06-1.58)	All: HR, 1.26 (1.00-1.57)	All: HR, 1.43 (1.11-1.84)
Lopez-Jimenez (2001)	USA	88,882		≅5		Mod	Over	All: RR, 1.14 (1.02-1.26); CVD: RR, 1.09 (0.9-1.3)
Lund Håheim (2017)	Norway	6,434		12.5		Low	Adeq	All: HR, 1.02 (0.84-1.24)		All: HR, 1.49 (1.19-1.87)
Matsuyama (2017)	Japan	77,397	3.76		3.01	Mod	Adeq			All: only subgroup analysis for gender
Michaud (2018)	USA	7,466	16	14.7		Low	Under	Can: RR, 1.45 (1.15-1.83)	Can: RR, 1.50 (1.20-1.86)	Can: RR, 1.61 (1.34-1.92)
Morrison (1999)	Canada	9,331	23			Low	Under	CVD: RR, 2.92 (2.33-3.67); CHD: 2.73 (1.99-3.48); Cer: 3.69 (2.43-5.60)		CVD: RR, 3.59 (3.11-4.15); CHD: 3.49 (2.93-4.17); Cer: 3.83 (2.92-5.01)
Österberg (2008)	Sweden	1,803	7	7.0	7	Mod	Under			All: RR, 1.64 (1.37-1.96)
Padilha (2008)^e	USA	500	26	≅10		Low	Over			All: HR, 1.76 (1.04-2.98)
Paganini-Hill (2011)	USA	5,611	17		9	Mod	Adeq			All: HR, 1.20 (1.09-1.30)
Park (2019)	South Korea	247,696	11		9.5	Low	Over	All: HR, 0.91 (0.87-0.95); Card: 0.91 (0.83-1.00)
Ragnarsson (2004)	Iceland	2,613	15			Low	Adeq			All: HR, 1.15 (0.94-1.50); CVD: 1.46 (0.88-2.43)
Ricardo (2015)^f	USA	10,755	18		14	Low	Over	All: HR, 1.39 (1.06-1.81); CVD: 1.33 (0.88-2.01)
Schwahn (2013)	Germany	1,803	12		9.9	Mod	Under			All: RR, 2.10 (1.75-2.51); CVD: 2.15 (1.54-3.00)
Shimazaki (2001)	Japan	1,762	6	6.0	6	Mod	Under			All: RR, 1.18 (1.07-1.30)
Söder (2007)	Sweden	1,676	16	16.0	16	Mod	Under	All: RR, 6.58 (3.56-12.15); CVD: 0.61 (0.08-4.84); Can: 2.16 (0.67-7.00); Dig: 2.43 (0.45-13.20)
Suma (2018)	Japan	19,775	11.33	9.53	9.5	Mod	Adeq			Pne: HR, 1.67 (0.96-2.89)
Tsou and Wu (2019)^f	USA	10,165	27			Low	Under	Can: RR, 1.40 (1.24-1.58); Pne: 0.96 (0.66-1.38); CLRD: 1.05 (0.77-1.42); DM: 1.53 (1.12-2.08); AD: 0.93 (0.61-1.44); KD: 1.42 (0.88-2.32)
Tuominen (2003)	Finland	6,527		≅12		Low	Under	CVD: RR, 1.12 (0.81-1.56)	CVD: RR, 1.40 (1.03-1.90)
Watt (2012)	Scotland	12,871	13	8.0		Low	Adeq			All: HR, 1.40 (1.22-1.62); CVD: 1.63 (1.27-2.11); Can: HR, 1.17 (0.92-1.48)
Wu (2000)^d	USA	9,962	21			Low	Under	Cer: RR, 2.83 (2.08-3.84)		Cer: RR, 2.68 (2.13-3.38)
Xavier (2010)	Brazil	1,533	12			Mod	Under			All: RR, 1.31 (1.14-1.51)
Xu (2011)^f	USA	10,849	18		14	Low	Under		All: RR, 1.54 (1.38-1.71); CVD: 1.42 (1.16-1.73)
Yang (2017)	Finland	29,096	27	17.0	17.99	Low	Adeq			All: HR, 1.20 (1.16-1.23)
Zhao (2019)	Honk Kong (China)	488	21			Mod	Under	All: RR, 7.78 (3.52-17.19)

See Appendix References.

AD, Alzheimer disease; Adeq, adequately adjusted; All, all-cause mortality; Can, cancer mortality; Card, cardiac death; Cer, cerebrovascular mortality; CHD, coronary heart disease mortality; CLRD, chronic lower respiratory disease; CVD, cardiovascular mortality; Dig, digestive disease; DM, diabetes mellitus; HR, hazard ratio; KD, kidney disease; Max, maximum; Mod, moderate; NSW, New South Wales; Over, possibly overadjusted; Pne, pneumonia mortality; RoB, risk of bias; RR, risk ratio; Under, possibly underadjusted.

Sample analyzed.

Same cohort: Glostrup Aging Study.

Same cohort: VA Dental Longitudinal Study in Normative Aging Study.

Same cohort: NHANES I (1971 to 1975; National Health and Nutrition Examination Survey).

Same cohort: Baltimore Longitudinal Study of Aging.

Same cohort: NHANES III (1988 to 1994; National Health and Nutrition Examination Survey).

Figure 1.

PRISMA 2009 flow diagram for study selection. From Moher et al. (2009). For more information, visit http://www.prisma-statement.org.

Finally, 57 studies, involving 48 cohorts and 5.71 million participants, met the inclusion criteria and were then included in this systematic review (see Appendix References).

Characteristics of the Included Studies

The Table depicts the general characteristics of the included studies, while Appendix Tables 2 to 5 provide detailed information on participants, exposures/comparisons, outcomes, and results, respectively. Twenty studies were performed in Europe, 22 in North America, 13 in Asia, and the remaining 2 in other continents. Most studies (n = 36) had a follow-up >10 y. Periodontitis as an exposure was reported in 33 studies, with 25 reporting only on periodontitis, 4 only on severe periodontitis, and 4 on both. Edentulism was reported in 40 studies. Periodontitis, severe periodontitis, and edentulism were clinically verified in 25 (of 29), 8 (of 8), and 28 (of 40) studies, respectively, while they were self-reported or not clearly reported in the remaining ones. Comparison groups for periodontitis and severe periodontitis were represented by all remaining participants nonidentified as exposed, with the exception of 3 and 2 studies, respectively, which used a restricted extreme group with the best periodontal conditions as a comparison. The comparison group for edentulism was represented by the presence of at least 1 tooth in 30 studies, while the remaining 10 studies used as comparison group the presence of different number of teeth with different periodontal conditions. All-cause mortality was analyzed in 40 of the included studies, while cardiovascular and cancer mortality was studied in 16 and 6 studies, respectively. Other causes of mortality included pneumonia, coronary heart disease (CHD), and cerebrovascular events.

The tabulated studies included >5.71 million participants, 149,227 all-cause deaths, 15,992 deaths from CVD, and 3,683 from cancer.

Appendix Table 6 reports the risk-of-bias assessment of the included studies. Most studies (n = 38) were considered low risk of bias, 19 unclear risk, and none as high risk. Twenty studies were categorized as adequately adjusted, 10 as possibly overadjusted, and 27 as possibly underadjusted.

Analysis of funnel plots and, when in the presence of >10 studies, the application of the Begg’s or Egger’s test generally showed no obvious evidence of publication bias (Appendix). However, these plots should be interpreted with caution, due to the small number of studies in some meta-analyses. In some cases (e.g., periodontitis/all-cause mortality main analysis), a visual non–statistically significant asymmetry of the funnel plots was observed, which could be due to publication bias or other reasons (e.g., the high heterogeneity observed across the included studies).

Periodontitis and All-Cause/Cause-Specific Mortality

Figure 2, Appendix Table 7, and the Appendix depict the meta-analyses relating periodontitis with the risk of all-cause and cause-specific mortality. Periodontitis was associated with increased risk of all-cause mortality (n = 19 studies [n = 640,446 participants]; RR, 1.46 [95% CI, 1.15 to 1.85]; P = 0.002; I² = 98.9%), CVD mortality (n = 11 [n = 376,250]; 1.47 [1.14 to 1.90]; P = 0.003; I² = 93.1%), cancer mortality (n = 5 [n = 98,908]; 1.38 [1.24 to 1.53]; P < 0.001; I² = 29.8%), CHD mortality (n = 3 [n = 10,862]; 2.58 [2.20 to 3.03]; P < 0.001;I² = 0.0%), and cerebrovascular diseases mortality (n = 2 [n = 20,185]; 3.11 [2.42 to 3.98]; P < 0.001; I² = 0.8%). However, it was not associated with an increase in pneumonia mortality (n = 2 [n = 19,293]; 0.98 [0.69 to 1.38]; P = 0.889; I² = 0.0%).

Figure 2.

Meta-analyses: periodontitis as exposure. All-cause mortality: 21 studies provided estimates, with 660,371 participants. CVD mortality: 11 studies, 376,250 participants. Cancer mortality: 5 studies, 98,908 participants. Pneumonia mortality: 2 studies, 10,862 participants. CHD mortality: 3 studies, 20,185 participants. Cerebrovascular mortality: 2 studies, 19,293 participants. The number of studies changes in each meta-analysis, as some studies provided only subgroup analysis estimates (e.g., age or sex) while others were included twice in some subgroup analyses, as they reported the estimates for >1 subgroup (e.g., <65 y and >65 y old or males and females). Subgroup analysis for periodontitis assessment method in periodontitis and all-cause mortality included 18 studies (not 19), as 1 (Lund Håheim et al. 2017) did not specify whether periodontitis was clinically verified or self-reported. In the presence of at least 1 RR (a priori from the number of HRs), the estimate is expressed as RR; in the presence of all estimates as HRs, it is expressed as HR. CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; RR, risk ratio. ^†P < 0.05. ^‡P < 0.01. *P < 0.001.

Sensitivity analyses restricted to the highest-quality studies increased the estimates, accounting for an HR of 2.19 (n = 2 studies [n = 101,058 participants]; 95% CI, 1.32 to 3.66; P = 0.003; I² = 77.2%) for the risk of all-cause mortality and for an HR of 2.02 (n = 2 [n = 101,058]; 1.87 to 2.18; P < 0.001; I² = 0.0%) for the risk of CVD mortality.

Severe Periodontitis and All-Cause/Cause-Specific Mortality

Figure 3, Appendix Table 8, and the Appendix depict the meta-analyses relating severe periodontitis with the risk of all-cause and cause-specific mortality. Severe periodontitis was associated with increased risk of all-cause mortality (n = 6 studies [n = 21,917 participants]; RR, 1.47 [95% CI, 1.34 to 1.62]; P < 0.001; I² = 4.1%) and CVD mortality (n = 3 [n = 25,050]; 1.42 [1.20 to 1.67]; P < 0.001; I² = 0.0%). One study was available reporting an increase in cancer mortality (Michaud et al. 2018; n = 7,466 participants; RR, 1.50 [1.20 to 1.86]; P < 0.001) and 1 reporting an increased risk of pneumonia mortality (Awano et al. 2008; n = 697 participants; HR, 3.90 [1.10 to 13.90]; P < 0.05). No cohort studies evaluated the risk of CHD and cerebrovascular mortalities in cases of severe periodontitis.

Figure 3.

Meta-analyses: severe periodontitis as exposure. All-cause mortality: 6 studies provided estimates, with 21,917 participants. CVD mortality: 3 studies, 25,050 participants. Cancer mortality: 1 study, 7,466 participants. Pneumonia mortality: 1 study, 697 participants. CHD mortality and cerebrovascular mortality: no studies provided estimates. The number of studies changes in each meta-analysis, as some studies provided only subgroup analysis estimates (e.g., age or sex) while others were included twice in some subgroup analyses, as they reported the estimates for >1 subgroup (e.g., <65 y and >65 y old or males and females). In the presence of at least 1 RR (a priori from the number of HRs), the estimate is expressed as RR; in the presence of all estimates as HRs, it is expressed as HR. CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; RR, risk ratio. ^†P < 0.05. ^‡P < 0.01. *P < 0.001.

A sensitivity analysis restricted to the highest-quality studies was possible for severe periodontitis and the risk of all-cause mortality, with an HR of 1.53 (n = 3 studies [n = 8,813 participants]; 95% CI, 1.21 to 1.94; P < 0.001; I² = 0.0%).

Edentulism and All-Cause/Cause-Specific Mortality

Figure 4, Appendix Table 9, and the Appendix depict the meta-analyses relating edentulism with the risk of all-cause and cause-specific mortality. Edentulism was associated with increased risk of all-cause mortality (n = 29 studies [n = 4,981,158 participants]; RR, 1.64 [95% CI, 1.45 to 1.86]; P < 0.001; I² = 96.7%), CVD mortality (n = 9 [n = 92,519]; 2.03 [1.50 to 2.74]; P < 0.001; I² = 87.2%), cancer mortality (n = 4 [n = 39,444]; 1.55 [1.24 to 1.94]; P < 0.001; I² = 75.1%), pneumonia mortality (n = 2 [n = 20,472]; 1.72 [1.07 to 2.78]; P = 0.026; I² = 0.0%), CHD mortality (n = 3 [n = 20,288]; 2.98 [2.43 to 3.65]; P < 0.001; I² = 60.6%), and cerebrovascular diseases mortality (n = 2 [n = 19,293]; 3.18 [2.24 to 4.51]; P < 0.001; I² = 74.2%).

Figure 4.

Meta-analyses: edentulism as exposure. All-cause mortality: 33 studies provided estimates, with 4,991,196 participants. CVD mortality: 9 studies, 92,519 participants. Cancer mortality: 4 studies, 39,444 participants. Pneumonia mortality: 2 studies, 20,472 participants. CHD mortality: 3 studies, 20,288 participants. Cerebrovascular mortality: 2 studies, 19,293 participants. The number of studies changes in each meta-analysis, as some studies provided only subgroup analysis estimates (e.g., age or sex) while others were included twice in some subgroup analyses, as they reported the estimates for >1 subgroup (e.g., <65 y and >65 y old or males and females). Subgroup analysis for edentulism assessment method in edentulism/all-cause mortality included 18 studies (and not 19), as one included study (Haheim et al. 2017) did not specify whether edentulism was clinically verified or self-reported. In presence of at least 1 RR (a priori from the number of HRs), the estimate is expressed as RR; in presence of all estimates as HRs, it is expressed as HR. CHD, coronary heart disease; CVD, cardiovascular disease; HR, hazard ratio; RR, risk ratio. ^†P < 0.05. ^‡P < 0.01. *P < 0.001.

Sensitivity analyses restricted to the highest-quality studies slightly decreased the estimates, accounting for an HR of 1.39 (n = 5 studies [n = 12,025 participants]; 95% CI, 1.00 to 1.92; P = 0.049; I² = 0.0%) for the risk of all-cause mortality and for an HR of 1.44 (n = 2 [n = 2,977]; 0.97 to 2.12; P = 0.070; I² = 0.0%) for the risk of CVD mortality.

Discussion

Principal Findings

In this systematic review with meta-analyses of 57 studies on 48 cohorts with 5.71 million participants, periodontitis and edentulism were associated with an increased risk of mortality. Specifically, both were associated with all-cause mortality, CVD mortality, cancer mortality, CHD mortality, and cerebrovascular diseases mortality. Edentulism, but not periodontitis, was also associated with an increased risk of pneumonia mortality.

In regard to severe periodontitis, the evidence is supported by a limited number of studies (n = 8), although the estimates were very similar when compared with the periodontitis studies, thus not supporting a dose-dependent relationship. The exception was for pneumonia mortality, for which the only available study suggested an increased risk for people affected by severe periodontitis.

The associations between periodontitis and all-cause mortality and between edentulism and CVD mortality appeared to be greater for people <65 y old.

Between-study heterogeneity was statistically significant in most meta-analyses involving periodontitis and edentulism, while this was not the case for severe periodontitis. It was not possible to identify a single factor accounting for that observed heterogeneity, as it was still present in many subgroup analyses. However, the sensitivity analyses restricted to the highest-quality studies resulted in very similar estimates to the main analyses but with almost no heterogeneity in most cases, which may imply that heterogeneity had little effect on the results of the meta-analyses.

Interpretation in the Context of the Available Literature

Even in the absence of a previous systematic review studying the association between periodontitis and death, the hypothesis that this oral disease could lead to an increase in mortality rates has been substantiated by epidemiological evidence, biological plausibility, and interventional studies. A summary is reported in the Appendix.

Although dental caries may partially account as a cause of edentulism, total tooth loss in adult patients clearly represents the final sequela of severe periodontitis. Indeed, the increase in the estimates observed in the present systematic review for the associations between edentulism and all-cause/cause-specific mortality could be the result of a possible dose-dependent relationship, where the effect of periodontitis on mortality is maximized in the most severe cases. In this scenario, intermediate estimates would have been expected for the meta-analyses assessing the studies reporting severe periodontitis as an exposure for all-cause and cause-specific mortality. However, there were no differences when compared with the studies reporting periodontitis, probably since cases of severe periodontitis were included in the category of periodontitis and because case definitions for severe periodontitis allowed in most cases the potential inclusion of nonsevere cases.

Finally, despite the preferred use of adjusted estimates in the present systematic review, the possible role of common risk factors (residual confounding) as a potential source of the association between periodontitis/edentulism and mortality cannot be excluded, since it is difficult to assess the true effect of confounding in epidemiologic studies. Indeed, restricting the analyses to adequately adjusted studies resulted in some cases to the loss of significance of the association between periodontitis and mortality. However, it needs to be considered that some of these adequately adjusted studies had other important issues, including short follow-ups and partial-mouth periodontal examination protocols. The sensitivity analyses—which, in addition to the adjustment level, considered other critical methodological points—indicated very similar results to the main analyses. As a consequence, the possible role of residual confounding in influencing the reported associations needs to be determined in future studies.

Strengths and Limitations of This Study

This systematic review was carried out in accordance with the recommendations of the Cochrane Collaboration and reported per the statements of PRISMA, PRISMA for abstracts, and MOOSE. It followed an a priori protocol registered in PROSPERO and included a comprehensive search strategy and a prespecified analysis plan. This systematic review including meta-analysis not only represents the first systematic review on the topic but is based on the analysis of a large sample size (>5.7 million participants) with different levels of exposure (periodontitis, severe periodontitis and edentulism) and outcomes (mortality types). This allowed the realization of numerous subgroup and sensitivity analyses. Publication bias was minimized by asking study authors for additional unpublished estimates from the primary samples, and finally, the included studies were conducted in many parts of the world, thus favoring the generalizability of the results to most populations.

However, this systematic review has some limitations, mainly related to the available studies. While periodontal and edentulism status was often clinically verified, in many cases periodontitis was identified on the basis of partial-mouth assessment protocols, which may lead to its underrecognition. The causes of tooth loss were not available in most of the primary studies, thus preventing an analysis on whether the increased risk in edentulousness was related to periodontitis, caries, or both. Moreover, periodontal/edentulism status was measured only once in almost all the included studies, which may have led to including in the control groups some participants who developed periodontitis after baseline, thus potentially diluting its effect. Although we found additional studies, it was not possible to include them since the available data, even after contacting the authors, were based on continuous measures of periodontal status or tooth count, which made it impossible to clearly distinguish exposed from nonexposed participants. Many studies reported either crude numbers or estimates from possibly underadjusted models. Moreover, residual confounding (e.g., due to common genetic susceptibility or the effect of smoking) may still exist even in studies presenting adequately adjusted estimates (Hujoel et al. 2002). Due to limited information available in the literature, it was not possible to carry out subgroup analyses for relevant potential effect modifiers, such as smoking status, health status at baseline, treatment of periodontitis, and rehabilitation of edentulism. Finally, heterogeneity was also present in most meta-analyses involving periodontitis and edentulism, although it had only a small effect on the general results, as sensitivity analyses including only the highest-quality studies resulted in no heterogeneity, with very similar estimates to the main analyses.

Implications for Research

The findings of the present systematic review need to be completed and expanded through new research. Due to the proven efficacy of periodontal treatment to reduce tooth loss (Hirschfeld and Wasserman 1978) and its systemic health consequences (D’Aiuto et al. 2005; Tonetti et al. 2007; Teeuw et al. 2014; D’Aiuto et al. 2018; Sanz et al. 2018; Czesnikiewicz-Guzik et al. 2019; Sanz et al. 2020), such studies cannot be designed as long-term randomized clinical trials due to ethical reasons. Short-term randomized clinical trials may be useful to study surrogate outcomes of general health and risk of mortality, in addition to the ones already available (D’Aiuto et al. 2005; Tonetti et al. 2007). Nevertheless, epidemiological studies are still needed for true outcomes variables, including the risk of all-cause and cause-specific mortality. They should be designed as long-term prospective cohort studies, with a clear initial hypothesis focused on the relationship between periodontitis and the risk of mortality. They should be ideally carried out on population-based representative samples, and the periodontal status assessment should be performed by applying the new classification system of periodontal diseases (Caton et al. 2018; Papapanou et al. 2018) or quantitative inflammatory measures of periodontitis (e.g., PISA; Nesse et al. 2008) following a full-mouth periodontal examination protocol. Finally, there is a need to expand the generalizability of these findings, carrying out such studies in areas of the world (e.g., Africa, Oceania, and South America) that have been less studied and are characterized by sociocultural features that may influence/jeopardize the effect of periodontitis on all-cause and cause-specific mortality.

Conclusion

According to this systematic review with meta-analyses, periodontitis and its most advanced sequela (edentulism) are associated with an increased risk of all-cause and cause-specific mortality. However, the present findings should be evaluated carefully due to primary studies’ limitations and the possible presence of residual confounding.

Author Contributions

M. Romandini, contributed to conception, design, data acquisition, analysis, and interpretation, drafted the manuscript; G. Baima, contributed to design and data acquisition, critically revised the manuscript; G. Antonoglou, contributed to data acquisition and analysis, critically revised the manuscript; J. Bueno, contributed to data acquisition, critically revised the manuscript; E. Figuero, contributed to design and data analysis, critically revised the manuscript; M. Sanz, contributed to design and data interpretation, critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Supplemental Material

DS_10.1177_0022034520952401 – Supplemental material for Periodontitis, Edentulism, and Risk of Mortality: A Systematic Review with Meta-analyses

Supplemental material, DS_10.1177_0022034520952401 for Periodontitis, Edentulism, and Risk of Mortality: A Systematic Review with Meta-analyses by M. Romandini, G. Baima, G. Antonoglou, J. Bueno, E. Figuero and M. Sanz in Journal of Dental Research

Footnotes

Acknowledgements

The authors are extremely grateful to Julian Higgins for advising them on how to merge different estimates of risk in the meta-analyses of the present systematic review. Moreover, the authors kindly thank Christian Abnet, Jun Aida, Shilpi Ajwani, James Beck, Philippe Bouchard, Daniel Brown, Daniel Caplan, Gunnar Carlsson, Xi Chen, Ek Choi, Ryan Demmer, Thomas Dietrich, Larry Ellison, Maximiliano Gomes, Maria Hach, Kazuki Hayasaka, Piia Heikkilä, Toshinobu Hirotomi, Philippe Hujoel, Masanori Iwasaki, Sok-Ja Janket, Leif Jansson, Torsten Jemt, Grace Joshy, Si-Hyuck Kang, Chia-Hung Kao, Takamasa Komiyama, Gerard Linden, Yusuke Matsuyama, Katherine McGlynn, Dominique Michaud, Annlia Paganini-Hill, Ana Ricardo, Howard Sesso, Birgitta Söder, Shino Suma, Pelling Tsou, Sthepany Weinstein, and Mitsuyoshi Yoshida for providing more information and estimates about their studies, regardless the final decision to include or not include them in the present systematic review.

A supplemental appendix to this article is available online.

The authors received no financial support and declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

ORCID iD

M. Romandini

References

Awano

Ansai

Takata

Soh

Akifusa

Hamasaki

Yoshida

Sonoki

Fujisawa

Takehara

. 2008. Oral health and mortality risk from pneumonia in the elderly. J Dent Res. 87(4):334–339.

Bernabe

Marcenes

Hernandez

Bailey

Abreu

Alipour

Amini

Arabloo

Arefi

Arora

, et al.; GBD 2017 Oral Disorders Collaborators. 2020. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: a systematic analysis for the global burden of disease 2017 study. J Dent Res. 99(4):362–373.

Caton

Armitage

Berglundh

Chapple

ILC

Jepsen

Kornman

Mealey

Papapanou

Sanz

Tonetti

. 2018. A new classification scheme for periodontal and peri-implant diseases and conditions: introduction and key changes from the 1999 classification. J Clin Periodontol. 45 Suppl 20:S1–S8.

Chapple

Genco

; Working Group 2 of the Joint EFPAAP Workshop. 2013. Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol. 84 Suppl 4:S106–S112.

Czesnikiewicz-Guzik

Osmenda

Siedlinski

Nosalski

Pelka

Nowakowski

Wilk

Mikolajczyk

Schramm-Luc

Furtak

, et al. 2019. Causal association between periodontitis and hypertension: evidence from mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy. Eur Heart J. 40(42):3459–3470.

D’Aiuto

Gkranias

Bhowruth

Khan

Orlandi

Suvan

Masi

Tsakos

Hurel

Hingorani

, et al. 2018. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 6(12):954–965.

D’Aiuto

Nibali

Parkar

Suvan

Tonetti

. 2005. Short-term effects of intensive periodontal therapy on serum inflammatory markers and cholesterol. J Dent Res. 84(3):269–273.

DerSimonian

Kacker

. 2007. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trials. 28(2):105–114.

Eke

Borgnakke

Genco

. 2020. Recent epidemiologic trends in periodontitis in the USA. Periodontol 2000. 82(1):257–267.

10.

Eke

Dye

Wei

Thornton-Evans

Genco

. 2012. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 91(10):914–920.

11.

Eke

Wei

Thornton-Evans

Borrell

Borgnakke

Dye

Genco

. 2016. Risk indicators for periodontitis in US adults: NHANES 2009 to 2012. J Periodontol. 87(10):1174–1185.

12.

Genco

Sanz

. 2020. Clinical and public health implications of periodontal and systemic diseases: an overview. Periodontol 2000. 83(1):7–13.

13.

Gomes-Filho

Cruz

SSD

Trindade

Passos-Soares

Carvalho-Filho

Figueiredo

ACMG

Lyrio

Hintz

Pereira

Scannapieco

. 2020. Periodontitis and respiratory diseases: a systematic review with meta-analysis. Oral Dis. 26(2):439–446.

14.

Hajishengallis

Korostoff

. 2017. Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000. 75(1):116–151.

15.

Higgins

Soares-Weiser

López-López

Kakourou

Chaplin

Christensen

Martin

Sterne

Reingold

. 2016. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 355:i5170.

16.

Higgins

Thompson

Deeks

Altman

. 2003. Measuring inconsistency in meta-analyses. BMJ. 327(7414):557–560.

17.

Hirschfeld

Wasserman

. 1978. A long-term survey of tooth loss in 600 treated periodontal patients. J Periodontol. 49(5):225–237.

18.

Hobbins

Chapple

Sapey

Stockley

. 2017. Is periodontitis a comorbidity of copd or can associations be explained by shared risk factors/behaviors? Int J Chron Obstruct Pulmon Dis. 12:1339–1349.

19.

Hujoel

Drangsholt

Spiekerman

DeRouen

. 2002. Periodontitis-systemic disease associations in the presence of smoking—causal or coincidental? Periodontol 2000. 30:51–60.

20.

Jha

Ramasundarahettige

Landsman

Rostron

Thun

Anderson

McAfee

Peto

. 2013. 21st-Century hazards of smoking and benefits of cessation in the United States. N Engl J Med. 368(4):341–350.

21.

LaMonte

Genco

Hovey

Wallace

Freudenheim

Michaud

Mai

Tinker

Salazar

Andrews

, et al. 2017. History of periodontitis diagnosis and edentulism as predictors of cardiovascular disease, stroke, and mortality in postmenopausal women. J Am Heart Assoc. 6(4):e004518.

22.

Loos

. 2005. Systemic markers of inflammation in periodontitis. J Periodontol. 76 Suppl 11:2106–2115.

23.

Lund Håheim

Rønningen

Enersen

Olsen

. 2017. The predictive role of tooth extractions, oral infections, and hs-c-reactive protein for mortality in individuals with and without diabetes: a prospective cohort study of a 12 1/2-year follow-up. J Diabetes Res 2017:9590740.

24.

Mattila

Nieminen

Valtonen

Rasi

Kesaniemi

Syrjala

Jungell

Isoluoma

Hietaniemi

Jokinen

. 1989. Association between dental health and acute myocardial infarction. BMJ. 298(6676):779–781.

25.

Michaud

Peacock-Villada

Barber

Joshu

Prizment

Beck

Offenbacher

Platz

. 2018. Periodontal disease assessed using clinical dental measurements and cancer risk in the ARIC study. J Natl Cancer Inst. 110(8):843–854.

26.

Moher

Liberati

Tetzlaff

Altman

; PRISMA Group. 2009. Preferred Reporting Items for Systematic Reviews and Meta-analyses: the PRISMA statement. PLoS Med. 6(7):e1000097.

27.

Muñoz Aguilera

Suvan

Buti

Czesnikiewicz-Guzik

Barbosa Ribeiro

Orlandi

Guzik

Hingorani

Nart

D’Aiuto

. 2020. Periodontitis is associated with hypertension: a systematic review and meta-analysis. Cardiovasc Res. 116(1):28–39.

28.

Nesse

Abbas

van der Ploeg

Spiijkervet

FKL

Dijkstra

Vissink

. 2008. Periodontal inflamed surface area: quantifying inflammatory burden. J Clin Periodontol. 35(8):668–673.

29.

Nwizu

Wactawski-Wende

Genco

. 2020. Periodontal disease and cancer: epidemiologic studies and possible mechanisms. Periodontol 2000. 83(1):213–233.

30.

Papapanou

Sanz

Buduneli

Dietrich

Feres

Fine

Flemmig

Garcia

Giannobile

Graziani

, et al. 2018. Periodontitis: consensus report of Workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions. J Clin Periodontol. 45 Suppl 20:S162–S170.

31.

Peres

Macpherson

LMD

Weyant

Daly

Venturelli

Mathur

Listl

Celeste

Guarnizo-Herreño

Kearns

, et al. 2019. Oral diseases: a global public health challenge. Lancet. 394(10194):249–260.

32.

Romandini

Laforí

Romandini

Baima

Cordaro

. 2018. Periodontitis and platelet count: a new potential link with cardiovascular and other systemic inflammatory diseases. J Clin Periodontol. 45(11):1299–1310.

33.

Sanz

Ceriello

Buysschaert

Chapple

Demmer

Graziani

Herrera

Jepsen

Lione

Madianos

, et al. 2018. Scientific evidence on the links between periodontal diseases and diabetes: consensus report and guidelines of the Joint Workshop on Periodontal Diseases and Diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol. 45(2):138–149.

34.

Sanz

Marco Del Castillo

Jepsen

Gonzalez-Juanatey

D’Aiuto

Bouchard

Chapple

Dietrich

Gotsman

Graziani

, et al. 2020. Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol. 47(3):268–288.

35.

Sharma

Dietrich

Ferro

Cockwell

Chapple

. 2016. Association between periodontitis and mortality in stages 3-5 chronic kidney disease: NHANES III and linked mortality study. J Clin Periodontol. 43(2):104–113.

36.

Stroup

Berlin

Morton

Olkin

Williamson

Rennie

Moher

Becker

Sipe

Thacker

; MOOSE Group (Meta-analysis of Observational Studies in Epidemiology). 2000. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 283(15):2008–2012.

37.

Suvan

Petrie

Nibali

Darbar

Rakmanee

Donos

D’Aiuto

. 2015. Association between overweight/obesity and increased risk of periodontitis. J Clin Periodontol. 42(8):733–739.

38.

Teeuw

Slot

Susanto

Gerdes

Abbas

D’Aiuto

Kastelein

Loos

. 2014. Treatment of periodontitis improves the atherosclerotic profile: a systematic review and meta-analysis. J Clin Periodontol. 41(1):70–79.

39.

Tonetti

Claffey

; European Workshop in Periodontology Group C. 2005. Advances in the progression of periodontitis and proposal of definitions of a periodontitis case and disease progression for use in risk factor research: Group C consensus report of the 5th European Workshop in Periodontology. J Clin Periodontol. 32 Suppl 6:210–213.

40.

Tonetti

D’Aiuto

Nibali

Donald

Storry

Parkar

Suvan

Hingorani

Vallance

Deanfield

. 2007. Treatment of periodontitis and endothelial function. N Engl J Med. 356(9):911–920.

41.

Tonetti

Jepsen

Jin

Otomo-Corgel

. 2017. Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: a call for global action. J Clin Periodontol. 44(5):456–462.

42.

Tonetti

Van Dyke

; Working Group 1 of the Joint EFP/AAP Workshop. 2013. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol. 84 Suppl 4:S24–S29.

43.

Watt

Daly

Allison

Macpherson

LMD

Venturelli

Listl

Weyant

Mathur

Guarnizo-Herreño

Celeste

, et al. 2019. Ending the neglect of global oral health: time for radical action. Lancet. 394(10194):261–272.

44.

Wells

Shea

O’Connell

Peterson

Welch

Losos

Tugwell

. 2000. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa (Canada): Ottawa Hospital Research Institute.

45.

World Health Organization. 2020. WHO Mortality Database [accessed 2020 Apr 8]. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

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