Obstructive sleep apnea (OSA) is a respiratory disorder characterized by recurrent episodes of an obstruction of the upper airways during sleep called apneas (if the airways are completely obstructed) or hypopneas (if the obstruction is only partial).¹ Recent epidemiological studies show a high prevalence of this disease, with significant health, social, and economic consequences.² It is estimated that it affects from 10% to 50% of the general population, with some subgroups at a higher risk.³ However, the data may be underestimated due to the difficulty of diagnosing this condition.⁴ These pathological respiratory occurrences may be followed by transient arousals leading to the restoration of patency of the upper airways. In most cases, the awakenings are not complete, and the patient remains unaware of it. These alterations induce oxidative stress, sympathetic activation, and metabolic dysregulation.⁵ Periodontitis is a chronic infection and an inflammatory disease caused by bacterial pathogens that initiate an inflammatory response by the host.⁶ The synergetic effect of bacterial toxins and host immune response results in the destruction of periodontal tissues, manifested clinically as loss of alveolar bone, progressive loss of periodontal attachment, pocket formation, and, ultimately, tooth loss.⁷ Periodontitis can affect subjects of any age: from children still in primary dentition to the elderly. The prevalence of periodontitis in the population varies with age: It is <1% in pediatric age but can reach 43% in the adult or geriatric population.⁸ There is convincing evidence in literature about an association between periodontitis and other systemic diseases such as ischemic cardiovascular disease, type 2 diabetes mellitus, and obstetric complications (birth of premature and/or underweight babies). Similarly, for OSA, there is scientific evidence supporting an association with cardiovascular diseases, cerebrovascular diseases, gastroesophageal reflux, and type 2 diabetes mellitus.⁹ In recent years, there has also been increasing interest in the potential association between periodontitis and OSA as they are frequent disorders, which have common risk factors, and they are both associated with systemic inflammation and cardiovascular morbidity.¹⁰

This correlation could imply coexisting periodontitis as an important mediator of inflammation in OSA or vice versa. The possibility that coexisting periodontitis may still be an unknown confounder in the relationship between OSA and cardiovascular morbidity needs consideration. The purpose of this systematic review is to evaluate whether there is scientific evidence regarding the association between periodontitis and OSA by analyzing the available literature.

The protocol for this systematic review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹¹ The proposed focus question was: “Is there a relationship between OSA and periodontitis, considering the existing scientific literature?”

Inclusion/exclusion criteria

In this systematic review, Participant, Intervention, Comparison, and Outcome (PICO) criteria were used. The PICO system was designed to answer the following question: “Is there a relationship between OSA and periodontitis, considering the existing scientific literature?” (P) Population: human male and female adults; (I) Intervention: comorbidity of OSA syndrome and periodontal disease; (C) Control: human adults not affected by both OSA and periodontal disease; (O) Outcome: any relationship between OSA and periodontitis.

Epidemiological studies concerning the relationship between OSA and periodontitis were included. Male and female subjects over the age of 18 affected by both OSA and periodontitis were considered. It was chosen to consider only the studies in which diagnosis of periodontitis was formulated following the classification systems of periodontal and peri-implant diseases and conditions resulting from the 2017 World Workshop organized jointly by the American Academy of Periodontology and the European Federation of Periodontology¹² or the classification system of periodontal diseases of 1999.¹³ In these articles, the authors used parameters such as probing depth (PPD), clinical attachment level (CAL), plaque index (PI), and bleeding on probing (POB) to diagnose periodontal disease. The diagnosis of OSA, on the other hand, had to be done by polysomnography (PSG) conducted in a sleep laboratory or at home with portable devices (HST). Studies that determined the risk of OSA through the evaluation of the Mallampati index,¹⁴ tonsillar hypertrophy, and the use of validated questionnaires such as Epworth Sleepiness Scale (ESS),¹⁵ Berlin questionnaire,¹⁶ and STOP-BANG questionnaire¹⁷ were also taken into consideration.

This review included prospective and retrospective longitudinal studies, cohort studies, case–control studies, in human adults, with no restrictions on sample size and geographical location, published between 2000 and December 2021. The comparison group was represented by samples with non-OSA and nonperiodontitis subjects. Clinical cases, systematic reviews, review articles, abstracts, animal studies, and publications not in English were excluded from this review. Studies that did not directly assess the relationship between OSA and periodontitis were also excluded.

Search strategy and selection process

To ensure a complete and exhaustive evaluation of the scientific evidence, a bibliographic search was performed, with the contribution of a clinician (EM), using electronic databases. Search was conducted on MEDLINE/PubMed to identify articles published from 2000 to December 2021. Two limitations were applied to the literature search: human studies and year of publication. The following databases were searched using a combination of keyword terms and subject headings to represent sleep apnea and periodontal disease. The search strings for identifying the studies are shown in Table 1. The first search strategy (# 1 search MEDLINE), relating to the terms MeSH and Free Terms descriptors of OSA, found 55,954 publications, and the second search (# 2 search MEDLINE), relating to the MeSH terms descriptors of periodontitis, identified 91,449 citations. The joint use of the two searches with the Boolean operator “AND” produced 70 articles.{Table 1}

The literature search enabled the identification of studies potentially eligible for inclusion in the systematic review. The selection of articles to be included in the review was carried out in several stages. The first phase made it possible to identify the works of possible interest by reading the title and abstract of each individual contribution; in the second phase, the reviewers examined the full text of the selected articles and identified the pertinent ones. To ensure an objective, transparent, and reproducible evaluation of the literature, the identified studies were independently analyzed and evaluated by two reviewers (GR and EM). Any discrepancy on the work evaluation outcome was discussed and resolved by consensus.

Data extraction

A customized Excel spreadsheet was prepared to organize and collect the main information of the studies included in the systematic review. While one reviewer extracted the data, another verified the extracted data. Any disagreements were resolved through discussion between the two.

From each included publication, information was extracted relating to surname of the first author, country in which the study was carried out, article's year of publication, study design, reference population (sample size, females, males, and mean age), diagnostic criteria of OSA and periodontitis, study objective, study results, and authors' conclusions.

Quality assessment

Before conducting the analysis, in order to explore the study result variability (heterogeneity), it has been hypothesized that the effect size may differ in relation to the methodological quality of the studies. To define the validity of the studies selected during the full-text phase, an independent evaluation has been carried out for each article.

The quality of the studies that met the inclusion criteria was independently assessed by two authors using the Newcastle–Ottawa Scale (NOS) based on study type. The NOS was then used for the evaluation of nonrandomized studies to assess the risk of bias in case–control studies,¹⁸ while cross-sectional observational studies were evaluated using an adapted form of NOS, developed by Herzog et al.¹⁹ These tools allow the evaluator to assign a quality score at three levels (”good”, “fair,” or “poor”) based on the consideration of different elements. The tool for case–control studies evaluates 8 elements divided into 3 groups: selection of study groups, comparability of groups, and exposure assessment. The tool for cross-sectional studies evaluates 7 elements divided into 3 groups: selection of study groups, comparability of groups, and results.

A Star system was used, which provides up to a maximum of 9 for case–control studies and 10 for cross-sectional ones. Studies are therefore classified into 3 groups of bias: low (score >8), medium (score 6–8), and high risk (score <6). The high risk of bias results in a poor-quality evaluation, while the low risk of bias implies a good-quality assessment. Therefore, the greater the risk of bias, the lower the study quality. If the ratings differed, the authors discussed the findings to reach an agreement.

The flowchart proposed by Moher et al. was used to outline the phases of the inclusion of the articles in the PRISMA document Figure 1.¹¹Figure 1

Preferred reporting items for systematic reviews and meta-analyses 2009 flow diagram.¹¹

The main purpose of this systematic review was to investigate the association between OSA and periodontitis, through a qualitative evaluation of the available literature. These diseases share multiple risk factors, and it has been suggested that both are associated with systemic inflammation and have an impact on the development of hypertension, cardiovascular disease, cerebrovascular disease, and type 2 diabetes.³⁴

To date, very few studies have been conducted that have assessed the relationship between OSA and periodontitis.

Lembo et al.³⁵ also performed a systematic review to investigate a possible correlation between the two conditions: they concluded that although there is evidence of a plausible association between OSAS and periodontitis, it should be considered as low evidence and it is still unclear the pathophysiological mechanism that could link these two conditions, if there is a cause–effect relationship nor whether there is a dose–response relationship.

Among the articles included in the present review, those that demonstrated an association between the two pathologies justified it by formulating different hypotheses: systemic inflammation, oral respiration, and comorbid relationship.

Systemic inflammation

Some studies suggest an inflammatory link between OSA and periodontitis, considering that both diseases present an increase in some inflammation mediator molecules. Hypoxia in patients with OSA would promote an increase in adhesion molecules, C-reactive protein, transcription factor (nuclear factor-κB), some inflammatory cytokines (interleukin IL-1B, IL-6, and tumor necrosis factor-alpha), and an activation of circulating neutrophils.²⁹,³² The resulting inflammatory response could then potentiate the disease in those who already suffer from inflammatory diseases (such as cardiovascular, cerebrovascular, pulmonary, and neurocognitive diseases, as well as type 2 diabetes and arthritis), or trigger inflammatory diseases in people with a genetic, behavioral, and environmental predispositions.³⁰,³¹ Increased levels of pro-inflammatory mediators and C-reactive protein have also been observed in patients with periodontitis.²⁸

In periodontitis, the host's response to periodontal pathogenic microorganisms causes an increase in systemic inflammatory factors and the destruction of the integrity of periodontal tissues.³⁶,³⁷

Mouth breathing

Another factor that may explain the association between the two conditions could be dry mouth due to oral breathing during sleep. In OSA, oral breathing is a classic feature that leads to dry mouth and therefore could be indirectly associated with periodontitis through the changes it can cause to the oral environment. In a healthy patient without nasal involvement, mouth breathing accounts for approximately 4% of total ventilation; this percentage tends to increase with aging. In their study, Seo et al.²² affirm that the prevalence of oral respiration appears to be higher in patients with OSA. By generating dry mouth, this type of breathing tends to decrease the self-cleaning and antibacterial effect of saliva. It is therefore possible to notice an increase in bacterial colonization and consequent gingival inflammation. These two factors can increase the risk of developing periodontal disease or trigger its progression.

Comorbidity

Finally, a possible comorbid relationship between the two conditions has emerged from the literature. OSA and periodontitis have several common risk factors such as tobacco use, male sex, aging, alcohol consumption, obesity, and diabetes, which increase the vulnerability of the development of the two diseases. The simultaneous presence of periodontitis and OSA in an individual would therefore be attributable to common risk factors that would act as a link to comorbidities, in contrast to the first two hypotheses in which there is a causal link. It should also be noted that periodontitis is a common disease which affects up to 43% of the general population.⁸ According to a study by Heinzer,³ OSA would reach 10%–50% of the general population. It is therefore presumable that these two conditions can coexist in the same individual without causing a link between them.

Limitations

It is necessary to consider that the findings summarized in this systematic review present some limitations. Although most studies indicated a statistically significant association between periodontitis and OSA, the results need to be interpreted with caution because of the low quality of evidence in many studies.

First, most of the included studies had a cross-sectional design and therefore it is not possible to identify a causality or directionality between OSA and periodontal disease. The diversity and limited number of studies did not allow a convincing level of evidence or perform quantitative analyses.

One-third of the studies were found to be of poor quality, mainly due to the lack of calibration of the periodontal examiners, the lack of sample size estimation, and the absence of control for potential confounders. The remaining studies were classified as having a moderate-to-low risk of bias. Three³⁰,³¹ of the four high risk of bias studies were conducted by the same authors and were based on the same sample. They had some limitations such as the small number of subjects (n = 52) and the absence of subgroups based on periodontal disease status (healthy, gingivitis, or periodontitis). Their results should be therefore interpreted with caution.

The assessment of periodontal disease and the definitions used differed between studies; this may have led to an over- or underestimation of the disease prevalence. Despite the calibrated classification of periodontal disease, the case–control division is performed using several measures that can be influenced by the operator. Measuring the level of plaque, bleeding, mobility, furcation defect, and attachment loss by different operators using different techniques can create some variability and a margin of error. In addition, some studies are limited to a partial periodontal assessment of the mouth compared to others with six measurement points for each tooth.

By being aware of the initial assumptions, the examiner's objectivity can be subject to bias during periodontal data collection, hence the need for a blinded approach.

Similarly, the AHI cutoffs for OSA assessment varied between studies.

The use of concurrent control subjects was not done in two studies. Instead, their results were compared to historical controls from data published in the Australian National Survey of Adult Oral Health²⁹ and the Longitudinal Health Insurance Database 2000.³³ CAL is a measure of past disease and not necessarily current disease; therefore, the time between exposure and illness cannot be confirmed. Case selection in studies can be done either by using databases of patients who responded positively to questionnaires or by clinical examination. It is desirable that an individualized and standardized approach is more accurate for the diagnosis of periodontitis and OSA.

Since the included studies came from different regions, and periodontal prevalence and severity are influenced by demographic and social factors, the results may have been influenced. Another probable limitation is found in studies that have not distinguished smokers from nonsmokers. In fact, smoking affects not only the increased levels of salivary cytokines but also the risk of OSA and periodontitis. Likewise, the possibility of having control group members with undiagnosed asymptomatic OSA or other sleep disorders (e.g., snoring) can lead to a lack of uniformity in control groups.

In general, OSA is also more likely to be diagnosed in a patient being treated for periodontitis than in a person unaware of having the condition. This could increase the correlation rate again. None of the studies were completely corrected for known confounders.

The standardization of study groups according to each of these categories is therefore necessary to improve the internal validity of the studies.

This review highlights some evidence of a plausible association between periodontitis and OSA. Several theories have been hypothesized to explain a link between the two conditions: (1) periodontitis causes chronic inflammatory responses in sensitive hosts and acts as a mediator of inflammation for OSA or vice versa; (2) oral breathing associated with OSA increases the expression of periodontitis; and (3) the relationship between the two conditions is comorbid rather than causal as they both share common risk factors.

No conclusions can be drawn about the efficacy of periodontal disease treatment modalities due to insufficient evidence. Future research should therefore provide evidence from observational prospective studies trying to overcome the limitations currently found in the literature. Furthermore, as most of the papers had a cross-sectional design, it was not possible to clearly define the cause–effect relationship. Therefore, better structured observational studies are needed to confirm this association and randomized controlled studies are needed to clarify the interaction mechanism between the two conditions.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article.