Impact of Stress on Periodontal Health: Literature Revision

Stress is a physiological response of the body to stressful life events but may not be when the individual is persistently exposed to the stress trigger, and it negatively affects certain physiological functions, thus triggering psychosomatic diseases. In literature, chronic stress and inadequate coping strategies are found to mediate the risk and development of periodontitis; mechanisms have therefore been proposed to explain the effects of stress on the periodontium. Since stress is a prevalent problem in modern life and given the importance of maintaining oral health, the present literature review aimed to estimate the association between stress and periodontal disease. The research question adopted is the following: “Are psychological stress and periodontal disease related?” The search was conducted in August 2022 and limited to articles in electronic databases from 2017 to 2022 in English, excluding reviews and literature reviews. From the electronic databases, a total of 532 articles were identified and became 306 after reviews and duplicates were removed. An additional bibliographic search was conducted through the same electronic databases, controlled terms and keywords including only systematic reviews, which were previously excluded. Through the bibliography cited in the systematic reviews, an additional 18 articles were identified, with a new total of 324. As a result of reading the title and abstract of these 324 articles, an additional 295 were excluded. Reading the full text of the remaining 29 studies, 2 articles were excluded due to non-adherence to the eligibility criteria. The remaining 27 results were included in our literature review. It has been suggested in the literature that adverse socioeconomic conditions elicit a stress response, which can trigger periodontal inflammation. Most of the 27 articles included in the study confirm and demonstrate a positive association between psychological stress and periodontal disease. Numerous studies have shown the mechanisms through which chronic stress negatively affects periodontal tissues. Therefore, in the light of the results obtained from this review, it is important that oral health professionals, also for general health purposes, consider stress factors among the risk factors of periodontal disease, its severity and decreased efficacy of treatments. It is therefore advisable to act preventively through the interception of chronic stress.


Introduction
Stress is defined as a physical, emotional, or mental response to stressful life events; it is a physiological response of the body but may not be when the individual is persistently exposed to the stress trigger. Additionally, it negatively affects certain physiological functions, thus triggering psychosomatic diseases [1].
Nowadays, the term stress is used with extreme frequency to describe recurring negative experiences related to everything from everyday inconveniences, relationship problems and work pressures to health problems and debilitating phobias. periodontal disease through a literature review investigating the main relations highlighted in the literature regarding this topic.

Materials and Methods
This systematic review was conducted following the criteria of the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) Statement (Liberati et al., 2009).
The PECO (Population, Exposure, Comparator, and Outcome) model was used for formulating the scientific question and as guidance of the inclusion and exclusion criteria of this review. This acronym represents the characteristics of the patient (P), the exposure (E), the comparator (C), and the outcome (O) of the eligible question. The research question adopted is as follows: "Are psychological stress and periodontal disease related?" -Population (P): human subjects with periodontal disease; -Exposure (E): psychological stress assessed by specialized questionnaires or biological biomarkers; -Comparison (C): periodontally healthy subjects not exposed to psychological stress; -Outcome/Results (O): association between psychological stress and the presence of periodontal disease.
The search was conducted in August 2022 and limited to articles in electronic databases from 2017 to 2022 in English, excluding reviews and literature reviews.
Bibliographic research was conducted by two independent operators through the electronic databases-Pubmed, Scopus and Web of Science-using combinations of selected terms and different keywords, depending on the search mode allowed by each electronic database as shown in Table 1. Additional research was conducted through the bibliography of systematic reviews with the same topic.  The research began in July 2022, continued in August and ended on 6 September 2022. Study selection was performed by two independent operators following the process of Identification, Screening, Eligibility and Inclusion of studies.
Articles were saved in the Zotero software (version 6.0.11, 18 July 2022), where duplicates were removed. A preliminary screening was then performed by two independent operators, which involved reading the titles and abstracts of the articles, in order to remove the studies not relevant to the purpose of this review.
The eligibility process was carried out by reviewing and analyzing the full texts for further inclusion or exclusion. Access to the full texts of the articles was obtained through the "Nilde" (Network Interlibrary Document Exchange) system, in collaboration with Sapienza University of Rome.
The papers included in the study were randomized controlled trials (RCTs) and controlled clinical trials (CCTs), cohort studies, case-control studies and transversal studies.
The excluded studies were literature reviews, articles that were not in English, articles whose full text was not available and studies not carried out on humans.
The entire selection process was schematized in the PRISMA Flow Diagram (Figure 1). Data collection was carried out by reading the full texts of the included studies. with related and subsequent manual entry into the tables, using the Microsoft Excel spreadsheet ( Table 2 in result section).
The following information was extracted from the studies: author; year of publication; country; study type; sample size/(case/control numbers); gender; age group/middle age; inclusion and exclusion criteria; diagnosis of periodontal disease; instruments used to measure stress; and conclusions.
The methodological quality of the included studies was performed by two independent practitioners using "The modified JADAD scale" (Oremus et al., 2001). The modified scale includes nine criteria or items to which scores are assigned. The score for each study ranges from 0 (the lowest quality) to 8 (the highest quality), where 0 represents the highest risk of bias and 8 represents the lowest risk of bias. Studies with scores of 7 and 8 were classified as low risk, those with scores of 4, 5 and 6 were classified as moderate risk and studies with scores less than or equal to 3 as high risk. Studies scoring less than 4 were considered low quality, studies scoring 4 or more (with a maximum of 6), were considered medium quality and studies scoring more than 6 were considered high quality.
The quality of the selected studies was assessed using the modified version of the Newcastle-Ottawa scale for cross-sectional studies by Wells et al. [17].
Study quality was rated on a scale from 0 (high risk of bias) to 8 (low risk of bias). The scale assessed the parameters of sample selection, comparability and outcome/exposure. Studies that showed a summary score greater than the median value were considered to be at low risk of bias. Each parameter was awarded 1 point. Any disagreements among the reviewers in assessing study quality were resolved by consensus or by consulting a third reviewer.
To reduce the bias and time spent in the study selection process, a Cohen's kappa statistic system was used in the process of selecting studies. An iterative process based on the use of this statistic during which the criteria were refined until obtaining almost perfect agreement (k > 0.85). At this point, the two researchers interpret the selection criteria in the same way; therefore, the bias is reduced.

Results
From the electronic databases Pubmed (n = 76), Scopus (n = 438) and Web of Science (n = 18), a total of 532 articles were identified, 306 after duplicates were removed. In addition, an additional bibliographic search was conducted through the same electronic databases, controlled terms and keywords including only systematic reviews, which were previously excluded. Through the bibliography of the latter, an additional 18 articles were identified, with a total of 324.
As a result of reading the title and abstract of the latter, an additional 295 were excluded. Reading the full text of the remaining 29 studies resulted in the exclusion of 2 articles due to non-adherence to the eligibility criteria. The remaining 27 results were included in the literature review. The process was schematized in the PRISMA Flow Diagram (Figure 1).
The characteristics of the included studies are shown in Table 2     Mild depression was associated with higher probabilities of moderate/severe gingivitis in the study population and was a modifying factor for the association with plaque accumulation and refined carbohydrate consumption.

Risk of Bias in Studies
To assess the quality of the studies included in the review and define the most relevant ones, a Quality Assessment table was designed, compiled according to the criteria of the modified JADAD Scale. Using the data, a histogram was developed ( Figure 2).  [19,20,22,[28][29][30][31][32][33]35,36,42].
All case-control observational studies and cross-sectional studies were evaluated with a low risk of bias, obtaining a quality assessment score of 6 to 8 points, with most of these studies having adjusted for confounding variables. In addition, appropriate case and control definitions and periodontal examination were provided, and validated tools for the assessment of psychological stress and anxiety were used.

Discussion
It has been suggested in the literature that adverse socioeconomic conditions elicit a stress response, which can trigger periodontal inflammation. Wellappulli et al. [38], Gomaa et al. [42] limited themselves to determining the association between psychological distress and chronic periodontitis and socioeconomic standing and determining the contribution of psychosocial stress and its hormones in these relationships. The likelihood of having chronic periodontitis was higher in those with psychological distress than in those without psychological distress. In the study by Tanveer et al. [39], it was hypothesized that increased levels of psychological stress among socially disadvantaged women would show a clinically compromising influence on their periodontal health. The association between psychosocial stress and periodontitis among socially disadvantaged women residing in nursing homes was significant.
The goal set by Varshini and Rajasekar [16], Wijayaa et al. [41], Maruyama et al. [26] and Coelho et al. [37] was to determine the effect of stress on periodontal healt, through the administration of questionnaires for the evaluation of depression, anxiety and stress to students at the university faculty of dentistry. The results of that study suggest that students with severe levels of depression, anxiety and stress had greater pocket depth and clinical attachment loss. Therefore, psychological factors have a negative effect on periodontal health. In the study of Varshini and Rajasekar, the instrument does not only measure stress. It suggests that dental students with extremely severe levels of depression, anxiety and stress presented with increased pocket depth and clinical attachment loss. Therefore, psychological factors have an adverse effect on periodontal health.
Several studies presented used saliva samples, cortisol, α-amylase, β-endorphin, chromogranin (CgA), salivary IgA, and various other reactive oxygen metabolites ROM to investigate their relationship to periodontitis. The severity of chronic periodontitis was found to increase, with the increase in cortisol levels and salivary reactive. This therefore indicates that the probability of the onset of periodontitis being greater in subjects with a level of cortisol and another reactive is increased.
Clinical depression could be a probable risk factor in the development of periodontal disease, especially aggressive periodontitis. As demonstrated by the studies by Ramesh et al. [23] and Folayan et al. [40], mild depression was associated with a higher likelihood of moderate/severe gingivitis in the study population. The study by Fenol et al. [21], conducted on a total of 70 male inmates, aimed to in-vestigate a possible relationship between psychosocial stress and periodontal disease, demonstrating a significant correlation between clinical parameters, stress and salivary cortisol levels.
Rajhans et al. [23] aimed to correlate the possible stress relationship in patients with chronic periodontitis (CP) and diabetes mellitus (DM), in a sample of 60 individuals aged between 35 and 50 years. All patients underwent psychological assessment using the Perceived Stress Scale (PSS), Social Readaptation Rating Scale (SRRS) and biochemical analysis for serum cortisol estimation. From the results of this study, there seems to be a strong correlation between inflammation of the periodontal tissues, DM stress and serum cortisol levels.
To evaluate the association between the influence of work stress and coping style on periodontitis among Japanese workers, Islam et al. [25] used the Co-Labo57+ selfadministered questionnaire and assessed periodontal status based on the inspection vision by dentists, suggesting that low coping style versus high work stress is significantly associated with an increased risk of periodontitis.
In the study performed by Haririan et al. [36], the aim was to compare stress-related neuropeptides in serum and saliva in periodontal health and disease, as well as deter-mine if these markers are related to periodontal parameters and situations of psychological stress. Due to a low response rate to stress questionnaires, this study states that among the different neuropeptides screened, only salivary levels of NPY and VIP were detected in high concentrations in patients with AgP and CP, who could be potential salivary biomarkers for periodontal disease independent of psychological stress.
The primary purpose of the study performed by Deng et al. [32] was to explore the validity and reliability of the hospital anxiety and depression scale (HANS) and the 10-item perceived stress scale (PSS-10) in patients with periodontitis. The secondary aim was to evaluate the psychological characteristics of patients with periodontitis. The latter two parameters, at the end of the study, proved to have good psychometric properties in terms of internal reliability; in this regard, they can be used as general measures for the psychological evaluation in patients with periodontitis. Furthermore, the present study showed a higher prevalence of anxiety, depression and stress in patients with periodontitis.
The aim in the study by Petit et al. [30,31] was to evaluate the influence of psychological stress on the outcomes of non-surgical periodontal treatment in patients of the French population diagnosed with severe chronic periodontitis and with follow-up at six months. Their psychological state was assessed at baseline using self-administered questionnaires, Depression, Anxiety, Stress Scale (DASS) and Toulouse Coping Scale (TCS). At the baseline, before the treatment and six months after the latter, a blood sample was taken to evaluate the plasma levels of cortisol and chromogranin-A and the periodontal indices were recorded. At the end of the study, patients with increased stress, anxiety and depression scores, as well as those using negative coping strategies, showed worse nonsurgical periodontal treatment outcomes.
The cross-sectional study by Rahate et al. [22] and Zhang et al. [33] aimed to study the serum and salivary levels of ghrelin and cortisol and the level of IL-1B in smoking and non-smoking periodontitis patients. In conclusion, the study demonstrated a positive association between stress, smoking and staged periodontitis. Clinical parameters suggest that, in patients with periodontitis, the presence of stress and smoking habits increase the severity of destruction.
Most of the 28 articles included in the study confirm and demonstrate a positive as-sociation between psychological stress and periodontal disease; in detail, two articles examined the positive correlation between stress and gingivitis [28,40], while the remainder demonstrated a relationship between periodontitis and stress.
The only study, of moderate quality, that was unable to detect this association is that of Haririan et al. [36]. While two studies, (Develioglu et al. [27]; Dubar et al. [29]), the first of low quality and the second of moderate quality, found a correlation between the presence of high levels of salivary cortisol in patients with periodontitis, these results did not match those of self-administered questionnaires to patients. Additionally, in the study of Develioglu et al., there was no relationship between STAI 1 and STAI 2 scores and the severity of chronic periodontitis However, since most of the studies have reported positive results, it can be said that psychological stress is a risk factor for periodontitis.

Conclusions
Numerous studies have shown the mechanisms through which chronic stress negatively affects periodontal tissues. Stress indirectly affects periodontal health through behavioral and lifestyle changes, amplifying the consumption and abuse of smoking and alcohol, poor diet, negligence in oral hygiene and poor compliance with dental care; it would also seem to influence periodontal health through direct biological impact, mediated through saliva alteration, changes in gingival blood circulation and influencing the host immune response. Future studies should focus on the correlation between the pathology and stress and mainly on possible ways of preventing it.
In light of the results obtained from this review, it is important that oral health professionals, also for general health purposes, consider stress factors among the risk factors of periodontal disease, its severity and decreased efficacy of treatments. In patients with chronic stress, it is advisable to carry out brief reminders for periodontal maintenance through constant motivation, strengthening oral hygiene procedures and educating patients on the negative consequences of behaviors used to cope with stress.